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Chen J, Meng A. Maternal control of embryonic dorsal organizer in vertebrates. Cells Dev 2025:204020. [PMID: 40058595 DOI: 10.1016/j.cdev.2025.204020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Revised: 03/02/2025] [Accepted: 03/06/2025] [Indexed: 03/17/2025]
Abstract
The establishment of the body axis and developmental blueprint in embryos has remained to be a central question in developmental biology, captivating scientists for centuries. A milestone in this field was achieved in 1924 when Hans Spemann and Hilde Mangold discovered the dorsal organizer for embryonic body axis formation in amphibians. Since then, extensive studies have demonstrated that the dorsal organizer is evolutionarily conserved in vertebrates. This organizer functions as a signaling center, directing adjacent cells toward specific fates and orchestrating pattern formation to establish the embryonic axis. After 70 years since the discovery of the organizer, studies in different model animal species had revealed that locally activated β-catenin signaling during blastulation plays an indispensable role in organizer induction. Then, efforts have been made to identify initiators of β-catenin activation in blastulas. Now, it appears that maternal Huluwa, a transmembrane protein, is a bona fide organizer inducer at least in teleost fish and frog, which can activate downstream signaling pathways, including but probably not limited to β-catenin pathway. More studies are needed to decode the complete molecular network controlling organizer induction.
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Affiliation(s)
- Jing Chen
- Department of Pediatric Surgery and Laboratory of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Anming Meng
- Laboratory of Molecular Developmental Biology, State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
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Miao J, Zhang Y, Su C, Zheng Q, Guo J. Insulin-Like Growth Factor Signaling in Alzheimer's Disease: Pathophysiology and Therapeutic Strategies. Mol Neurobiol 2025; 62:3195-3225. [PMID: 39240280 PMCID: PMC11790777 DOI: 10.1007/s12035-024-04457-1] [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: 04/24/2024] [Accepted: 08/27/2024] [Indexed: 09/07/2024]
Abstract
Alzheimer's disease (AD) is the leading cause of dementia among the elderly population, posing a significant public health challenge due to limited therapeutic options that merely delay cognitive decline. AD is associated with impaired energy metabolism and reduced neurotrophic signaling. The insulin-like growth factor (IGF) signaling pathway, crucial for central nervous system (CNS) development, metabolism, repair, cognition, and emotion regulation, includes IGF-1, IGF-2, IGF-1R, IGF-2R, insulin receptor (IR), and six insulin-like growth factor binding proteins (IGFBPs). Research has identified abnormalities in IGF signaling in individuals with AD and AD models. Dysregulated expression of IGFs, receptors, IGFBPs, and disruptions in downstream phosphoinositide 3-kinase-protein kinase B (PI3K/AKT) and mitogen-activated protein kinase (MAPK) pathways collectively increase AD susceptibility. Studies suggest modulating the IGF pathway may ameliorate AD pathology and cognitive decline. This review explores the CNS pathophysiology of IGF signaling in AD progression and assesses the potential of targeting the IGF system as a novel therapeutic strategy. Further research is essential to elucidate how aberrant IGF signaling contributes to AD development, understand underlying molecular mechanisms, and evaluate the safety and efficacy of IGF-based treatments.
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Affiliation(s)
- Jie Miao
- Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Yanli Zhang
- Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China
- Department of Neurology, Sixth Hospital of Shanxi Medical University (General Hospital of Tisco), Taiyuan, 030001, Shanxi, China
| | - Chen Su
- Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Qiandan Zheng
- Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Junhong Guo
- Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China.
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Khan MZ, Zugaza JL, Torres Aleman I. The signaling landscape of insulin-like growth factor 1. J Biol Chem 2025; 301:108047. [PMID: 39638246 PMCID: PMC11748690 DOI: 10.1016/j.jbc.2024.108047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 11/22/2024] [Accepted: 11/26/2024] [Indexed: 12/07/2024] Open
Abstract
The sheer amplitude of biological actions of insulin-like growth factor I (IGF-1) affecting all types of cells in all tissues suggests a vast signaling landscape for this ubiquitous humoral signal. While the canonical signaling pathways primarily involve the Ras/MAPK and PI3K/AKT cascades, the evolutionary conservation of insulin-like peptides (ILPs) and their pathways hints at the potential for novel functions to emerge over time. Indeed, the evolutionary trajectory of ILPs opens the possibility of either novel functions for these two pathways, novel downstream routes, or both. Evidence supporting this notion includes observations of neofunctionalization in bony fishes or crustaceans, and the involvement of ILPs pathways in invertebrate eusociality or in vertebrate bone physiology, respectively. Such evolutionary processes likely contribute to the rich diversity of ILPs signaling observed today. Moreover, the interplay between conserved signaling pathways, such as those implicated in aging (predominantly involving the PI3K-AKT route), and lesser known pathways, such as those mediated by biased G-protein coupled receptors and others even less known, may underpin the context-dependent actions characteristic of ILPs signaling. While canonical IGF-1 signaling is often assumed to account for the intracellular pathways utilized by this growth factor, a comprehensive analysis of all the pathways mediated by the IGF-1 receptor (IGF-1R) remains lacking. This review aims to explore both canonical and non-canonical routes of IGF-1R action across various cell types, offering a detailed examination of the mechanisms underlying IGF-1 signaling and highlighting the significant gaps in our current understanding.
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Affiliation(s)
- Muhammad Zahid Khan
- Achucarro Basque Center for Neuroscience, Leioa, Spain; CIBERNED, Madrid, Spain
| | - Jose Luis Zugaza
- Achucarro Basque Center for Neuroscience, Leioa, Spain; Ikerbasque Science Foundation, Bilbao, Spain
| | - Ignacio Torres Aleman
- Achucarro Basque Center for Neuroscience, Leioa, Spain; CIBERNED, Madrid, Spain; Ikerbasque Science Foundation, Bilbao, Spain.
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Pascolini G, Scaglione GL, Chandramouli B, Castiglia D, Di Zenzo G, Didona B. Broadening the PHIP-Associated Neurodevelopmental Phenotype. CHILDREN (BASEL, SWITZERLAND) 2024; 11:1395. [PMID: 39594970 PMCID: PMC11593145 DOI: 10.3390/children11111395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 11/08/2024] [Accepted: 11/11/2024] [Indexed: 11/28/2024]
Abstract
BACKGROUND Monoallelic damaging variants in PHIP (MIM*612870), encoding the Pleckstrin Homology Domain Interacting Protein, have been associated with a novel neurodevelopmental disorder, also termed Chung-Jansen syndrome (CHUJANS, MIM#617991). Most of the described individuals show developmental delay (DD)/intellectual disability (ID), obesity/overweight, and variable congenital anomalies, so the condition can be considered as an ID-overweight syndrome. CASE DESCRIPTION We evaluated a child presenting with DD/ID and a craniofacial phenotype reminiscent of a Pitt-Hopkins syndrome (PTHS)-like condition. We performed a clinical exome analysis on his biological sample, as well as an in silico prediction of the obtained data. At the same time, we interrogated the DeepGestalt technology powered by Face2Gene (F2G), using a frontal image of the proband, and clinically reviewed the earlier CHUJANS patients. In this child, we found a novel PHIP pathogenetic variant, which we corroborated through a protein modeling approach. The F2G platform supported the initial clinical hypothesis of a PTHS-like condition, while the clinical review highlighted the lack of the main frequent CHUJANS clinical features in this child. CONCLUSIONS The unusual clinical presentation of this novel patient resembles a PTHS-like condition. However, a novel variant in PHIP has been unexpectedly detected, expanding the phenotypic spectrum of CHUJANS. Notably, PTHS (MIM#610954), which is a different ID syndrome caused by heterozygous variants in TCF4 (MIM*610954), is not classically considered in the differential diagnosis of CHUJANS nor has been cited in the previous studies. This could support other complex diagnoses and invite further patients' descriptions.
