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1
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Li J, Luo X, Wu C, Duan Y, Wei Y. Barbatula nuda: an economically valuable freshwater fish that accepts phytoplankton as first food. JOURNAL OF FISH BIOLOGY 2025; 106:1021-1035. [PMID: 39635957 DOI: 10.1111/jfb.16009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 10/22/2024] [Accepted: 11/13/2024] [Indexed: 12/07/2024]
Abstract
Barbatula nuda is considered a promising emerging species to diversify small cold-water fish aquaculture worldwide due to its rapid growth and delicious flesh. However, limited information on larval development and nutrition is available. In this study, 7-day feeding experiments were performed to evaluate three different initial diets (zooplankton, phytoplankton, and artificial microdiet) in the zoo group, algae group, and AD group on growth, development, and digestion of larvae B. nuda. The results showed that there was no significant difference in survival rate among the three groups (p > 0.05). The algae group exhibited the highest feed intake success rate and body weight (p < 0.05), the best intestinal development with the protruded intestinal mucosa, and visible intestinal microvillus. Pepsase and trypsin enzyme activities in the algae group larvae were significantly higher than those in the other two groups (p < 0.05). Transcriptome data showed that the mechanistic target of rapamycin pathway of B. nuda fed with phytoplankton was activated, and the metabolisms of carbohydrate were significantly more active than those in the other two groups. As omnivorous fish, B. nuda could accept zooplankton, phytoplankton, and microdiet as initial diets with its survival unaffected, but B. nuda fed with phytoplankton exhibited better growth status and digestive tract development and higher digestive enzyme activities than those fed with other two diets. Therefore, phytoplankton was a suitable initial diet for B. nuda. Our findings provide guidance for the artificial breeding of B. nuda and a theoretical basis for research on fish initial diet.
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Affiliation(s)
- Jiao Li
- College of Fisheries and Life, Dalian Ocean University, Dalian, China
- Key Laboratory of Mariculture & Stock Enhancement in North China's Sea, Ministry of Agriculture, Dalian Ocean University, Dalian, China
| | - Xiaonian Luo
- College of Fisheries and Life, Dalian Ocean University, Dalian, China
- Key Laboratory of Mariculture & Stock Enhancement in North China's Sea, Ministry of Agriculture, Dalian Ocean University, Dalian, China
| | - Chen Wu
- College of Fisheries and Life, Dalian Ocean University, Dalian, China
- Key Laboratory of Mariculture & Stock Enhancement in North China's Sea, Ministry of Agriculture, Dalian Ocean University, Dalian, China
| | - Youjian Duan
- College of Fisheries and Life, Dalian Ocean University, Dalian, China
- Key Laboratory of Mariculture & Stock Enhancement in North China's Sea, Ministry of Agriculture, Dalian Ocean University, Dalian, China
| | - Yong Wei
- College of Fisheries and Life, Dalian Ocean University, Dalian, China
- Key Laboratory of Mariculture & Stock Enhancement in North China's Sea, Ministry of Agriculture, Dalian Ocean University, Dalian, China
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2
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Ren S, Wei Y, Liu W, Zhang Y, Wang Y, Yang J, Liu B, Shi T, Wei J. Clinical Characteristics, Prognostic Factors and Therapeutic Strategies in Gastric Cancer Patients With Bone Metastasis: A Retrospective Analysis. Cancer Med 2025; 14:e70781. [PMID: 40105370 PMCID: PMC11921140 DOI: 10.1002/cam4.70781] [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: 11/06/2024] [Revised: 02/09/2025] [Accepted: 03/07/2025] [Indexed: 03/20/2025] Open
Abstract
BACKGROUND Bone metastases are highly refractory and are associated with extremely poor survival. Despite the increasing incidence of bone metastasis in gastric cancer (GC), comprehensive analyses regarding the clinicopathological features, prognosis, and treatment of bone-metastatic GC remain limited. METHODS We obtained data from 120 bone-metastatic GC patients from Nanjing Drum Tower Hospital and 36,139 GC patients from the SEER database. Chi-square and Mann-Whitney U-tests evaluated clinicopathological features, while Cox models identified prognostic factors. Kaplan-Meier curves and forest plots assessed the effects of different treatment strategies on overall survival after bone metastasis (OS-BM). RESULTS Among 120 bone-metastatic GC patients, 55 (45.83%) were diagnosed with poorly cohesive gastric carcinoma (PCC). The higher incidence of bone metastasis was also observed in SRCC patients from the SEER database (p < 0.0001). PCC patients exhibited distinct pathological features compared to non-PCC patients, including lower PD-L1 (p = 0.042) and E-cadherin expression (p = 0.049). Multivariate analysis identified various negative prognostic factors such as metachronous bone metastasis (p < 0.001, HR = 2.35, 95% CI:1.47-3.74) and CA125 expression (p = 0.036, HR = 1.60, 95% CI:1.03-2.48), whereas immunotherapy was a positive prognostic factor (p < 0.001, HR = 0.44, 95% CI:0.29-0.66). Subgroup analysis also showed improved survival among different populations of bone-metastatic GC patients receiving immunotherapy. Moreover, combinational therapies including immunotherapy and other treatments (anti-angiogenic therapy and/or local radiotherapy) further improved patient OS-BM. CONCLUSION Our results suggest bone-metastatic GC patients exhibit distinct clinicopathological features, with a high incidence of bone metastasis in PCC. Immunotherapy-based combination therapies offer improved survival benefits, thus supporting the application of immunotherapy in GC patients at high risk of bone metastasis.
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Affiliation(s)
- Shiji Ren
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Yutao Wei
- Department of Oncology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenqi Liu
- Department of Oncology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China
| | - Yipeng Zhang
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Yue Wang
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Ju Yang
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Baorui Liu
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Tao Shi
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Jia Wei
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Department of Oncology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
- Nanjing Medical Key Laboratory of Oncology, Nanjing, China
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3
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Low BSH, Asimaki A. Targeting Canonical Wnt-signaling Through GSK-3β in Arrhythmogenic Cardiomyopathy: Conservative or Progressive? J Cardiovasc Transl Res 2025; 18:121-132. [PMID: 39392548 PMCID: PMC11885336 DOI: 10.1007/s12265-024-10567-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 10/02/2024] [Indexed: 10/12/2024]
Abstract
Arrhythmogenic cardiomyopathy is a primary myocardial disease and a major cause of sudden death in all populations of the world. Canonical Wnt signalling is a critical pathway controlling numerous processes including cellular differentiation, hypertrophy and development. GSK3β is a ubiquitous serine/threonine kinase, which acts downstream of Wnt to promote protein ubiquitination and proteasomal degradation. Several studies now suggest that inhibiting GSK3β can prevent and reverse key pathognomonic features of ACM in a range of experimental models. However, varying concerns are reported throughout the literature including the risk of paradoxical arrhythmias, cancer and off-target effects in upstream or downstream pathways. CLINICAL RELEVANCE: In light of the start of the phase 2 TaRGET clinical trial, designed to evaluate the potential therapeutic efficacy of GSK3β inhibition in patients with arrhythmogenic cardiomyopathy, this report aims to review the advantages and disadvantages of this strategy.
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Affiliation(s)
| | - Angeliki Asimaki
- Cardiovascular and Genomics Research Institute, City St. George's, University of London, London, UK.
- Cardiovascular Clinical Academic Group, City & St George's University of London, Cranmer Terrace, London, SW17 0RE, UK.
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4
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Li Y, Du J, Deng S, Liu B, Jing X, Yan Y, Liu Y, Wang J, Zhou X, She Q. The molecular mechanisms of cardiac development and related diseases. Signal Transduct Target Ther 2024; 9:368. [PMID: 39715759 DOI: 10.1038/s41392-024-02069-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 09/28/2024] [Accepted: 11/04/2024] [Indexed: 12/25/2024] Open
Abstract
Cardiac development is a complex and intricate process involving numerous molecular signals and pathways. Researchers have explored cardiac development through a long journey, starting with early studies observing morphological changes and progressing to the exploration of molecular mechanisms using various molecular biology methods. Currently, advancements in stem cell technology and sequencing technology, such as the generation of human pluripotent stem cells and cardiac organoids, multi-omics sequencing, and artificial intelligence (AI) technology, have enabled researchers to understand the molecular mechanisms of cardiac development better. Many molecular signals regulate cardiac development, including various growth and transcription factors and signaling pathways, such as WNT signaling, retinoic acid signaling, and Notch signaling pathways. In addition, cilia, the extracellular matrix, epigenetic modifications, and hypoxia conditions also play important roles in cardiac development. These factors play crucial roles at one or even multiple stages of cardiac development. Recent studies have also identified roles for autophagy, metabolic transition, and macrophages in cardiac development. Deficiencies or abnormal expression of these factors can lead to various types of cardiac development abnormalities. Nowadays, congenital heart disease (CHD) management requires lifelong care, primarily involving surgical and pharmacological treatments. Advances in surgical techniques and the development of clinical genetic testing have enabled earlier diagnosis and treatment of CHD. However, these technologies still have significant limitations. The development of new technologies, such as sequencing and AI technologies, will help us better understand the molecular mechanisms of cardiac development and promote earlier prevention and treatment of CHD in the future.
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Affiliation(s)
- Yingrui Li
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jianlin Du
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Songbai Deng
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bin Liu
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaodong Jing
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuling Yan
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yajie Liu
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jing Wang
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaobo Zhou
- Department of Cardiology, Angiology, Haemostaseology, and Medical Intensive Care, Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Germany; DZHK (German Center for Cardiovascular Research), Partner Site, Heidelberg-Mannheim, Mannheim, Germany
| | - Qiang She
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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5
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Minghua S, Jiwei T, Lei Z, Jizhou Q, Zhiyuan L, Jiangang C. Wnt5a manipulate the progression of osteoarthritis via MMP-13 dependent signaling pathway. Medicine (Baltimore) 2024; 103:e40676. [PMID: 39686437 PMCID: PMC11651448 DOI: 10.1097/md.0000000000040676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 11/06/2024] [Indexed: 12/18/2024] Open
Abstract
The object of this study was to propose a Wnt5a-matrix metalloproteinase (MMP)-13 dependent signaling axis for osteoarthritis (OA) progression. To this end, the chondrocytes were isolated from both OA patients and normal controls. The chondrocytes were treated with diverse concentrations of Wnt5a (0, 50, 100, and 200 ng/mL), respectively. The expression levels of Wnt5a, MMP-13, and Collagen type II were examined using reverse transcription-polymerase chain reaction and western blotting. At the same time, the cell proliferation and cell apoptosis of chondrocytes were also observed. Compared with control tissues, the activities of Wnt5a and MMP-13 were significantly enhanced in chondrocytes of OA patients. Treated with different concentrations of Wnt5a (0, 50, 100, and 200 ng/mL), chondrocyte cell proliferation was clearly downregulated. At the same time, the chondrocyte cell apoptosis was obviously accelerated. The expression pattern of Collagen type II was same as cell proliferation manner. Co-treatment of MMP-13 siRNA could significantly compensate the functions of Wnt-5a administration, suggesting MMP-13 was a direct target of Wnt-5a. Collectively, the study speculated a novel Wnt5a-MMP-13 molecular mechanism for OA progression and shed an innovative signaling axis for the disorder.
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Affiliation(s)
- Sun Minghua
- Department of Orthopaedics, NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Tian Jiwei
- Department of Orthopaedics, NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Zhang Lei
- Department of Orthopaedics, NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Qi Jizhou
- Department of Orthopaedics, NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Liu Zhiyuan
- Department of Orthopaedics, NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Cao Jiangang
- Department of Sports Injury and Arthroscopy, Tianjin Hospital, Tianjin, P.R. China
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6
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Shi V, Morgan EF. Estrogen and estrogen receptors mediate the mechanobiology of bone disease and repair. Bone 2024; 188:117220. [PMID: 39106937 PMCID: PMC11392539 DOI: 10.1016/j.bone.2024.117220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 07/28/2024] [Accepted: 07/30/2024] [Indexed: 08/09/2024]
Abstract
It is well understood that the balance of bone formation and resorption is dependent on both mechanical and biochemical factors. In addition to cell-secreted cytokines and growth factors, sex hormones like estrogen are critical to maintaining bone health. Although the direct osteoprotective function of estrogen and estrogen receptors (ERs) has been reported extensively, evidence that estrogen signaling also has a role in mediating the effects of mechanical loading on maintenance of bone mass and healing of bone injuries has more recently emerged. Recent studies have underscored the role of estrogen and ERs in many pathways of bone mechanosensation and mechanotransduction. Estrogen and ERs have been shown to augment integrin-based mechanotransduction as well as canonical Wnt/b-catenin, RhoA/ROCK, and YAP/TAZ pathways. Estrogen and ERs also influence the mechanosensitivity of not only osteocytes but also osteoblasts, osteoclasts, and marrow stromal cells. The current review will highlight these roles of estrogen and ERs in cellular mechanisms underlying bone mechanobiology and discuss their implications for management of osteoporosis and bone fractures. A greater understanding of the mechanisms behind interactions between estrogen and mechanical loading may be crucial to addressing the shortcomings of current hormonal and pharmaceutical therapies. A combined therapy approach including high-impact exercise therapy may mitigate adverse side effects and allow an effective long-term solution for the prevention, treatment, and management of bone fragility in at-risk populations. Furthermore, future implications to novel local delivery mechanisms of hormonal therapy for osteoporosis treatment, as well as the effects on bone health of applications of sex hormone therapy outside of bone disease, will be discussed.
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Affiliation(s)
- Vivian Shi
- Boston University, Department of Biomedical Engineering, 44 Cummington St, Boston 02215, MA, USA; Center for Multiscale and Translational Mechanobiology, Boston University, 44 Cummington St, Boston 02215, MA, USA
| | - Elise F Morgan
- Boston University, Department of Biomedical Engineering, 44 Cummington St, Boston 02215, MA, USA; Center for Multiscale and Translational Mechanobiology, Boston University, 44 Cummington St, Boston 02215, MA, USA.
