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1
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Jin L, Zhao Y, Qian X, Pan L, Chen L, Feng J, Liu X, Lu X. LC-MS/MS-based metabolomics and proteomics reveal the intervention of Kangnian decoction on the postoperative intestinal adhesion of rats. Front Pharmacol 2024; 15:1382760. [PMID: 39351093 PMCID: PMC11439705 DOI: 10.3389/fphar.2024.1382760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 09/03/2024] [Indexed: 10/04/2024] Open
Abstract
Background Postoperative Intestinal Adhesions (PIAs) remain a significant complication of abdominal surgery that can cause pain, infertility, and a potentially lethal bowel obstruction. Kangnian (KN) decoction, a Traditional Chinese Medicine prescription, has been shown to be effective in treating PIAs. Nevertheless, its underlying mechanisms remain unclear. Objective This study aims to explore the therapeutic effects of KN decoction in a PIA rat model, as well as its potential mechanisms via metabolomics and proteomics analyses. Materials and methods 60 rats were randomly assigned to six groups: Normal Control (NC), PIA model, Dexamethasone, KN-Low, KN-Medium, and KN-High. The PIA model was created by abdominal surgery under anesthesia. Pathological damage was evaluated through H&E staining and adhesion grading of affected tissues. The levels of serum cytokines (IL-1β, IL-6, TNF-α, and TGF-1), Connective Tissue Growth Factor (CTGF), and Motilin (MTL) in adherent intestinal tissues were detected using ELISA kits. Untargeted metabolomics was used to investigate potential metabolic pathways of the KN decoction intervention in intestinal adhesions and to screen for differential biomarkers. The label-free quantitative proteomics technique was employed to detect Differentially Expressed Proteins and for biological function and pathway enrichment analyses. Results In PIA rats, KN decoction significantly improved the pathological injury associated with intestinal adhesions and effectively regulated the blood inflammation indicators. Furthermore, KN presented a favorable anti-fibrotic and protective effect against abdominal adhesions, effectively modifying gastrointestinal motility disorders in PIA rats. We identified 58 variables as potential biomarkers and discovered seven main pathological pathways that may be associated with PIAs. Proteomics analysis revealed 75 DEPs that were primarily involved in Valine, leucine, and isoleucine degradation, the MAPK signaling pathway, and retrograde endocannabinoid signaling. Conclusion This study proved that KN reduces intestinal mucosal injury, downregulates inflammatory factors, and alleviates intestinal adhesions, thus protecting the intestinal barrier function in PIA rats. The combination of proteomics and metabolomics provided a feasible approach for unraveling the therapeutic mechanism of KN decoction in PIAs.
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Affiliation(s)
- Liang Jin
- Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yuan Zhao
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaojing Qian
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lingyun Pan
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Long Chen
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jingwen Feng
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xinhua Liu
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaotong Lu
- Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
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2
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Li X, Bai L, Zhang X, Fang Q, Chen G, Xu G. Application of Bletilla striata polysaccharide hydrogel for wound healing among in diabetes. Colloids Surf B Biointerfaces 2024; 241:114033. [PMID: 38936033 DOI: 10.1016/j.colsurfb.2024.114033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 05/17/2024] [Accepted: 06/10/2024] [Indexed: 06/29/2024]
Abstract
Diabetes has become an increasingly serious global health crisis. Long-term hyperglycemia can lead to vascular and neurological disorders, thus deterring wound healing. Therefore, exploring treatment modalities for wounds in individuals with diabetes is clinically significant. Bletilla striata polysaccharide and bioactive natural polymers carbomer 940 and carboxymethyl chitosan (CMC) are cross-linked to form the Bletilla striata polysaccharide hydrogel (named CCHG/BSP). Upon characterization, we found that the hydrogel has a porous structure and good mechanical and moisture retention properties. A hemolysis test revealed that the hydrogel had high safety. Furthermore, the hydrogel effectively promoted proliferation and migration in mouse L929 fibroblasts. In back wounds inflicted in a streptozotocin-induced mouse model of diabetes, the CCHG/BSP hydrogel significantly promoted wound healing. Hematoxylin-eosin, Masson's trichrome, and immunohistochemical staining of tissues around the wound suggest that the mechanism underlying wound healing in diabetes may involve the promotion of angiogenesis, regulation of inflammation, and promotion of collagen regeneration. This provides a foundation for studies on and the development of new BSP pharmacotherapeutic products and the clinical application of its hydrogel dressing, and provide novel avenues for treating wounds in individuals with diabetes.
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Affiliation(s)
- Xiaomei Li
- Department of Burn and Plastic Surgery, Northern Jiangsu People's Hospital, 225001, PR China
| | - Limin Bai
- Department of Burn and Plastic Surgery, Northern Jiangsu People's Hospital, 225001, PR China
| | - Xiaowei Zhang
- Department of Burn and Plastic Surgery, Northern Jiangsu People's Hospital, 225001, PR China
| | - Qiangwei Fang
- Department of Burn and Plastic Surgery, Northern Jiangsu People's Hospital, 225001, PR China
| | - Gang Chen
- School of Rehabilitation Sciences and Engineering, University of Health and Rehabilitation Sciences, Qingdao 266024, PR China; Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao 266024, PR China.
| | - Gang Xu
- Department of Burn and Plastic Surgery, Northern Jiangsu People's Hospital, 225001, PR China; Clinical Medical College, Yangzhou University, Yangzhou 225009, PR China.
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3
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Lee DH, Lee EC, Lee JY, Lee MR, Shim JW, Oh JS. Neuronal Cell Differentiation of iPSCs for the Clinical Treatment of Neurological Diseases. Biomedicines 2024; 12:1350. [PMID: 38927557 PMCID: PMC11201423 DOI: 10.3390/biomedicines12061350] [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: 04/20/2024] [Revised: 06/05/2024] [Accepted: 06/14/2024] [Indexed: 06/28/2024] Open
Abstract
Current chemical treatments for cerebrovascular disease and neurological disorders have limited efficacy in tissue repair and functional restoration. Induced pluripotent stem cells (iPSCs) present a promising avenue in regenerative medicine for addressing neurological conditions. iPSCs, which are capable of reprogramming adult cells to regain pluripotency, offer the potential for patient-specific, personalized therapies. The modulation of molecular mechanisms through specific growth factor inhibition and signaling pathways can direct iPSCs' differentiation into neural stem cells (NSCs). These include employing bone morphogenetic protein-4 (BMP-4), transforming growth factor-beta (TGFβ), and Sma-and Mad-related protein (SMAD) signaling. iPSC-derived NSCs can subsequently differentiate into various neuron types, each performing distinct functions. Cell transplantation underscores the potential of iPSC-derived NSCs to treat neurodegenerative diseases such as Parkinson's disease and points to future research directions for optimizing differentiation protocols and enhancing clinical applications.
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Affiliation(s)
- Dong-Hun Lee
- Industry-Academic Cooperation Foundation, The Catholic University of Korea, 222, Banpo-daro, Seocho-gu, Seoul 06591, Republic of Korea
| | - Eun Chae Lee
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Ji young Lee
- Department of Neurosurgery, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Man Ryul Lee
- Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheonan-si 31151, Republic of Korea
| | - Jae-won Shim
- Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheonan-si 31151, Republic of Korea
- Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan-si 31151, Republic of Korea
| | - Jae Sang Oh
- Department of Neurosurgery, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
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Kasamatsu S, Takano K, Aoki M, Takahashi Y, Suzuki T. Rosemary extract and rosmarinic acid accelerate elastic fiber formation by increasing the expression of elastic fiber components in dermal fibroblasts. J Dermatol 2024; 51:816-826. [PMID: 38470170 DOI: 10.1111/1346-8138.17185] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 02/05/2024] [Accepted: 02/20/2024] [Indexed: 03/13/2024]
Abstract
Ultraviolet (UV)-induced skin photoaging is caused by qualitative and quantitative degradation of dermal extracellular matrix components such as collagen and elastic fibers. Elastic fibers are important for maintaining cutaneous elasticity, despite their small amount in the skin. Previously, microfibril-associated protein 4 (MFAP-4), which is downregulated in photoaging dermis, has been found to be essential for elastic fiber formation by interaction with both fibrillin-1 and elastin, which are core components of elastic fiber. In addition, enhanced cutaneous MFAP-4 expression in a human skin-xenografted murine photoaging model protects against UV-induced photodamage accompanied by the prevention of elastic fiber degradation and aggravated elasticity. We therefore hypothesized that the upregulation of MFAP-4 in dermal fibroblasts may more efficiently accelerate elastic fiber formation. We screened botanical extracts for MFAP-4 expression-promoting activity in normal human dermal fibroblasts (NHDFs). We found that rosemary extract markedly promotes early microfibril formation and mature elastic fiber formation along with a significant upregulation of not only MFAP-4 but also fibrillin-1 and elastin in NHDFs. Furthermore, rosmarinic acid, which is abundant in rosemary extract, accelerated elastic fiber formation via upregulation of transforming growth factor β-1. This was achieved by the induction of cAMP response element-binding protein phosphorylation, demonstrating that rosmarinic acid represents one of the active ingredients in rosemary extract. Based on the findings in this study, we conclude that rosemary extract and rosmarinic acid represent promising materials that exert a preventive or ameliorative effect on skin photoaging by accelerating elastic fiber formation.
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Affiliation(s)
- Shinya Kasamatsu
- Biological Science Research Laboratories, Kao Corporation, Kanagawa, Japan
| | - Kei Takano
- Biological Science Research Laboratories, Kao Corporation, Kanagawa, Japan
| | - Mika Aoki
- Biological Science Research Laboratories, Kao Corporation, Kanagawa, Japan
| | - Yoshito Takahashi
- Biological Science Research Laboratories, Kao Corporation, Kanagawa, Japan
| | - Tamio Suzuki
- Department of Dermatology, Faculty of Medicine, Yamagata University, Yamagata, Japan
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5
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Wang Y, Li J. Current progress in growth factors and extracellular vesicles in tendon healing. Int Wound J 2023; 20:3871-3883. [PMID: 37291064 PMCID: PMC10588330 DOI: 10.1111/iwj.14261] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 05/20/2023] [Indexed: 06/10/2023] Open
Abstract
Tendon injury healing is a complex process that involves the participation of a significant number of molecules and cells, including growth factors molecules in a key role. Numerous studies have demonstrated the function of growth factors in tendon healing, and the recent emergence of EV has also provided a new visual field for promoting tendon healing. This review examines the tendon structure, growth, and development, as well as the physiological process of its healing after injury. The review assesses the role of six substances in tendon healing: insulin-like growth factor-I (IGF-I), transforming growth factor β (TGFβ), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), and EV. Different growth factors are active at various stages of healing and exhibit separate physiological activities. IGF-1 is expressed immediately after injury and stimulates the mitosis of various cells while suppressing the response to inflammation. VEGF, which is also active immediately after injury, accelerates local metabolism by promoting vascular network formation and positively impacts the activities of other growth factors. However, VEGF's protracted action could be harmful to tendon healing. PDGF, the earliest discovered cytokine to influence tendon healing, has a powerful cell chemotaxis and promotes cell proliferation, but it can equally accelerate the response to inflammation and relieve local adhesions. Also useful for relieving tendon adhesion is TGF- β, which is active almost during the entire phase of tendon healing. As a powerful active substance, in addition to its participation in the field of cardiovascular and cerebrovascular vessels, tumour and chronic wounds, TGF- β reportedly plays a role in promoting cell proliferation, activating growth factors, and inhibiting inflammatory response during tendon healing.
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Affiliation(s)
- Yufeng Wang
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jin Li
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Keyan KS, Salim S, Gowda S, Abdelrahman D, Amir SS, Islam Z, Vargas C, Bengoechea-Alonso MT, Alwa A, Dahal S, Kolatkar PR, Da'as S, Torrisani J, Ericsson J, Mohammad F, Khan OM. Control of TGFβ signalling by ubiquitination independent function of E3 ubiquitin ligase TRIP12. Cell Death Dis 2023; 14:692. [PMID: 37863914 PMCID: PMC10589240 DOI: 10.1038/s41419-023-06215-y] [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: 06/19/2023] [Revised: 09/27/2023] [Accepted: 10/05/2023] [Indexed: 10/22/2023]
Abstract
Transforming growth factor β (TGFβ) pathway is a master regulator of cell proliferation, differentiation, and death. Deregulation of TGFβ signalling is well established in several human diseases including autoimmune disorders and cancer. Thus, understanding molecular pathways governing TGFβ signalling may help better understand the underlying causes of some of those conditions. Here, we show that a HECT domain E3 ubiquitin ligase TRIP12 controls TGFβ signalling in multiple models. Interestingly, TRIP12 control of TGFβ signalling is completely independent of its E3 ubiquitin ligase activity. Instead, TRIP12 recruits SMURF2 to SMAD4, which is most likely responsible for inhibitory monoubiquitination of SMAD4, since SMAD4 monoubiquitination and its interaction with SMURF2 were dramatically downregulated in TRIP12-/- cells. Additionally, genetic inhibition of TRIP12 in human and murine cells leads to robust activation of TGFβ signalling which was rescued by re-introducing wildtype TRIP12 or a catalytically inactive C1959A mutant. Importantly, TRIP12 control of TGFβ signalling is evolutionary conserved. Indeed, genetic inhibition of Drosophila TRIP12 orthologue, ctrip, in gut leads to a reduced number of intestinal stem cells which was compensated by the increase in differentiated enteroendocrine cells. These effects were completely normalised in Drosophila strain where ctrip was co-inhibited together with Drosophila SMAD4 orthologue, Medea. Similarly, in murine 3D intestinal organoids, CRISPR/Cas9 mediated genetic targeting of Trip12 enhances TGFβ mediated proliferation arrest and cell death. Finally, CRISPR/Cas9 mediated genetic targeting of TRIP12 in MDA-MB-231 breast cancer cells enhances the TGFβ induced migratory capacity of these cells which was rescued to the wildtype level by re-introducing wildtype TRIP12. Our work establishes TRIP12 as an evolutionary conserved modulator of TGFβ signalling in health and disease.