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Affiliation(s)
- Giulia Pascolini
- Genetic Counselling Unit, Istituto Dermopatico dell’Immacolata, IDI-IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy
| | | | - Balasubramanian Chandramouli
- Super Computing Applications and Innovation, Department High Performance Computing (HPC), CINECA, 40033 Bologna, Italy;
| | - Daniele Castiglia
- Molecular and Cell Biology Laboratory, Istituto Dermopatico dell’Immacolata, IDI-IRCCS, 00167 Rome, Italy; (D.C.); (G.D.Z.)
| | - Giovanni Di Zenzo
- Molecular and Cell Biology Laboratory, Istituto Dermopatico dell’Immacolata, IDI-IRCCS, 00167 Rome, Italy; (D.C.); (G.D.Z.)
| | - Biagio Didona
- Rare Diseases Center, Istituto Dermopatico dell’Immacolata, IDI-IRCCS, 00167 Rome, Italy;
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Liu J, Chen M, Xia X, Wang Z, Wang Y, Xi L. Causal associations between the insulin-like growth factor family and sarcopenia: a bidirectional Mendelian randomization study. Front Endocrinol (Lausanne) 2024; 15:1422472. [PMID: 39507055 PMCID: PMC11537870 DOI: 10.3389/fendo.2024.1422472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 10/08/2024] [Indexed: 11/08/2024] Open
Abstract
Objective Insulin-like growth factor (IGF) is closely associated with sarcopenia, yet the causal relationship of this association remains unclear. This study aims to explore the potential causal relationship between members of the IGF family and sarcopenia from a genetic perspective through bidirectional Mendelian randomization (MR) analysis using two-sample datasets. Methods Five genetically predicted factors of the IGF family (IGF-1, IGF-1R, IGF-2R, IGFBP-3, IGFBP-7) as one sample, while four relevant features of sarcopenia (low hand grip strength, appendicular lean mass, whole body fat-free mass, and walking pace) as another sample, in conducting a two-sample MR analysis. Results The forward MR results of the relationship between IGF and sarcopenia showed that elevated levels of IGF-1 reduced the risk of low hand grip strength (OR = 0.936, 95% CI=0.892-0.983, P = 0.008) and increased appendicular lean mass of the extremities and whole body fat-free mass (OR = 1.125, 95% CI=1.070-1.182,P = 0.000; OR =1.076, 95% CI=1.047-1.106, P=0.000), reduced the risk of sarcopenia. Elevated IGF-1R also favored an increase in whole body fat-free mass (OR=1.023, 95% CI=1.008-1.038, P =0.002), and the appendicular lean mass trait was more pronounced with elevated IGFBP-3 and IGFBP-7 (OR=1.034, 95% CI=1.024-1.044, P =0.000; OR=1.020, 95% CI=1.010-1.030, P=0.000). Inverse MR results of the effect of sarcopenia on IGF showed that decreased hand grip strength may elevate IGF-1 levels (OR=1.243, 95% CI=1.026-1.505,P =0.027), whereas improvements in appendicular lean mass, whole body fat-free mass traits, and increased walking pace decreased IGF-1 levels (OR=0.902, 95% CI: 0.877-0.927, P = 0.000; OR=0.903, 95% CI=0.859-0.949,P = 0.000; OR=0.209, 95% CI=0.051-0.862,P = 0.045). Also decreased hand grip strength may elevate IGF-1R levels (OR=1.454, 95% CI=1.108-1.909, P =0.007), and appendicular lean mass stimulated high expression of IGFBP-1 (OR=1.314, 95% CI=1.003-1.722, P =0.047). Heterogeneity and pleiotropy were not detected in all results, and the results were stable and reliable. Conclusion There is a bi-directional causal association between IGF family members and the risk of sarcopenia, which provides a more adequate basis for early biological monitoring of sarcopenia and may provide new targets for early intervention and treatment of sarcopenia.
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Affiliation(s)
- Jili Liu
- Department of Geriatrics, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Meng Chen
- Department of Geriatrics and Special Needs Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Xin Xia
- The Center of Gerontology and Geriatrics and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zhaolin Wang
- Department of Traditional Chinese Medicine, The Second Hospital, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yanqin Wang
- Department of Hematology, Shanxi Hospital of Traditional Chinese Medicine, Taiyuan, Shanxi, China
| | - Ling Xi
- Department of Geriatrics, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi, China
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Sakthivel D, Brown-Suedel AN, Lopez KE, Salgar S, Coutinho LE, Keane F, Huang S, Sherry KM, Charendoff CI, Dunne KP, Robichaux DJ, Vargas-Hernández A, Le B, Shin CS, Carisey AF, Poreba M, Flanagan JM, Bouchier-Hayes L. Caspase-2 is essential for proliferation and self-renewal of nucleophosmin-mutated acute myeloid leukemia. SCIENCE ADVANCES 2024; 10:eadj3145. [PMID: 39093977 PMCID: PMC11296348 DOI: 10.1126/sciadv.adj3145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 06/28/2024] [Indexed: 08/04/2024]
Abstract
Mutation in nucleophosmin (NPM1) causes relocalization of this normally nucleolar protein to the cytoplasm (NPM1c+). Despite NPM1 mutation being the most common driver mutation in cytogenetically normal adult acute myeloid leukemia (AML), the mechanisms of NPM1c+-induced leukemogenesis remain unclear. Caspase-2 is a proapoptotic protein activated by NPM1 in the nucleolus. Here, we show that caspase-2 is also activated by NPM1c+ in the cytoplasm and DNA damage-induced apoptosis is caspase-2 dependent in NPM1c+ but not in NPM1wt AML cells. Strikingly, in NPM1c+ cells, caspase-2 loss results in profound cell cycle arrest, differentiation, and down-regulation of stem cell pathways that regulate pluripotency including impairment of the AKT/mTORC1 pathways, and inhibition of Rictor cleavage. In contrast, there were minimal differences in proliferation, differentiation, or the transcriptional profile of NPM1wt cells lacking caspase-2. Our results show that caspase-2 is essential for proliferation and self-renewal of AML cells expressing mutated NPM1. This study demonstrates that caspase-2 is a major effector of NPM1c+ function.
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Affiliation(s)
- Dharaniya Sakthivel
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
- Texas Children’s Hospital William T. Shearer Center for Human Immunobiology, Houston, TX 77030, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Alexandra N. Brown-Suedel
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
- Texas Children’s Hospital William T. Shearer Center for Human Immunobiology, Houston, TX 77030, USA
| | - Karla E. Lopez
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
- Texas Children’s Hospital William T. Shearer Center for Human Immunobiology, Houston, TX 77030, USA
| | - Suruchi Salgar
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
- Texas Children’s Hospital William T. Shearer Center for Human Immunobiology, Houston, TX 77030, USA
| | - Luiza E. Coutinho
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
- Texas Children’s Hospital William T. Shearer Center for Human Immunobiology, Houston, TX 77030, USA
| | - Francesca Keane
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Shixia Huang
- Advanced Technology Cores, Department of Molecular and Cellular Biology, Huffington Department of Education, Innovation & Technology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Kenneth Mc Sherry
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Chloé I. Charendoff
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Kevin P. Dunne
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Dexter J. Robichaux
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Alexander Vargas-Hernández
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
- Texas Children’s Hospital William T. Shearer Center for Human Immunobiology, Houston, TX 77030, USA
| | - BaoChau Le
- Texas Children’s Hospital William T. Shearer Center for Human Immunobiology, Houston, TX 77030, USA
| | - Crystal S. Shin
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA
| | - Alexandre F. Carisey
- Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
| | - Marcin Poreba
- Department of Chemical Biology and Bioimaging, Faculty of Chemistry, Wroclaw University of Science and Technology, Wroclaw 50370, Poland
| | - Jonathan M. Flanagan
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
- Texas Children’s Hospital William T. Shearer Center for Human Immunobiology, Houston, TX 77030, USA
| | - Lisa Bouchier-Hayes
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
- Texas Children’s Hospital William T. Shearer Center for Human Immunobiology, Houston, TX 77030, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
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Xiong JL, Wang YX, Luo JY, Wang SM, Sun JJ, Xi QY, Chen T, Zhang YL. Pituitary-derived small extracellular vesicles promote liver repair by its cargo miR-143-3p. Sci Rep 2024; 14:16635. [PMID: 39025906 PMCID: PMC11258314 DOI: 10.1038/s41598-024-67434-7] [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: 03/04/2024] [Accepted: 07/11/2024] [Indexed: 07/20/2024] Open
Abstract
The small Extracellular vesicles (sEV) has been recognized to be significant for intercellular communication due to their ability to transfer important cellular cargoes like miRNAs through circulation. The pituitary gland has not been clearly known about the role of its secreted sEV under normal physiological conditions. And Liver disease is a global public health burden. The present study is the first to investigate the effect of pituitary sEV on the liver. Sequencing and qRT-PCR revealed miR-143-3p is one of the richest in the pituitary sEV. MiR-143 Knockout (KO) mice resulted in a remarkable decrease in insulin-like growth factor 1 (IGF-1) levels and a significant increase in insulin-like growth factor binding protein 5 (IGFBP5) levels along with a reduction in liver primary cell growth. More importantly, compared with miR-143-KO-sEV, WT-sEV possesses a more robust capacity to improve miR-143 KO mice liver repair through the Wnt/β-catenin pathway after an acute injury caused by carbon tetrachloride (CCl4). Our results indicate that pituitary-derived sEV promotes hepatocyte proliferation and liver repair by its cargo miR-143-3p and provides new insight into the regulation mechanism of the pituitary-liver axis, and open a new window for endocrine regulation by using sEV.