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7
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Vijay A, Mukherjee A. Unraveling the folding-assisted unbinding mechanism of TCF with its binding partner β-catenin. Phys Chem Chem Phys 2024; 26:17481-17488. [PMID: 38887991 DOI: 10.1039/d4cp01451k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/20/2024]
Abstract
This study utilizes molecular dynamics simulations aided with multiple walker parallel bias metadynamics to investigate the TCF unbinding mechanism from the β-catenin interface. The results, consistent with experimental binding affinity calculations, unveil a folding-assisted unbinding mechanism.
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Affiliation(s)
- Amal Vijay
- Department of Chemistry, Indian Institute of Science Education and Research, Pune-411008, Maharashtra, India.
| | - Arnab Mukherjee
- Department of Chemistry, Indian Institute of Science Education and Research, Pune-411008, Maharashtra, India.
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8
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Syed RU, Afsar S, Aboshouk NAM, Salem Alanzi S, Abdalla RAH, Khalifa AAS, Enrera JA, Elafandy NM, Abdalla RAH, Ali OHH, Satheesh Kumar G, Alshammari MD. LncRNAs in necroptosis: Deciphering their role in cancer pathogenesis and therapy. Pathol Res Pract 2024; 256:155252. [PMID: 38479121 DOI: 10.1016/j.prp.2024.155252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 03/02/2024] [Accepted: 03/04/2024] [Indexed: 04/14/2024]
Abstract
Necroptosis, a controlled type of cell death that is different from apoptosis, has become a key figure in the aetiology of cancer and offers a possible target for treatment. A growing number of biological activities, including necroptosis, have been linked to long noncoding RNAs (lncRNAs), a varied family of RNA molecules with limited capacity to code for proteins. The complex interactions between LncRNAs and important molecular effectors of necroptosis, including mixed lineage kinase domain-like pseudokinase (MLKL) and receptor-interacting protein kinase 3 (RIPK3), will be investigated. We will explore the many methods that LncRNAs use to affect necroptosis, including protein-protein interactions, transcriptional control, and post-transcriptional modification. Additionally, the deregulation of certain LncRNAs in different forms of cancer will be discussed, highlighting their dual function in influencing necroptotic processes as tumour suppressors and oncogenes. The goal of this study is to thoroughly examine the complex role that LncRNAs play in controlling necroptotic pathways and how that regulation affects the onset and spread of cancer. In the necroptosis for cancer treatment, this review will also provide insight into the possible therapeutic uses of targeting LncRNAs. Techniques utilising LncRNA-based medicines show promise in controlling necroptotic pathways to prevent cancer from spreading and improve the effectiveness of treatment.
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Affiliation(s)
- Rahamat Unissa Syed
- Department of Pharmaceutics, College of Pharmacy, University of Ha'il, Hail 81442, Saudi Arabia.
| | - S Afsar
- Department of Virology, Sri Venkateswara University, Tirupathi, Andhra Pradesh 517502, India.
| | - Nayla Ahmed Mohammed Aboshouk
- Department of Clinical laboratory Sciences, College of Applied Medical Sciences, University of Hail, Hail 81442, Saudi Arabia
| | | | | | - Amna Abakar Suleiman Khalifa
- Department of Clinical laboratory Sciences, College of Applied Medical Sciences, University of Hail, Hail 81442, Saudi Arabia
| | - Jerlyn Apatan Enrera
- Department of Clinical laboratory Sciences, College of Applied Medical Sciences, University of Hail, Hail 81442, Saudi Arabia
| | - Nancy Mohammad Elafandy
- Department of Clinical laboratory Sciences, College of Applied Medical Sciences, University of Hail, Hail 81442, Saudi Arabia
| | - Randa Abdeen Husien Abdalla
- Department of Clinical laboratory Sciences, College of Applied Medical Sciences, University of Hail, Hail 81442, Saudi Arabia
| | - Omar Hafiz Haj Ali
- Department of Clinical laboratory Sciences, College of Applied Medical Sciences, University of Hail, Hail 81442, Saudi Arabia
| | - G Satheesh Kumar
- Department of Pharmaceutical Chemistry, College of Pharmacy, Seven Hills College of Pharmacy, Venkataramapuram, Tirupati, India
| | - Maali D Alshammari
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Hail, Hail 81442, Saudi Arabia
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9
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Crossley RM, Johnson S, Tsingos E, Bell Z, Berardi M, Botticelli M, Braat QJS, Metzcar J, Ruscone M, Yin Y, Shuttleworth R. Modeling the extracellular matrix in cell migration and morphogenesis: a guide for the curious biologist. Front Cell Dev Biol 2024; 12:1354132. [PMID: 38495620 PMCID: PMC10940354 DOI: 10.3389/fcell.2024.1354132] [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: 12/11/2023] [Accepted: 02/12/2024] [Indexed: 03/19/2024] Open
Abstract
The extracellular matrix (ECM) is a highly complex structure through which biochemical and mechanical signals are transmitted. In processes of cell migration, the ECM also acts as a scaffold, providing structural support to cells as well as points of potential attachment. Although the ECM is a well-studied structure, its role in many biological processes remains difficult to investigate comprehensively due to its complexity and structural variation within an organism. In tandem with experiments, mathematical models are helpful in refining and testing hypotheses, generating predictions, and exploring conditions outside the scope of experiments. Such models can be combined and calibrated with in vivo and in vitro data to identify critical cell-ECM interactions that drive developmental and homeostatic processes, or the progression of diseases. In this review, we focus on mathematical and computational models of the ECM in processes such as cell migration including cancer metastasis, and in tissue structure and morphogenesis. By highlighting the predictive power of these models, we aim to help bridge the gap between experimental and computational approaches to studying the ECM and to provide guidance on selecting an appropriate model framework to complement corresponding experimental studies.
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Affiliation(s)
- Rebecca M. Crossley
- Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, United Kingdom
| | - Samuel Johnson
- Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, United Kingdom
| | - Erika Tsingos
- Computational Developmental Biology Group, Institute of Biodynamics and Biocomplexity, Utrecht University, Utrecht, Netherlands
| | - Zoe Bell
- Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Massimiliano Berardi
- LaserLab, Department of Physics and Astronomy, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Optics11 life, Amsterdam, Netherlands
| | | | - Quirine J. S. Braat
- Department of Applied Physics and Science Education, Eindhoven University of Technology, Eindhoven, Netherlands
| | - John Metzcar
- Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN, United States
- Department of Informatics, Indiana University, Bloomington, IN, United States
| | | | - Yuan Yin
- Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, United Kingdom
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10
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Saghati S, Avci ÇB, Hassani A, Nazifkerdar S, Amini H, Saghebasl S, Mahdipour M, Banimohamad-Shotorbani B, Namjoo AR, Abrbekoh FN, Rahbarghazi R, Nasrabadi HT, Khoshfetrat AB. Phenolated alginate hydrogel induced osteogenic properties of mesenchymal stem cells via Wnt signaling pathway. Int J Biol Macromol 2023; 253:127209. [PMID: 37804896 DOI: 10.1016/j.ijbiomac.2023.127209] [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: 08/20/2022] [Revised: 09/06/2023] [Accepted: 10/01/2023] [Indexed: 10/09/2023]
Abstract
Osteogenic properties of phenolated alginate (1.2 %) hydrogel containing collagen (0.5 %)/nano-hydroxyapatite (1 %) were studied on human mesenchymal stem cells in vitro. The phenolation rate and physical properties of the hydrogel were assessed using nuclear magnetic resonance (NMR), Fourier-transform infrared spectroscopy (FTIR), Scanning electron microscope (SEM), swelling ratio, gelation time, mechanical assay, and degradation rate. The viability of encapsulated cells was monitored on days 7, 14, and 21 using an MTT assay. Osteoblast differentiation was studied using western blotting, and real-time PCR. Using PCR array analysis, the role of the Wnt signaling pathway was also investigated. Data showed that the combination of alginate/collagen/nanohydroxyapatite yielded proper mechanical features. The addition of nanohydroxyapatite, and collagen reduced degradation, swelling rate coincided with increased stiffness. Elasticity and pore size were also diminished. NMR and FTIR revealed suitable incorporation of collagen and nanohydroxyapatite in the structure of alginate. Real-time PCR analysis and western blotting indicated the expression of osteoblast-related genes such as Runx2 and osteocalcin. PCR array revealed the induction of numerous genes related to Wnt signaling pathways during the maturation of human stem cells toward osteoblast-like cells. In vivo data indicated that transplantation of phenolated alginate/collagen/nanohydroxyapatite hydrogel led to enhanced de novo bone formation in rats with critical-sized calvarial defects. Phenolated alginate hydrogel can promote the osteogenic capacity of human amniotic membrane mesenchymal stem cells in the presence of nanohydroxyapatite and collagen via engaging the Wnt signaling pathway.
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Affiliation(s)
- Sepideh Saghati
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Tissue Engineering, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Çığır Biray Avci
- Department of Medical Biology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Ayla Hassani
- Chemical Engineering Faculty, Sahand University of Technology, Tabriz 51335-1996, Iran; Stem Cell and Tissue Engineering Research Laboratory, Sahand University of Technology, Tabriz 51335-1996, Iran
| | - Sajed Nazifkerdar
- Chemical Engineering Faculty, Sahand University of Technology, Tabriz 51335-1996, Iran; Stem Cell and Tissue Engineering Research Laboratory, Sahand University of Technology, Tabriz 51335-1996, Iran
| | - Hassan Amini
- Department of General and Vascular Surgery, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Solmaz Saghebasl
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdi Mahdipour
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behnaz Banimohamad-Shotorbani
- Department of Tissue Engineering, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Atieh Rezaei Namjoo
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Hamid Tayefi Nasrabadi
- Department of Tissue Engineering, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Ali Baradar Khoshfetrat
- Department of Medical Biology, Faculty of Medicine, Ege University, Izmir, Turkey; Chemical Engineering Faculty, Sahand University of Technology, Tabriz 51335-1996, Iran.
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11
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Augustyniak A, McMahon H. Effect of Marine-Derived Saccharides on Human Skin Fibroblasts and Dermal Papilla Cells. Mar Drugs 2023; 21:330. [PMID: 37367655 DOI: 10.3390/md21060330] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 05/19/2023] [Accepted: 05/25/2023] [Indexed: 06/28/2023] Open
Abstract
The skin is the largest organ of the human body, composed of a diverse range of cell types, non-cellular components, and an extracellular matrix. With aging, molecules that are part of the extracellular matrix undergo qualitative and quantitative changes and the effects, such as a loss of skin firmness or wrinkles, can be visible. The changes caused by the aging process do not only affect the surface of the skin, but also extend to skin appendages such as hair follicles. In the present study, the ability of marine-derived saccharides, L-fucose and chondroitin sulphate disaccharide, to support skin and hair health and minimize the effects of intrinsic and extrinsic aging was investigated. The potential of the tested samples to prevent adverse changes in the skin and hair through stimulation of natural processes, cellular proliferation, and production of extracellular matrix components collagen, elastin, or glycosaminoglycans was investigated. The tested compounds, L-fucose and chondroitin sulphate disaccharide, supported skin and hair health, especially in terms of anti-aging effects. The obtained results indicate that both ingredients support and promote the proliferation of dermal fibroblasts and dermal papilla cells, provide cells with a supply of sulphated disaccharide GAG building blocks, increase ECM molecule production (collagen and elastin) by HDFa, and support the growth phase of the hair cycle (anagen).
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Affiliation(s)
- Aleksandra Augustyniak
- Circular Bioeconomy Research Group, Shannon Applied Biotechnology Centre, Munster Technological University-Kerry, Clash, V92CX88 Tralee, Co. Kerry, Ireland
| | - Helena McMahon
- Circular Bioeconomy Research Group, Shannon Applied Biotechnology Centre, Munster Technological University-Kerry, Clash, V92CX88 Tralee, Co. Kerry, Ireland
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Augustyniak A, Mc Mahon H. Dietary marine-derived ingredients for stimulating hair cell cycle. Biomed Pharmacother 2023; 163:114838. [PMID: 37156114 DOI: 10.1016/j.biopha.2023.114838] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 04/24/2023] [Accepted: 05/02/2023] [Indexed: 05/10/2023] Open
Abstract
In normal condition human hair growth occurs through three phases, anagen (growth phase included about 85 % of hairs, last from 2 to 6 years), catagen (transitional phase lasting up to 2 weeks) and telogen (resting phase which last from 1 to 4 months). Natural dynamics of the hair growth process can be impaired by several factors, such as genetic predisposition, hormonal disorders, aging, poor nutrition or stress, which can lead to the slowdown in the growth of hair or even hair loss. The aim of the study was to assess the hair growth promotion effect of marine-derived ingredients, hair supplement Viviscal® and its raw components (marine protein complex AminoMarC®, shark and oyster extract). Cytotoxicity, production of alkaline phosphatase and glycosaminoglycans, as well as expression of genes involved in hair cycle-related pathways were investigated using dermal papilla cells, both immortalized and primary cell lines. Tested marine compounds showed no evidence of cytotoxicity under in vitro conditions. Viviscal® significantly increased proliferation of dermal papilla cells. Moreover, tested samples stimulated cells to produce alkaline phosphatase and glycosaminoglycans. Increased expression of hair cell cycle-related genes was also observed. The obtained results indicate that marine-derived ingredients stimulate hair growth through anagen activation.