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Affiliation(s)
- Kripa S Keyan
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
| | - Safa Salim
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
| | - Swetha Gowda
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
| | | | - Syeda Sakina Amir
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
| | - Zeyaul Islam
- Qatar Biomedical Research Institute, Doha, Qatar
| | - Claire Vargas
- Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Inserm, CNRS, Université Toulouse III-Paul Sabatier, Toulouse, France
| | | | - Amira Alwa
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
| | - Subrat Dahal
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
| | | | - Sahar Da'as
- Department of Research, Sidra Medicine, Doha, Qatar
| | - Jerome Torrisani
- Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Inserm, CNRS, Université Toulouse III-Paul Sabatier, Toulouse, France
| | - Johan Ericsson
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
| | - Farhan Mohammad
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
| | - Omar M Khan
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
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7
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Galal MA, Alouch SS, Alsultan BS, Dahman H, Alyabis NA, Alammar SA, Aljada A. Insulin Receptor Isoforms and Insulin Growth Factor-like Receptors: Implications in Cell Signaling, Carcinogenesis, and Chemoresistance. Int J Mol Sci 2023; 24:15006. [PMID: 37834454 PMCID: PMC10573852 DOI: 10.3390/ijms241915006] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 09/22/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023] Open
Abstract
This comprehensive review thoroughly explores the intricate involvement of insulin receptor (IR) isoforms and insulin-like growth factor receptors (IGFRs) in the context of the insulin and insulin-like growth factor (IGF) signaling (IIS) pathway. This elaborate system encompasses ligands, receptors, and binding proteins, giving rise to a wide array of functions, including aspects such as carcinogenesis and chemoresistance. Detailed genetic analysis of IR and IGFR structures highlights their distinct isoforms, which arise from alternative splicing and exhibit diverse affinities for ligands. Notably, the overexpression of the IR-A isoform is linked to cancer stemness, tumor development, and resistance to targeted therapies. Similarly, elevated IGFR expression accelerates tumor progression and fosters chemoresistance. The review underscores the intricate interplay between IRs and IGFRs, contributing to resistance against anti-IGFR drugs. Consequently, the dual targeting of both receptors could present a more effective strategy for surmounting chemoresistance. To conclude, this review brings to light the pivotal roles played by IRs and IGFRs in cellular signaling, carcinogenesis, and therapy resistance. By precisely modulating these receptors and their complex signaling pathways, the potential emerges for developing enhanced anti-cancer interventions, ultimately leading to improved patient outcomes.
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Affiliation(s)
- Mariam Ahmed Galal
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
- Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1QU, UK
| | - Samhar Samer Alouch
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Buthainah Saad Alsultan
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Huda Dahman
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Nouf Abdullah Alyabis
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Sarah Ammar Alammar
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Ahmad Aljada
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
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8
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Liu T, Gao H, Ren X, Xu G, Liu B, Wu N, Luo H, Wang Y, Tu T, Yao B, Guan F, Teng Y, Huang H, Tian J. Protein-protein interaction and site prediction using transfer learning. Brief Bioinform 2023; 24:bbad376. [PMID: 37870286 DOI: 10.1093/bib/bbad376] [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: 07/26/2023] [Revised: 09/14/2023] [Accepted: 10/02/2023] [Indexed: 10/24/2023] Open
Abstract
The advanced language models have enabled us to recognize protein-protein interactions (PPIs) and interaction sites using protein sequences or structures. Here, we trained the MindSpore ProteinBERT (MP-BERT) model, a Bidirectional Encoder Representation from Transformers, using protein pairs as inputs, making it suitable for identifying PPIs and their respective interaction sites. The pretrained model (MP-BERT) was fine-tuned as MPB-PPI (MP-BERT on PPI) and demonstrated its superiority over the state-of-the-art models on diverse benchmark datasets for predicting PPIs. Moreover, the model's capability to recognize PPIs among various organisms was evaluated on multiple organisms. An amalgamated organism model was designed, exhibiting a high level of generalization across the majority of organisms and attaining an accuracy of 92.65%. The model was also customized to predict interaction site propensity by fine-tuning it with PPI site data as MPB-PPISP. Our method facilitates the prediction of both PPIs and their interaction sites, thereby illustrating the potency of transfer learning in dealing with the protein pair task.
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Affiliation(s)
- Tuoyu Liu
- Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Han Gao
- Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Xiaopu Ren
- Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Guoshun Xu
- Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Bo Liu
- Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Ningfeng Wu
- Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Huiying Luo
- Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Yuan Wang
- Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Tao Tu
- Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Bin Yao
- Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Feifei Guan
- Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Yue Teng
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing 100071, China
| | - Huoqing Huang
- Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Jian Tian
- Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China
- Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing 100081, China
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9
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Edsfeldt A, Singh P, Matthes F, Tengryd C, Cavalera M, Bengtsson E, Dunér P, Volkov P, Karadimou G, Gisterå A, Orho-Melander M, Nilsson J, Sun J, Gonçalves I. Transforming growth factor-β2 is associated with atherosclerotic plaque stability and lower risk for cardiovascular events. Cardiovasc Res 2023; 119:2061-2073. [PMID: 37200403 PMCID: PMC10478752 DOI: 10.1093/cvr/cvad079] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 01/27/2023] [Accepted: 02/21/2023] [Indexed: 05/20/2023] Open
Abstract
AIMS Transforming growth factor-beta (TGF-β) exists in three isoforms TGF-β1, -β2, and -β3. TGF-β1 has been suggested to be important for maintaining plaque stability, yet the role of TGF-β2 and -β3 in atherosclerosis remains to be investigated.This study explores the association of the three isoforms of TGF-β with plaque stability in the human atherosclerotic disease. METHODS AND RESULTS TGF-β1, -β2, and -β3 proteins were quantified in 223 human carotid plaques by immunoassays. Indications for the endarterectomy were: symptomatic carotid plaque with stenosis >70% or without symptoms and >80% stenosis. Plaque mRNA levels were assessed by RNA sequencing. Plaque components and extracellular matrix were measured histologically and biochemically. Matrix metalloproteinases and monocyte chemoattractant protein-1 (MCP-1) was measured with immunoassays. The effect of TGF-β2 on inflammation and protease activity was investigated in vitro using THP-1 and RAW264.7 macrophages. Patients were followed longitudinally for cardiovascular (CV) events.TGF-β2 was the most abundant isoform and was increased at both protein and mRNA levels in asymptomatic plaques. TGF-β2 was the main determinant separating asymptomatic plaques in an Orthogonal Projections to Latent Structures Discriminant Analysis. TGF-β2 correlated positively to features of plaque stability and inversely to markers of plaque vulnerability. TGF-β2 was the only isoform inversely correlated to the matrix-degrading matrix metalloproteinase-9 and inflammation in the plaque tissue. In vitro, TGF-β2 pre-treatment reduced MCP-1 gene and protein levels as well as matrix metalloproteinase-9 gene levels and activity. Patients with plaques with high TGF-β2 levels had a lower risk to suffer from future CV events. CONCLUSIONS TGF-β2 is the most abundant TGF-β isoform in human plaques and may maintain plaque stability by decreasing inflammation and matrix degradation.
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Affiliation(s)
- Andreas Edsfeldt
- Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden
- Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden
- Department of Cardiology, Skåne University Hospital, Malmö, Sweden
| | - Pratibha Singh
- Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden
| | - Frank Matthes
- Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden
| | | | - Michele Cavalera
- Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden
| | - Eva Bengtsson
- Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden
- Faculty of Health and Society, Malmö University, Malmö, Sweden
- Biofilms—Research Center for Biointerfaces, Malmö University, Malmö, Sweden
| | - Pontus Dunér
- Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden
| | - Petr Volkov
- Department of Clinical Sciences, LUDC Bioinformatics Unit, Malmö, Lund University, Lund, Sweden
- Data Science and Quantitative Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Glykeria Karadimou
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
| | - Anton Gisterå
- Department of Medicine, Center for Molecular Medicine, Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | | | - Jan Nilsson
- Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden
| | - Jiangming Sun
- Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden
| | - Isabel Gonçalves
- Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden
- Department of Cardiology, Skåne University Hospital, Malmö, Sweden
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10
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Agnihotri TG, Salave S, Shinde T, Srikanth I, Gyanani V, Haley JC, Jain A. Understanding the role of endothelial cells in brain tumor formation and metastasis: a proposition to be explored for better therapy. JOURNAL OF THE NATIONAL CANCER CENTER 2023; 3:222-235. [PMID: 39035200 PMCID: PMC11256543 DOI: 10.1016/j.jncc.2023.08.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 07/31/2023] [Accepted: 08/02/2023] [Indexed: 07/23/2024] Open
Abstract
Glioblastoma is one of the most devastating central nervous system disorders. Being a highly vascular brain tumor, it is distinguished by aberrant vessel architecture. This lends credence to the idea that endothelial cells (ECs) linked with glioblastoma vary fundamentally from ECs seen in the healthy human brain. To effectively design an antiangiogenic treatment, it is crucial to identify the functional and phenotypic characteristics of tumor-associated ECs. The ECs associated with glioblastoma are less prone to apoptosis than control cells and are resistant to cytotoxic treatments. Additionally, ECs associated with glioblastoma migrate more quickly than control ECs and naturally produce large amounts of growth factors such as endothelin-1, interleukin-8, and vascular endothelial growth factor (VEGF). For designing innovative antiangiogenic drugs that particularly target tumor-related ECs in gliomas, it is critical to comprehend these distinctive features of ECs associated with gliomas. This review discusses the process of angiogenesis, other factors involved in the genesis of tumors, and the possibility of ECs as a potential target in combating glioblastoma. It also sheds light on the association of tumor microenvironment and ECs with immunotherapy. This review, thus gives us the hope that neuro endothelial targeting with growth factors and angiogenesis regulators combined with gene therapy would open up new doorways and change our traditional perspective of treating cancer.
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Affiliation(s)
- Tejas Girish Agnihotri
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, India
| | - Sagar Salave
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, India
| | - Tanuja Shinde
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, India
| | - Induri Srikanth
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, India
| | - Vijay Gyanani
- Long Acting Drug Delivery, Celanese Corporation, Irving, United States
| | - Jeffrey C. Haley
- Long Acting Drug Delivery, Celanese Corporation, Irving, United States
| | - Aakanchha Jain
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, India
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11
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Kabbani N, Stepan H, Blüher M, Ebert T, Baber R, Vogel M, Kiess W, Stumvoll M, Breitfeld J, Lössner U, Tönjes A, Schrey-Petersen S. Association between TGFβ1 Levels in Cord Blood and Weight Progress in the First Year of Life. Biomedicines 2023; 11:2220. [PMID: 37626717 PMCID: PMC10452394 DOI: 10.3390/biomedicines11082220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/01/2023] [Accepted: 08/02/2023] [Indexed: 08/27/2023] Open
Abstract
Transforming growth factor beta-1 (TGFβ1) is an adipokine secreted from adipose tissue, placental tissue and immune cells with a role in cell proliferation, cell apoptosis and angiogenic proliferation. The role of TGFβ1 in pregnancy and child growth and the source of cord TGFβ1 are yet unknown. In this study, we sought to clarify the correlation of TGFβ1 levels with parameters of intrauterine growth and child growth during the first year of life, and to determine whether their source is primarily of fetal or maternal origin. Serum samples and anthropometric measurements were obtained from the LIFE Child cohort of 79 healthy mother-child pairs. Measurements were conducted using enzyme-linked immunosorbent assays. Statistical analyses including Mann-Whitney U-test, correlation analyses and linear regression analyses were performed using GraphPad Prism and R. TGFβ1 levels were significantly higher in cord than in maternal serum, suggesting a fetal origin. Multivariate regression analyses revealed strong positive associations between cord TGFβ1 levels at birth and child weight at U6. Furthermore, cord TGFβ1 was significantly correlated with child weight at approximately one year of age. An increase of 10,000 pg/mL in cord TGFβ1 concentrations at birth was associated with a higher body weight of 201 g at roughly one year of age when adjusted for sex.
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Affiliation(s)
- Noura Kabbani
- Department of Obstetrics, University of Leipzig Medical Center, 04103 Leipzig, Germany
| | - Holger Stepan
- Department of Obstetrics, University of Leipzig Medical Center, 04103 Leipzig, Germany
| | - Matthias Blüher
- Medical Department III—Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München, The University of Leipzig and University Hospital Leipzig, 04103 Leipzig, Germany
| | - Thomas Ebert
- Medical Department III—Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany
| | - Ronny Baber
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, 04103 Leipzig, Germany
- Leipzig Medical Biobank, University of Leipzig, 04103 Leipzig, Germany
| | - Mandy Vogel
- LIFE Child, Hospital for Children and Adolescents, Department of Pediatrics, University of Leipzig Medical Center, 04103 Leipzig, Germany
- Center for Pediatric Research (CPL), Hospital for Children and Adolescents, University of Leipzig Medical Center, 04103 Leipzig, Germany
| | - Wieland Kiess
- LIFE Child, Hospital for Children and Adolescents, Department of Pediatrics, University of Leipzig Medical Center, 04103 Leipzig, Germany
- Center for Pediatric Research (CPL), Hospital for Children and Adolescents, University of Leipzig Medical Center, 04103 Leipzig, Germany
| | - Michael Stumvoll
- Medical Department III—Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany
| | - Jana Breitfeld
- Medical Department III—Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany
| | - Ulrike Lössner
- Medical Department III—Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany
| | - Anke Tönjes
- Medical Department III—Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany
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12
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Klumpe HE, Garcia-Ojalvo J, Elowitz MB, Antebi YE. The computational capabilities of many-to-many protein interaction networks. Cell Syst 2023; 14:430-446. [PMID: 37348461 PMCID: PMC10318606 DOI: 10.1016/j.cels.2023.05.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 04/14/2023] [Accepted: 05/11/2023] [Indexed: 06/24/2023]
Abstract
Many biological circuits comprise sets of protein variants that interact with one another in a many-to-many, or promiscuous, fashion. These architectures can provide powerful computational capabilities that are especially critical in multicellular organisms. Understanding the principles of biochemical computations in these circuits could allow more precise control of cellular behaviors. However, these systems are inherently difficult to analyze, due to their large number of interacting molecular components, partial redundancies, and cell context dependence. Here, we discuss recent experimental and theoretical advances that are beginning to reveal how promiscuous circuits compute, what roles those computations play in natural biological contexts, and how promiscuous architectures can be applied for the design of synthetic multicellular behaviors.