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Affiliation(s)
- Jia-Li Xiong
- College of Animal Science, Guangdong Province Key Laboratory of Animal Nutritional Regulation, National Engineering Research Center for Breeding Swine Industry, State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou, 510642, Guangdong, China
- College of Medicine, Jiaxing University, Jiaxing, 314000, Zhejiang, China
| | - Yu-Xuan Wang
- College of Animal Science, Guangdong Province Key Laboratory of Animal Nutritional Regulation, National Engineering Research Center for Breeding Swine Industry, State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou, 510642, Guangdong, China
| | - Jun-Yi Luo
- College of Animal Science, Guangdong Province Key Laboratory of Animal Nutritional Regulation, National Engineering Research Center for Breeding Swine Industry, State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou, 510642, Guangdong, China
| | - Shu-Meng Wang
- College of Animal Science, Guangdong Province Key Laboratory of Animal Nutritional Regulation, National Engineering Research Center for Breeding Swine Industry, State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou, 510642, Guangdong, China
| | - Jia-Jie Sun
- College of Animal Science, Guangdong Province Key Laboratory of Animal Nutritional Regulation, National Engineering Research Center for Breeding Swine Industry, State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou, 510642, Guangdong, China
| | - Qian-Yun Xi
- College of Animal Science, Guangdong Province Key Laboratory of Animal Nutritional Regulation, National Engineering Research Center for Breeding Swine Industry, State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou, 510642, Guangdong, China
| | - Ting Chen
- College of Animal Science, Guangdong Province Key Laboratory of Animal Nutritional Regulation, National Engineering Research Center for Breeding Swine Industry, State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou, 510642, Guangdong, China.
| | - Yong-Liang Zhang
- College of Animal Science, Guangdong Province Key Laboratory of Animal Nutritional Regulation, National Engineering Research Center for Breeding Swine Industry, State Key Laboratory of Livestock and Poultry Breeding, South China Agricultural University, Guangzhou, 510642, Guangdong, China.
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Pliszka M, Szablewski L. Associations between Diabetes Mellitus and Selected Cancers. Int J Mol Sci 2024; 25:7476. [PMID: 39000583 PMCID: PMC11242587 DOI: 10.3390/ijms25137476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 06/15/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
Cancer is one of the major causes of mortality and is the second leading cause of death. Diabetes mellitus is a serious and growing problem worldwide, and its prevalence continues to grow; it is the 12th leading cause of death. An association between diabetes mellitus and cancer has been suggested for more than 100 years. Diabetes is a common disease diagnosed among patients with cancer, and evidence indicates that approximately 8-18% of patients with cancer have diabetes, with investigations suggesting an association between diabetes and some particular cancers, increasing the risk for developing cancers such as pancreatic, liver, colon, breast, stomach, and a few others. Breast and colorectal cancers have increased from 20% to 30% and there is a 97% increased risk of intrahepatic cholangiocarcinoma or endometrial cancer. On the other hand, a number of cancers and cancer therapies increase the risk of diabetes mellitus. Complications due to diabetes in patients with cancer may influence the choice of cancer therapy. Unfortunately, the mechanisms of the associations between diabetes mellitus and cancer are still unknown. The aim of this review is to summarize the association of diabetes mellitus with selected cancers and update the evidence on the underlying mechanisms of this association.
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Affiliation(s)
- Monika Pliszka
- Chair and Department of General Biology and Parasitology, Medical University of Warsaw, Chałubińskiego Str. 5, 02-004 Warsaw, Poland
| | - Leszek Szablewski
- Chair and Department of General Biology and Parasitology, Medical University of Warsaw, Chałubińskiego Str. 5, 02-004 Warsaw, Poland
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9
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Bimonte VM, Catanzaro G, Spinello Z, Massari MC, Curreli M, Terrana G, Defeudis G, Halupczok-Żyła J, Mantovani G, Ferretti E, Migliaccio S. Hypocalcemia in combination with hyperphosphatemia impairs muscle cell differentiation in vitro. J Endocrinol Invest 2024; 47:947-957. [PMID: 37819413 DOI: 10.1007/s40618-023-02212-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 09/25/2023] [Indexed: 10/13/2023]
Abstract
PURPOSE Hypoparathyroidism is a rare endocrine disorder characterized by low or absent secretion of parathyroid hormone (PTH), which leads to decreased calcium and increased phosphorus levels in the serum. The diagnosis of hypoparathyroidism is based on the identification of the aforementioned biochemical abnormalities, which may be accompanied by clinical manifestations. Symptoms of hypoparathyroidism, primarily attributed to hypocalcemia, include muscle cramps or spasms, facial, leg, and foot pain, seizures, and tingling in the lips or fingers. The treatment of hypoparathyroidism depends on the severity of symptoms and the underlying pathology. Over the long term, calcium supplements, active vitamin D analogs, and thiazide diuretics may be needed. In fact, in patient cohorts in which optimal disease control still remains elusive, replacement therapy with recombinant parathyroid hormone analogs may be contemplated. Despite the predominantly neuromuscular symptoms of hypoparathyroidism, further effects of parathyroid hormone deficiency at the muscle cell level remain poorly understood. Thus, the aim of our study was to evaluate the effects of hypocalcemia in combination with hyperphosphatemia on muscle cells differentiation in vitro. METHODS C2C12 cells, an in vitro model of muscle cells, were differentiated for 2 or 6 days in the presence of hypocalcemia (CaCl2 0.9 mmol/l) and moderate (PO4 1.4 mmol/l) or severe (PO4 2.9 mmol/l) hyperphosphatemia, or combinations of both conditions. Cell differentiation and expression of genes linked to muscle differentiation were evaluated. RESULTS The combination of hypocalcemia with hyperphosphatemia induced a significant reduction (50%) in differentiation marker levels, such as MyoD (protein 1 for myoblast determination) and myogenin on the 1st day of differentiation, and MHC (myosin heavy chains) after 6 days of differentiation compared to control. Furthermore, this condition induced a statistically significant reduction of insulin-like growth factor-1 (IGF-1) mRNA expression and inhibition of IGF signaling and decrease in ERK phosphorylation compared to control cells. CONCLUSIONS Our results showed that a condition of hypocalcemia with hyperphosphatemia induced an alteration of muscle cell differentiation in vitro. In particular, we observed the reduction of myogenic differentiation markers, IGF-1 signaling pathway, and ERK phosphorylation in differentiated skeletal myoblasts. These data suggest that this altered extracellular condition might contribute to the mechanisms causing persistence of symptoms in patients affected by hypoparathyroidism.