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Affiliation(s)
- Aleksandra Augustyniak
- Circular Bioeconomy Research Group, Shannon Applied Biotechnology Centre, Munster Technological University, V92CX88 Tralee, Ireland.
| | - Helena Mc Mahon
- Circular Bioeconomy Research Group, Shannon Applied Biotechnology Centre, Munster Technological University, V92CX88 Tralee, Ireland
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13
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Critical review on anti-obesity effects of phytochemicals through Wnt/β-catenin signaling pathway. Pharmacol Res 2022; 184:106461. [PMID: 36152739 DOI: 10.1016/j.phrs.2022.106461] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 09/06/2022] [Accepted: 09/19/2022] [Indexed: 11/23/2022]
Abstract
Phytochemicals have been used as one of the sources for the development of anti-obesity drugs. Plants are rich in a variety of bioactive compounds including polyphenols, saponins and terpenes. Phytochemicals inhibit adipocyte differentiation by inhibiting the transcription and translation of adipogenesis transcription factors such as C/EBPα and PPARγ. It has been proved that phytochemicals inhibit the genes and proteins associated with adipogenesis and lipid accumulation by activating Wnt/β-catenin signaling pathway. The activation of Wnt/β-catenin signaling pathway by phytochemicals is multi-target regulation, including the regulation of pathway critical factor β-catenin and its target gene, the downregulation of destruction complex, and the up-regulation of Wnt ligands, its cell surface receptor and Wnt antagonist. In this review, the literature on the anti-obesity effect of phytochemicals through Wnt/β-catenin signaling pathway is collected from Google Scholar, Scopus, PubMed, and Web of Science, and summarizes the regulation mechanism of phytochemicals in this pathway. As one of the alternative methods of weight loss drugs, Phytochemicals inhibit adipogenesis through Wnt/β-catenin signaling pathway. More progress in relevant fields may pose phytochemicals as the main source of anti-obesity treatment.
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14
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Jaiswal A, Singh R. Homeostases of epidermis and hair follicle, and development of basal cell carcinoma. Biochim Biophys Acta Rev Cancer 2022; 1877:188795. [PMID: 36089203 DOI: 10.1016/j.bbcan.2022.188795] [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: 12/29/2021] [Revised: 03/10/2022] [Accepted: 09/03/2022] [Indexed: 10/14/2022]
Abstract
Hedgehog signaling (Hh) plays a critical role in embryogenesis. On the other hand, its overactivity may cause basal cell carcinoma (BCC), the most common human cancer. Further, epidermal and hair follicle homeostases may have a key role in the development of BCC. This article describes the importance of different signaling pathways in the different stages of the two processes. The description of the homeostases brought up the importance of the Notch signaling along with the sonic hedgehog (Shh) and the Wnt pathways. Loss of the Notch signaling adversely affects the late stages of hair follicle formation and allows the bulge cells in the hair follicles to take the fate of the keratinocytes in the interfollicular epidermis. Further, the loss of Notch activity upregulates the Shh and Wnt activities, adversely affecting the homeostases. Notably, the Notch signaling is suppressed in BCC, and the peripheral BCC cells, which have low Notch activity, show drug resistance in comparison to the interior suprabasal BCC cells, which have high Notch activity.
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Affiliation(s)
- Alok Jaiswal
- Department of Chemical Engineering, Indian Institute of Technology Kanpur, Kanpur 208016, India
| | - Raghvendra Singh
- Department of Chemical Engineering, Indian Institute of Technology Kanpur, Kanpur 208016, India.
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15
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Lin YC, Chen BS. Identifying Drug Targets of Oral Squamous Cell Carcinoma through a Systems Biology Method and Genome-Wide Microarray Data for Drug Discovery by Deep Learning and Drug Design Specifications. Int J Mol Sci 2022; 23:ijms231810409. [PMID: 36142321 PMCID: PMC9499358 DOI: 10.3390/ijms231810409] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/06/2022] [Accepted: 09/07/2022] [Indexed: 11/22/2022] Open
Abstract
In this study, we provide a systems biology method to investigate the carcinogenic mechanism of oral squamous cell carcinoma (OSCC) in order to identify some important biomarkers as drug targets. Further, a systematic drug discovery method with a deep neural network (DNN)-based drug–target interaction (DTI) model and drug design specifications is proposed to design a potential multiple-molecule drug for the medical treatment of OSCC before clinical trials. First, we use big database mining to construct the candidate genome-wide genetic and epigenetic network (GWGEN) including a protein–protein interaction network (PPIN) and a gene regulatory network (GRN) for OSCC and non-OSCC. In the next step, real GWGENs are identified for OSCC and non-OSCC by system identification and system order detection methods based on the OSCC and non-OSCC microarray data, respectively. Then, the principal network projection (PNP) method was used to extract core GWGENs of OSCC and non-OSCC from real GWGENs of OSCC and non-OSCC, respectively. Afterward, core signaling pathways were constructed through the annotation of KEGG pathways, and then the carcinogenic mechanism of OSCC was investigated by comparing the core signal pathways and their downstream abnormal cellular functions of OSCC and non-OSCC. Consequently, HES1, TCF, NF-κB and SP1 are identified as significant biomarkers of OSCC. In order to discover multiple molecular drugs for these significant biomarkers (drug targets) of the carcinogenic mechanism of OSCC, we trained a DNN-based drug–target interaction (DTI) model by DTI databases to predict candidate drugs for these significant biomarkers. Finally, drug design specifications such as adequate drug regulation ability, low toxicity and high sensitivity are employed to filter out the appropriate molecular drugs metformin, gefitinib and gallic-acid to combine as a potential multiple-molecule drug for the therapeutic treatment of OSCC.
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Kulkarni NP, Vaidya B, Narula AS, Sharma SS. Caffeic Acid Phenethyl Ester (CAPE) Attenuates Paclitaxel-induced Peripheral Neuropathy: A Mechanistic Study. Curr Neurovasc Res 2022; 19:293-302. [PMID: 36043777 DOI: 10.2174/1567202619666220829104851] [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: 06/12/2022] [Revised: 07/05/2022] [Accepted: 07/07/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Chemotherapy-induced peripheral neuropathy is a debilitating pain syndrome produced as a side effect of antineoplastic drugs like paclitaxel. Despite efforts, the currently available therapeutics suffer from serious drawbacks like unwanted side effects and poor efficacy and provide only symptomatic relief. Hence, there is a need to find new therapeutic alternatives for the treatment of chemotherapy-induced peripheral neuropathy. OBJECTIVE The objective of this study was to explore the protective potential of caffeic acid phenethyl ester in paclitaxel-induced neuropathic pain. METHODS We examined the effects of caffeic acid phenethyl ester by administering paclitaxel (2 mg/kg, intraperitoneal) to female Sprague Dawley rats on four alternate days to induce neuropathic pain, followed by the administration of caffeic acid phenethyl ester (10 and 30 mg/kg, intraperitoneally). RESULTS Rats that were administered paclitaxel showed a substantially diminished pain threshold and nerve functions after 28 days. A significantly increased protein expression of Wnt signalling protein (β-catenin), inflammatory marker (matrix metalloproteinase 2) and a decrease in endogenous antioxidant (nuclear factor erythroid 2-related factor 2) levels were found in paclitaxel administered rats in comparison to the naïve control group. Caffeic acid phenethyl ester (10 and 30 mg/kg, intraperitoneal) showed improvements in behavioural and nerve function parameters along with reduced expression of β-catenin, matrix metalloproteinase 2 and an increase in nuclear factor erythroid 2- related factor 2 protein expression. CONCLUSION The present study suggests that caffeic acid phenethyl ester attenuates chemotherapyinduced peripheral neuropathy via inhibition of β-catenin and matrix metalloproteinase 2 and increases nuclear factor erythroid 2-related factor 2 activation.
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Affiliation(s)
- Namrata Pramod Kulkarni
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Sector 67, Punjab 160062, India
| | - Bhupesh Vaidya
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Sector 67, Punjab 160062, India
| | - Acharan S Narula
- Narula Research Llc, 107 Boulder Bluff, Chapel Hill, North Carolina, NC 27516, USA
| | - Shyam Sunder Sharma
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Sector 67, Punjab 160062, India
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Peng L, Zhao Y. Genome-Wide Identification and Expression Profiling of the Wnt Gene Family in Three Rice Planthoppers: Sogatella furcifera, Laodelphax striatellus, and Nilaparvata lugens. JOURNAL OF INSECT SCIENCE (ONLINE) 2022; 22:2. [PMID: 36082678 PMCID: PMC9459440 DOI: 10.1093/jisesa/ieac049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Indexed: 06/15/2023]
Abstract
The Wnt gene family plays essential roles in regulating many developmental processes, including the maintenance of stem cells, cell division, and cell migration. The number of Wnt genes varies among species. Due to the diversity and importance of their functions, the Wnt gene family has gained extensive research interest in various animal species from invertebrates to vertebrates. However, knowledge of the Wnt gene family is limited in rice planthoppers. Three planthopper species, the white-backed planthopper (Sogatella furcifera Horvath), the small brown planthopper (Laodelphax striatellus Fallén) and the brown planthopper (Nilaparvata lugens Stål) (Hemiptera: Delphacidae), are devastating specialist pests of rice and cause serious damage to rice plants. To better study the evolution and function of the Wnt gene family in rice planthoppers, we identified 8 Wnt family genes in three rice planthoppers with both genomic and extensive transcriptomic resources available. We conducted a systematic analysis of the three kinds of rice planthoppers and analyzed the dynamic patterns of gene conservation, as well as Wnt gene loss and duplication. The expression profiles in different developmental stages of S. furcifera and different adult organs and tissues of L. striatellus provide preliminary functional implications for the Wnt genes in rice planthopper. This study presents the first genome-wide study of the Wnt gene family in rice planthoppers, and our findings provide insights into Wnt function and evolution in rice planthoppers.
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Affiliation(s)
- Lei Peng
- College of Life Science, Guizhou Normal University, Guiyang, China
| | - Yan Zhao
- Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
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18
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ALTINIŞIK HB, ALTINIŞIK U, AŞIK M. SIRS tanılı hastalarda enflamasyon ve kemik döngüsü arasındaki ilişkinin sklerostin ve Dickkopf-1 (DKK-1) düzeyleri ile değerlendirilmesi. FAMILY PRACTICE AND PALLIATIVE CARE 2022. [DOI: 10.22391/fppc.1102573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Introduction: In intensive care units (ICU), patients remain bedridden for a long time. In addition, severe infections are frequently seen in ICUs. Both prolonged immobilization and serious infections are associated with bone tissue loss. The Wnt pathway has recently been focused on evaluating bone tissue loss. The Wnt pathway participates in both infections and the formation of bone tissue. Wnt pathway inhibitors sclerostin and Dickkopf-1 (DKK-1) inhibit bone formation and increase osteoclastic activity. In this study, we aimed to examine bone turnover by the Wnt inhibitors sclerostin and DKK-1 and their possible associations with inflammation in SIRS patients.Methods: We included 30 patients diagnosed with systemic inflammatory response syndrome (SIRS) in the study group and 16 in the control group. Serum sclerostin, DKK-1, white blood cell (WBC), and C-Reactive Protein (CRP) levels on the day of SIRS diagnosis (basal), the 7th, 14th, and 21stdays were evaluated in the study group, and the results were compared with the control group.Results: When the control group was compared with the basal SIRS, there was a significant elevation in both sclerostin (p=0.003) and DKK-1 (p=0.001). Statistical analysis showed significant decreases in sclerostin levels between basal and the 7th, 14th, and 21st days (p=0.033, p=0.003, p=0.002, respectively). Similarly, significant decreases in DKK-1 levels between basal and the 7th and 21st days (p=0.015, p=0.001, respectively) and an insignificant decrease on the 14th day (p=0.191) was observed. Sclerostin was positively and significantly correlated with WBC and CRP in basal and 7th-day measurements and WBC in 7th and 14th days. DKK-1 is positively and significantly correlated with WBC in basal and 7th-daymeasurements, while DKK-1 negatively correlates with CRP in basal-7th-day measurements.Conclusion: In this study, it was shown for the first time that the Wnt antagonists sclerostin and DKK-1 values are high in SIRS patients in ICU. Both biomarker levels decreased in parallel with the treatment. However, it could not be associated with disease severity and inflammatory marker levels. We believe that monitoring the change of Wnt antagonists will be useful in demonstrating bone turnover in patients with SIRS.Keywords: Dickkopf-1, Intensive care unit, Sclerostin, Systemic inflammatory response syndrome, Wnt signaling pathway, Bone turnover
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Affiliation(s)
- Hatice Betül ALTINIŞIK
- Department of Anesthesiology and Reanimation, Faculty of Medicine, Canakkale Onsekiz Mart University, Canakkale
| | - Uğur ALTINIŞIK
- Department of Anesthesiology and Reanimation, Birinci International Hospital, Istanbul
| | - Mehmet AŞIK
- Department of Endocrinology And Metabolic Diseases, Mugla
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19
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Asif M, Kaygusuz E, Shinawi M, Nickelsen A, Hsieh TC, Wagle P, Budde BS, Hochscherf J, Abdullah U, Höning S, Nienberg C, Lindenblatt D, Noegel AA, Altmüller J, Thiele H, Motameny S, Fleischer N, Segal I, Pais L, Tinschert S, Samra NN, Savatt JM, Rudy NL, De Luca C, Paola Fortugno, White SM, Krawitz P, Hurst ACE, Niefind K, Jose J, Brancati F, Nürnberg P, Hussain MS. De novo variants of CSNK2B cause a new intellectual disability-craniodigital syndrome by disrupting the canonical Wnt signaling pathway. HGG ADVANCES 2022; 3:100111. [PMID: 35571680 PMCID: PMC9092267 DOI: 10.1016/j.xhgg.2022.100111] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 04/13/2022] [Indexed: 11/29/2022] Open
Abstract
CSNK2B encodes for casein kinase II subunit beta (CK2β), the regulatory subunit of casein kinase II (CK2), which is known to mediate diverse cellular pathways. Variants in this gene have been recently identified as a cause of Poirier-Bienvenu neurodevelopmental syndrome (POBINDS), but functional evidence is sparse. Here, we report five unrelated individuals: two of them manifesting POBINDS, while three are identified to segregate a new intellectual disability-craniodigital syndrome (IDCS), distinct from POBINDS. The three IDCS individuals carried two different de novo missense variants affecting the same codon of CSNK2B. Both variants, NP_001311.3; p.Asp32His and NP_001311.3; p.Asp32Asn, lead to an upregulation of CSNK2B expression at transcript and protein level, along with global dysregulation of canonical Wnt signaling. We found impaired interaction of the two key players DVL3 and β-catenin with mutated CK2β. The variants compromise the kinase activity of CK2 as evident by a marked reduction of phosphorylated β-catenin and consequent absence of active β-catenin inside nuclei of the patient-derived lymphoblastoid cell lines (LCLs). In line with these findings, whole-transcriptome profiling of patient-derived LCLs harboring the NP_001311.3; p.Asp32His variant confirmed a marked difference in expression of genes involved in the Wnt signaling pathway. In addition, whole-phosphoproteome analysis of the LCLs of the same subject showed absence of phosphorylation for 313 putative CK2 substrates, enriched in the regulation of nuclear β-catenin and transcription of the target genes. Our findings suggest that discrete variants in CSNK2B cause dominant-negative perturbation of the canonical Wnt signaling pathway, leading to a new craniodigital syndrome distinguishable from POBINDS.