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Affiliation(s)
- Heidi E Klumpe
- Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA; Biological Design Center, Boston University, Boston, MA 02215, USA
| | - Jordi Garcia-Ojalvo
- Department of Medicine and Life Sciences, Pompeu Fabra University, 08003 Barcelona, Spain.
| | - Michael B Elowitz
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
| | - Yaron E Antebi
- Department of Molecular Genetics, Weizmann Institute of Science 76100, Rehovot, Israel.
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13
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Zheng SY, Wan XX, Kambey PA, Luo Y, Hu XM, Liu YF, Shan JQ, Chen YW, Xiong K. Therapeutic role of growth factors in treating diabetic wound. World J Diabetes 2023; 14:364-395. [PMID: 37122434 PMCID: PMC10130901 DOI: 10.4239/wjd.v14.i4.364] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/16/2023] [Accepted: 03/21/2023] [Indexed: 04/12/2023] Open
Abstract
Wounds in diabetic patients, especially diabetic foot ulcers, are more difficult to heal compared with normal wounds and can easily deteriorate, leading to amputation. Common treatments cannot heal diabetic wounds or control their many complications. Growth factors are found to play important roles in regulating complex diabetic wound healing. Different growth factors such as transforming growth factor beta 1, insulin-like growth factor, and vascular endothelial growth factor play different roles in diabetic wound healing. This implies that a therapeutic modality modulating different growth factors to suit wound healing can significantly improve the treatment of diabetic wounds. Further, some current treatments have been shown to promote the healing of diabetic wounds by modulating specific growth factors. The purpose of this study was to discuss the role played by each growth factor in therapeutic approaches so as to stimulate further therapeutic thinking.
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Affiliation(s)
- Shen-Yuan Zheng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, Hunan Province, China
| | - Xin-Xing Wan
- Department of Endocrinology, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, China
| | - Piniel Alphayo Kambey
- Department of Neurobiology and Anatomy, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
| | - Yan Luo
- Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Xi-Min Hu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, Hunan Province, China
| | - Yi-Fan Liu
- Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Jia-Qi Shan
- Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Yu-Wei Chen
- Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Kun Xiong
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, Hunan Province, China
- Key Laboratory of Emergency and Trauma, College of Emergency and Trauma, Hainan Medical University, Haikou 571199, Hainan Province, China
- Hunan Key Laboratory of Ophthalmology, Central South University, Changsha 410013, Hunan Province, China
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14
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Hatamzade Esfahani N, Day AS. The Role of TGF-β, Activin and Follistatin in Inflammatory Bowel Disease. GASTROINTESTINAL DISORDERS 2023; 5:167-186. [DOI: 10.3390/gidisord5020015] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/10/2023] Open
Abstract
Inflammatory bowel disease (IBD) is an immune-mediated inflammatory condition predominantly affecting the gastrointestinal (GI) tract. An increasing prevalence of IBD has been observed globally. The pathogenesis of IBD includes a complex interplay between the intestinal microbiome, diet, genetic factors and immune responses. The consequent imbalance of inflammatory mediators ultimately leads to intestinal mucosal damage and defective repair. Growth factors, given their specific roles in maintaining the homeostasis and integrity of the intestinal epithelium, are of particular interest in the setting of IBD. Furthermore, direct targeting of growth factor signalling pathways involved in the regeneration of the damaged epithelium and the regulation of inflammation could be considered as therapeutic options for individuals with IBD. Several members of the transforming growth factor (TGF)-β superfamily, particularly TGF-β, activin and follistatin, are key candidates as they exhibit various roles in inflammatory processes and contribute to maintenance and homeostasis in the GI tract. This article aimed firstly to review the events involved in the pathogenesis of IBD with particular emphasis on TGF-β, activin and follistatin and secondly to outline the potential role of therapeutic manipulation of these pathways.
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Affiliation(s)
| | - Andrew S. Day
- Paediatric Department, University of Otago Christchurch, Christchurch 8140, New Zealand
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15
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Alpoim-Moreira J, Szóstek-Mioduchowska A, Słyszewska M, Rebordão MR, Skarzynski DJ, Ferreira-Dias G. 5-Aza-2′-Deoxycytidine (5-Aza-dC, Decitabine) Inhibits Collagen Type I and III Expression in TGF-β1-Treated Equine Endometrial Fibroblasts. Animals (Basel) 2023; 13:ani13071212. [PMID: 37048467 PMCID: PMC10093662 DOI: 10.3390/ani13071212] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/03/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023] Open
Abstract
Endometrosis negatively affects endometrial function and fertility in mares, due to excessive deposition of type I (COL1) and type III (COL3) collagens. The pro-fibrotic transforming growth factor (TGF-β1) induces myofibroblast differentiation, characterized by α-smooth muscle actin (α-SMA) expression, and collagen synthesis. In humans, fibrosis has been linked to epigenetic mechanisms. To the best of our knowledge, this has not been described in mare endometrium. Therefore, this study aimed to investigate the in vitro epigenetic regulation in TGF-β1-treated mare endometrial fibroblasts and the use of 5-aza-2′-deoxycytidine (5-aza-dC), an epigenetic modifier, as a putative treatment option for endometrial fibrosis. Methods and Results: The in vitro effects of TGF-β1 and of 5-aza-dC on DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B), COL1A1, COL3A1, and α-SMA transcripts were analyzed in endometrial fibroblasts, and COL1 and COL3 secretion in a co-culture medium. TGF-β1 upregulated DNMT3A transcripts and collagen secretion. In TGF-β1-treated endometrial fibroblasts, DNA methylation inhibitor 5-aza-dC decreased collagen transcripts and secretion, but not α-SMA transcripts. Conclusion: These findings suggest a possible role of epigenetic mechanisms during equine endometrial fibrogenesis. The in vitro effect of 5-aza-dC on collagen reduction in TGF-β1-treated fibroblasts highlights this epigenetic involvement. This may pave the way to different therapeutic approaches for endometrosis.
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16
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Jakubina P, Meloux A, Duloquin G, Aho S, Vergely C, Béjot Y. Plasma growth differentiation factor - 8 / Myostatin level as prognostic biomarker of patients with ischemic stroke and acute revascularization therapy. PARADISE study. J Neurol Sci 2023; 448:120611. [PMID: 36958132 DOI: 10.1016/j.jns.2023.120611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 03/01/2023] [Accepted: 03/02/2023] [Indexed: 03/18/2023]
Abstract
BACKGROUND Identifying biological markers of ischemic stroke (IS) is an important research approach to develop innovative therapeutic strategies. This study aimed to assess the association between plasma Growth Differentiation Factor-8 (GDF-8)/Myostatin levels and outcome of IS patients. METHODS Consecutive patients with acute IS treated with either intravenous thrombolysis and/or mechanical thrombectomy at Dijon University Hospital, France were prospectively included. Clinical variables were recorded, and plasma GDF-8 was collected just after the revascularization procedure. Primary endpoint was functional outcome at 3 months assessed by the modified Rankin Scale (mRS) score. Secondary endpoints included mRS scores at 6 and 12 months, and overall mortality over 1-year of follow-up. RESULTS Among the 173 included patients (median age: 76 years, Interquartile range (IQR): 66-85; 49% women), median plasma GDF-8 levels at admission were significantly lower in those with a poor outcome at 3 months defined as a mRS score > 2 (2073 (IQR: 1564-2757) pg/mL versus 1471 (1192-2241) pg/mL, p < 0.001). Lower GDF-8 levels at admission were associated with higher 3-months mRS score in multivariable ordinal logistic regression analysis (OR = 0.9995; 95% CI: 0.9991-0.9999, p = 0.011). The association was also observed with 6- and 12-month mRS scores. Although mortality was higher in patients with lower GDF-8 levels, the association was not significant in multivariable Cox analysis. CONCLUSION Lower plasma GDF-8 levels were associated with a poorer functional outcome in IS patients treated with acute revascularization therapy. Underlying pathophysiological mechanisms involving GDF-8 in post-stroke outcome remain to be elucidated.
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Affiliation(s)
- Pauline Jakubina
- Dijon Stroke Registry, Department of Neurology, University Hospital of Dijon, France.; EA7460, Pathophysiology and Epidemiology of Cerebro-Cardiovascular Diseases (PEC2), University of Burgundy, France
| | - Alexandre Meloux
- EA7460, Pathophysiology and Epidemiology of Cerebro-Cardiovascular Diseases (PEC2), University of Burgundy, France
| | - Gauthier Duloquin
- Dijon Stroke Registry, Department of Neurology, University Hospital of Dijon, France.; EA7460, Pathophysiology and Epidemiology of Cerebro-Cardiovascular Diseases (PEC2), University of Burgundy, France
| | - Serge Aho
- Department of Epidemiology and Biostatistics, University Hospital of Dijon, France
| | - Catherine Vergely
- EA7460, Pathophysiology and Epidemiology of Cerebro-Cardiovascular Diseases (PEC2), University of Burgundy, France
| | - Yannick Béjot
- Dijon Stroke Registry, Department of Neurology, University Hospital of Dijon, France.; EA7460, Pathophysiology and Epidemiology of Cerebro-Cardiovascular Diseases (PEC2), University of Burgundy, France.
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17
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Słota D, Piętak K, Jampilek J, Sobczak-Kupiec A. Polymeric and Composite Carriers of Protein and Non-Protein Biomolecules for Application in Bone Tissue Engineering. MATERIALS (BASEL, SWITZERLAND) 2023; 16:2235. [PMID: 36984115 PMCID: PMC10059071 DOI: 10.3390/ma16062235] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/02/2023] [Accepted: 03/08/2023] [Indexed: 06/18/2023]
Abstract
Conventional intake of drugs and active substances is most often based on oral intake of an appropriate dose to achieve the desired effect in the affected area or source of pain. In this case, controlling their distribution in the body is difficult, as the substance also reaches other tissues. This phenomenon results in the occurrence of side effects and the need to increase the concentration of the therapeutic substance to ensure it has the desired effect. The scientific field of tissue engineering proposes a solution to this problem, which creates the possibility of designing intelligent systems for delivering active substances precisely to the site of disease conversion. The following review discusses significant current research strategies as well as examples of polymeric and composite carriers for protein and non-protein biomolecules designed for bone tissue regeneration.
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Affiliation(s)
- Dagmara Słota
- Department of Materials Science, Faculty of Materials Engineering and Physics, Cracow University of Technology, 37 Jana Pawła II Av., 31-864 Krakow, Poland
| | - Karina Piętak
- Department of Materials Science, Faculty of Materials Engineering and Physics, Cracow University of Technology, 37 Jana Pawła II Av., 31-864 Krakow, Poland
| | - Josef Jampilek
- Department of Analytical Chemistry, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, 842 15 Bratislava, Slovakia
- Department of Chemical Biology, Faculty of Science, Palacky University Olomouc, Slechtitelu 27, 783 71 Olomouc, Czech Republic
| | - Agnieszka Sobczak-Kupiec
- Department of Materials Science, Faculty of Materials Engineering and Physics, Cracow University of Technology, 37 Jana Pawła II Av., 31-864 Krakow, Poland
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18
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Kubo E, Shibata S, Shibata T, Sasaki H, Singh DP. Role of Decorin in the Lens and Ocular Diseases. Cells 2022; 12:cells12010074. [PMID: 36611867 PMCID: PMC9818407 DOI: 10.3390/cells12010074] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 12/15/2022] [Accepted: 12/19/2022] [Indexed: 12/28/2022] Open
Abstract
Decorin is an archetypal member of the small leucine-rich proteoglycan gene family and is involved in various biological functions and many signaling networks, interacting with extra-cellular matrix (ECM) components, growth factors, and receptor tyrosine kinases. Decorin also modulates the growth factors, cell proliferation, migration, and angiogenesis. It has been reported to be involved in many ischemic and fibrotic eye diseases, such as congenital stromal dystrophy of the cornea, anterior subcapsular fibrosis of the lens, proliferative vitreoretinopathy, et al. Furthermore, recent evidence supports its role in secondary posterior capsule opacification (PCO) after cataract surgery. The expression of decorin mRNA in lens epithelial cells in vitro was found to decrease upon transforming growth factor (TGF)-β-2 addition and increase upon fibroblast growth factor (FGF)-2 addition. Wound healing of the injured lens in mice transgenic for lens-specific human decorin was promoted by inhibiting myofibroblastic changes. Decorin may be associated with epithelial-mesenchymal transition and PCO development in the lens. Gene therapy and decorin administration have the potential to serve as excellent therapeutic approaches for modifying impaired wound healing, PCO, and other eye diseases related to fibrosis and angiogenesis. In this review, we present findings regarding the roles of decorin in the lens and ocular diseases.