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Affiliation(s)
- V M Bimonte
- Department of Movement, Human and Health Sciences, University of Foro Italico, Largo Lauro De Bosis 6, 00195, Rome, Italy
| | - G Catanzaro
- Department of Experimental Medicine, University "Sapienza" of Rome, 00161, Rome, Italy
| | - Z Spinello
- Department of Experimental Medicine, University "Sapienza" of Rome, 00161, Rome, Italy
| | - M C Massari
- Department of Experimental Medicine, University "Sapienza" of Rome, 00161, Rome, Italy
| | - M Curreli
- Department of Movement, Human and Health Sciences, University of Foro Italico, Largo Lauro De Bosis 6, 00195, Rome, Italy
| | - G Terrana
- Department of Experimental Medicine, University "Sapienza" of Rome, 00161, Rome, Italy
| | - G Defeudis
- Department of Movement, Human and Health Sciences, University of Foro Italico, Largo Lauro De Bosis 6, 00195, Rome, Italy
| | - J Halupczok-Żyła
- Department of Endocrinology, Diabetes and Isotope Therapy, Wroclaw Medical University, 50004, Wrocław, Poland
| | - G Mantovani
- Department of Clinical Sciences and Community Health, University of Milan, 20122, Milan, Italy
- Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122, Milan, Italy
| | - E Ferretti
- Department of Experimental Medicine, University "Sapienza" of Rome, 00161, Rome, Italy
| | - S Migliaccio
- Department of Movement, Human and Health Sciences, University of Foro Italico, Largo Lauro De Bosis 6, 00195, Rome, Italy.
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10
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Went M, Sud A, Mills C, Hyde A, Culliford R, Law P, Vijayakrishnan J, Gockel I, Maj C, Schumacher J, Palles C, Kaiser M, Houlston R. Phenome-wide Mendelian randomisation analysis of 378,142 cases reveals risk factors for eight common cancers. Nat Commun 2024; 15:2637. [PMID: 38527997 PMCID: PMC10963765 DOI: 10.1038/s41467-024-46927-z] [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: 03/07/2023] [Accepted: 03/08/2024] [Indexed: 03/27/2024] Open
Abstract
For many cancers there are only a few well-established risk factors. Here, we use summary data from genome-wide association studies (GWAS) in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to identify potentially causal relationships for over 3,000 traits. Our outcome datasets comprise 378,142 cases across breast, prostate, colorectal, lung, endometrial, oesophageal, renal, and ovarian cancers, as well as 485,715 controls. We complement this analysis by systematically mining the literature space for supporting evidence. In addition to providing supporting evidence for well-established risk factors (smoking, alcohol, obesity, lack of physical activity), we also find sex steroid hormones, plasma lipids, and telomere length as determinants of cancer risk. A number of the molecular factors we identify may prove to be potential biomarkers. Our analysis, which highlights aetiological similarities and differences in common cancers, should aid public health prevention strategies to reduce cancer burden. We provide a R/Shiny app to visualise findings.
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Affiliation(s)
- Molly Went
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
| | - Amit Sud
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
- Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Charlie Mills
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Abi Hyde
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
- Department of Engineering, University of Cambridge, Cambridge, UK
| | - Richard Culliford
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Philip Law
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | | | - Ines Gockel
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Carlo Maj
- Center for Human Genetics, University Hospital of Marburg, Marburg, Germany
| | | | - Claire Palles
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Martin Kaiser
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
- The Royal Marsden Hospital NHS Foundation Trust, London, UK
| | - Richard Houlston
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
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11
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Song M, Shim J, Song K. Oral Administration of Lactilactobacillus curvatus LB-P9 Promotes Hair Regeneration in Mice. Food Sci Anim Resour 2024; 44:204-215. [PMID: 38229856 PMCID: PMC10789551 DOI: 10.5851/kosfa.2023.e74] [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: 10/25/2023] [Revised: 11/03/2023] [Accepted: 11/13/2023] [Indexed: 01/18/2024] Open
Abstract
This study was designed to examine the effect of Lactilactobacillus curvatus LB-P9 on hair regeneration. The treatment of LB-P9 conditioned medium increased the proliferation of both hair follicle dermal papilla cells and hair germinal matrix cells (hGMCs). Moreover, the expression levels of hair growth factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor 7 were significantly elevated in hGMCs co-cultured with LB-P9. After time-synchronized depilation, mice were orally administered with either 4×107 colony forming unit (CFU) of LB-P9 (low dose) or 4×108 CFU of LB-P9 (high dose), once daily for 4 weeks. Compared with the vehicle (phosphate-buffered saline)-administrated group, the LB-P9-treated groups exhibited accelerated hair regrowth rate and enhanced hair thickness in a dose-dependent manner. Supporting this observation, both hair follicle numbers and the dermal thickness in skin tissues of the LB-P9-treated groups were increased, compared to those of the vehicle-treated group. These results might be explained by the increased level of β-catenin and number of hair follicle stem cells (CD34+CD49f+ cells) in the skin tissues of mice administered with LB-P9, compared to the vehicle-treated mice. Also, increased serum levels of hair growth factors such as VEGF and insulin-like growth factor-1, and superoxide dismutase were found in the LB-P9-treated groups, compared to those of the vehicle-treated group. Taken together, these results might demonstrate that the oral administration of LB-P9 promotes hair regeneration by the enhancement of dermal papilla proliferation through the stimulation of hair growth factor production.
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Affiliation(s)
- Mikyung Song
- R&D Center, LISCure Biosciences
Inc., Seongnam 13486, Korea
| | - Jaeseok Shim
- R&D Center, LISCure Biosciences
Inc., Seongnam 13486, Korea
| | - Kyoungsub Song
- R&D Center, LISCure Biosciences
Inc., Seongnam 13486, Korea
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12
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Zegarra-Valdivia JA, Pignatelli J, Nuñez A, Torres Aleman I. The Role of Insulin-like Growth Factor I in Mechanisms of Resilience and Vulnerability to Sporadic Alzheimer's Disease. Int J Mol Sci 2023; 24:16440. [PMID: 38003628 PMCID: PMC10671249 DOI: 10.3390/ijms242216440] [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: 10/11/2023] [Revised: 11/06/2023] [Accepted: 11/14/2023] [Indexed: 11/26/2023] Open
Abstract
Despite decades of intense research, disease-modifying therapeutic approaches for Alzheimer's disease (AD) are still very much needed. Apart from the extensively analyzed tau and amyloid pathological cascades, two promising avenues of research that may eventually identify new druggable targets for AD are based on a better understanding of the mechanisms of resilience and vulnerability to this condition. We argue that insulin-like growth factor I (IGF-I) activity in the brain provides a common substrate for the mechanisms of resilience and vulnerability to AD. We postulate that preserved brain IGF-I activity contributes to resilience to AD pathology as this growth factor intervenes in all the major pathological cascades considered to be involved in AD, including metabolic impairment, altered proteostasis, and inflammation, to name the three that are considered to be the most important ones. Conversely, disturbed IGF-I activity is found in many AD risk factors, such as old age, type 2 diabetes, imbalanced diet, sedentary life, sociality, stroke, stress, and low education, whereas the Apolipoprotein (Apo) E4 genotype and traumatic brain injury may also be influenced by brain IGF-I activity. Accordingly, IGF-I activity should be taken into consideration when analyzing these processes, while its preservation will predictably help prevent the progress of AD pathology. Thus, we need to define IGF-I activity in all these conditions and develop a means to preserve it. However, defining brain IGF-I activity cannot be solely based on humoral or tissue levels of this neurotrophic factor, and new functionally based assessments need to be developed.