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Affiliation(s)
- Maria Asif
- Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany.,Center for Biochemistry, Medical Faculty, University of Cologne, 50931 Cologne, Germany.,Center for Molecular Medicine Cologne (CMMC), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany
| | - Emrah Kaygusuz
- Center for Biochemistry, Medical Faculty, University of Cologne, 50931 Cologne, Germany.,Bilecik Şeyh Edebali University, Molecular Biology and Genetics, Gülümbe Campus, 11230 Bilecik, Turkey
| | - Marwan Shinawi
- Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
| | - Anna Nickelsen
- Institute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms-University, Münster, Germany
| | - Tzung-Chien Hsieh
- Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich Wilhelms, Universität Bonn, Bonn, Germany
| | - Prerana Wagle
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Birgit S Budde
- Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany
| | - Jennifer Hochscherf
- Department of Chemistry, Institute of Biochemistry, University of Cologne, Cologne, Germany
| | - Uzma Abdullah
- University Institute of Biochemistry and Biotechnology (UIBB), PMAS-Arid Agriculture University, Rawalpindi, Pakistan
| | - Stefan Höning
- Center for Biochemistry, Medical Faculty, University of Cologne, 50931 Cologne, Germany
| | - Christian Nienberg
- Institute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms-University, Münster, Germany
| | - Dirk Lindenblatt
- Department of Chemistry, Institute of Biochemistry, University of Cologne, Cologne, Germany
| | - Angelika A Noegel
- Center for Biochemistry, Medical Faculty, University of Cologne, 50931 Cologne, Germany.,Center for Molecular Medicine Cologne (CMMC), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany
| | - Janine Altmüller
- Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany.,Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Core Facility Genomics, Charitéplatz 1, 10117 Berlin, Germany.,Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Holger Thiele
- Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany
| | - Susanne Motameny
- Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany
| | | | | | - Lynn Pais
- Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Sigrid Tinschert
- Zentrum Medizinische Genetik, Medizinische Universität, Innsbruck, Austria
| | - Nadra Nasser Samra
- Hospital Center, Safed, Israel.,Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | | | - Natasha L Rudy
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Chiara De Luca
- Department of Life, Health and Environmental Science, University of L'Aquila, 67100 L'Aquila, Italy
| | | | - Paola Fortugno
- Department of Life, Health and Environmental Science, University of L'Aquila, 67100 L'Aquila, Italy.,IRCCS, San Raffaele Roma, 00163 Roma, Italy
| | - Susan M White
- Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.,Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
| | - Peter Krawitz
- Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich Wilhelms, Universität Bonn, Bonn, Germany
| | - Anna C E Hurst
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Karsten Niefind
- Department of Chemistry, Institute of Biochemistry, University of Cologne, Cologne, Germany
| | - Joachim Jose
- Institute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms-University, Münster, Germany
| | - Francesco Brancati
- Department of Life, Health and Environmental Science, University of L'Aquila, 67100 L'Aquila, Italy.,IRCCS, San Raffaele Roma, 00163 Roma, Italy
| | - Peter Nürnberg
- Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany.,Center for Molecular Medicine Cologne (CMMC), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany
| | - Muhammad Sajid Hussain
- Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany.,Center for Biochemistry, Medical Faculty, University of Cologne, 50931 Cologne, Germany.,Center for Molecular Medicine Cologne (CMMC), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany
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Withanolide modulates the potential crosstalk between apoptosis and autophagy in different colorectal cancer cell lines. Eur J Pharmacol 2022; 928:175113. [PMID: 35750234 DOI: 10.1016/j.ejphar.2022.175113] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 06/16/2022] [Accepted: 06/16/2022] [Indexed: 11/20/2022]
Abstract
Withaferin A (WFA), a withanolide, is isolated from plants of Withania somnifera (L.) Dual (Solanaceae), known as Indian ginseng, Indian winter cherry or Ashwagandha. It has been reported to exert multifaceted anti-neoplastic effects. Here, we analyzed the impact of WFA on apoptosis and autophagy activation in different human colorectal cancer cell lines. We observed that WFA exposure caused an increased aggregation of cells in the subG1 arrest in cell cycle, and increased the number of late apoptotic cells. WFA also induced the apoptosis via PARP and caspase-3 cleavage accompanied with suppression of levels of anti-apoptotic proteins like Bcl-2 and Bcl-xl. The influence of WFA on autophagy was validated by acridine orange, MDC staining, and immunocytochemistry of LC3. It was found that 24 h treatment of WFA increased the acridine and MDC stained autophagosome with induced the LC3 and other autophagy markers Atg7 and beclin-1 activation. We used Z-DEVD-FMK, a caspase-3 blocker, and 3-MA, an autophagy inhibitor, to confirm whether these effects were specific to apoptosis and autophagy, and observed the recovery of both these processes upon exposure to WFA. Moreover, the activation of β-catenin protein was attenuated by WFA. Interestingly, small interfering RNA (siRNA)-promoted β-catenin knockdown augmented the WFA-induced active form of p-GSK-3β, and stimulated autophagy and apoptosis through PARP and LC3 activation. These findings suggested that WFA could stimulate activation of both apoptosis and autophagy process via modulating β-catenin pathway.
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Wen X, Liu HX, Chen LZ, Qu W, Yan HY, Hou LF, Zhao WH, Feng YT, Ping J. Asthma susceptibility in prenatal nicotine-exposed mice attributed to β-catenin increase during CD4 + T cell development. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 238:113572. [PMID: 35533447 DOI: 10.1016/j.ecoenv.2022.113572] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 04/24/2022] [Accepted: 04/26/2022] [Indexed: 06/14/2023]
Abstract
Cigarette smoke is a common global environmental pollutant. Asthma, the most frequent allergic airway disease, is related to maternal exposure to cigarette smoke. Our previous studies demonstrated that prenatal exposure to nicotine (PNE), the major active product of smoking, impairs fetal thymopoiesis and CD4+ T cell development after birth. This study aimed to investigate whether PNE contributes to asthma susceptibility through CD4+ T cell development alterations. First, A PNE model was established by administering 3 mg/kg/day nicotine to maternal mice, and then an ovalbumin-induced asthma model was established in the offspring. Further, β-catenin and downstream pathways were inhibited in vitro to confirm the molecular mechanisms underlying the phenotype observed during the in vivo phase. The results showed that PNE induced Th2 and Th17 biases at developmental checkpoints and aggravated asthma symptoms in the offspring. In fetuses, PNE up-regulated α7 nAChR, activated PI3K-AKT, promoted β-catenin level increase, and established potential Th2- and Th17-biased gene expression patterns during thymopoiesis, which persisted after birth. Similar results were also observed in 1 μM nicotine-treated thymocytes in vitro. Moreover, inhibiting PI3K-AKT by LY294002 abrogated nicotine-mediated β-catenin level increase and thymopoiesis abnormalities, and an α7 nAChR antagonist (α-btx) also reversed nicotine-induced PI3K-AKT activation. Our findings provide strong evidence that PNE is a risk factor for T cell deviation and postnatal asthma, and revealed that nicotine-induced β-catenin level increase induces thymopoiesis abnormalities.
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Affiliation(s)
- Xiao Wen
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China
| | - Han-Xiao Liu
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China
| | - Lan-Zhou Chen
- Hubei Key Laboratory of Biomass-Resources Chemistry and Environmental Biotechnology, Wuhan University School of Resource and Environmental Sciences, Wuhan 430079, China
| | - Wen Qu
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China
| | - Hui-Yi Yan
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China
| | - Li-Fang Hou
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China
| | - Wen-Hao Zhao
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China
| | - Yi-Ting Feng
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China
| | - Jie Ping
- Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China.
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22
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Li A, Gu Y, Zhang X, Yu H, Liu D, Pang Q. Betaine Regulates the Production of Reactive Oxygen Species Through Wnt10b Signaling in the Liver of Zebrafish. Front Physiol 2022; 13:877178. [PMID: 35574489 PMCID: PMC9096094 DOI: 10.3389/fphys.2022.877178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 03/17/2022] [Indexed: 11/26/2022] Open
Abstract
When fish are under oxidative stress, levels of reactive oxygen species (ROS) are chronically elevated, which play a crucial role in fish innate immunity. In the present study, the mechanism by which betaine regulates ROS production via Wnt10b/β-catenin signaling was investigated in zebrafish liver. Our results showed that betaine enrichment of diet at 0.1, 0.2 and 0.4 g/kg induced Wnt10b and β-catenin gene expression, but suppressed GSK-3β expression in zebrafish liver. In addition, the content of superoxide anion (O2·−), hydrogen peroxide (H2O2) and hydroxyl radical (·OH) was decreased by all of the experimental betaine treatments. However, betaine enrichment of diet at 0.1, 0.2 and 0.4 g/kg enhanced gene expression and activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) and catalase (CAT) in zebrafish liver. In addition, Wnt10b RNA was further interfered in zebrafish, and the results of Wnt10b RNAi indicated that Wnt10b plays a key role in regulating ROS production and antioxidant enzyme activity. In conclusion, betaine can inhibit ROS production in zebrafish liver through the Wnt10b/β-catenin signaling pathway.
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Affiliation(s)
- Ao Li
- Anti-Aging & Regenerative Medicine Research Institution, School of Life Sciences and Medicine, Shandong University of Technology, Zibo, China
| | - Yaqi Gu
- Anti-Aging & Regenerative Medicine Research Institution, School of Life Sciences and Medicine, Shandong University of Technology, Zibo, China
| | - Xiuzhen Zhang
- Anti-Aging & Regenerative Medicine Research Institution, School of Life Sciences and Medicine, Shandong University of Technology, Zibo, China
| | - Hairui Yu
- College of Biological and Agricultural Engineering, Weifang Bioengineering Technology Research Center, Weifang University, Weifang, China
| | - Dongwu Liu
- Anti-Aging & Regenerative Medicine Research Institution, School of Life Sciences and Medicine, Shandong University of Technology, Zibo, China
- School of Agricultural Engineering and Food Science, Shandong University of Technology, Zibo, China
- *Correspondence: Dongwu Liu, ; Qiuxiang Pang,
| | - Qiuxiang Pang
- Anti-Aging & Regenerative Medicine Research Institution, School of Life Sciences and Medicine, Shandong University of Technology, Zibo, China
- *Correspondence: Dongwu Liu, ; Qiuxiang Pang,
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23
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Zuieva A, Can S, Boelke F, Reuter S, Schattscheider S, Töpfer E, Westphal A, Mrowka R, Wölfl S. Real-time monitoring of immediate drug response and adaptation upon repeated treatment in a microfluidic chip system. Arch Toxicol 2022; 96:1483-1487. [PMID: 35304627 PMCID: PMC9013683 DOI: 10.1007/s00204-022-03272-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 03/01/2022] [Indexed: 11/02/2022]
Abstract
Microfluidic tissue culture and organ-on-a-chip models provide efficient tools for drug testing in vivo and are considered to become the basis of in vitro test systems to analyze drug response, drug interactions and toxicity to complement and reduce animal testing. A major limitation is the efficient recording of drug action. Here we present an efficient experimental setup that allows long-term cultivation of cells in a microfluidic system in combination with continuous recording of luciferase reporter gene expression. The system combines a sensitive cooled luminescence camera system in combination with a custom build miniaturized incubation chamber. The setup allows to monitor time-dependent activation, but also the end of drug response. Repeated activation and recovery as well as varying durations of drug treatment periods can be monitored, and different modes of drug activity can be visualized.
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Affiliation(s)
- Anastasiia Zuieva
- Institute of Pharmacy and Molecular Biotechnology, Pharmaceutical Biology, Heidelberg University, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany
| | - Suzan Can
- Institute of Pharmacy and Molecular Biotechnology, Pharmaceutical Biology, Heidelberg University, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany
| | - Franziska Boelke
- Microfluidic ChipShop GmbH, Jena, Germany, Stockholmer Str. 20, 07747, Jena, Germany
| | - Stefanie Reuter
- Experimentelle Nephrologie, KIM III, 12 Universitätsklinikum Jena, Stockholmer Str. 20, 07747, Jena, Germany
| | | | - Elfi Töpfer
- Microfluidic ChipShop GmbH, Jena, Germany, Stockholmer Str. 20, 07747, Jena, Germany
| | - Anika Westphal
- Experimentelle Nephrologie, KIM III, 12 Universitätsklinikum Jena, Stockholmer Str. 20, 07747, Jena, Germany
| | - Ralf Mrowka
- Experimentelle Nephrologie, KIM III, 12 Universitätsklinikum Jena, Stockholmer Str. 20, 07747, Jena, Germany
| | - Stefan Wölfl
- Institute of Pharmacy and Molecular Biotechnology, Pharmaceutical Biology, Heidelberg University, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany.
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24
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Vallée A. Neuroinflammation in Schizophrenia: The Key Role of the WNT/β-Catenin Pathway. Int J Mol Sci 2022; 23:ijms23052810. [PMID: 35269952 PMCID: PMC8910888 DOI: 10.3390/ijms23052810] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 02/24/2022] [Accepted: 02/27/2022] [Indexed: 02/06/2023] Open
Abstract
Schizophrenia is a very complex syndrome involving widespread brain multi-dysconnectivity. Schizophrenia is marked by cognitive, behavioral, and emotional dysregulations. Recent studies suggest that inflammation in the central nervous system (CNS) and immune dysfunction could have a role in the pathogenesis of schizophrenia. This hypothesis is supported by immunogenetic evidence, and a higher incidence rate of autoimmune diseases in patients with schizophrenia. The dysregulation of the WNT/β-catenin pathway is associated with the involvement of neuroinflammation in schizophrenia. Several studies have shown that there is a vicious and positive interplay operating between neuroinflammation and oxidative stress. This interplay is modulated by WNT/β-catenin, which interacts with the NF-kB pathway; inflammatory factors (including IL-6, IL-8, TNF-α); factors of oxidative stress such as glutamate; and dopamine. Neuroinflammation is associated with increased levels of PPARγ. In schizophrenia, the expression of PPAR-γ is increased, whereas the WNT/β-catenin pathway and PPARα are downregulated. This suggests that a metabolic-inflammatory imbalance occurs in this disorder. Thus, this research’s triptych could be a novel therapeutic approach to counteract both neuroinflammation and oxidative stress in schizophrenia.