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Affiliation(s)
- Eri Kubo
- Department of Ophthalmology, Kanazawa Medical University, Kanazawa 920-0293, Ishikawa, Japan
- Correspondence: ; Tel.: +81-76-286-2211 (ext. 3412); Fax: +81-76-286-1010
| | - Shinsuke Shibata
- Department of Ophthalmology, Kanazawa Medical University, Kanazawa 920-0293, Ishikawa, Japan
| | - Teppei Shibata
- Department of Ophthalmology, Kanazawa Medical University, Kanazawa 920-0293, Ishikawa, Japan
| | - Hiroshi Sasaki
- Department of Ophthalmology, Kanazawa Medical University, Kanazawa 920-0293, Ishikawa, Japan
| | - Dhirendra P. Singh
- Department of Ophthalmology, University of Nebraska Medical Center, Omaha, NE 68198, USA
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Zhong Y, Ren X, Cao X, Xu Y, Song Y, Zhou Y, Mao F, Shen S, Wang Z, Sun Q. Insulin-like growth factor 2 receptor is a key immune-related gene that is correlated with a poor prognosis in patients with triple-negative breast cancer: A bioinformatics analysis. Front Oncol 2022; 12:871786. [PMID: 36330486 PMCID: PMC9624382 DOI: 10.3389/fonc.2022.871786] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 09/27/2022] [Indexed: 10/15/2023] Open
Abstract
BACKGROUND Immunotherapy plays an important role in the treatment of triple-negative breast cancer (TNBC). This study aimed to identify immune-related genes that are associated with the prognosis of patients with TNBC as possible targets of immunotherapy, alongside their related tumor-infiltrating lymphocytes (TILs). METHODS The clinical data and gene expression profiles of patients with breast cancer were extracted from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and divided into training (n = 1,053) and verification (n = 508) groups. CIBERSORT was used to predict the differences in immune cell infiltration in patient subsets that were stratified according to risk. Gene Ontology (GO) enrichment analysis was used to identify pathways associated with immune-related genes in patient subsets that were stratified according to risk. The clinical data and insulin-like growth factor 2 receptor (IGF2R) expression profiles of patients with breast cancer were extracted from METABRIC. The expression of IGF2R and TILs were evaluated in a cohort containing 282 untreated patients with TNBC. The correlations of IGF2R expression, TILs, and clinicopathological parameters with patient prognosis were analyzed in the whole cohort. RESULTS The prognostic model, which was composed of 26 immune-related gene pairs, significantly distinguished between high- and low-risk patients. Univariate and multivariate analyses indicated that the model was an independent prognostic factor for breast cancer. Among the identified genes, the expression of IGF2R significantly distinguished between high- and low-risk patients in TCGA (P = 0.008) and in METABRIC patients (P < 0.001). The expression of IGF2R was significantly associated with clinical risk factors such as TNBC, estrogen receptor (ER)-negative expression, human epidermal growth factor receptor 2 (HER2)-positive expression, and age ≤60 years old in METABRIC patients. In addition, the patients with IGF2R-positive expression had lower disease-free survival (DFS) rates than those with IGF2R-negative expression in the TNBC cohort (67.8% vs. 78.5%, P = 0.023). IGF2R expression also was significantly negatively correlated with TILs, particularly with CD8+ TILs and CD19+ TILs in the cohort of patients with TNBC. CONCLUSION IGF2R can be used as an indicator of a poor prognosis in patients with TNBC and as a potential target and research direction for TNBC immunotherapy in the future.
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Affiliation(s)
- Ying Zhong
- Department of Breast Disease, Peking Union Medical College Hospital, Beijing, China
| | - Xinyu Ren
- Department of Pathology, Peking Union Medical College Hospital, Beijing, China
| | - Xi Cao
- Department of Breast Disease, Peking Union Medical College Hospital, Beijing, China
| | - Yali Xu
- Department of Breast Disease, Peking Union Medical College Hospital, Beijing, China
| | - Yu Song
- Department of Breast Disease, Peking Union Medical College Hospital, Beijing, China
| | - Yidong Zhou
- Department of Breast Disease, Peking Union Medical College Hospital, Beijing, China
| | - Feng Mao
- Department of Breast Disease, Peking Union Medical College Hospital, Beijing, China
| | - Songjie Shen
- Department of Breast Disease, Peking Union Medical College Hospital, Beijing, China
| | - Zhe Wang
- Department of Breast Disease, Peking Union Medical College Hospital, Beijing, China
| | - Qiang Sun
- Department of Breast Disease, Peking Union Medical College Hospital, Beijing, China
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Hayashi T, Asakura M, Kawase M, Matsubara M, Uematsu Y, Mieki A, Kawai T. Bone Tissue Engineering in Rat Calvarial Defects Using Induced Bone-like Tissue by rhBMPs from Immature Muscular Tissues In Vitro. Int J Mol Sci 2022; 23:ijms23136927. [PMID: 35805943 PMCID: PMC9266849 DOI: 10.3390/ijms23136927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/15/2022] [Accepted: 06/21/2022] [Indexed: 01/27/2023] Open
Abstract
This study aimed to induce bone-like tissue from immature muscular tissue (IMT) in vitro using commercially available recombinant human bone morphogenetic protein (rhBMP)-2, rhBMP-4, and rhBMP-7, and then implanting this tissue into a calvarial defect in rats to assess healing. IMTs were extracted from 20-day-old Sprague-Dawley (SD) fetal rats, placed on expanded polytetrafluoroethylene (ePTFE) with 10 ng/μL each of rhBMP-2, BMP-4, and BMP-7, and cultured for two weeks. The specimens were implanted into calvarial defects in 3-week-old SD rats for up to three weeks. Relatively strong radiopacity was observed on micro-CT two weeks after culture, and bone-like tissue, comprising osteoblastic cells and osteoids, was partially observed by H&E staining. Calcium, phosphorus, and oxygen were detected in the extracellular matrix using an electron probe micro analyzer, and X-ray diffraction patterns and Fourier transform infrared spectroscopy spectra of the specimen were found to have typical apatite crystal peaks and spectra, respectively. Furthermore, partial strong radiopacity and ossification were confirmed one week after implantation, and a dominant novel bone was observed after two weeks in the defect site. Thus, rhBMP-2, BMP-4, and BMP-7 differentiated IMT into bone-like tissue in vitro, and this induced bone-like tissue has ossification potential and promotes the healing of calvarial defects. Our results suggest that IMT is an effective tissue source for bone tissue engineering.
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Murase H, El-Sheikh Ali H, Ruby RE, Scoggin KE, Ball BA. Transcriptomic analysis of the chorioallantois in equine premature placental separation. Equine Vet J 2022; 55:405-418. [PMID: 35622344 DOI: 10.1111/evj.13602] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 05/12/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Equine premature placental separation (PPS) is poorly understood and represents an important risk factor for fetal/neonatal hypoxia. OBJECTIVES To examine transcriptomic changes in the chorioallantois (CA) from mares with clinical PPS compared to the CA from normal foaling mares. Differential gene expression was determined and gene ontology as well as molecular pathways related to PPS were characterised. STUDY DESIGN Retrospective case: control study. METHODS CA were collected from Thoroughbred mares with a clinical history of PPS (n=33) and from control Thoroughbred mares (n=4) with normal parturition for examination of transcriptional changes in the placenta associated with PPS. Transcriptomic changes in the villous CA near the cervical star were determined by Illumina® sequencing and subsequent bioinformatic analysis. PPS samples were divided by k-means clustering, and differentially expressed genes (DEGs) in each PPS cluster were identified by comparing to controls. Shared DEGs between PPS clusters were used for gene ontology analysis and pathway analysis. RESULTS A total of 1204 DEGs were identified between PPS and control. Gene ontology revealed extracellular matrix (ECM) and cell adhesion, and pathway analysis revealed fatty acid, p-53, hypoxia, and inflammation. Eleven key regulator genes of PPS including growth factors (IGF1, TGFB2, TGFB3), transcription factors (HIF1A, JUNB, SMAD3), and transmembrane receptors (FGFR1, TNFRSF1A, TYROBP) were also identified. MAIN LIMITATIONS The use of clinical history of PPS, in the absence of other criteria, may have led to misidentification of some cases as PPS. CONCLUSIONS Transcriptomic analysis indicated that changes in ECM and cell adhesion were important factors in equine PPS. Key predicted upstream events include genes associated with hypoxia, inflammation and growth factors related to the pathogenesis of equine PPS.
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Affiliation(s)
- Harutaka Murase
- Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Lexington, KY, USA.,Equine Science Division, Hidaka Training and Research Center, Japan Racing Association, Urakawa, Hokkaido, Japan
| | - Hossam El-Sheikh Ali
- Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Lexington, KY, USA.,Faculty of Veterinary Medicine, Mansoura University, Egypt
| | - Rebecca E Ruby
- Veterinary Diagnostic Laboratory, University of Kentucky, Lexington, KY, USA
| | - Kirsten E Scoggin
- Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Lexington, KY, USA
| | - Barry A Ball
- Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Lexington, KY, USA
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22
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Vicidomini R, Serpe M. Local BMP signaling: A sensor for synaptic activity that balances synapse growth and function. Curr Top Dev Biol 2022; 150:211-254. [PMID: 35817503 PMCID: PMC11102767 DOI: 10.1016/bs.ctdb.2022.04.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Synapse development is coordinated by intercellular communication between the pre- and postsynaptic compartments, and by neuronal activity itself. In flies as in vertebrates, neuronal activity induces input-specific changes in the synaptic strength so that the entire circuit maintains stable function in the face of many challenges, including changes in synapse number and strength. But how do neurons sense synapse activity? In several studies carried out using the Drosophila neuromuscular junction (NMJ), we demonstrated that local BMP signaling provides an exquisite sensor for synapse activity. Here we review the main features of this exquisite sensor and discuss its functioning beyond monitoring the synapse activity but rather as a key controller that operates in coordination with other BMP signaling pathways to balance synapse growth, maturation and function.
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Affiliation(s)
- Rosario Vicidomini
- Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shiver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Mihaela Serpe
- Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shiver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States.
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23
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Chen X, Yang Q, Bai W, Yao W, Liu L, Xing Y, Meng C, Qi P, Dang Y, Qi X. Dapagliflozin Attenuates Myocardial Fibrosis by Inhibiting the TGF-β1/Smad Signaling Pathway in a Normoglycemic Rabbit Model of Chronic Heart Failure. Front Pharmacol 2022; 13:873108. [PMID: 35645838 PMCID: PMC9136228 DOI: 10.3389/fphar.2022.873108] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 04/13/2022] [Indexed: 11/14/2022] Open
Abstract
Recent studies have shown that sodium-glucose cotransporter-2 (SGLT2) inhibitors play a beneficial role for normoglycemic patients with heart failure (HF). However, the underlying mechanism remains largely unexplored. In the present study, we aimed to investigate the cardioprotective effect of SGLT2 inhibitors in a normoglycemic rabbit model of chronic heart failure (CHF) and its potential mechanism was also explored. A total of 24 male New Zealand white rabbits were randomly divided into the sham group, HF group, perindopril group, and dapagliflozin (DAPA) group. The normoglycemic CHF model was established by aortic constriction for 12 weeks. In the 13th week, DAPA (1 mg/kg/day) or perindopril (0.5 mg/kg/day) was administered by oral gavage daily for 10 weeks. Both the sham group and HF group were given normal saline via gavage. After 10 weeks, the heart structure and function were evaluated by echocardiography and plasma NT-proBNP. Moreover, cardiac fibrosis was analyzed using immunohistochemistry, Masson’s trichrome staining, and Western blotting analysis. The results showed that DAPA improved the myocardial structure and function of normoglycemic CHF rabbits and ameliorated myocardial fibrosis. Further study indicated that DAPA suppressed cardiac fibrosis by inhibiting the transforming growth factor β1 (TGF-β1)/Smad signaling pathway. Collectively, our findings showed that DAPA could ameliorate cardiac fibrosis in normoglycemic CHF rabbits by inhibiting the TGF-β1/Smad signaling pathway.
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Affiliation(s)
- Xuefeng Chen
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, China
- Department of Cardiology Center, Hebei General Hospital, Shijiazhuang, China
| | - Qian Yang
- Department of Cardiology Center, Hebei General Hospital, Shijiazhuang, China
| | - Wenlou Bai
- Department of Cardiology Center, Hebei General Hospital, Shijiazhuang, China
| | - Wenjing Yao
- Department of Cardiology Center, Hebei General Hospital, Shijiazhuang, China
| | - Litian Liu
- Department of Cardiology Center, Hebei General Hospital, Shijiazhuang, China
| | - Yuanyuan Xing
- Department of Cardiology Center, Hebei General Hospital, Shijiazhuang, China
| | - Cunliang Meng
- Department of Cardiology Center, Hebei General Hospital, Shijiazhuang, China
| | - Peng Qi
- Department of Cardiology Center, Hebei General Hospital, Shijiazhuang, China
| | - Yi Dang
- Department of Cardiology Center, Hebei General Hospital, Shijiazhuang, China
| | - Xiaoyong Qi
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, China
- Department of Cardiology Center, Hebei General Hospital, Shijiazhuang, China
- *Correspondence: Xiaoyong Qi,
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24
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TGF-β1 Reduces Neutrophil Adhesion and Prevents Acute Vaso-Occlusive Processes in Sickle Cell Disease Mice. Cells 2022; 11:cells11071200. [PMID: 35406764 PMCID: PMC8998040 DOI: 10.3390/cells11071200] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 03/28/2022] [Accepted: 03/29/2022] [Indexed: 12/26/2022] Open
Abstract
Sickle cell disease (SCD) patients experience chronic inflammation and recurrent vaso-occlusive episodes during their entire lifetime. Inflammation in SCD occurs with the overexpression of several inflammatory mediators, including transforming growth factor beta-1 (TGF-β1), a major immune regulator. In this study, we aimed to investigate the role played by TGF-β1 in vascular inflammation and vaso-occlusion in an animal model of SCD. Using intravital microscopy, we found that a daily dose of recombinant TGF-β1 administration for three consecutive days significantly reduced TNFα-induced leukocyte rolling, adhesion, and extravasation in the microcirculation of SCD mice. In contrast, immunological neutralization of TGF-β, in the absence of inflammatory stimulus, considerably increased these parameters. Our results indicate, for the first time, that TGF-β1 may play a significant ameliorative role in vascular SCD pathophysiology, modulating inflammation and vaso-occlusion. The mechanisms by which TGF-β1 exerts its anti-inflammatory effects in SCD, however, remains unclear. Our in vitro adhesion assays with TNFα-stimulated human neutrophils suggest that TGF-β1 can reduce the adhesive properties of these cells; however, direct effects of TGF-β1 on the endothelium cannot be ruled out. Further investigation of the wide range of the complex biology of this cytokine in SCD pathophysiology and its potential therapeutical use is needed.
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25
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García-García M, Sánchez-Perales S, Jarabo P, Calvo E, Huyton T, Fu L, Ng SC, Sotodosos-Alonso L, Vázquez J, Casas-Tintó S, Görlich D, Echarri A, Del Pozo MA. Mechanical control of nuclear import by Importin-7 is regulated by its dominant cargo YAP. Nat Commun 2022; 13:1174. [PMID: 35246520 PMCID: PMC8897400 DOI: 10.1038/s41467-022-28693-y] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 01/19/2022] [Indexed: 12/31/2022] Open
Abstract
Mechanical forces regulate multiple essential pathways in the cell. The nuclear translocation of mechanoresponsive transcriptional regulators is an essential step for mechanotransduction. However, how mechanical forces regulate the nuclear import process is not understood. Here, we identify a highly mechanoresponsive nuclear transport receptor (NTR), Importin-7 (Imp7), that drives the nuclear import of YAP, a key regulator of mechanotransduction pathways. Unexpectedly, YAP governs the mechanoresponse of Imp7 by forming a YAP/Imp7 complex that responds to mechanical cues through the Hippo kinases MST1/2. Furthermore, YAP behaves as a dominant cargo of Imp7, restricting the Imp7 binding and the nuclear translocation of other Imp7 cargoes such as Smad3 and Erk2. Thus, the nuclear import process is an additional regulatory layer indirectly regulated by mechanical cues, which activate a preferential Imp7 cargo, YAP, which competes out other cargoes, resulting in signaling crosstalk. The translation of mechanical cues into gene expression changes is dependent on the nuclear import of mechanoresponsive transcriptional regulators. Here the authors identify that Importin-7 drives the nuclear import of one such regulator YAP while YAP then controls Importin-7 response to mechanical cues and restricts Importin-7 binding to other cargoes.