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Affiliation(s)
- Jonathan A. Zegarra-Valdivia
- Achucarro Basque Center for Neuroscience, 48940 Leioa, Spain;
- Biomedical Research Networking Center on Neurodegenerative Diseases (CIBERNED), 28029 Madrid, Spain;
- School of Medicine, Universidad Señor de Sipán, Chiclayo 14000, Peru
| | - Jaime Pignatelli
- Biomedical Research Networking Center on Neurodegenerative Diseases (CIBERNED), 28029 Madrid, Spain;
- Cajal Institute (CSIC), 28002 Madrid, Spain
| | - Angel Nuñez
- Department of Anatomy, Histology and Neuroscience, Universidad Autónoma de Madrid, 28049 Madrid, Spain;
| | - Ignacio Torres Aleman
- Achucarro Basque Center for Neuroscience, 48940 Leioa, Spain;
- Biomedical Research Networking Center on Neurodegenerative Diseases (CIBERNED), 28029 Madrid, Spain;
- Ikerbasque, Basque Foundation for Science, 48009 Bilbao, Spain
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13
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Li Q, Li J, Li C, Wu X, Si S, Yang P, Li W, Han R, Li G, Liu X, Kang X, Tian Y. Transcriptome identification and characterization of long non-coding RNAs in the ovary of hens at four stages. Anim Biotechnol 2023; 34:1342-1353. [PMID: 35209802 DOI: 10.1080/10495398.2021.2024217] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
Long non-coding RNAs (lncRNAs) play important roles in transcriptional and post-transcriptional regulation. LncRNAs, which are defined as non-coding RNAs more than 200 bp in length, are involved in key biological processes, such as cell proliferation and differentiation, epigenetic regulation, and gene transcriptional translation. Recent studies have shown that lncRNAs also play major regulatory roles in the reproduction of mammals. However, knowledge of the roles of lncRNAs in the chicken ovary lacking. In this study, we performed RNA-seq analyses of ovarian tissue from Hy-Line brown laying hens at four physiological stages [15, 20, 30, and 68 weeks of age (W)]. We identified 657 lncRNA transcripts that were differentially expressed during ovarian development, the number of down-regulated lncRNAs was higher than the number of up-regulated lncRNAs during development. We predicted the cis and trans target genes of the DE lncRNAs and constructed a lncRNA-mRNA interaction network, which indicated that the DE genes (DEGs) and the target genes of the DE lncRNAs are mainly involved in signaling pathways associated with ovarian development, including oocyte meiosis, calcium signaling pathways, ECM-receptor interactions, and ribosome and focal adhesion. Overall, we found that twelve lncRNAs were strongly involved in ovarian development: LNC_013443, LNC_001029, LNC_005713, LNC_016762, ENSGALT00000101857, LNC_003913, LNC_013692, LNC_012219, LNC_004140, ENSGALT00000096941, LNC_009356, and ENSGALT00000098716. In summary, our study utilized RNA-seq analysis of hen ovaries to explore key lncRNAs involved in ovarian development and function. Furthermore, the comprehensive analysis identified the target genes of these lncRNAs providing a better understanding of the mechanisms underlying ovarian development in hens and a theoretical basis for further research.
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Affiliation(s)
- Qi Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, China
| | - Jing Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, China
| | - Chong Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, China
| | - Xing Wu
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, China
| | - Sujin Si
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, China
| | - Pengkun Yang
- College of Animal Science and Technology, Henan University of Animal Husbandry and Economy, Zhengzhou, China
| | - Wenting Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, China
- Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou, China
| | - Ruili Han
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, China
- Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou, China
| | - Guoxi Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, China
- Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou, China
| | - Xiaojun Liu
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, China
- Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou, China
| | - Xiangtao Kang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, China
- Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou, China
| | - Yadong Tian
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, China
- Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou, China
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14
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Taghavi SF, Ghorbani M, Panahi M, Nazem S, Karimi M, Salimi V, Tavakoli-Yaraki M. Differential expression levels of β-catenin are associated with invasive behavior of both functional and non-functional pituitary neuroendocrine tumor (PitNET). Mol Biol Rep 2023; 50:6425-6434. [PMID: 37326745 DOI: 10.1007/s11033-023-08523-0] [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: 01/10/2023] [Accepted: 05/12/2023] [Indexed: 06/17/2023]
Abstract
BACKGROUND Although research continues to elucidate the molecular mechanism underlying pituitary tumor pathogenesis, limited information is available on the potential role and expression profile of β-catenin in functional and non-functional pituitary neuroendocrine tumors (PitNETs). METHODS AND RESULTS In the current study, 104 pituitary samples (tumors and cadaveric healthy pituitary tissues) were included and the gene and protein expression levels of β-catenin were assessed by Real-Time PCR and immunohistochemistry, respectively. The correlation between expression level of β-catenin and tumor invasive feature and size as well as patient age, gender, and hormonal level was measured. The data showed that PitNET samples expressed higher levels of the β-catenin gene and protein compared to healthy pituitary tissues. Although there was no difference in β-catenin expression level between non-functioning (NF-PitNETs) and growth hormone-producing tumors (GH-PitNETs), both tumor types showed significantly elevated β-catenin levels compared to healthy pituitary tissues. The high level of β-catenin in the invasive functional and non-functional tumors is indicative of the association of β-catenin with PitNETs invasion. The expression pattern of the β-catenin gene and protein was consistently and significantly associated with these tumor types. The correlation between β-catenin and insulin-like growth factor 1 (IGF-1) in GH-PitNETs indicates the potential relevance of β-catenin and IGF-1 for GH-PitNETs. CONCLUSIONS The simultaneous increase in the expression of β-catenin gene and protein level in PitNET tissues and their relationship to the tumor severity indicates the possible contributing role of β-catenin and its underlying signaling mediators in PitNET pathogenesis.
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Affiliation(s)
- S Fahimeh Taghavi
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, P.O. Box: 1449614535, Tehran, Iran
| | - Mohammad Ghorbani
- Division of Vascular and Endovascular Neurosurgery, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Mahshid Panahi
- Pathology Department, Firozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Shima Nazem
- Department of Laboratory Medicine, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Milad Karimi
- Department of Immunology, School of medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Vahid Salimi
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoumeh Tavakoli-Yaraki
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, P.O. Box: 1449614535, Tehran, Iran.
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15
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Maurya NS, Kushwah S, Kushwaha S, Chawade A, Mani A. Prognostic model development for classification of colorectal adenocarcinoma by using machine learning model based on feature selection technique boruta. Sci Rep 2023; 13:6413. [PMID: 37076536 PMCID: PMC10115869 DOI: 10.1038/s41598-023-33327-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 04/11/2023] [Indexed: 04/21/2023] Open
Abstract
Colorectal cancer (CRC) is the third most prevalent cancer type and accounts for nearly one million deaths worldwide. The CRC mRNA gene expression datasets from TCGA and GEO (GSE144259, GSE50760, and GSE87096) were analyzed to find the significant differentially expressed genes (DEGs). These significant genes were further processed for feature selection through boruta and the confirmed features of importance (genes) were subsequently used for ML-based prognostic classification model development. These genes were analyzed for survival and correlation analysis between final genes and infiltrated immunocytes. A total of 770 CRC samples were included having 78 normal and 692 tumor tissue samples. 170 significant DEGs were identified after DESeq2 analysis along with the topconfects R package. The 33 confirmed features of importance-based RF prognostic classification model have given accuracy, precision, recall, and f1-score of 100% with 0% standard deviation. The overall survival analysis had finalized GLP2R and VSTM2A genes that were significantly downregulated in tumor samples and had a strong correlation with immunocyte infiltration. The involvement of these genes in CRC prognosis was further confirmed on the basis of their biological function and literature analysis. The current findings indicate that GLP2R and VSTM2A may play a significant role in CRC progression and immune response suppression.
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Affiliation(s)
- Neha Shree Maurya
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj, 211004, India
| | - Shikha Kushwah
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj, 211004, India
| | - Sandeep Kushwaha
- National Institute of Animal Biotechnology, Hyderabad, 500032, India
| | - Aakash Chawade
- Department of Plant Breeding, Swedish University of Agricultural Sciences, 230 53, Alnarp, Sweden.
| | - Ashutosh Mani
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj, 211004, India.