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Affiliation(s)
- Alexandre Vallée
- Department of Clinical Research and Innovation (DRCI), Foch Hospital, 92150 Suresnes, France
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25
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Sun Y, Wang P, Zhang Q, Wu H. CDK14/β-catenin/TCF4/miR-26b positive feedback regulation modulating pancreatic cancer cell phenotypes in vitro and tumor growth in mice model in vivo. J Gene Med 2022; 24:e3343. [PMID: 33871149 DOI: 10.1002/jgm.3343] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 03/09/2021] [Accepted: 03/24/2021] [Indexed: 11/06/2022] Open
Abstract
INTRODUCTION Chemotherapy and radiotherapy have been reported to be basically ineffective for pancreatic ductal adenocarcinoma patients; thus, gene therapy might provide a novel approach. CDK14, a new oncogenic member of the CDK family involved in the pancreatic cancer cell response to gemcitabine treatment, has been reported to be regulated by microRNAs. In the present study, we aimed to investigate whether miR-26b regulated CDK14 expression to affect the phenotype of pancreatic cancer cells. METHODS Overexpression or knockdown of CDK14 or miR-26b was generated in pancreatic cancer cell lines and the function of CDK14 and miR-26b on cell phenotype and the Wnt signaling pathway was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, 5-ethynyl-2'-deoxyuridine and transwell assays, as well as a xenograft model and western blotting. The predicted binding site between the 3'-untranslated region of CDK14 and miR-26b, miR-26b promoter and TCF4 was verified by luciferase or chromatin immunoprecipitation assays. RESULTS CDK14 overexpression inhibited p-GSK3β, whereas it promoted p-LRP6, the nuclear translocation of β-catenin and the transactivation of TCF4 transcription factor, thus promoting pancreatic cancer cell aggressiveness. miR-26b directly targeted CDK14 and inhibited CDK14 expression. In vitro and in vivo, miR-26b overexpression inhibited, and CDK14 overexpression promoted, cancer cell aggressiveness; CDK14 overexpression partially attenuated the miR-26b overexpression effects on cancer cells. The effects of miR-26b overexpression on tumor growth and the Wnt/β-catenin/TCF4 signaling were partially reversed by CDK14 overexpression. TCF4 inhibited the expression of miR-26b by targeting its promoter region. CONCLUSIONS CDK14, β-catenin, TCF4 and miR-26b form a positive feedback regulation for modulating pancreatic cancer cell phenotypes in vitro and tumor growth in vivo.
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Affiliation(s)
- Yunpeng Sun
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Pengfei Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qiyu Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Huanhuan Wu
- Department of Post-anesthetic ICU, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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26
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Janssen R, Pechmann M, Turetzek N. A chelicerate Wnt gene expression atlas: novel insights into the complexity of arthropod Wnt-patterning. EvoDevo 2021; 12:12. [PMID: 34753512 PMCID: PMC8579682 DOI: 10.1186/s13227-021-00182-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 10/27/2021] [Indexed: 11/24/2022] Open
Abstract
The Wnt genes represent a large family of secreted glycoprotein ligands that date back to early animal evolution. Multiple duplication events generated a set of 13 Wnt families of which 12 are preserved in protostomes. Embryonic Wnt expression patterns (Wnt-patterning) are complex, representing the plentitude of functions these genes play during development. Here, we comprehensively investigated the embryonic expression patterns of Wnt genes from three species of spiders covering both main groups of true spiders, Haplogynae and Entelegynae, a mygalomorph species (tarantula), as well as a distantly related chelicerate outgroup species, the harvestman Phalangium opilio. All spiders possess the same ten classes of Wnt genes, but retained partially different sets of duplicated Wnt genes after whole genome duplication, some of which representing impressive examples of sub- and neo-functionalization. The harvestman, however, possesses a more complete set of 11 Wnt genes but with no duplicates. Our comprehensive data-analysis suggests a high degree of complexity and evolutionary flexibility of Wnt-patterning likely providing a firm network of mutational protection. We discuss the new data on Wnt gene expression in terms of their potential function in segmentation, posterior elongation, and appendage development and critically review previous research on these topics. We conclude that earlier research may have suffered from the absence of comprehensive gene expression data leading to partial misconceptions about the roles of Wnt genes in development and evolution.
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Affiliation(s)
- Ralf Janssen
- Department of Earth Sciences, Palaeobiology, Uppsala University, Villavägen 16, 75236, Uppsala, Sweden.
| | - Matthias Pechmann
- Department of Developmental Biology, Biocenter, Institute for Zoology, University of Cologne, Zuelpicher Str. 47b, 50674, Cologne, Germany
| | - Natascha Turetzek
- Evolutionary Ecology, Faculty of Biology, Ludwig-Maximilians Universität München, Grosshaderner Strasse 2, 82152, Biozentrum, Germany
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27
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Khadri FZ, Issac MSM, Gaboury LA. Impact of Epithelial-Mesenchymal Transition on the Immune Landscape in Breast Cancer. Cancers (Basel) 2021; 13:5099. [PMID: 34680248 PMCID: PMC8533811 DOI: 10.3390/cancers13205099] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/02/2021] [Accepted: 10/07/2021] [Indexed: 12/12/2022] Open
Abstract
The impact of epithelial-mesenchymal transition (EMT) signature on the immune infiltrate present in the breast cancer tumor microenvironment (TME) is still poorly understood. Since there is mounting interest in the use of immunotherapy for the treatment of subsets of breast cancer patients, it is of major importance to understand the fundamental tumor characteristics which dictate the inter-tumor heterogeneity in immune landscapes. We aimed to assess the impact of EMT-related markers on the nature and magnitude of the inflammatory infiltrate present in breast cancer TME and their association with the clinicopathological parameters. Tissue microarrays were constructed from 144 formalin-fixed paraffin-embedded invasive breast cancer tumor samples. The protein expression patterns of Snail, Twist, ZEB1, N-cadherin, Vimentin, GRHL2, E-cadherin, and EpCAM were examined by immunohistochemistry (IHC). The inflammatory infiltrate in the TME was assessed semi-quantitatively on hematoxylin and eosin (H&E)-stained whole sections and was characterized using IHC. The inflammatory infiltrate was more intense in poorly differentiated carcinomas and triple-negative carcinomas in which the expression of E-cadherin and GRHL2 was reduced, while EpCAM was overexpressed. Most EMT-related markers correlated with plasma cell infiltration of the TME. Taken together, our findings reveal that the EMT signature might impact the immune response in the TME.
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Affiliation(s)
- Fatima-Zohra Khadri
- Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, QC H3T 1J4, Canada; (F.-Z.K.); (M.S.M.I.)
- Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada
| | - Marianne Samir Makboul Issac
- Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, QC H3T 1J4, Canada; (F.-Z.K.); (M.S.M.I.)
- Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo 11956, Egypt
| | - Louis Arthur Gaboury
- Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, QC H3T 1J4, Canada; (F.-Z.K.); (M.S.M.I.)
- Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada
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28
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Prado LG, Barbosa AS. Understanding the Renal Fibrotic Process in Leptospirosis. Int J Mol Sci 2021; 22:ijms221910779. [PMID: 34639117 PMCID: PMC8509513 DOI: 10.3390/ijms221910779] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/29/2021] [Accepted: 10/02/2021] [Indexed: 12/12/2022] Open
Abstract
Leptospirosis is a neglected infectious disease caused by pathogenic species of the genus Leptospira. The acute disease is well-described, and, although it resembles other tropical diseases, it can be diagnosed through the use of serological and molecular methods. While the chronic renal disease, carrier state, and kidney fibrosis due to Leptospira infection in humans have been the subject of discussion by researchers, the mechanisms involved in these processes are still overlooked, and relatively little is known about the establishment and maintenance of the chronic status underlying this infectious disease. In this review, we highlight recent findings regarding the cellular communication pathways involved in the renal fibrotic process, as well as the relationship between renal fibrosis due to leptospirosis and CKD/CKDu.
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Affiliation(s)
- Luan Gavião Prado
- Laboratório de Bacteriologia, Instituto Butantan, Avenida Vital Brasil, 1500, São Paulo 05503-900, Brazil;
- Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Avenida Lineu Prestes 1374, São Paulo 05508-000, Brazil
| | - Angela Silva Barbosa
- Laboratório de Bacteriologia, Instituto Butantan, Avenida Vital Brasil, 1500, São Paulo 05503-900, Brazil;
- Correspondence:
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29
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Chekmarev J, Azad MG, Richardson DR. The Oncogenic Signaling Disruptor, NDRG1: Molecular and Cellular Mechanisms of Activity. Cells 2021; 10:cells10092382. [PMID: 34572031 PMCID: PMC8465210 DOI: 10.3390/cells10092382] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/03/2021] [Accepted: 09/06/2021] [Indexed: 12/12/2022] Open
Abstract
NDRG1 is an oncogenic signaling disruptor that plays a key role in multiple cancers, including aggressive pancreatic tumors. Recent studies have indicated a role for NDRG1 in the inhibition of multiple tyrosine kinases, including EGFR, c-Met, HER2 and HER3, etc. The mechanism of activity of NDRG1 remains unclear, but to impart some of its functions, NDRG1 binds directly to key effector molecules that play roles in tumor suppression, e.g., MIG6. More recent studies indicate that NDRG1s-inducing drugs, such as novel di-2-pyridylketone thiosemicarbazones, not only inhibit tumor growth and metastasis but also fibrous desmoplasia, which leads to chemotherapeutic resistance. The Casitas B-lineage lymphoma (c-Cbl) protein may be regulated by NDRG1, and is a crucial E3 ligase that regulates various protein tyrosine and receptor tyrosine kinases, primarily via ubiquitination. The c-Cbl protein can act as a tumor suppressor by promoting the degradation of receptor tyrosine kinases. In contrast, c-Cbl can also promote tumor development by acting as a docking protein to mediate the oncogenic c-Met/Crk/JNK and PI3K/AKT pathways. This review hypothesizes that NDRG1 could inhibit the oncogenic function of c-Cbl, which may be another mechanism of its tumor-suppressive effects.
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Affiliation(s)
- Jason Chekmarev
- Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, QLD 4111, Australia; (J.C.); (M.G.A.)
| | - Mahan Gholam Azad
- Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, QLD 4111, Australia; (J.C.); (M.G.A.)
| | - Des R. Richardson
- Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, QLD 4111, Australia; (J.C.); (M.G.A.)
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
- Correspondence: ; Tel.: +61-7-3735-7549
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El-Rashidy AA, El Moshy S, Radwan IA, Rady D, Abbass MMS, Dörfer CE, Fawzy El-Sayed KM. Effect of Polymeric Matrix Stiffness on Osteogenic Differentiation of Mesenchymal Stem/Progenitor Cells: Concise Review. Polymers (Basel) 2021; 13:2950. [PMID: 34502988 PMCID: PMC8434088 DOI: 10.3390/polym13172950] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/04/2021] [Accepted: 08/05/2021] [Indexed: 01/23/2023] Open
Abstract
Mesenchymal stem/progenitor cells (MSCs) have a multi-differentiation potential into specialized cell types, with remarkable regenerative and therapeutic results. Several factors could trigger the differentiation of MSCs into specific lineages, among them the biophysical and chemical characteristics of the extracellular matrix (ECM), including its stiffness, composition, topography, and mechanical properties. MSCs can sense and assess the stiffness of extracellular substrates through the process of mechanotransduction. Through this process, the extracellular matrix can govern and direct MSCs' lineage commitment through complex intracellular pathways. Hence, various biomimetic natural and synthetic polymeric matrices of tunable stiffness were developed and further investigated to mimic the MSCs' native tissues. Customizing scaffold materials to mimic cells' natural environment is of utmost importance during the process of tissue engineering. This review aims to highlight the regulatory role of matrix stiffness in directing the osteogenic differentiation of MSCs, addressing how MSCs sense and respond to their ECM, in addition to listing different polymeric biomaterials and methods used to alter their stiffness to dictate MSCs' differentiation towards the osteogenic lineage.
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Affiliation(s)
- Aiah A. El-Rashidy
- Biomaterials Department, Faculty of Dentistry, Cairo University, Cairo 11562, Egypt;
- Stem Cells and Tissue Engineering Research Group, Faculty of Dentistry, Cairo University, Cairo 11562, Egypt; (S.E.M.); (I.A.R.); (D.R.); (M.M.S.A.)
| | - Sara El Moshy
- Stem Cells and Tissue Engineering Research Group, Faculty of Dentistry, Cairo University, Cairo 11562, Egypt; (S.E.M.); (I.A.R.); (D.R.); (M.M.S.A.)
- Oral Biology Department, Faculty of Dentistry, Cairo University, Cairo 11562, Egypt
| | - Israa Ahmed Radwan
- Stem Cells and Tissue Engineering Research Group, Faculty of Dentistry, Cairo University, Cairo 11562, Egypt; (S.E.M.); (I.A.R.); (D.R.); (M.M.S.A.)
- Oral Biology Department, Faculty of Dentistry, Cairo University, Cairo 11562, Egypt
| | - Dina Rady
- Stem Cells and Tissue Engineering Research Group, Faculty of Dentistry, Cairo University, Cairo 11562, Egypt; (S.E.M.); (I.A.R.); (D.R.); (M.M.S.A.)
- Oral Biology Department, Faculty of Dentistry, Cairo University, Cairo 11562, Egypt
| | - Marwa M. S. Abbass
- Stem Cells and Tissue Engineering Research Group, Faculty of Dentistry, Cairo University, Cairo 11562, Egypt; (S.E.M.); (I.A.R.); (D.R.); (M.M.S.A.)