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Affiliation(s)
- María García-García
- Mechanoadaptation and Caveolae Biology Laboratory. Area of Cell & Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Calle Melchor Fernández Almagro, 3, 28029, Madrid, Spain
| | - Sara Sánchez-Perales
- Mechanoadaptation and Caveolae Biology Laboratory. Area of Cell & Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Calle Melchor Fernández Almagro, 3, 28029, Madrid, Spain
| | - Patricia Jarabo
- Instituto Cajal-CSIC, Avda. Doctor Arce, 37, 28002, Madrid, Spain
| | - Enrique Calvo
- Proteomics Unit. Area of Vascular Physiopathology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Calle Melchor Fernández Almagro, 3, 28029, Madrid, Spain.,CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Trevor Huyton
- Department of Cellular Logistics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077, Göttingen, Germany
| | - Liran Fu
- Department of Cellular Logistics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077, Göttingen, Germany
| | - Sheung Chun Ng
- Department of Cellular Logistics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077, Göttingen, Germany
| | - Laura Sotodosos-Alonso
- Mechanoadaptation and Caveolae Biology Laboratory. Area of Cell & Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Calle Melchor Fernández Almagro, 3, 28029, Madrid, Spain
| | - Jesús Vázquez
- Proteomics Unit. Area of Vascular Physiopathology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Calle Melchor Fernández Almagro, 3, 28029, Madrid, Spain.,CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | | | - Dirk Görlich
- Department of Cellular Logistics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077, Göttingen, Germany
| | - Asier Echarri
- Mechanoadaptation and Caveolae Biology Laboratory. Area of Cell & Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Calle Melchor Fernández Almagro, 3, 28029, Madrid, Spain.
| | - Miguel A Del Pozo
- Mechanoadaptation and Caveolae Biology Laboratory. Area of Cell & Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Calle Melchor Fernández Almagro, 3, 28029, Madrid, Spain.
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26
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Shi R, Li X, Cheng P, Yang Q, Chen Z, Chen S, Wang N. Characterization of growth differentiation factor 9 and bone morphogenetic factor 15 in Chinese tongue sole (Cynoglossus semilaevis): Sex-biased expression pattern and promoter regulation. Theriogenology 2022; 182:119-128. [DOI: 10.1016/j.theriogenology.2022.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 01/31/2022] [Accepted: 02/03/2022] [Indexed: 10/19/2022]
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27
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Oller-Rodríguez JE, Vicens Bernabeu E, Gonzalez-Mazarío R, Grau García E, Ortiz Sanjuan FM, Román Ivorra JA. Utility of cytokines CXCL4, CXCL8 and GDF15 as biomarkers in systemic sclerosis. Med Clin (Barc) 2022; 159:359-365. [PMID: 35039167 DOI: 10.1016/j.medcli.2021.12.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 11/25/2021] [Accepted: 12/03/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND AND OBJECTIVES Systemic sclerosis (SSc) is an autoinmune disease that can affect several organs and its mortality is fundamentally related to its pulmonary involvement. There are some cytokines with high serum levels of patients with SSc. Our goal is to determine the role of CXCL4, CXCL8 and GDF15 in the physiopathology of SSc and whether they can be considered organic damage biomarkers. PATIENTS AND METHODS Observational case-control study of SSc patients (ACR/EULAR 2013 criteria). Demographic, clinical, analytical, activity, severity, health perception, and disability variables were collected. Moreover, Videocapillaroscopy, Echocardiography and Respiratory Function Test were made. Serum levels of CXCL4, CXCL8 and GDF15 were measured both in SSc patients and in healthy controls. RESULTS A total of 42 patients were included (95.4% women), with an average age of 59.2 years and a median of 4 years from diagnosis. We also included 42 healthy controls. We found significantly higher levels of GDF15 in SSc patients than in controls (p<0.001), but no higher CXCL4 or CXCL8 levels. GDF15 was associated with Diffuse SSc, pulmonary arterial hypertension, interstitial lung disease, less forced vital capacity, high titles of antiScl70, disease activity, and dilated loops in capillaroscopy. CXCL4 levels were associated to a higher Rodnan punctuation, while CXCL8 was associated to C4 fraction consumption and tortuosities in capillaroscopy. CONCLUSIONS GDF15 high levels were associated with diffuse SSc, lung impairment, disease activity and changes in capillaroscopy. Moreover, CXCL4 was only associated with skin impairment, while CXCL8 was not related to organic damage.
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Affiliation(s)
- José E Oller-Rodríguez
- Servicio de Reumatología, Hospital UyP La Fe, Valencia, Spain; Escuela de Doctorado. Universidad Católica de Valencia San Vicente Mártir, Valencia, Spain.
| | | | | | | | | | - José A Román Ivorra
- Servicio de Reumatología, Hospital UyP La Fe, Valencia, Spain; Escuela de Doctorado. Universidad Católica de Valencia San Vicente Mártir, Valencia, Spain
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28
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Abstract
Transforming growth factor-β (TGFβ) signalling controls multiple cell fate decisions during development and tissue homeostasis; hence, dysregulation of this pathway can drive several diseases, including cancer. Here we discuss the influence that TGFβ exerts on the composition and behaviour of different cell populations present in the tumour immune microenvironment, and the context-dependent functions of this cytokine in suppressing or promoting cancer. During homeostasis, TGFβ controls inflammatory responses triggered by exposure to the outside milieu in barrier tissues. Lack of TGFβ exacerbates inflammation, leading to tissue damage and cellular transformation. In contrast, as tumours progress, they leverage TGFβ to drive an unrestrained wound-healing programme in cancer-associated fibroblasts, as well as to suppress the adaptive immune system and the innate immune system. In consonance with this key role in reprogramming the tumour microenvironment, emerging data demonstrate that TGFβ-inhibitory therapies can restore cancer immunity. Indeed, this approach can synergize with other immunotherapies - including immune checkpoint blockade - to unleash robust antitumour immune responses in preclinical cancer models. Despite initial challenges in clinical translation, these findings have sparked the development of multiple therapeutic strategies that inhibit the TGFβ pathway, many of which are currently in clinical evaluation.
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Affiliation(s)
- Daniele V F Tauriello
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
| | - Elena Sancho
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain
| | - Eduard Batlle
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain.
- Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
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29
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Huang J, Yin H, Zhang Y, Qiao H, Su L, Wang J. Expression of TGF-β/Smads in Cecum and Spleen of Chicken Infected with E. Tenella. BRAZILIAN JOURNAL OF POULTRY SCIENCE 2022. [DOI: 10.1590/1806-9061-2021-1446] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- J Huang
- Henan University of Technology, China; State Administration of Grain, China
| | - H Yin
- Henan University of Technology, China; State Administration of Grain, China
| | - Y Zhang
- Henan University of Technology, China
| | - H Qiao
- Henan University of Technology, China
| | - L Su
- Henan University of Technology, China
| | - J Wang
- Henan University of Technology, China
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30
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Kim YC, Kim J, Kim S, Bae B, Kim RL, Jeong EM, Cho SH, Kang HR. Transglutaminase 2 mediates lung inflammation and remodeling by transforming growth factor beta 1 via alveolar macrophage modulation. Exp Lung Res 2021; 47:465-475. [PMID: 34818962 DOI: 10.1080/01902148.2021.1998733] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Transforming growth factor beta 1 (TGF-β1) induces pulmonary fibrosis by enhancing epithelial apoptosis and affects the enzymatic activity of transglutaminase 2 (TG2). The aim of this study was to determine the role of TG2 in TGF-β1-induced lung remodeling and alveolar macrophage modulation. We characterized the in vivo effects of TGF-β1 and TG2 on lung inflammation, fibrosis, and macrophage activity using transgenic C57BL/6 mice with wild and null TG2 loci. The effect of TG2 inhibition on in vitro TGF-β1-stimulated alveolar macrophages was assessed through mRNA analysis. TG2 was remarkably upregulated in the lungs of TGF-β1 transgenic (TGF-β1 Tg) mice, especially in alveolar macrophages and epithelial cells. In the absence of TG2, TGF-β1-induced inflammation was suppressed, decreasing the number of macrophages in the bronchoalveolar lavage fluid. In addition, the alveolar destruction and peribronchial fibrosis induced by TGF-β1 overexpression were significantly reduced, which correlated with decreases in the expression of fibroblast growth factor and matrix metallopeptidase 12, respectively. However, TG2 deficiency did not compromise the phagocytic activity of alveolar macrophages in TGF-β1 Tg mice. At the same time, TG2 contributed to the regulation of TGF-β1-induced macrophage activation. Inhibition of TG2 did not affect the TGF-β1-induced expression of CD86, an M1 marker, in macrophages, but it did reverse the TGF-β1-induced expression of CD206. This result suggests that TG2 mediates TGF-β1-induced M2-like polarization but does not contribute to TGF-β1-induced M1 polarization. In conclusion, TG2 regulates macrophage modulation and plays an important role in TGF-β1-induced lung inflammation, destruction, and fibrosis.
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Affiliation(s)
- Young Chan Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.,Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea
| | - Jeonghyeon Kim
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea.,Department of Translational Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Subin Kim
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea
| | - Boram Bae
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea
| | - Ruth Lee Kim
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea.,Department of Translational Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Eui-Man Jeong
- Department of Pharmacy, Jeju National University College of Pharmacy, Jeju, Korea
| | - Sang-Heon Cho
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.,Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea
| | - Hye-Ryun Kang
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.,Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea
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31
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Parihar N, Bhatt LK. Deubiquitylating enzymes: potential target in autoimmune diseases. Inflammopharmacology 2021; 29:1683-1699. [PMID: 34792672 DOI: 10.1007/s10787-021-00890-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Accepted: 10/28/2021] [Indexed: 12/28/2022]
Abstract
The ubiquitin-proteasome pathway is responsible for the turnover of different cellular proteins, such as transport proteins, presentation of antigens to the immune system, control of the cell cycle, and activities that promote cancer. The enzymes which remove ubiquitin, deubiquitylating enzymes (DUBs), play a critical role in central and peripheral immune tolerance to prevent the development of autoimmune diseases and thus present a potential therapeutic target for the treatment of autoimmune diseases. DUBs function by removing ubiquitin(s) from target protein and block ubiquitin chain elongation. The addition and removal of ubiquitin molecules have a significant impact on immune responses. DUBs and E3 ligases both specifically cleave target protein and modulate protein activity and expression. The balance between ubiquitylation and deubiquitylation modulates protein levels and also protein interactions. Dysregulation of the ubiquitin-proteasome pathway results in the development of various autoimmune diseases such as inflammatory bowel diseases (IBD), psoriasis, multiple sclerosis (MS), systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). This review summarizes the current understanding of ubiquitination in autoimmune diseases and focuses on various DUBs responsible for the progression of autoimmune diseases.
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Affiliation(s)
- Niraj Parihar
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai, India
| | - Lokesh Kumar Bhatt
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai, India.
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Eka Widiastuti IA, Arsyad A, Idris I, Patellongi I, Kadriyan H, Buanayuda GW, Sari DP, Rosyidi RM. Exercise adaptations and TGF-β1 levels in recreational cyclists. Ann Med Surg (Lond) 2021; 70:102872. [PMID: 34691420 PMCID: PMC8519766 DOI: 10.1016/j.amsu.2021.102872] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 09/16/2021] [Accepted: 09/16/2021] [Indexed: 01/09/2023] Open
Abstract
Background Cycling is a physical exercise that is widely performed to improve physical fitness. Regular physical exercise will lead to adaptations to exercise. This adaptation is useful in suppressing the production of reactive oxygen stress (ROS) generated in response to cellular metabolism that uses oxygen. Transforming growth factor beta-1 (TGF-β1) plays a role in increasing the production of ROS, thus, when the concentration is low, it would lead to an improvement in physical fitness. This study aims to compare levels of TGF-β1 between recreational cyclists and sedentary groups. In addition, this research also compares several other parameters, which are fasting blood sugar levels and lipid profiles (triglycerides, total cholesterol, HDL cholesterol, and LDL cholesterol) between cyclists and sedentaries. Methods This was an observational analytical study with a cross-sectional design. The research subjects consisted of 2 groups, each consisting of 21 participants, namely the recreational cyclist and the sedentary group. Anthropometric examinations were carried out, including body weight, height, body mass index, waist circumference, and body fat percentage. Fasting blood glucose concentration and lipid profile (Triglyceride – TG, Total Cholesterol – Total C, HDL Cholesterol – HDL-C, and LDL Cholesterol – LDL-C) were determined by the enzymatic colorimetric methods, and TGF-β1 levels were determined using the fluorescence of specific antibodies for TGF-β1 (pg/ml) using ELISA method. Statistical analysis was performed using IBM SPSS v. 25. Results The anthropometric variables, other than body height, did not differ significantly between the two groups, so did the fasting blood glucose concentration. Nevertheless, the lipid profile (TG, Total C, HDL-C and LDL-C) were found to be significantly better in the cyclist group (p < 0.05). The mean level of TGF-β1 in recreational cyclists was 8, 908.48 pg/ml, lower than the control group, 10, 229.28 pg/ml. The results of the unpaired t-test showed significant mean differences between the two groups, (p = 0.001; p < 0.05). Conclusion The levels of TGF-β1 in the recreational cyclist group were lower than the sedentary group. Regular physical exercise will trigger exercise adaptations that can suppress latent TGF-β1 activation.