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16
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Went M, Sud A, Mills C, Hyde A, Culliford R, Law P, Vijayakrishnan J, Gockel I, Maj C, Schumacher J, Palles C, Kaiser M, Houlston R. Risk factors for eight common cancers revealed from a phenome-wide Mendelian randomisation analysis of 378,142 cases and 485,715 controls. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.02.15.23285952. [PMID: 37066289 PMCID: PMC10104236 DOI: 10.1101/2023.02.15.23285952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/28/2023]
Abstract
For many cancers there are few well-established risk factors. Summary data from genome-wide association studies (GWAS) can be used in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to identify causal relationships. We performed a MR-PheWAS of breast, prostate, colorectal, lung, endometrial, oesophageal, renal, and ovarian cancers, comprising 378,142 cases and 485,715 controls. To derive a more comprehensive insight into disease aetiology we systematically mined the literature space for supporting evidence. We evaluated causal relationships for over 3,000 potential risk factors. In addition to identifying well-established risk factors (smoking, alcohol, obesity, lack of physical activity), we provide evidence for specific factors, including dietary intake, sex steroid hormones, plasma lipids and telomere length as determinants of cancer risk. We also implicate molecular factors including plasma levels of IL-18, LAG-3, IGF-1, CT-1, and PRDX1 as risk factors. Our analyses highlight the importance of risk factors that are common to many cancer types but also reveal aetiological differences. A number of the molecular factors we identify have the potential to be biomarkers. Our findings should aid public health prevention strategies to reduce cancer burden. We provide a R/Shiny app (https://mrcancer.shinyapps.io/mrcan/) to visualise findings.
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Affiliation(s)
- Molly Went
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Amit Sud
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
- Haemato-oncology Unit, The Royal Marsden Hospital NHS Foundation Trust, Sutton, UK
| | - Charlie Mills
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Abi Hyde
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Richard Culliford
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Philip Law
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | | | - Ines Gockel
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Carlo Maj
- Center for Human Genetics, University Hospital of Marburg, Marburg, Germany
| | | | - Claire Palles
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Martin Kaiser
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
- Haemato-oncology Unit, The Royal Marsden Hospital NHS Foundation Trust, Sutton, UK
| | - Richard Houlston
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
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17
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Davies EM, Gurung R, Le KQ, Roan KT, Harvey RP, Mitchell GM, Schwarz Q, Mitchell CA. PI(4,5)P 2-dependent regulation of endothelial tip cell specification contributes to angiogenesis. SCIENCE ADVANCES 2023; 9:eadd6911. [PMID: 37000875 PMCID: PMC10065449 DOI: 10.1126/sciadv.add6911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 02/24/2023] [Indexed: 06/19/2023]
Abstract
Dynamic positioning of endothelial tip and stalk cells, via the interplay between VEGFR2 and NOTCH signaling, is essential for angiogenesis. VEGFR2 activates PI3K, which phosphorylates PI(4,5)P2 to PI(3,4,5)P3, activating AKT; however, PI3K/AKT does not direct tip cell specification. We report that PI(4,5)P2 hydrolysis by the phosphoinositide-5-phosphatase, INPP5K, contributes to angiogenesis. INPP5K ablation disrupted tip cell specification and impaired embryonic angiogenesis associated with enhanced DLL4/NOTCH signaling. INPP5K degraded a pool of PI(4,5)P2 generated by PIP5K1C phosphorylation of PI(4)P in endothelial cells. INPP5K ablation increased PI(4,5)P2, thereby releasing β-catenin from the plasma membrane, and concurrently increased PI(3,4,5)P3-dependent AKT activation, conditions that licensed DLL4/NOTCH transcription. Suppression of PI(4,5)P2 in INPP5K-siRNA cells by PIP5K1C-siRNA, restored β-catenin membrane localization and normalized AKT signaling. Pharmacological NOTCH or AKT inhibition in vivo or genetic β-catenin attenuation rescued angiogenesis defects in INPP5K-null mice. Therefore, PI(4,5)P2 is critical for β-catenin/DLL4/NOTCH signaling, which governs tip cell specification during angiogenesis.
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Affiliation(s)
- Elizabeth M. Davies
- Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia
| | - Rajendra Gurung
- Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia
| | - Kai Qin Le
- Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia
| | - Katherine T. T. Roan
- Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia
| | - Richard P. Harvey
- Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia
- School of Clinical Medicine and School of Biotechnology and Biomolecular Science, University of New South Wales, Kensington, New South Wales 2052, Australia
| | - Geraldine M. Mitchell
- O’Brien Institute Department of St Vincent’s Institute and University of Melbourne, Department of Surgery, St. Vincent’s Hospital, Fitzroy, Victoria 3065, Australia
- Health Sciences Faculty, Australian Catholic University, Fitzroy, Victoria 3065, Australia
| | - Quenten Schwarz
- Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia 5001, Australia
| | - Christina A. Mitchell
- Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia
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18
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Sharma S, Behl T, Sehgal A, Singh S, Sharma N, Bhatia S, Al-Harassi A, Bungau S, Mostafavi E. Possible Role of Wnt Signaling Pathway in Diabetic Retinopathy. Curr Drug Targets 2022; 23:1372-1380. [PMID: 35232336 DOI: 10.2174/1389450123666220301110140] [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: 08/10/2021] [Revised: 12/08/2021] [Accepted: 12/30/2021] [Indexed: 01/25/2023]
Abstract
The core of impaired vision in working people suffering from insulin-dependent and noninsulin- dependent diabetes mellitus is diabetic retinopathy (DR). The Wnt Protein Ligands family influences various processes; this ensures the cells are able to interact and co-ordinate various mobile functions, including cell growth, division, survival, apoptosis, migration, and cell destiny. The extracellular Wnt signal activates other signals. It is seen that Wnt pathways play an important role in inflammation, oxidative stress, and angiogenesis. It has been illustrated that the canonically preserved Wnt signaling system has a vital role in the homeostasis of adulthood. Developmental disorders in each of these stages will lead to serious eye problems and eventually blindness. There is, therefore, a need to specifically organize and regulate the growth of ocular tissues. In tissue specification and polarities, axonal exhaust, and maintenance of cells, especially in the central nervous system, Wnt/frizzled pathways play an important role. Thus, Wnt route antagonists may act as have been possible therapeutic options in DR by inhibiting aberrant Wnt signals. Elaborative and continued research in this area will help in the advancement of current knowledge in the field of DR, and eventually, this can lead to the development of new therapeutic approaches.
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Affiliation(s)
- Sheetu Sharma
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Tapan Behl
- School of Health Sciences and Technology, University of Petroleum and Energy Studies, Bidholi, Dehradun, India
| | - Aayush Sehgal
- GHG Khalsa College of Pharmacy, Gurusar Sadhar, Ludhiana, Punjab, India
| | - Sukhbir Singh
- Department of Pharmaceutics, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana, India
| | - Neelam Sharma
- Department of Pharmaceutics, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana, India
| | - Saurabh Bhatia
- Natural & Medical Sciences Research Centre, University of Nizwa, Nizwa, Oman
| | - Ahmed Al-Harassi
- Natural & Medical Sciences Research Centre, University of Nizwa, Nizwa, Oman
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
| | - Ebrahim Mostafavi
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States.,Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
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19
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Liu M, Xu Q, Zhao J, Guo Y, Zhang C, Chao X, Cheng M, Schinckel AP, Zhou B. Comprehensive Transcriptome Analysis of Follicles from Two Stages of the Estrus Cycle of Two Breeds Reveals the Roles of Long Intergenic Non-Coding RNAs in Gilts. BIOLOGY 2022; 11:biology11050716. [PMID: 35625443 PMCID: PMC9138455 DOI: 10.3390/biology11050716] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 04/28/2022] [Accepted: 05/05/2022] [Indexed: 11/21/2022]
Abstract
Simple Summary This study provides new perspectives about the roles of lincRNAs in the estrus expression of gilts, which is correlated with ovarian steroid hormone and follicular development. Follicular tissues from two stages of the estrus cycle of Large White and Mi gilts were used for RNA-seq. Some genes and lincRNAs related to estrus expression in pigs were discovered. PPI and ceRNA networks related to the estrus expression were constructed. These results suggest that the estrus expression may be affected by lincRNAs and their target genes. Abstract Visible and long-lasting estrus expression of gilts and sows effectively sends a mating signal. To reveal the roles of Long Intergenic Non-coding RNAs (lincRNAs) in estrus expression, RNA-seq was used to investigate the lincRNAs expression of follicular tissues from Large White gilts at diestrus (LD) and estrus (LE), and Chinese Mi gilts at diestrus (MD) and estrus (ME). Seventy-three differentially expressed lincRNAs (DELs) were found in all comparisons (LE vs. ME, LD vs. LE, and MD vs. ME comparisons). Eleven lincRNAs were differentially expressed in both LD vs. LE and MD vs. ME comparisons. Fifteen DELs were mapped onto the pig corpus luteum number Quantitative Trait Loci (QTL) fragments. A protein–protein interaction (PPI) network that involved estrus expression using 20 DEGs was then constructed. Interestingly, three predicted target DEGs (PTGs) (CYP19A1 of MSTRG.10910, CDK1 of MSTRG.10910 and MSTRG.23984, SCARB1 of MSTRG.1559) were observed in the PPI network. A competitive endogenous RNA (ceRNA) network including three lincRNAs, five miRNAs, and five genes was constructed. Our study provides new insight into the lincRNAs associated with estrus expression and follicular development in gilts.