- Oral Biology Department, Faculty of Dentistry, Cairo University, Cairo 11562, Egypt
| | - Christof E. Dörfer
- Clinic for Conservative Dentistry and Periodontology, School of Dental Medicine, Christian Albrechts University, 24105 Kiel, Germany;
| | - Karim M. Fawzy El-Sayed
- Stem Cells and Tissue Engineering Research Group, Faculty of Dentistry, Cairo University, Cairo 11562, Egypt; (S.E.M.); (I.A.R.); (D.R.); (M.M.S.A.)
- Clinic for Conservative Dentistry and Periodontology, School of Dental Medicine, Christian Albrechts University, 24105 Kiel, Germany;
- Oral Medicine and Periodontology Department, Faculty of Dentistry, Cairo University, Cairo 11562, Egypt
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Liu Z, Yang J, Fang Q, Shao H, Yang D, Sun J, Gao L. MiRNA-199a-5p targets WNT2 to regulate depression through the CREB/BDNF signaling in hippocampal neuron. Brain Behav 2021; 11:e02107. [PMID: 34333859 PMCID: PMC8413827 DOI: 10.1002/brb3.2107] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 02/24/2021] [Accepted: 02/26/2021] [Indexed: 11/13/2022] Open
Abstract
INTRODUCTION This study mainly investigated the role of miR-199a-5p in depression. METHODS qRT-PCR and western blotting were employed to detect the expressions of miR-199a-5p, CREB and BDNF. Sucrose preference test, forced swimming test, and tail suspension test were performed to evaluate depression-related symptoms. MTT assays and flow cytometry were used to examine the cell reproduction and apoptotic cells of hippocampal neuron. RESULTS The data demonstrated that the expression levels of miR-199a-5p in the cerebrospinal fluids and serums of depression patient and the hippocampus of chronic unpredictable mild stress (CUMS) mouse were significantly increased. However, the expressions of WNT2, p-CREB, and BDNF were inhibited. In addition, miR-199a-5p-inhibitor enhanced sucrose preferences of CUMS mouse and decreased immobile time in sucrose preference test and forced swimming test. Knockdown of WNT2 attenuated the effects of miR-199a-5p-inhibitor on cell reproduction and apoptotic cells of hippocampal neuron and the expression of WNT2, p-CREB, and BDNF. CONCLUSION MiR-199a-5p can target WNT2 to enhance the development of depression through regulation of the CREB/BDNF signaling. TRIAL REGISTRATION JNU-Hos-49284.
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Affiliation(s)
- Zheng Liu
- Department of Graduate School, Tianjin Medical University, Tianjin, China.,Department of department of neurology, The Second Affiliated Hospital of Baotou Medical College, Baotou, China
| | - Jianli Yang
- Department of Clinical Psychology, Tianjin Medical University General Hospital, Tianjin, China
| | - Qing Fang
- Department of Clinical Psychology, Tianjin Medical University General Hospital, Tianjin, China
| | - Hua Shao
- Department of Clinical Psychology, Tianjin Medical University General Hospital, Tianjin, China
| | - Dalu Yang
- Department of Clinical Psychology, Tianjin Medical University General Hospital, Tianjin, China
| | - Junfang Sun
- Department of department of neurology, The Second Affiliated Hospital of Baotou Medical College, Baotou, China
| | - Lizhi Gao
- Department of department of neurology, The Second Affiliated Hospital of Baotou Medical College, Baotou, China
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Herlan CN, Sonnefeld A, Gloge T, Brückel J, Schlee LC, Muhle-Goll C, Nieger M, Bräse S. Macrocyclic Tetramers-Structural Investigation of Peptide-Peptoid Hybrids. Molecules 2021; 26:molecules26154548. [PMID: 34361700 PMCID: PMC8348019 DOI: 10.3390/molecules26154548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 07/23/2021] [Accepted: 07/24/2021] [Indexed: 11/16/2022] Open
Abstract
Outstanding affinity and specificity are the main characteristics of peptides, rendering them interesting compounds for basic and medicinal research. However, their biological applicability is limited due to fast proteolytic degradation. The use of mimetic peptoids overcomes this disadvantage, though they lack stereochemical information at the α-carbon. Hybrids composed of amino acids and peptoid monomers combine the unique properties of both parent classes. Rigidification of the backbone increases the affinity towards various targets. However, only little is known about the spatial structure of such constrained hybrids. The determination of the three-dimensional structure is a key step for the identification of new targets as well as the rational design of bioactive compounds. Herein, we report the synthesis and the structural elucidation of novel tetrameric macrocycles. Measurements were taken in solid and solution states with the help of X-ray scattering and NMR spectroscopy. The investigations made will help to find diverse applications for this new, promising compound class.
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Affiliation(s)
- Claudine Nicole Herlan
- Institute of Organic Chemistry, Karlsruhe Institute of Technology, Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany; (C.N.H.); (J.B.); (L.C.S.)
| | - Anna Sonnefeld
- Institute for Biological Interfaces 4, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany; (A.S.); (T.G.); (C.M.-G.)
| | - Thomas Gloge
- Institute for Biological Interfaces 4, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany; (A.S.); (T.G.); (C.M.-G.)
| | - Julian Brückel
- Institute of Organic Chemistry, Karlsruhe Institute of Technology, Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany; (C.N.H.); (J.B.); (L.C.S.)
| | - Luisa Chiara Schlee
- Institute of Organic Chemistry, Karlsruhe Institute of Technology, Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany; (C.N.H.); (J.B.); (L.C.S.)
| | - Claudia Muhle-Goll
- Institute for Biological Interfaces 4, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany; (A.S.); (T.G.); (C.M.-G.)
| | - Martin Nieger
- Department of Chemistry, University of Helsinki, P.O. Box 55 (A.I. Virtasen aukio 1), FIN-00014 Helsinki, Finland;
| | - Stefan Bräse
- Institute of Organic Chemistry, Karlsruhe Institute of Technology, Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany; (C.N.H.); (J.B.); (L.C.S.)
- Institute of Biological and Chemical Systems—Functional Molecular Systems, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
- Correspondence:
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Overview of oral cavity squamous cell carcinoma: Risk factors, mechanisms, and diagnostics. Oral Oncol 2021; 121:105451. [PMID: 34329869 DOI: 10.1016/j.oraloncology.2021.105451] [Citation(s) in RCA: 231] [Impact Index Per Article: 57.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 07/01/2021] [Accepted: 07/04/2021] [Indexed: 02/07/2023]
Abstract
Oral cavity squamous cell carcinoma (OCSCC) is the most common malignancy of the oral cavity. The substantial risk factors for OCSCC are the consumption of tobacco products, alcohol, betel quid, areca nut, and genetic alteration. However, technological advancements have occurred in treatment, but the survival decreases with late diagnosis; therefore, new methods are continuously being investigated for treatment. In addition, the rate of secondary tumor formation is 3-7% yearly, which is incomparable to other malignancies and can lead to the disease reoccurrence. Oral cavity cancer (OCC) arises from genetic alterations, and a complete understanding of the molecular mechanism involved in OCC is essential to develop targeted treatments. This review aims to update the researcher on oral cavity cancer, risk factors, genetic alterations, molecular mechanism, classification, diagnostic approaches, and treatment.
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Zhou N, Yan B, Ma J, Jiang H, Li L, Tang H, Ji F, Yao Z. Expression of TCF3 in Wilms' tumor and its regulatory role in kidney tumor cell viability, migration and apoptosis in vitro. Mol Med Rep 2021; 24:642. [PMID: 34278464 PMCID: PMC8299189 DOI: 10.3892/mmr.2021.12281] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 06/10/2021] [Indexed: 12/23/2022] Open
Abstract
Wilms' tumor (WT) is a major type of kidney cancer in children; however, the therapeutic measures for control of tumor metastasis, recurrence and death for this type of cancer remain unsatisfactory. The present study aimed to verify the expression of T-cell factor 3 (TCF3) in WT, and to explore its role in regulating the viability, migration and apoptosis of kidney tumor cells. Tumor tissues were collected from 10 patients with WT, and adjacent tissues were collected as normal controls. The expression levels of TCF3 were detected in WT tissues and adjacent tissues by reverse transcription-quantitative PCR (RT-qPCR), western blotting and immunohistochemistry. In addition, TCF3 expression was silenced in G401 kidney tumor cells via small interfering RNA transfection. Cell viability, cell cycle progression and cell apoptosis were assessed using the MTT assay and flow cytometry; the migration and invasion of kidney tumor cells were examined using Transwell and wound-healing assays; and the expression levels of Wnt signaling pathway-related genes (Wnt1, β-catenin and c-myc) were detected by RT-qPCR and western blotting. The results revealed that the expression levels of TCF3 were high in WT tissues from patients. Silencing TCF3 expression in G401 kidney tumor cells in vitro significantly inhibited cell viability and migration, and promoted cell apoptosis. Moreover, silencing TCF3 expression in G401 cells inhibited the expression levels of Wnt signaling pathway-related genes. Overall, these data indicated that TCF3 may be involved in WT development through regulation of Wnt signaling pathways. The findings of the present study provide a novel potential marker for the treatment and prognostic evaluation of WT.
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Affiliation(s)
- Nian Zhou
- Department of Skin, Kunming Children's Hospital, Kunming, Yunnan 650228, P.R. China
| | - Bing Yan
- Department of Urology Surgery, Kunming Children's Hospital, Kunming, Yunnan 650228, P.R. China
| | - Jing Ma
- Department of Otorhinolaryngology, Kunming Children's Hospital, Kunming, Yunnan 650228, P.R. China
| | - Hongchao Jiang
- Institute of Pediatrics, Kunming Children's Hospital, Kunming, Yunnan 650228, P.R. China
| | - Li Li
- Institute of Pediatrics, Kunming Children's Hospital, Kunming, Yunnan 650228, P.R. China
| | - Haoyu Tang
- Department of Urology Surgery, Kunming Children's Hospital, Kunming, Yunnan 650228, P.R. China
| | - Fengming Ji
- Department of Urology Surgery, Kunming Children's Hospital, Kunming, Yunnan 650228, P.R. China
| | - Zhigang Yao
- Department of Urology Surgery, Kunming Children's Hospital, Kunming, Yunnan 650228, P.R. China
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Zhang Q, Yu J, Chen Q, Yan H, Du H, Luo W. Regulation of pathophysiological and tissue regenerative functions of MSCs mediated via the WNT signaling pathway (Review). Mol Med Rep 2021; 24:648. [PMID: 34278470 PMCID: PMC8299209 DOI: 10.3892/mmr.2021.12287] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 06/22/2021] [Indexed: 12/18/2022] Open
Abstract
Tissues have remarkable natural capabilities to regenerate for the purpose of physiological turnover and repair of damage. Adult mesenchymal stem cells (MSCs) are well known for their unique self-renewal ability, pluripotency, homing potential, paracrine effects and immunomodulation. Advanced research of the unique properties of MSCs have opened up new horizons for tissue regenerative therapies. However, certain drawbacks of the application of MSCs, such as the low survival rate of transplanted MSCs, unsatisfactory efficiency and even failure to regenerate under an unbalanced microenvironment, are concerning with regards to their wider therapeutic applications. The activity of stem cells is mainly regulated by the anatomical niche; where they are placed during their clinical and therapeutic applications. Crosstalk between various niche signals maintains MSCs in homeostasis, in which the WNT signaling pathway plays vital roles. Several external or internal stimuli have been reported to interrupt the normal bioactivity of stem cells. The irreversible tissue loss that occurs during infection at the site of tissue grafting suggests an inhibitory effect mediated by microbial infections within MSC niches. In addition, MSC-seeded tissue engineering success is difficult in various tissues, when sites of injury are under the effects of a severe infection despite the immunomodulatory properties of MSCs. In the present review, the current understanding of the way in which WNT signaling regulates MSC activity modification under physiological and pathological conditions was summarized. An effort was also made to illustrate parts of the underlying mechanism, including the inflammatory factors and their interactions with the regulatory WNT signaling pathway, aiming to promote the clinical translation of MSC-based therapy.
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Affiliation(s)
- Qingtao Zhang
- Department of Stomatology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310085, P.R. China
| | - Jian Yu
- Department of Stomatology, Zhejiang Hospital, Hangzhou, Zhejiang 310030, P.R. China
| | - Qiuqiu Chen
- Department of Stomatology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310085, P.R. China
| | - Honghai Yan
- Department of Stomatology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310085, P.R. China
| | - Hongjiang Du
- Department of Stomatology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310085, P.R. China
| | - Wenjing Luo
- Department of General Dentistry, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA 02118, USA
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Yang MH, Ha IJ, Lee SG, Lee J, Um JY, Ahn KS. Ginkgolide C promotes apoptosis and abrogates metastasis of colorectal carcinoma cells by targeting Wnt/β-catenin signaling pathway. IUBMB Life 2021; 73:1222-1234. [PMID: 34273236 DOI: 10.1002/iub.2532] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 07/09/2021] [Indexed: 01/20/2023]
Abstract
Ginkgolide C (GGC), isolated from Ginkbiloba, has been reported to display various pharmacological actions, although, anti-cancer effect of GGC has been poorly understood till now. This study aimed to investigate whether GGC can exhibit anti-neoplastic effects against colon cancer cells and explore underlying mechanism. The Wnt/β-catenin signaling can regulate cell proliferation, survival, metastasis, and migration. Wnt/β-catenin signaling pathway plays important role in colorectal cancer (CRC) and acts as a potential therapeutic target. Abnormal activation of this signaling cascades has been reported in colon CRC. We found that GGC down-regulated Wnt/β-catenin signaling cascade. GGC inhibited the expression of Wnt3a, β-catenin, and β-catenin down-stream signals (Axin-1, p-GSK3β, and β-TrCP). Also, GGC suppressed the expression of Wnt/β-catenin pathway target genes including c-myc, cyclin D1, and survivin. Additionally, GGC induced apoptosis and suppressed cell proliferation, invasion, and migration. GGC down-regulated the expressions of matrix metalloproteinase (MMP)-9 and MMP-2 proteins. Moreover, silencing of β-catenin by small interfering RNA (siRNA) enhanced the GGC-induced apoptosis and inhibitory action of GGC on invasion. Overall, our results indicate that GGC can reduce proliferation and promote apoptosis in colon cancer cells through inhibition of the Wnt/β-catenin signaling pathway. Thus, GGC can serve as a potent therapeutic agent for management of colon cancer as a novel wnt signaling inhibitor.