This study aims to compare levels of TGF-β1 between recreational cyclists and sedentary groups The research subjects consisted of 2 groups, each consisting of 21 participants, namely the recreational cyclist and the sedentary group. Anthropometric examinations were carried out, including body weight, height, body mass index, waist circumference, and body fat percentage The levels of TGF-β1 in the recreational cyclist group were lower than the sedentary group
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Affiliation(s)
- Ida Ayu Eka Widiastuti
- Department of Physiology, Medical Faculty of Mataram University, Mataram, Indonesia.,Postgraduate Program, Medical Faculty of Hasanuddin University, Makassar, Indonesia
| | - Aryadi Arsyad
- Postgraduate Program, Medical Faculty of Hasanuddin University, Makassar, Indonesia.,Department of Physiology, Medical Faculty of Hasanuddin University, Makassar, Indonesia
| | - Irfan Idris
- Postgraduate Program, Medical Faculty of Hasanuddin University, Makassar, Indonesia.,Department of Physiology, Medical Faculty of Hasanuddin University, Makassar, Indonesia
| | - Ilhamjaya Patellongi
- Postgraduate Program, Medical Faculty of Hasanuddin University, Makassar, Indonesia.,Department of Physiology, Medical Faculty of Hasanuddin University, Makassar, Indonesia
| | - Hamsu Kadriyan
- Department of Otolaryngology Head and Neck Surgery, Medical Faculty of Mataram University, Mataram, Indonesia
| | - Gede Wira Buanayuda
- Department of Biomedical Sciences, Medical Faculty of Mataram University, Mataram, Indonesia
| | - Dian Puspita Sari
- Department of Medical Education, Medical Faculty of Mataram University, Mataram, Indonesia
| | - Rohadi Muhammad Rosyidi
- Department of Neurosurgery Medical Faculty of Mataram University, West Nusa Tenggara General Hospital, Mataram, Indonesia
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Angiogenic Effects and Crosstalk of Adipose-Derived Mesenchymal Stem/Stromal Cells and Their Extracellular Vesicles with Endothelial Cells. Int J Mol Sci 2021; 22:ijms221910890. [PMID: 34639228 PMCID: PMC8509224 DOI: 10.3390/ijms221910890] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/02/2021] [Accepted: 10/04/2021] [Indexed: 12/13/2022] Open
Abstract
Adipose-derived mesenchymal stem/stromal cells (ASCs) are an adult stem cell population able to self-renew and differentiate into numerous cell lineages. ASCs provide a promising future for therapeutic angiogenesis due to their ability to promote blood vessel formation. Specifically, their ability to differentiate into endothelial cells (ECs) and pericyte-like cells and to secrete angiogenesis-promoting growth factors and extracellular vesicles (EVs) makes them an ideal option in cell therapy and in regenerative medicine in conditions including tissue ischemia. In recent angiogenesis research, ASCs have often been co-cultured with an endothelial cell (EC) type in order to form mature vessel-like networks in specific culture conditions. In this review, we introduce co-culture systems and co-transplantation studies between ASCs and ECs. In co-cultures, the cells communicate via direct cell-cell contact or via paracrine signaling. Most often, ASCs are found in the perivascular niche lining the vessels, where they stabilize the vascular structures and express common pericyte surface proteins. In co-cultures, ASCs modulate endothelial cells and induce angiogenesis by promoting tube formation, partly via secretion of EVs. In vivo co-transplantation of ASCs and ECs showed improved formation of functional vessels over a single cell type transplantation. Adipose tissue as a cell source for both mesenchymal stem cells and ECs for co-transplantation serves as a prominent option for therapeutic angiogenesis and blood perfusion in vivo.
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Yaish I, Tordjman K, Amir H, Malinger G, Salemnick Y, Shefer G, Serebro M, Azem F, Golani N, Sofer Y, Stern N, Greenman Y. Functional ovarian reserve in transgender men receiving testosterone therapy: evidence for preserved anti-Müllerian hormone and antral follicle count under prolonged treatment. Hum Reprod 2021; 36:2753-2760. [PMID: 34411251 DOI: 10.1093/humrep/deab169] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 06/19/2021] [Indexed: 11/14/2022] Open
Abstract
STUDY QUESTION Is the functional ovarian reserve in transgender men affected by testosterone therapy? SUMMARY ANSWER Serum anti-Müllerian Hormone (AMH) levels slightly decrease during testosterone treatment but remain within the normal range, suggesting preserved follicular ovarian reserve. WHAT IS KNOWN ALREADY Few small studies have investigated the impact of gender-affirming treatment on reproduction in transgender men. Conflicting results were reached concerning ovarian morphology and AMH levels in this context. STUDY DESIGN, SIZE, DURATION The study consisted of two arms. The first arm was a prospective pilot study, which enrolled 56 transgender men (median age 22.5 [interquartile range (IQR)-19-27.7] years), 27 of whom had polycystic ovary syndrome (PCOS), prior to the initiation of gender-affirming testosterone therapy. A structured assessment was conducted prior to, and at 3 and 12 months after treatment initiation. The second arm was a cross-sectional study that comprised 47 transgender men (median age 24 [IQR-20-31] years) who received testosterone for a median duration of 35 [IQR 13-62] months. The main outcome measures were serum AMH and antral follicle count (AFC) as indices of ovarian follicular reserve. PARTICIPANTS/MATERIALS, SETTING, METHODS The study was conducted at a tertiary center for transgender health. Gender-affirming therapy was administered according to standard practice. AFC was determined by pelvic (abdominal or transvaginal) ultrasound and blood collection for measurements of AMH, testosterone, estradiol, LH and FSH was performed at the designated time-points. MAIN RESULTS AND THE ROLE OF CHANCE Prospective arm for the entire group we observed a decrease of 0.71 ng/ml in AMH levels between baseline and 12 months (P = 0.01). When expressed in age-specific percentiles, AMH went from the 47.37th to the 40.25th percentile at 12 months (P < 0.001). In a sub-group analysis, a decline of 9.52 points in age-specific percentile was seen in subjects with PCOS (P < 0.001), while no changes were detected in the non-PCOS group. Testosterone treatment did not affect AFC over time in the entire cohort. In the sub-group analysis, a mean decrease of 5.0 follicles was detected between baseline and the 12 months assessment (P = 0.047) only in subjects with PCOS. In the cross-sectional study, AMH inversely correlated with age but not with treatment duration. Notably AMH did not deviate from the 50th age-specific percentile. Finally, four men fathered biological children after being under testosterone treatment for up to 12 years. LIMITATIONS, REASONS FOR CAUTION The limited sample size of the pilot study should be kept in mind. An additional limitation is the lack of a control group in the prospective study, as each participant served as his own control. Also, roughly 40% of the ultrasound examinations were performed transabdominally, potentially affecting the accuracy of the AFC measurements.As study participants were quite young, our reassuring data may not apply to older transgender men, either because of an age-related decline in ovarian reserve or to possible long-term effects of testosterone therapy. Furthermore, the chances for fertility preservation may be more limited in subjects with PCOS. WIDER IMPLICATIONS OF THE FINDINGS This is an additional contribution to the emerging evidence that prolonged testosterone treatment may not be a major obstacle to later fertility potential in transgender men desirous of having children. Larger confirmatory studies, and particularly more with reproductive outcome data, are needed for evidence-based fertility counseling prior to treatment initiation in these subjects. STUDY FUNDING/COMPETING INTEREST(S) This study received no funding. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER N/A.
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Affiliation(s)
- I Yaish
- Institute of Endocrinology, Diabetes, Metabolism and Hypertension, Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - K Tordjman
- Institute of Endocrinology, Diabetes, Metabolism and Hypertension, Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - H Amir
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Lis Maternity Hospital, Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel
| | - G Malinger
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Lis Maternity Hospital, Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel
| | - Y Salemnick
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Lis Maternity Hospital, Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel
| | - G Shefer
- Institute of Endocrinology, Diabetes, Metabolism and Hypertension, Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - M Serebro
- Institute of Endocrinology, Diabetes, Metabolism and Hypertension, Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel
| | - F Azem
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Lis Maternity Hospital, Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel
| | - N Golani
- Institute of Endocrinology, Diabetes, Metabolism and Hypertension, Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel
| | - Y Sofer
- Institute of Endocrinology, Diabetes, Metabolism and Hypertension, Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel
| | - N Stern
- Institute of Endocrinology, Diabetes, Metabolism and Hypertension, Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Y Greenman
- Institute of Endocrinology, Diabetes, Metabolism and Hypertension, Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Gomes T, Martin-Malpartida P, Ruiz L, Aragón E, Cordeiro TN, Macias MJ. Conformational landscape of multidomain SMAD proteins. Comput Struct Biotechnol J 2021; 19:5210-5224. [PMID: 34630939 PMCID: PMC8479633 DOI: 10.1016/j.csbj.2021.09.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 09/08/2021] [Accepted: 09/09/2021] [Indexed: 12/21/2022] Open
Abstract
SMAD transcription factors, the main effectors of the TGFβ (transforming growth factor β) network, have a mixed architecture of globular domains and flexible linkers. Such a complicated architecture precluded the description of their full-length (FL) structure for many years. In this study, we unravel the structures of SMAD4 and SMAD2 proteins through an integrative approach combining Small-angle X-ray scattering, Nuclear Magnetic Resonance spectroscopy, X-ray, and computational modeling. We show that both proteins populate ensembles of conformations, with the globular domains tethered by disordered and flexible linkers, which defines a new dimension of regulation. The flexibility of the linkers facilitates DNA and protein binding and modulates the protein structure. Yet, SMAD4FL is monomeric, whereas SMAD2FL is in different monomer-dimer-trimer states, driven by interactions of the MH2 domains. Dimers are present regardless of the SMAD2FL activation state and concentration. Finally, we propose that SMAD2FL dimers are key building blocks for the quaternary structures of SMAD complexes.
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Affiliation(s)
- Tiago Gomes
- Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, Barcelona 08028, Spain
| | - Pau Martin-Malpartida
- Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, Barcelona 08028, Spain
| | - Lidia Ruiz
- Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, Barcelona 08028, Spain
| | - Eric Aragón
- Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, Barcelona 08028, Spain
| | - Tiago N. Cordeiro
- Instituto de Tecnologia Química e Biológica António Xavier (ITQB), Universidade NOVA de Lisboa, Av. da República, 2780-157 Oeiras, Portugal
| | - Maria J. Macias
- Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, Barcelona 08028, Spain
- ICREA, Passeig Lluís Companys 23, Barcelona 08010, Spain
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Qiu W, Kuo CY, Tian Y, Su GH. Dual Roles of the Activin Signaling Pathway in Pancreatic Cancer. Biomedicines 2021; 9:biomedicines9070821. [PMID: 34356885 PMCID: PMC8301451 DOI: 10.3390/biomedicines9070821] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 06/29/2021] [Accepted: 07/08/2021] [Indexed: 12/12/2022] Open
Abstract
Activin, a member of the TGF-β superfamily, is involved in many physiological processes, such as embryonic development and follicle development, as well as in multiple human diseases including cancer. Genetic mutations in the activin signaling pathway have been reported in many cancer types, indicating that activin signaling plays a critical role in tumorigenesis. Recent evidence reveals that activin signaling may function as a tumor-suppressor in tumor initiation, and a promoter in the later progression and metastasis of tumors. This article reviews many aspects of activin, including the signaling cascade of activin, activin-related proteins, and its role in tumorigenesis, particularly in pancreatic cancer development. The mechanisms regulating its dual roles in tumorigenesis remain to be elucidated. Further understanding of the activin signaling pathway may identify potential therapeutic targets for human cancers and other diseases.
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Affiliation(s)
- Wanglong Qiu
- The Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; (W.Q.); (C.K.); (Y.T.)
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Chia-Yu Kuo
- The Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; (W.Q.); (C.K.); (Y.T.)
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Yu Tian
- The Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; (W.Q.); (C.K.); (Y.T.)
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Gloria H. Su
- The Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; (W.Q.); (C.K.); (Y.T.)
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA
- Department of Otolaryngology and Head and Neck Surgery, Columbia University Irving Medical Center, New York, NY 10032, USA
- Correspondence:
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Wan Mohd Tajuddin WNB, Abas F, Othman I, Naidu R. Molecular Mechanisms of Antiproliferative and Apoptosis Activity by 1,5-Bis(4-Hydroxy-3-Methoxyphenyl)1,4-Pentadiene-3-one (MS13) on Human Non-Small Cell Lung Cancer Cells. Int J Mol Sci 2021; 22:ijms22147424. [PMID: 34299042 PMCID: PMC8307969 DOI: 10.3390/ijms22147424] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 06/30/2021] [Accepted: 07/04/2021] [Indexed: 01/12/2023] Open
Abstract
Diarylpentanoid (DAP), an analog that was structurally modified from a naturally occurring curcumin, has shown to enhance anticancer efficacy compared to its parent compound in various cancers. This study aims to determine the cytotoxicity, antiproliferative, and apoptotic activity of diarylpentanoid MS13 on two subtypes of non-small cell lung cancer (NSCLC) cells: squamous cell carcinoma (NCI-H520) and adenocarcinoma (NCI-H23). Gene expression analysis was performed using Nanostring PanCancer Pathways Panel to determine significant signaling pathways and targeted genes in these treated cells. Cytotoxicity screening revealed that MS13 exhibited greater inhibitory effect in NCI-H520 and NCI-H23 cells compared to curcumin. MS13 induced anti-proliferative activity in both cells in a dose- and time-dependent manner. Morphological analysis revealed that a significant number of MS13-treated cells exhibited apoptosis. A significant increase in caspase-3 activity and decrease in Bcl-2 protein concentration was noted in both MS13-treated cells in a time- and dose-dependent manner. A total of 77 and 47 differential expressed genes (DEGs) were regulated in MS13 treated-NCI-H520 and NCI-H23 cells, respectively. Among the DEGs, 22 were mutually expressed in both NCI-H520 and NCI-H23 cells in response to MS13 treatment. The top DEGs modulated by MS13 in NCI-H520—DUSP4, CDKN1A, GADD45G, NGFR, and EPHA2—and NCI-H23 cells—HGF, MET, COL5A2, MCM7, and GNG4—were highly associated with PI3K, cell cycle-apoptosis, and MAPK signaling pathways. In conclusion, MS13 may induce antiproliferation and apoptosis activity in squamous cell carcinoma and adenocarcinoma of NSCLC cells by modulating DEGs associated with PI3K-AKT, cell cycle-apoptosis, and MAPK pathways. Therefore, our present findings could provide an insight into the anticancer activity of MS13 and merits further investigation as a potential anticancer agent for NSCLC cancer therapy.