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Affiliation(s)
- Mingzheng Liu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (M.L.); (Q.X.); (J.Z.); (Y.G.); (C.Z.); (X.C.); (M.C.)
| | - Qinglei Xu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (M.L.); (Q.X.); (J.Z.); (Y.G.); (C.Z.); (X.C.); (M.C.)
| | - Jing Zhao
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (M.L.); (Q.X.); (J.Z.); (Y.G.); (C.Z.); (X.C.); (M.C.)
| | - Yanli Guo
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (M.L.); (Q.X.); (J.Z.); (Y.G.); (C.Z.); (X.C.); (M.C.)
| | - Chunlei Zhang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (M.L.); (Q.X.); (J.Z.); (Y.G.); (C.Z.); (X.C.); (M.C.)
| | - Xiaohuan Chao
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (M.L.); (Q.X.); (J.Z.); (Y.G.); (C.Z.); (X.C.); (M.C.)
| | - Meng Cheng
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (M.L.); (Q.X.); (J.Z.); (Y.G.); (C.Z.); (X.C.); (M.C.)
| | - Allan P. Schinckel
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907-2054, USA;
| | - Bo Zhou
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (M.L.); (Q.X.); (J.Z.); (Y.G.); (C.Z.); (X.C.); (M.C.)
- Correspondence:
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20
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Down-Regulation of Insulin Like Growth Factor 1 Involved in Alzheimer’s Disease via MAPK, Ras, and FoxO Signaling Pathways. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8169981. [PMID: 35571248 PMCID: PMC9096571 DOI: 10.1155/2022/8169981] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 04/07/2022] [Accepted: 04/19/2022] [Indexed: 11/18/2022]
Abstract
The inability to halt or even delay the course of Alzheimer's disease (AD) forces the development of new molecular signatures and therapeutic strategies. Insulin like growth factor 1 (IGF1) is a promising target for AD treatment, yet exact mechanisms of AD ascribed to IGF1 remain elusive. Herein, gene expression profiles of 195 samples were analyzed and 19,245 background genes were generated, among which 4,424 differentially expressed genes (DEGs) were overlapped between AD/control and IGF1-low/high groups. Based on such DEGs, seven co-expression modules were established by weight gene correlation network analysis (WGCNA). The turquoise module had the strongest correlation with AD and IGF1-low expression, the DEGs of which were enriched in GABAergic synapse, long-term potentiation, mitogen-activated protein kinase (MAPK), Ras, and forkhead box O (FoxO) signaling pathways. Furthermore, cross-talking pathways of IGF1, including MAPK, Ras, and FoxO signaling pathways were identified in the protein-protein interaction network. According to the area under the curve (AUC) analysis, down-regulation of IGF1 exhibited good diagnostic performance in AD prediction. Collectively, our findings highlight the involvement of low IGF1 in AD pathogenesis via MAPK, Ras, and FoxO signaling pathways, which might advance strategies for the prevention and therapy of AD based on IGF1 target.
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21
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Sharma V, Joshi J, Yeh IJ, Doughman Y, Blankenberg D, Wald D, Montano MM. Re-Expression of ERα and AR in Receptor Negative Endocrine Cancers via GSK3 Inhibition. Front Oncol 2022; 12:824594. [PMID: 35402240 PMCID: PMC8988137 DOI: 10.3389/fonc.2022.824594] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 02/28/2022] [Indexed: 01/04/2023] Open
Abstract
DNA methylation, catalyzed by DNA methyltransferase (DNMT), is a well-characterized epigenetic modification in cancer cells. In particular, promoter hypermethylation of AR and ESR1 results in loss of expression on Androgen Receptor (AR) and Estrogen Receptor (ER), respectively, and is associated with a hormone refractory state. We now report that Glycogen Synthase Kinase 3 (GSK3) phosphorylates DNMT1 at S714, which is localized to a 62 amino acid region referred to as auto-inhibitory linker, which functions to occlude the DNA from the active site of DNMT1 to prevent the methylation of unmethylated DNA. Molecular Dynamics simulation indicates that phosphorylation at S714 resulted in conformational rearrangement of the autoinhibitory domain that inactivated its ability to block the methylation of unmethylated DNA and resulted in enhanced DNA binding. Treatment with a novel and more selective inhibitor of GSK3 resulted in decreased methylation of the promoter region of genes encoding the Androgen Receptor (AR) and Estrogen Receptor alpha (ERa) and re-expression of the AR and ERa in AR negative prostate cancer and ER negative breast cancer cells, respectively. As a result, concurrent treatment with the GSK3 inhibitor resulted in responsiveness of AR negative prostate cancer and ER negative breast cancer cells to inhibitors of the AR or ER, respectively, in in vitro and in vivo experimental models.
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Affiliation(s)
- Vikas Sharma
- Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH, United States
| | - Jayadev Joshi
- Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, Cleveland, OH, United States
| | - I-Ju Yeh
- Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH, United States
| | - YongQiu Doughman
- Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH, United States
| | - Daniel Blankenberg
- Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, Cleveland, OH, United States
| | - David Wald
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, United States
| | - Monica M. Montano
- Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH, United States
- *Correspondence: Monica M. Montano,
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22
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Rao KS, Kloppenburg JE, Marquis T, Solomon L, McElroy-Yaggy KL, Spees JL. CTGF-D4 Amplifies LRP6 Signaling to Promote Grafts of Adult Epicardial-derived Cells That Improve Cardiac Function After Myocardial Infarction. Stem Cells 2022; 40:204-214. [PMID: 35257185 PMCID: PMC9199845 DOI: 10.1093/stmcls/sxab016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 11/24/2020] [Indexed: 01/26/2023]
Abstract
Transplantation of stem/progenitor cells holds promise for cardiac regeneration in patients with myocardial infarction (MI). Currently, however, low cell survival and engraftment after transplantation present a major barrier to many forms of cell therapy. One issue is that ligands, receptors, and signaling pathways that promote graft success remain poorly understood. Here, we prospectively isolate uncommitted epicardial cells from the adult heart surface by CD104 (β-4 integrin) and demonstrate that C-terminal peptide from connective tissue growth factor (CTGF-D4), when combined with insulin, effectively primes epicardial-derived cells (EPDC) for cardiac engraftment after MI. Similar to native epicardial derivatives that arise from epicardial EMT at the heart surface, the grafted cells migrated into injured myocardial tissue in a rat model of MI with reperfusion. By echocardiography, at 1 month after MI, we observed significant improvement in cardiac function for animals that received epicardial cells primed with CTGF-D4/insulin compared with those that received vehicle-primed (control) cells. In the presence of insulin, CTGF-D4 treatment significantly increased the phosphorylation of Wnt co-receptor LRP6 on EPDC. Competitive engraftment assays and neutralizing/blocking studies showed that LRP6 was required for EPDC engraftment after transplantation. Our results identify LRP6 as a key target for increasing EPDC engraftment after MI and suggest amplification of LRP6 signaling with CTGF-D4/insulin, or by other means, may provide an effective approach for achieving successful cellular grafts in regenerative medicine.