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Affiliation(s)
- Min Hee Yang
- KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul, Republic of Korea.,Department of Science in Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - In Jin Ha
- Korean Medicine Clinical Trial Center (K-CTC), Korean Medicine Hospital, Kyung Hee University, Seoul, Republic of Korea
| | - Seok-Geun Lee
- Department of Science in Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.,Korean Medicine Clinical Trial Center (K-CTC), Korean Medicine Hospital, Kyung Hee University, Seoul, Republic of Korea
| | - Junhee Lee
- Korean Medicine Clinical Trial Center (K-CTC), Korean Medicine Hospital, Kyung Hee University, Seoul, Republic of Korea
| | - Jae-Young Um
- Department of Science in Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Kwang Seok Ahn
- KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul, Republic of Korea.,Department of Science in Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
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Soh R, Hardy A, Zur Nieden NI. The FOXO signaling axis displays conjoined functions in redox homeostasis and stemness. Free Radic Biol Med 2021; 169:224-237. [PMID: 33878426 PMCID: PMC9910585 DOI: 10.1016/j.freeradbiomed.2021.04.022] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 04/09/2021] [Accepted: 04/12/2021] [Indexed: 02/07/2023]
Abstract
Previous views of reactive oxygen species (ROS) depicted them as harmful byproducts of metabolism as uncontrolled levels of ROS can lead to DNA damage and cell death. However, recent studies have shed light into the key role of ROS in the self-renewal or differentiation of the stem cell. The interplay between ROS levels, metabolism, and the downstream redox signaling pathways influence stem cell fate. In this review we will define ROS, explain how they are generated, and how ROS signaling can influence transcription factors, first and foremost forkhead box-O transcription factors, that shape not only the cellular redox state, but also stem cell fate. Now that studies have illustrated the importance of redox homeostasis and the role of redox signaling, understanding the mechanisms behind this interplay will further shed light into stem cell biology.
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Affiliation(s)
- Ruthia Soh
- Department of Molecular, Cell and Systems Biology, College of Natural and Agricultural Sciences, University of California Riverside, Riverside, 92521, CA, USA
| | - Ariana Hardy
- Department of Molecular, Cell and Systems Biology, College of Natural and Agricultural Sciences, University of California Riverside, Riverside, 92521, CA, USA
| | - Nicole I Zur Nieden
- Department of Molecular, Cell and Systems Biology, College of Natural and Agricultural Sciences, University of California Riverside, Riverside, 92521, CA, USA; Stem Cell Center, College of Natural and Agricultural Sciences, University of California Riverside, Riverside, 92521, CA, USA.
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38
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Yoon HH, Lee HJ, Min J, Kim JH, Park JH, Kim JH, Kim SW, Lee H, Jeon SR. Optimal Ratio of Wnt3a Expression in Human Mesenchymal Stem Cells Promotes Axonal Regeneration in Spinal Cord Injured Rat Model. J Korean Neurosurg Soc 2021; 64:705-715. [PMID: 34044494 PMCID: PMC8435649 DOI: 10.3340/jkns.2021.0003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 04/07/2021] [Indexed: 01/07/2023] Open
Abstract
Objective Through our previous clinical trials, the demonstrated therapeutic effects of MSC in chronic spinal cord injury (SCI) were found to be not sufficient. Therefore, the need to develop stem cell agent with enhanced efficacy is increased. We transplanted enhanced Wnt3asecreting human mesenchymal stem cells (hMSC) into injured spines at 6 weeks after SCI to improve axonal regeneration in a rat model of chronic SCI. We hypothesized that enhanced Wnt3a protein expression could augment neuro-regeneration after SCI. Methods Thirty-six Sprague-Dawley rats were injured using an Infinite Horizon (IH) impactor at the T9-10 vertebrae and separated into five groups : 1) phosphate-buffered saline injection (injury only group, n=7); 2) hMSC transplantation (MSC, n=7); 3) hMSC transfected with pLenti vector (without Wnt3a gene) transplantation (pLenti-MSC, n=7); 4) hMSC transfected with Wnt3a gene transplantation (Wnt3a-MSC, n=7); and 5) hMSC transfected with enhanced Wnt3a gene (1.7 fold Wnt3a mRNA expression) transplantation (1.7 Wnt3a-MSC, n=8). Six weeks after SCI, each 5×105 cells/15 µL at 2 points were injected using stereotactic and microsyringe pump. To evaluate functional recovery from SCI, rats underwent Basso-Beattie-Bresnahan (BBB) locomotor test on the first, second, and third days post-injury and then weekly for 14 weeks. Axonal regeneration was assessed using growth-associated protein 43 (GAP43), microtubule-associated protein 2 (MAP2), and neurofilament (NF) immunostaining. Results Fourteen weeks after injury (8 weeks after transplantation), BBB score of the 1.7 Wnt3a-MSC group (15.0±0.28) was significantly higher than that of the injury only (10.0±0.48), MSC (12.57±0.48), pLenti-MSC (12.42±0.48), and Wnt3a-MSC (13.71±0.61) groups (p<0.05). Immunostaining revealed increased expression of axonal regeneration markers GAP43, MAP2, and NF in the Wnt3a-MSC and 1.7 Wnt3a-MSC groups. Conclusion Our results showed that enhanced gene expression of Wnt3a in hMSC can potentiate axonal regeneration and improve functional recovery in a rat model of chronic SCI.
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Affiliation(s)
- Hyung Ho Yoon
- Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyang Ju Lee
- Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea
| | - Joongkee Min
- Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jeong Hoon Kim
- Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jin Hoon Park
- Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ji Hyun Kim
- Department of Microbiology, University of Ulsan College of Medicine, Seoul, Korea.,Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Korea
| | - Seong Who Kim
- Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea
| | - Heuiran Lee
- Department of Microbiology, University of Ulsan College of Medicine, Seoul, Korea.,Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Korea
| | - Sang Ryong Jeon
- Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Driscoll K, Cruz AD, Butcher JT. Inflammatory and Biomechanical Drivers of Endothelial-Interstitial Interactions in Calcific Aortic Valve Disease. Circ Res 2021; 128:1344-1370. [PMID: 33914601 DOI: 10.1161/circresaha.121.318011] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Calcific aortic valve disease is dramatically increasing in global burden, yet no therapy exists outside of prosthetic replacement. The increasing proportion of younger and more active patients mandates alternative therapies. Studies suggest a window of opportunity for biologically based diagnostics and therapeutics to alleviate or delay calcific aortic valve disease progression. Advancement, however, has been hampered by limited understanding of the complex mechanisms driving calcific aortic valve disease initiation and progression towards clinically relevant interventions.
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Affiliation(s)
| | - Alexander D Cruz
- Meinig School of Biomedical Engineering, Cornell University, Ithaca NY
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40
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Han D, Xu Y, Peng WP, Feng F, Wang Z, Gu C, Zhou X. Citrus Alkaline Extracts Inhibit Senescence of A549 Cells to Alleviate Pulmonary Fibrosis via the β-Catenin/P53 Pathway. Med Sci Monit 2021; 27:e928547. [PMID: 33707405 PMCID: PMC7962417 DOI: 10.12659/msm.928547] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a disease related to aging, which has become increasingly prevalent as the population has aged. However, there remains no effective treatment for the disease. Alveolar epithelial type II cell (AEC II) senescence plays an important role in the occurrence and development of IPF. Therefore, enhancing our understanding of aging AEC IIs might facilitate the development of a new therapeutic strategy for the prevention and treatment of IPF. The aim of this study was to investigate the effect of citrus alkaline extracts (CAE) on senescence in A549 cells and elucidate the mechanism by which CAE function. MATERIAL AND METHODS Adriamycin RD (ARD) induces the senescence of A549 cells. Relevant indicators were identified following administration of 3 concentrations of CAE (50 μg/mL, 100 μg/mL, and 200 μg/mL) to A549 cells. RESULTS CAE inhibited senescence in ARD-induced A549 cells. It inhibited p16, p21, p53, and a senescence-associated secretory phenotype, and reduced expression of the senescence-related positive cells of ß-galactosidase. Further study revealed that activation of the ß-catenin signaling pathway is closely associated with p53. CAE inhibited senescence in A549 cells via the ß-catenin/p53 pathway. Further, inhibition of b-catenin was associated with reduced expression levels of p53 and p21, and the anti-aging effects of CAE were enhanced. When expression of p53 was inhibited, expression levels of ß-catenin also tended to decrease. CONCLUSIONS In summary, our study showed that CAE can inhibit aging in A549 cells to alleviate pulmonary fibrosis, and thus limit the secretion of the extracellular matrix and collagen in lung fibroblasts.
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Affiliation(s)
- Di Han
- Department of Respiratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China (mainland)
| | - Yong Xu
- Department of Respiratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China (mainland)
| | - Wen-Pan Peng
- Department of Respiratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China (mainland)
| | - Fanchao Feng
- Department of Respiratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China (mainland).,Department of Respiratory Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, China (mainland)
| | - Zhichao Wang
- Department of Respiratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China (mainland)
| | - Cheng Gu
- Department of Respiratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China (mainland)
| | - Xianmei Zhou
- Department of Respiratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China (mainland).,Department of Respiratory Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, China (mainland)
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Dehghanbanadaki N, Taghdir M, Naderi-Manesh H. Investigation of Atrial Natriuretic Peptide as A Competitive Inhibitory Candidate Against Wnt/β-Catenin Signalling: A Molecular Dynamics Approach. Int J Pept Res Ther 2021. [DOI: 10.1007/s10989-020-10085-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Sarkar A, Saha S, Paul A, Maji A, Roy P, Maity TK. Understanding stem cells and its pivotal role in regenerative medicine. Life Sci 2021; 273:119270. [PMID: 33640402 DOI: 10.1016/j.lfs.2021.119270] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 02/06/2021] [Accepted: 02/14/2021] [Indexed: 02/07/2023]
Abstract
Stem cells (SCs) are clonogenic cells that develop into the specialized cells which later responsible for making up various types of tissue in the human body. SCs are not only the appropriate source of information for cell division, molecular and cellular processes, and tissue homeostasis but also one of the major putative biological aids to diagnose and cure various degenerative diseases. This study emphasises on various research outputs that occurred in the past two decades. This will give brief information on classification, differentiation, detection, and various isolation techniques of SCs. Here, the various signalling pathways which includes WNT, Sonic hedgehog, Notch, BMI1 and C-met pathways and how does it effect on the regeneration of various classes of SCs and factors that regulates the potency of the SCs are also been discussed. We also focused on the application of SCs in the area of regenerative medicine along with the cellular markers that are useful as salient diagnostic or curative tools or in both, by the process of reprogramming, which includes diabetes, cancer, cardiovascular disorders and neurological disorders. The biomarkers that are mentioned in various literatures and experiments include PDX1, FOXA2, HNF6, and NKX6-1 (for diabetes); CD33, CD24, CD133 (for cancer); c-Kit, SCA-1, Wilm's tumor 1 (for cardiovascular disorders); and OCT4, SOX2, c-MYC, EN1, DAT and VMAT2 (for neurological disorders). In this review, we come to know the advancements and scopes of potential SC-based therapies, its diverse applications in clinical fields that can be helpful in the near future.
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Affiliation(s)
- Arnab Sarkar
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700032, India
| | - Sanjukta Saha
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700032, India
| | - Abhik Paul
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700032, India
| | - Avik Maji
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700032, India
| | - Puspita Roy
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700032, India
| | - Tapan Kumar Maity
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700032, India.
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Dolmatov IY. Molecular Aspects of Regeneration Mechanisms in Holothurians. Genes (Basel) 2021; 12:250. [PMID: 33578707 PMCID: PMC7916379 DOI: 10.3390/genes12020250] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 02/05/2021] [Accepted: 02/08/2021] [Indexed: 02/07/2023] Open
Abstract
Holothurians, or sea cucumbers, belong to the phylum Echinodermata. They show good regenerative abilities. The present review provides an analysis of available data on the molecular aspects of regeneration mechanisms in holothurians. The genes and signaling pathways activated during the asexual reproduction and the formation of the anterior and posterior parts of the body, as well as the molecular mechanisms that provide regeneration of the nervous and digestive systems, are considered here. Damage causes a strong stress response, the signs of which are recorded even at late regeneration stages. In holothurian tissues, the concentrations of reactive oxygen species and antioxidant enzymes increase. Furthermore, the cellular and humoral components of the immune system are activated. Extracellular matrix remodeling and Wnt signaling play a major role in the regeneration in holothurians. All available morphological and molecular data show that the dedifferentiation of specialized cells in the remnant of the organ and the epithelial morphogenesis constitute the basis of regeneration in holothurians. However, depending on the type of damage, the mechanisms of regeneration may differ significantly in the spatial organization of regeneration process, the involvement of different cell types, and the depth of reprogramming of their genome (dedifferentiation or transdifferentiation).