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Affiliation(s)
- Wan Nur Baitty Wan Mohd Tajuddin
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia; (W.N.B.W.M.T.); (I.O.)
| | - Faridah Abas
- Laboratory of Natural Products, Faculty of Science, Universiti Putra Malaysia, UPM, Serdang 43400, Malaysia;
- Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, UPM, Serdang 43400, Malaysia
| | - Iekhsan Othman
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia; (W.N.B.W.M.T.); (I.O.)
- Global Asia in the 21s Century Platform, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia
| | - Rakesh Naidu
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia; (W.N.B.W.M.T.); (I.O.)
- Global Asia in the 21s Century Platform, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia
- Correspondence: ; Tel.: +60-3-5514-63-45
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Shen Z, Su T, Chen J, Xie Z, Li J. Collagen triple helix repeat containing-1 exerts antifibrotic effects on human skin fibroblast and bleomycin-induced dermal fibrosis models. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:801. [PMID: 34268414 PMCID: PMC8246160 DOI: 10.21037/atm-21-1884] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 05/08/2021] [Indexed: 11/29/2022]
Abstract
Background Systemic scleroderma (SSc) is an acquired disorder characterized by excessive deposition of extracellular matrix in the skin and internal organs. So far, the molecular mechanisms underpinning the pathogenesis of SSc have remained unknown. Collagen triple helix repeat containing-1 (CTHRC1) has been indicated to be a cell type-specific inhibitor of transforming growth factor-β (TGF-β), which could have the potential for extensive clinical application owing to its ability to reduce collagen deposition. Our previous studies showed that CTHRC1 inhibited TGF-β1-induced collagen type I synthesis in keloid fibroblasts. In our present research, we attempted to probe the role of CTHRC1 in dermal fibrosis in bleomycin (BLM)-treated mice. Methods CTHRC1 and TGF-β1 expression was detected in dermal tissues from patients with SSc and BLM-treated mice by immunohistochemistry. A 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay was used to assess TGF-β1-induced proliferation of human dermal fibroblasts. Collagen expression and fibroblast synthesis were evaluated by quantitative real-time polymerase chain reaction and the 3H-proline incorporation. Masson’s trichrome staining and western blotting were carried out to analyze the deposits and protein levels of type I collagen, respectively. Results Compared with those in normal tissues, the levels of CTHRC1 and TGF-β1 were elevated in dermal tissues from patients with SSc and in skin tissues from BLM-treated mice, respectively. Furthermore, recombinant CTHRC1 was found to inhibit TGF-β1-stimulated collagen deposition by fibroblasts. Finally, the in vivo experiments showed that CTHRC1 alleviated BLM-induced dermal fibrotic changes. Conclusions CTHRC1 can inhibit human dermal fibroblast collagen deposition and can also exert protective effects against BLM-induced dermal fibrosis in mice. This research provides an indication that CTHRC1 may be a promising treatment choice for dermal fibrosis in SSc patients.
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Affiliation(s)
- Zhu Shen
- Department of Dermatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Tangfeng Su
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jin Chen
- Department of Dermatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Zhen Xie
- Department of Dermatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Juan Li
- Department of Dermatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
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Cherifi C, Monteagudo S, Lories RJ. Promising targets for therapy of osteoarthritis: a review on the Wnt and TGF-β signalling pathways. Ther Adv Musculoskelet Dis 2021; 13:1759720X211006959. [PMID: 33948125 PMCID: PMC8053758 DOI: 10.1177/1759720x211006959] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 03/10/2021] [Indexed: 12/21/2022] Open
Abstract
Osteoarthritis (OA) is the most common chronic joint disorder worldwide, with a high personal burden for the patients and an important socio-economic impact. Current therapies are largely limited to pain management and rehabilitation and exercise strategies. For advanced cases, joint replacement surgery may be the only option. Hence, there is an enormous need for the development of effective and safe disease-modifying anti-OA drugs. A strong focus in OA research has been on the identification and role of molecular signalling pathways that contribute to the balance between anabolism and catabolism in the articular cartilage. In this context, most insights have been gained in understanding the roles of the transforming growth factor-beta (TGF-β) and the Wingless-type (Wnt) signalling cascades. The emerging picture demonstrates a high degree of complexity with context-dependent events. TGF-β appears to protect cartilage under healthy conditions, but shifts in its receptor use and subsequent downstream signalling may be deleterious in aged individuals or in damaged cartilage. Likewise, low levels of Wnt activity appear important to sustain chondrocyte viability but excessive activation is associated with progressive joint damage. Emerging clinical data suggest some potential for the use of sprifermin, a recombinant forms of fibroblast growth factor 18, a distant TGF-β superfamily member, and for lorecivivint, a Wnt pathway modulator.
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Affiliation(s)
- Chahrazad Cherifi
- Department of Development and Regeneration, KU Leuven, Skeletal Biology and Engineering Research Centre, Leuven, Belgium
| | - Silvia Monteagudo
- Department of Development and Regeneration, KU Leuven, Skeletal Biology and Engineering Research Centre, Leuven, Belgium
| | - Rik J Lories
- Department of Development and Regeneration, KU Leuven, Skeletal Biology and Engineering Research Centre, Box 813 O&N, Herestraat 49, Leuven 3000, Belgium; Division of Rheumatology, University Hospitals Leuven, Leuven, Belgium
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SMADS-Mediate Molecular Mechanisms in Sjögren's Syndrome. Int J Mol Sci 2021; 22:ijms22063203. [PMID: 33801157 PMCID: PMC8004153 DOI: 10.3390/ijms22063203] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 03/17/2021] [Accepted: 03/18/2021] [Indexed: 02/07/2023] Open
Abstract
There is considerable interest in delineating the molecular mechanisms of action of transforming growth factor-β (TGF-β), considered as central player in a plethora of human conditions, including cancer, fibrosis and autoimmune disease. TGF-β elicits its biological effects through membrane bound serine/threonine kinase receptors which transmit their signals via downstream signalling molecules, SMADs, which regulate the transcription of target genes in collaboration with various co-activators and co-repressors. Until now, therapeutic strategy for primary Sjögren’s syndrome (pSS) has been focused on inflammation, but, recently, the involvement of TGF-β/SMADs signalling has been demonstrated in pSS salivary glands (SGs) as mediator of the epithelial-mesenchymal transition (EMT) activation. Although EMT seems to cause pSS SG fibrosis, TGF-β family members have ambiguous effects on the function of pSS SGs. Based on these premises, this review highlights recent advances in unravelling the molecular basis for the multi-faceted functions of TGF-β in pSS that are dictated by orchestrations of SMADs, and describe TGF-β/SMADs value as both disease markers and/or therapeutic target for pSS.
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Sagaser S, Butterfield R, Kosiorek H, Kusne Y, Maldonado J, Fautsch MP, Patel D, Shen JF. Effects of Intense Pulsed Light on Tear Film TGF-β and Microbiome in Ocular Rosacea with Dry Eye. Clin Ophthalmol 2021; 15:323-330. [PMID: 33536740 PMCID: PMC7850425 DOI: 10.2147/opth.s280707] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 11/11/2020] [Indexed: 12/25/2022] Open
Abstract
Purpose To assess tear film transforming growth factor-beta (TGF-β) and ocular microbiome changes after intense pulsed light with meibomian gland expression (IPL-MGX) vs only MGX in treating ocular rosacea with dry eye symptoms. Methods Twenty patients were randomly assigned to IPL-MGX or MGX. Patients were examined, treated, and administered the ocular surface disease index (OSDI) survey every 4-6 weeks for four total treatments. Tear film and conjunctival samples were collected at first and last visits, and analyzed for TGF-β concentration and 16s rRNA amplicon sequencing of ocular microbiome. Wilcoxon Rank Sum and Sign-Rank were used to examine changes from baseline. Results OSDI revealed significantly greater improvement in symptoms after IPL-MGX (p=0.030) compared to MGX. There was no significant difference in mean TGF-β1, 2, or 3 concentration after IPL-MGX (p=0.385, 0.709, 0.948, respectively). Quantities of Clostridium, Klebsiella, Brevibacterium, Lactobacillus, Neisseria, Streptococcus, Corynebacterium, Butyricicoccus, and Actinomyces were significantly reduced from baseline in both groups but without a significant difference between the two treatment groups. Conclusion IPL-MGX improved dry eye symptoms more than MGX alone. IPL treatment offered no additional benefit to MGX in decreasing virulent bacteria present on the ocular surface and did not influence TGF-β levels in tears. Prospective studies on IPL-MGX with larger sample sizes are needed to further investigate cytokines and IPL in patients suffering from ocular rosacea with dry eye symptoms. ClinicalTrialsgov Identifier NCT03194698.
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Affiliation(s)
| | | | - Heidi Kosiorek
- Research Biostatistics, Mayo Clinic, Scottsdale, AZ, USA
| | - Yael Kusne
- Ophthalmology, Mayo Clinic, Scottsdale, AZ, USA
| | - Juan Maldonado
- Knowledge Enterprise, Genomics Core, Arizona State University, Tempe, AZ, USA.,Center for Fundamental and Applied Microbiomics, The Biodesign Institute, Arizona State University, Tempe, AZ, USA
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Sinha A, Iyengar PV, ten Dijke P. E3 Ubiquitin Ligases: Key Regulators of TGFβ Signaling in Cancer Progression. Int J Mol Sci 2021; 22:E476. [PMID: 33418880 PMCID: PMC7825147 DOI: 10.3390/ijms22020476] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 12/25/2020] [Accepted: 12/29/2020] [Indexed: 02/07/2023] Open
Abstract
Transforming growth factor β (TGFβ) is a secreted growth and differentiation factor that influences vital cellular processes like proliferation, adhesion, motility, and apoptosis. Regulation of the TGFβ signaling pathway is of key importance to maintain tissue homeostasis. Perturbation of this signaling pathway has been implicated in a plethora of diseases, including cancer. The effect of TGFβ is dependent on cellular context, and TGFβ can perform both anti- and pro-oncogenic roles. TGFβ acts by binding to specific cell surface TGFβ type I and type II transmembrane receptors that are endowed with serine/threonine kinase activity. Upon ligand-induced receptor phosphorylation, SMAD proteins and other intracellular effectors become activated and mediate biological responses. The levels, localization, and function of TGFβ signaling mediators, regulators, and effectors are highly dynamic and regulated by a myriad of post-translational modifications. One such crucial modification is ubiquitination. The ubiquitin modification is also a mechanism by which crosstalk with other signaling pathways is achieved. Crucial effector components of the ubiquitination cascade include the very diverse family of E3 ubiquitin ligases. This review summarizes the diverse roles of E3 ligases that act on TGFβ receptor and intracellular signaling components. E3 ligases regulate TGFβ signaling both positively and negatively by regulating degradation of receptors and various signaling intermediates. We also highlight the function of E3 ligases in connection with TGFβ's dual role during tumorigenesis. We conclude with a perspective on the emerging possibility of defining E3 ligases as drug targets and how they may be used to selectively target TGFβ-induced pro-oncogenic responses.
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Affiliation(s)
| | | | - Peter ten Dijke
- Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; (A.S.); (P.V.I.)
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Yazdani M, Shahdadfar A, Reppe S, Sapkota D, Vallenari EM, Lako M, Connon CJ, Figueiredo FC, Utheim TP. Response of human oral mucosal epithelial cells to different storage temperatures: A structural and transcriptional study. PLoS One 2020; 15:e0243914. [PMID: 33326470 PMCID: PMC7744058 DOI: 10.1371/journal.pone.0243914] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 11/30/2020] [Indexed: 11/26/2022] Open
Abstract
PURPOSE Seeking to improve the access to regenerative medicine, this study investigated the structural and transcriptional effects of storage temperature on human oral mucosal epithelial cells (OMECs). METHODS Cells were stored at four different temperatures (4°C, 12°C, 24°C and 37°C) for two weeks. Then, the morphology, cell viability and differential gene expression were examined using light and scanning electron microscopy, trypan blue exclusion test and TaqMan gene expression array cards, respectively. RESULTS Cells stored at 4°C had the most similar morphology to non-stored controls with the highest viability rate (58%), whereas the 37°C group was most dissimilar with no living cells. The genes involved in stress-induced growth arrest (GADD45B) and cell proliferation inhibition (TGFB2) were upregulated at 12°C and 24°C. Upregulation was also observed in multifunctional genes responsible for morphology, growth, adhesion and motility such as EFEMP1 (12°C) and EPHA4 (4°C-24°C). Among genes used as differentiation markers, PPARA and TP53 (along with its associated gene CDKN1A) were downregulated in all temperature conditions, whereas KRT1 and KRT10 were either unchanged (4°C) or downregulated (24°C and 12°C; and 24°C, respectively), except for upregulation at 12°C for KRT1. CONCLUSIONS Cells stored at 12°C and 24°C were stressed, although the expression levels of some adhesion-, growth- and apoptosis-related genes were favourable. Collectively, this study suggests that 4°C is the optimal storage temperature for maintenance of structure, viability and function of OMECs after two weeks.
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Affiliation(s)
- Mazyar Yazdani
- Department of Medical Biochemistry, Oslo University Hospital, Ullevål, Oslo, Norway
- Center for Eye Research, Department of Ophthalmology, Oslo University Hospital, Ullevål, Oslo, Norway
| | - Aboulghassem Shahdadfar
- Center for Eye Research, Department of Ophthalmology, Oslo University Hospital, Ullevål, Oslo, Norway
| | - Sjur Reppe
- Department of Medical Biochemistry, Oslo University Hospital, Ullevål, Oslo, Norway
- Department of Plastic and Reconstructive Surgery, Oslo University Hospital, Oslo, Norway
- Lovisenberg Diaconal Hospital, Unger-Vetlesen Institute, Oslo, Norway
| | - Dipak Sapkota
- Institute of Oral Biology, Faculty of Dentistry, University of Oslo, Oslo, Norway
| | - Evan M. Vallenari
- Institute of Oral Biology, Faculty of Dentistry, University of Oslo, Oslo, Norway
| | - Majlinda Lako
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, International Centre for Life, Bioscience West Building, Newcastle upon Tyne, United Kingdom
| | - Che J. Connon
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, International Centre for Life, Bioscience West Building, Newcastle upon Tyne, United Kingdom
| | - Francisco C. Figueiredo
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, International Centre for Life, Bioscience West Building, Newcastle upon Tyne, United Kingdom
- Department of Ophthalmology, Royal Victoria Infirmary & Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Tor Paaske Utheim
- Department of Medical Biochemistry, Oslo University Hospital, Ullevål, Oslo, Norway
- Department of Plastic and Reconstructive Surgery, Oslo University Hospital, Oslo, Norway
- Institute of Oral Biology, Faculty of Dentistry, University of Oslo, Oslo, Norway
- Department of Ophthalmology, Stavanger University Hospital, Stavanger, Norway
- Department of Ophthalmology, Sørlandet Hospital Arendal, Arendal, Norway
- Department of Computer Science, Oslo Metropolitan University, Oslo, Norway
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Ahmed BT, Saeed MY, Noori SH, Amin DM. TGF-β1 Gene Polymorphism and Its Correlation with Serum Level of TGF-β1 in Psoriasis Vulgaris Among Iraqi People. CLINICAL, COSMETIC AND INVESTIGATIONAL DERMATOLOGY 2020; 13:889-896. [PMID: 33262631 PMCID: PMC7699994 DOI: 10.2147/ccid.s281585] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 11/18/2020] [Indexed: 12/21/2022]
Abstract
PURPOSE Many cytokines have been implicated in the pathogenesis of psoriasis, among these the transforming growth factor-beta 1 (TGF-β1) can be endorsed by different mechanisms besides inhibiting keratinocytes proliferation. The role of genetic polymorphisms of TGF-β1 has been studied in various inflammatory diseases. Our aim is to study the correlation of TGF-β1 gene polymorphism at codon 10 and 25 with the expression of serum level of TGF-β1 in a sample of Iraqi psoriatic patients compared to the control group. MATERIALS AND METHODS A cross-sectional study involved 100 patients with psoriasis vulgaris and 50 sex- and age-matched healthy volunteers as control group. Serum and genomic DNA were prepared from peripheral blood samples. Amplification refractory mutation system-polymerase chain reaction technique (ARMS-PCR) had been applied for genotyping TGF-β1 codon 10 [rs1982073] and codon 25 [rs1800471] genetic polymorphisms. Enzyme-linked immunosorbent assay technique (ELISA) based on the sandwich principle was used for quantification of serum TGF-β1 level. Psoriasis Area and Severity Index (PASI) scoring was applied for determining the severity in psoriatic patients and classified accordingly to mild (PASI<7), moderate (PASI 7-12), severe (PASI>12) groups. RESULTS Statistically significant difference was found in TGF-β1 gene polymorphism between psoriatic patients and control group at codon 10 (T869C) polymorphism (p=0.021) and codon 25 (G915C) polymorphism (p=0.040). No significant association was detected with the mean serum TGF-β1 level, severity of the disease, disease onset, gender, history of psoriatic arthritis, and smoking in both codons. Significant lower mean serum TGF-β1 level was found among psoriatic group (192.17 ± 531.12 ng/L) compared with controls (565.89 ± 1372.30 ng/L) (p = 0.018). Relation of mean serum TGF-β1 level with the onset of the disease was statistically significant (p = 0.004), early-onset disease group was lower (105.92 ± 68.02 ng/L) compared with the late-onset disease group (450.92 ±1027.79 ng/L). The mean serum TGF-β1 level showed no significant differences with the severity of psoriasis, gender, history of psoriatic arthritis, and smoking. CONCLUSION Iraqi population showed a significant association between TGF-β1 gene polymorphism at codon 10 and 25 were with psoriasis susceptibility, and a significantly lower mean serum TGF-β1 level was detected in psoriatic patients.
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Affiliation(s)
- Bryar T Ahmed
- Department of Medicine/Dermatology, College of Medicine, University of Sulaimani, Sulaimani City, Kurdistan, Iraq
| | - Mohammad Y Saeed
- Department of Medicine/Dermatology, College of Medicine, University of Sulaimani, Sulaimani City, Kurdistan, Iraq
| | - Saman H Noori
- Department of Biochemistry, College of Medicine, University of Sulaimani, Sulaimani City, Kurdistan, Iraq
| | - Dashty M Amin
- Medical Laboratory Sciences, Komar University of Science and Technology, Sulaimani City, Kurdistan, Iraq
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Sampath TK, Vukicevic S. Biology of bone morphogenetic protein in bone repair and regeneration: A role for autologous blood coagulum as carrier. Bone 2020; 141:115602. [PMID: 32841742 DOI: 10.1016/j.bone.2020.115602] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/10/2020] [Accepted: 08/11/2020] [Indexed: 12/12/2022]
Abstract
BMPs were purified from demineralized bone matrix based on their ability to induce new bone in vivo and they represent a large member of the TGF-β superfamily of proteins. BMPs serve as morphogenic signals for mesenchymal stem cell migration, proliferation and subsequently differentiation into cartilage and bone during embryonic development. A BMP when implanted with a collagenous carrier in a rat subcutaneous site is capable of inducing new bone by mimicking the cellular events of embryonic bone formation. Based on this biological principle, BMP2 and BMP7 containing collagenous matrix as carrier have been developed as bone graft substitutes for spine fusion and long bone fractures. Here, we describe a novel autologous bone graft substitute that contains BMP6 delivered within an autologous blood coagulum as carrier and summarize the biology of osteogenic BMPs in the context of bone repair and regeneration specifically the critical role that carrier plays to support osteogenesis.
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Affiliation(s)
- T Kuber Sampath
- perForm Biologics Inc., Holliston, MA 01746, United States of America.
| | - Slobodan Vukicevic
- Laboratory for Mineralized Tissues, Center for Translational and Clinical Research, University of Zagreb School of Medicine, 10000 Zagreb, Croatia
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Inhibition of Wilms' Tumor Proliferation and Invasion by Blocking TGF- β Receptor I in the TGF- β/Smad Signaling Pathway. BIOMED RESEARCH INTERNATIONAL 2020; 2020:8039840. [PMID: 33282954 PMCID: PMC7685794 DOI: 10.1155/2020/8039840] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 09/09/2020] [Accepted: 10/27/2020] [Indexed: 12/13/2022]
Abstract
Wilms' tumor (WT) is a common embryonal tumor, and nephrogenic rests play a critical role in WT development. The transforming growth factor β (TGF-β) signaling pathway is fundamental to embryo development and cell growth and proliferation. Moreover, TGF-β contributes to WT development, but the mechanisms of disease pathogenicity are unknown. This study investigated whether the TGF-β signaling pathway was involved in WT and whether blocking TβRI receptor inhibited WT growth, proliferation, and invasion. A total of 60 WT patients with clinical data and surgical specimens were evaluated. Immunohistochemistry (IHC) was used to detect the expression of TGF-β1 and P-smad2/3. In vitro, the proliferation, migration, apoptosis, and epithelial-mesenchymal transition (EMT) protein expression were analyzed using the CCK8 assay, wound healing assay, transwell assay, flow cytometry, and western blot, respectively. In vivo, tumor morphology, tumor size, toxicity, and EMT protein expression were analyzed in tumor-bearing mice treated with a TβRI kinase inhibitor or PBS. High protein levels of TGF-β1 and P-samd2/3 were associated with clinical stage and metastasis or invasion. TβRI inhibition effectively suppressed WT proliferation and migration and promoted apoptosis in the human WT cell line G401, consequently decreasing EMT protein expression. In addition, the TβRI kinase inhibitor significantly impaired the subcutaneous growth of WT. It is worth noting that treatment with the TβRI kinase inhibitor did not cause liver and kidney injury. Our results indicate that the TGF-β/Smad signaling pathway plays a crucial role in WT progression. Blocking the TβRI receptor may be a novel strategy to treat and prevent WT.
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Oppezzo A, Bourseguin J, Renaud E, Pawlikowska P, Rosselli F. Microphthalmia transcription factor expression contributes to bone marrow failure in Fanconi anemia. J Clin Invest 2020; 130:1377-1391. [PMID: 31877112 DOI: 10.1172/jci131540] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 12/11/2019] [Indexed: 12/20/2022] Open
Abstract
Hematopoietic stem cell (HSC) attrition is considered the key event underlying progressive BM failure (BMF) in Fanconi anemia (FA), the most frequent inherited BMF disorder in humans. However, despite major advances, how the cellular, biochemical, and molecular alterations reported in FA lead to HSC exhaustion remains poorly understood. Here, we demonstrated in human and mouse cells that loss-of-function of FANCA or FANCC, products of 2 genes affecting more than 80% of FA patients worldwide, is associated with constitutive expression of the transcription factor microphthalmia (MiTF) through the cooperative, unscheduled activation of several stress-signaling pathways, including the SMAD2/3, p38 MAPK, NF-κB, and AKT cascades. We validated the unrestrained Mitf expression downstream of p38 in Fanca-/- mice, which display hallmarks of hematopoietic stress, including loss of HSC quiescence, DNA damage accumulation in HSCs, and reduced HSC repopulation capacity. Importantly, we demonstrated that shRNA-mediated downregulation of Mitf expression or inhibition of p38 signaling rescued HSC quiescence and prevented DNA damage accumulation. Our data support the hypothesis that HSC attrition in FA is the consequence of defects in the DNA-damage response combined with chronic activation of otherwise transiently activated signaling pathways, which jointly prevent the recovery of HSC quiescence.
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Affiliation(s)
- Alessia Oppezzo
- CNRS UMR8200 Equipe Labellisée "La Ligue Contre le Cancer,".,Gustave Roussy, Villejuif, France.,Université Paris-Saclay, Orsay, France
| | - Julie Bourseguin
- CNRS UMR8200 Equipe Labellisée "La Ligue Contre le Cancer,".,Gustave Roussy, Villejuif, France.,Université Paris-Saclay, Orsay, France
| | - Emilie Renaud
- CNRS UMR8200 Equipe Labellisée "La Ligue Contre le Cancer,".,Gustave Roussy, Villejuif, France
| | - Patrycja Pawlikowska
- CNRS UMR8200 Equipe Labellisée "La Ligue Contre le Cancer,".,Gustave Roussy, Villejuif, France.,Université Paris-Saclay, Orsay, France
| | - Filippo Rosselli
- CNRS UMR8200 Equipe Labellisée "La Ligue Contre le Cancer,".,Gustave Roussy, Villejuif, France.,Université Paris-Saclay, Orsay, France
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Sampath TK, Reddi AH. Discovery of bone morphogenetic proteins - A historical perspective. Bone 2020; 140:115548. [PMID: 32730937 DOI: 10.1016/j.bone.2020.115548] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/03/2020] [Accepted: 07/06/2020] [Indexed: 12/20/2022]
Abstract
Bone morphogenetic proteins (BMPs) were purified from demineralized bone matrix by their ability to induce new bone formation in vivo. BMPs represent a large sub-family of proteins structurally related to TGF-beta and activins. Two BMP bone graft substitutes, BMP2 (InFuse®) and BMP7 (OP1®) have been developed as products for the repair of long bone non-union fractures and lumbar spinal fusion in humans. The approval of BMP2 and BMP7 based products for use in the clinic supports that the signals responsible for bone formation at ectopic sites can form a basis as therapeutics for bone repair and regeneration. This article describes a historical perspective of the discovery BMPs.
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Affiliation(s)
- T Kuber Sampath
- perForm biologics Inc., Holliston, MA, United States of America.
| | - A Hari Reddi
- Lawrence Ellison Center for Musculoskeletal Regeneration, Department of Orthopedic Surgery, School of Medicine, University of California at Davis, Sacramento, CA, United States of America
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Peleli M, Moustakas A, Papapetropoulos A. Endothelial-Tumor Cell Interaction in Brain and CNS Malignancies. Int J Mol Sci 2020; 21:E7371. [PMID: 33036204 PMCID: PMC7582718 DOI: 10.3390/ijms21197371] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/28/2020] [Accepted: 10/03/2020] [Indexed: 02/07/2023] Open
Abstract
Glioblastoma and other brain or CNS malignancies (like neuroblastoma and medulloblastoma) are difficult to treat and are characterized by excessive vascularization that favors further tumor growth. Since the mean overall survival of these types of diseases is low, the finding of new therapeutic approaches is imperative. In this review, we discuss the importance of the interaction between the endothelium and the tumor cells in brain and CNS malignancies. The different mechanisms of formation of new vessels that supply the tumor with nutrients are discussed. We also describe how the tumor cells (TC) alter the endothelial cell (EC) physiology in a way that favors tumorigenesis. In particular, mechanisms of EC-TC interaction are described such as (a) communication using secreted growth factors (i.e., VEGF, TGF-β), (b) intercellular communication through gap junctions (i.e., Cx43), and (c) indirect interaction via intermediate cell types (pericytes, astrocytes, neurons, and immune cells). At the signaling level, we outline the role of important mediators, like the gasotransmitter nitric oxide and different types of reactive oxygen species and the systems producing them. Finally, we briefly discuss the current antiangiogenic therapies used against brain and CNS tumors and the potential of new pharmacological interventions that target the EC-TC interaction.
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Affiliation(s)
- Maria Peleli
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden;
- Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece;
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, 157 71 Athens, Greece
| | - Aristidis Moustakas
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden;
| | - Andreas Papapetropoulos
- Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece;
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, 157 71 Athens, Greece
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50
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Relationship between bone disorders and stroke. Neurol Sci 2020; 41:3579-3587. [PMID: 33006058 DOI: 10.1007/s10072-020-04748-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Accepted: 09/19/2020] [Indexed: 12/26/2022]
Abstract
Bone disorders are among the most uncommon causes of stroke, but they should be considered as stroke cause in particular clinical scenarios. On the other hand, osteoporosis/osteopenia and increased fracture risk are well documented post stroke complications. The relationship between stroke and bone health is complex. The current facts suggest that these two conditions share same risk factors, but also are risk factors for each other. However, the evidence shows more clear effect of stroke on the bone health, than in the opposite direction. This extensive review is aiming to fill the huge gap of evidence about this topic, and since bone pathology is extremely rare cause of cerebrovascular accident, although a complex connection between these two conditions definitely exists.
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