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Affiliation(s)
- Igor Yu Dolmatov
- A.V. Zhirmunsky National Scientifc Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Palchevsky 17, 690041 Vladivostok, Russia
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Sun C, Li Y, Li X, Sun J. Agonism of Gpr40 Protects the Capacities of Epidermal Stem Cells (ESCs) Against Ultraviolet-B (UV-B). DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:5143-5153. [PMID: 33262575 PMCID: PMC7699447 DOI: 10.2147/dddt.s252060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Accepted: 07/01/2020] [Indexed: 01/09/2023]
Abstract
Introduction Skin damage due to overexposure to ultraviolet B (UV-B) radiation can lead to the development of cancers and reduce the skin's functionality as a vital protective barrier. Epidermal stem cells (ESCs) are pluripotent cells responsible for skin regeneration and healing. Upon exposure to UV-B radiation, ESCs produce excess amounts of reactive oxygen species (ROS) and inflammatory cytokines. However, the functional protection of ESCs is not fully explored. G-protein coupled G protein-coupled receptor 40 (Gpr40) is a free fatty acid receptor that is emerging as a potential treatment target for various diseases. Gpr40 has been found to be expressed in various cell types. Methods ESCs were exposed to UV-B at the intensities of 25, 50, and 100 mJ/cm2 for 24 h using TL 20 W/12 RS UV lamps. ESCs were treated with UV-B at 50 mJ/cm2 in the presence or absence of 25 or 50 µM of the Gpr40 agonist GW9508 for 24 h. The gene expression of the Wnt1 pathway and proinflammatory cytokines were evaluated. To antagonize Gpr40 expression, ESCs were treated with 10 µM GW1100. Results Our findings demonstrate that Gpr40 agonism can reduce the production of ROS as well as the expression of interleukins 1β and 8, two key proinflammatory cytokines. We demonstrate that agonism of Gpr40 can rescue the reduction in integrin β1 and Krt19 induced by UV-B exposure, thereby improving the capacities of ESCs to resist UV-B damage. Moreover, we show that the effects of Gpr40 agonism observed in our experiments are mediated through the Wnt/β-catenin canonical signaling pathway, as evidenced by the expression of Wnt1 and cyclin D1. Conclusion Our findings present evidence of the role of Gpr40 agonism in mediating the protective capacities of ESCs against insult from UV-B radiation.
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Affiliation(s)
- Chengkuan Sun
- Department of Hand Surgery, The Third Hospital of Jilin University, Changchun, Jilin 130033, People's Republic of China
| | - Yulin Li
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, Jilin 130033, People's Republic of China
| | - Xianglan Li
- Departmentof Dermatology, The Third Hospital of Jilin University, Changchun, Jilin 130033, People's Republic of China
| | - Jing Sun
- Departmentof Dermatology, The Third Hospital of Jilin University, Changchun, Jilin 130033, People's Republic of China
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Azim N, Ahmad J, Iqbal N, Siddiqa A, Majid A, Ashraf J, Jalil F. Petri Net modelling approach for analysing the behaviour of Wnt/[inline-formula removed] -catenin and Wnt/Ca2+ signalling pathways in arrhythmogenic right ventricular cardiomyopathy. IET Syst Biol 2020; 14:350-367. [PMID: 33399099 PMCID: PMC8687399 DOI: 10.1049/iet-syb.2020.0038] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 06/20/2020] [Accepted: 08/03/2020] [Indexed: 12/20/2022] Open
Abstract
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease that may result in arrhythmia, heart failure and sudden death. The hallmark pathological findings are progressive myocyte loss and fibro fatty replacement, with a predilection for the right ventricle. This study focuses on the adipose tissue formation in cardiomyocyte by considering the signal transduction pathways including Wnt/[inline-formula removed]-catenin and Wnt/Ca2+ regulation system. These pathways are modelled and analysed using stochastic petri nets (SPN) in order to increase our comprehension of ARVC and in turn its treatment regimen. The Wnt/[inline-formula removed]-catenin model predicts that the dysregulation or absence of Wnt signalling, inhibition of dishevelled and elevation of glycogen synthase kinase 3 along with casein kinase I are key cytotoxic events resulting in apoptosis. Moreover, the Wnt/Ca2+ SPN model demonstrates that the Bcl2 gene inhibited by c-Jun N-terminal kinase protein in the event of endoplasmic reticulum stress due to action potential and increased amount of intracellular Ca2+ which recovers the Ca2+ homeostasis by phospholipase C, this event positively regulates the Bcl2 to suppress the mitochondrial apoptosis which causes ARVC.
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Affiliation(s)
- Nazia Azim
- Department of Computer Science, Abdul Wali Khan University Mardan, Mardan, Pakistan
| | - Jamil Ahmad
- Department of Computer Science and Information Technology, University of Malakand, Chakdara, Pakistan.
| | - Nadeem Iqbal
- Department of Computer Science, Abdul Wali Khan University Mardan, Mardan, Pakistan
| | - Amnah Siddiqa
- Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA
| | - Abdul Majid
- Department of Computer Science, Abdul Wali Khan University Mardan, Mardan, Pakistan
| | - Javaria Ashraf
- Research Centre for modeling and Simulation, National University of Sciences and Technology, Islamabad Pakistan
| | - Fazal Jalil
- Department of Biotechnology, Abdul Wali Khan University Mardan, Mardan, Pakistan
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miR-124-3p promotes BMSC osteogenesis via suppressing the GSK-3β/β-catenin signaling pathway in diabetic osteoporosis rats. In Vitro Cell Dev Biol Anim 2020; 56:723-734. [PMID: 33085064 DOI: 10.1007/s11626-020-00502-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 08/31/2020] [Indexed: 10/23/2022]
Abstract
The purpose of this study is to investigate miRNAs' effects, targeting the Wnt signaling pathway, on osteogenic differentiation to provide new targets for diabetic osteoporosis treatments. Twelve male rats were divided into a normal rat group (NOR group) and a model rat group (MOD group). Cluster analysis of differentially expressed miRNAs and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed. Primary rat bone marrow mesenchymal stem cells (BMSCs) were divided into a high-glucose group and a low-glucose group, and osteogenic differentiation was induced. Alkaline phosphatase (ALP) staining and Alizarin Red staining were used for pathological analysis of the cells. Western blot analysis was used to measure GSK-3β, β-catenin, p-β-catenin, c-Myc, and CyclinD1 expression. Immunofluorescence (IF) was used to analyze the effect of GSK-3β inhibitor (CHIR99021) on β-catenin and CyclinD1 expressions levels in BMSCs. A total of 428 differentially expressed miRNAs were found between the NOR and MOD groups. KEGG analysis showed that the target genes were mostly enriched in signaling pathways, including PI3K-Akt, focal adhesion, AGE-RAGE, HIF-1, and Wnt. qPCR verification demonstrated that miR-124-3p exhibited the greatest difference in expression level. In BMSCs, miR-124-3p overexpression could reverse the inhibited expression of BMSC osteogenic markers, including Alpl, Bglap, and Runx2, induced by high glucose. Western blot analysis revealed that the transfection of miR-124-3p mimics could further reverse the upregulated p-β-catenin and GSK-3β levels and the downregulated c-Myc and CyclinD1 levels induced by high glucose. IF results revealed that BMSCs treated CHIR99021 under high glucose showed the reduced GSK-3β and increased β-catenin and CyclinD1 expression levels. Our research highlighted miRNAs' important roles in regulating the Wnt pathway and provided new information for the diagnosis and treatment of diabetic osteoporosis.
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Mancia A, Abelli L, Fossi MC, Panti C. Skin distress associated with xenobiotics exposure: An epigenetic study in the Mediterranean fin whale (Balaenoptera physalus). Mar Genomics 2020; 57:100822. [PMID: 33069632 DOI: 10.1016/j.margen.2020.100822] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 09/14/2020] [Accepted: 10/05/2020] [Indexed: 12/21/2022]
Abstract
The phenotypic plasticity of many organisms is mediated in part by epigenetics, the heritable changes in gene activity that occur without any alterations to DNA sequence. A major mechanism in epigenetics is the DNA methylation (DNAm). Hypo- and hyper-methylation are generalized responses to control gene expression however recent studies have demonstrated that classes of contaminants could mark specific DNAm signatures, that could usefully signal prior environmental exposure. We collected skin and blubber from 6 free-ranging fin whale (Balaenoptera physalus) individuals sampled as a part of a previous published study in the northern Mediterranean Sea. Genomic DNA extracted from the skin of the fin whales and levels of contaminants measured in the blubber of the same individuals were used for DNAm profiling through reduced representation bisulfite sequencing (RRBS). We tested the hypothesis that differences in the methylation patterns could be related to environmental exposure to contaminants and load in the whale tissues. The aims of this study were to determine the DNAm profiles of the methylation contexts (CpGs and non-CpGs) of differently contaminated groups using the RRBS, and to identify potential contaminant exposure related genes. Amount and proportion of methylcytosines in CpG and non-CpG regions (CHH and CHG) was very similar across the 6 samples. The proportion of methylcytosines sites in CpG was n = 32,682, the highest among all the sequence contexts (n = 3216 in CHH; n = 1743 in CHG). The majority of the methylcytosine occurred in the intron regions, followed by exon and promoter regions in CpG, CHH and CHG. Gene Ontology results indicated that DNAm affected genes that take place in cell differentiation and function in cutaneous, vascular and nervous systems. The identification of cellular response pathways allows a better understanding of the organism biological reaction to a specific environmental challenge and the development of sensitive tools based on the predictive responses. Eco-epigenetics analyses have an extraordinary potential to address growing issues on pollution biomonitoring, ecotoxicity assessment, conservation and management planning.
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Affiliation(s)
- Annalaura Mancia
- Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy.
| | - Luigi Abelli
- Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy
| | - Maria Cristina Fossi
- Department of Physical Sciences, Earth and Environment, University of Siena, 53100 Siena, Italy
| | - Cristina Panti
- Department of Physical Sciences, Earth and Environment, University of Siena, 53100 Siena, Italy
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Han S, Kim J, Lee G, Kim D. Mechanical Properties of Materials for Stem Cell Differentiation. ACTA ACUST UNITED AC 2020; 4:e2000247. [DOI: 10.1002/adbi.202000247] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 09/28/2020] [Indexed: 12/16/2022]
Affiliation(s)
- Seong‐Beom Han
- KU‐KIST Graduate School of Converging Science and Technology Korea University 145, Anam‐ro, Seongbuk‐gu Seoul 02841 Republic of Korea
| | - Jeong‐Ki Kim
- KU‐KIST Graduate School of Converging Science and Technology Korea University 145, Anam‐ro, Seongbuk‐gu Seoul 02841 Republic of Korea
| | - Geonhui Lee
- KU‐KIST Graduate School of Converging Science and Technology Korea University 145, Anam‐ro, Seongbuk‐gu Seoul 02841 Republic of Korea
| | - Dong‐Hwee Kim
- KU‐KIST Graduate School of Converging Science and Technology Korea University 145, Anam‐ro, Seongbuk‐gu Seoul 02841 Republic of Korea
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Dong J, Xu X, Zhang Q, Yuan Z, Tan B. Dkk1 acts as a negative regulator in the osteogenic differentiation of the posterior longitudinal ligament cells. Cell Biol Int 2020; 44:2450-2458. [PMID: 32827333 DOI: 10.1002/cbin.11452] [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: 05/08/2020] [Revised: 07/22/2020] [Accepted: 08/16/2020] [Indexed: 12/13/2022]
Abstract
Ossification of the posterior longitudinal ligament (OPLL) is a spinal disorder characterized by progressive ectopic bone formation in the PLL of the spine. Dickkopf-1 (Dkk1) is a secreted inhibitor of the Wnt pathway that negatively regulates bone formation during skeletal development. However, whether Dkk1 impacts the pathogenesis of OPLL has not been reported. This study is to investigate the role of Dkk1 in the development of OPLL. Our results show that the serum levels of Dkk1 are decreased in OPLL patients compared with non-OPLL controls. The expression of Dkk1 is also reduced in OPLL ligament cells. Downregulation of Dkk1 in ligament cells is associated with activation of the Wnt/β-catenin signaling, as indicated by stabilized β-catenin and increased T-cell factor-dependent transcriptional activity. Functionally, Dkk1 exerts a growth-inhibitory effect by repressing proliferation but promoting apoptosis of ligament cells. Dkk1 also suppresses bone morphogenetic protein 2-induced entire osteogenic differentiation of ligament cells, and this suppression is mediated via its inhibition of the Wnt pathway. Our results demonstrate for the first time that Dkk1 acts as an important negative regulator in the ossification of the PLL. Targeting the Wnt pathway using Dkk1 may represent a potential therapeutic strategy for the treatment of OPLL.
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Affiliation(s)
- Jun Dong
- Department of Orthopaedics, Shangdong Provincial Hospital, Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Xiqiang Xu
- Department of Orthopaedics, Shangdong Provincial Hospital, Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Qingyu Zhang
- Department of Orthopaedics, Shangdong Provincial Hospital, Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Zenong Yuan
- Department of Orthopaedics, Shangdong Provincial Hospital, Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Bingyi Tan
- Department of Orthopaedics, Shangdong Provincial Hospital, Affiliated to Shandong First Medical University, Jinan, Shandong, China
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Molecular Characterisation of Canine Osteosarcoma in High Risk Breeds. Cancers (Basel) 2020; 12:cancers12092405. [PMID: 32854182 PMCID: PMC7564920 DOI: 10.3390/cancers12092405] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 08/13/2020] [Accepted: 08/14/2020] [Indexed: 02/07/2023] Open
Abstract
Dogs develop osteosarcoma (OSA) and the disease process closely resembles that of human OSA. OSA has a poor prognosis in both species and disease-free intervals and cure rates have not improved in recent years. Gene expression in canine OSAs was compared with non-tumor tissue utilising RNA sequencing, validated by qRT-PCR and immunohistochemistry (n = 16). Polymorphic polyglutamine (polyQ) tracts in the androgen receptor (AR/NR3C4) and nuclear receptor coactivator 3 (NCOA3) genes were investigated in control and OSA patients using polymerase chain reaction (PCR), Sanger sequencing and fragment analysis (n = 1019 Rottweilers, 379 Irish Wolfhounds). Our analysis identified 1281 significantly differentially expressed genes (>2 fold change, p < 0.05), specifically 839 lower and 442 elevated gene expression in osteosarcoma (n = 3) samples relative to non-malignant (n = 4) bone. Enriched pathways and gene ontologies were identified, which provide insight into the molecular pathways implicated in canine OSA. Expression of a subset of these genes (SLC2A1, DKK3, MMP3, POSTN, RBP4, ASPN) was validated by qRTPCR and immunohistochemistry (MMP3, DKK3, SLC2A1) respectively. While little variation was found in the NCOA3 polyQ tract, greater variation was present in both polyQ tracts in the AR, but no significant associations in length were made with OSA. The data provides novel insights into the molecular mechanisms of OSA in high risk breeds. This knowledge may inform development of new prevention strategies and treatments for OSA in dogs and supports utilising spontaneous OSA in dogs to improve understanding of the disease in people.
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