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Affiliation(s)
- Krithika S Rao
- Department of Medicine, Stem Cell Core, University of Vermont, Colchester, VT 05446, USA
- Cardiovascular Research Institute, University of Vermont, Colchester, VT 05446, USA
| | - Jessica E Kloppenburg
- Department of Medicine, Stem Cell Core, University of Vermont, Colchester, VT 05446, USA
| | - Taylor Marquis
- Department of Medicine, Stem Cell Core, University of Vermont, Colchester, VT 05446, USA
| | - Laura Solomon
- Department of Medicine, Stem Cell Core, University of Vermont, Colchester, VT 05446, USA
| | - Keara L McElroy-Yaggy
- Department of Medicine, Stem Cell Core, University of Vermont, Colchester, VT 05446, USA
- Cardiovascular Research Institute, University of Vermont, Colchester, VT 05446, USA
| | - Jeffrey L Spees
- Department of Medicine, Stem Cell Core, University of Vermont, Colchester, VT 05446, USA
- Cardiovascular Research Institute, University of Vermont, Colchester, VT 05446, USA
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23
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Kamstra K, Rizwan MZ, Grattan DR, Horsfield JA, Tups A. Leptin regulates glucose homeostasis via the canonical Wnt pathway in the zebrafish. FASEB J 2022; 36:e22207. [PMID: 35188286 DOI: 10.1096/fj.202101764r] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 01/12/2022] [Accepted: 02/01/2022] [Indexed: 11/11/2022]
Abstract
Leptin is best known for its role in adipostasis, but it also regulates blood glucose levels. The molecular mechanism by which leptin controls glucose homeostasis remains largely unknown. Here, we use a zebrafish model to show that Wnt signaling mediates the glucoregulatory effects of leptin. Under normal feeding conditions, leptin regulates glucose homeostasis but not adipostasis in zebrafish. In times of nutrient excess, however, we found that leptin also regulates body weight and size. Using a Wnt signaling reporter fish, we show that leptin activates the canonical Wnt pathway in vivo. Utilizing two paradigms for hyperglycemia, it is revealed that leptin regulates glucose homeostasis via the Wnt pathway, as pharmacological inhibition of this pathway impairs the glucoregulatory actions of leptin. Our results may shed new light on the evolution of the physiological function of leptin.
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Affiliation(s)
- Kaj Kamstra
- Centre for Neuroendocrinology and Brain Health Research Centre, University Otago, Dunedin, New Zealand.,Department of Physiology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Mohammed Z Rizwan
- Centre for Neuroendocrinology and Brain Health Research Centre, University Otago, Dunedin, New Zealand.,Department of Anatomy, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - David R Grattan
- Centre for Neuroendocrinology and Brain Health Research Centre, University Otago, Dunedin, New Zealand.,Department of Anatomy, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Julia A Horsfield
- Department of Pathology, University of Otago, Dunedin, New Zealand.,Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
| | - Alexander Tups
- Centre for Neuroendocrinology and Brain Health Research Centre, University Otago, Dunedin, New Zealand.,Department of Physiology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
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24
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Abstract
Rates of obesity and diabetes have increased significantly over the past decades and the prevalence is expected to continue to rise further in the coming years. Many observations suggest that obesity and diabetes are associated with an increased risk of developing several types of cancers, including liver, pancreatic, endometrial, colorectal, and post-menopausal breast cancer. The path towards developing obesity and diabetes is affected by multiple factors, including adipokines, inflammatory cytokines, growth hormones, insulin resistance, and hyperlipidemia. The metabolic abnormalities associated with changes in the levels of these factors in obesity and diabetes have the potential to significantly contribute to the development and progression of cancer through the regulation of distinct signaling pathways. Here, we highlight the cellular and molecular pathways that constitute the links between obesity, diabetes, cancer risk and mortality. This includes a description of the existing evidence supporting the obesity-driven morphological and functional alternations of cancer cells and adipocytes through complex interactions within the tumor microenvironment.
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Affiliation(s)
- Dae-Seok Kim
- Touchstone Diabetes Center, Department of Internal Medicine, Dallas, TX, USA
| | - Philipp E. Scherer
- Touchstone Diabetes Center, Department of Internal Medicine, Dallas, TX, USA
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Corresponding author: Philipp E. Scherer https://orcid.org/0000-0003-0680-3392 Touchstone Diabetes Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, USA E-mail:
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25
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Lu W, Xiao W, Xie W, Fu X, Pan L, Jin H, Yu Y, Zhang Y, Li Y. The Role of Osteokines in Sarcopenia: Therapeutic Directions and Application Prospects. Front Cell Dev Biol 2021; 9:735374. [PMID: 34650980 PMCID: PMC8505767 DOI: 10.3389/fcell.2021.735374] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 09/07/2021] [Indexed: 12/14/2022] Open
Abstract
Sarcopenia is an age-related disease in which muscle mass, strength and function may decline with age or can be secondary to cachexia or malnutrition and can lead to weakness, falls and even death. With the increase in life expectancy, sarcopenia has become a major threat to the health of the elderly. Currently, our understanding of bone-muscle interactions is not limited to their mechanical coupling. Bone and muscle have been identified as secretory endocrine organs, and their interaction may affect the function of each. Both muscle-derived factors and osteokines can play a role in regulating muscle and bone metabolism via autocrine, paracrine and endocrine mechanisms. Herein, we comprehensively summarize the latest research progress on the effects of the osteokines FGF-23, IGF-1, RANKL and osteocalcin on muscle to explore whether these cytokines can be utilized to treat and prevent sarcopenia.
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Affiliation(s)
- Wenhao Lu
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Wenfeng Xiao
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Wenqing Xie
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Xin Fu
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Linyuan Pan
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Hongfu Jin
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Yongle Yu
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Yi Zhang
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Yusheng Li
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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26
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Castillo-Rodríguez RA, Palencia G, Anaya-Rubio I, Pérez JCG, Jiménez-Farfán D, Escamilla-Ramírez Á, Zavala-Vega S, Cruz-Salgado A, Cervantes-Rebolledo C, Gracia-Mora I, Ruiz-Azuara L, Trejo-Solis C. Anti-proliferative, pro-apoptotic and anti-invasive effect of the copper coordination compound Cas III-La through the induction of reactive oxygen species and regulation of Wnt/β-catenin pathway in glioma. J Cancer 2021; 12:5693-5711. [PMID: 34475984 PMCID: PMC8408120 DOI: 10.7150/jca.59769] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 07/11/2021] [Indexed: 01/12/2023] Open
Abstract
Gliomas are the most aggressive neoplasms that affect the central nervous system, being glioblastoma multiforme (GBM) the most malignant. The resistance of GBM to therapies is attributed to its high rate of cell proliferation, angiogenesis, invasion, and resistance to apoptosis; thus, finding alternative therapeutic approaches is vital. In this work, the anti-proliferative, pro-apoptotic, and anti-invasive effect of the copper coordination compound Casiopeina III-La (Cas III-La) on human U373 MG cells was determined in vitro and in vivo. Our results indicate that Cas III-La exerts an anti-proliferative effect, promoting apoptotic cell death and inactivating the invasive process by generating reactive oxygen species (ROS), inactivating GSK3β, activating JNK and ERK, and promoting the nuclear accumulation of β-catenin. The inhibition of ROS generation by N-acetyl-l-cysteine not only recovered cell migration and viability, but also reduced β-catenin accumulation and JNK and ERK activation. Additionally, Cas III-La significantly reduced tumor volume, cell proliferation and mitotic indices, and increased the apoptotic index in mice xenotransplanted with U373 glioma cells. Thus, Cas III-La is a promising agent to treat GBM.
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Affiliation(s)
| | - Guadalupe Palencia
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía, Ciudad de México 14269, Tlalpan, México
| | - Isabel Anaya-Rubio
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía, Ciudad de México 14269, Tlalpan, México
| | | | - Dolores Jiménez-Farfán
- Laboratorio de Inmunología, División de Estudios de Posgrado e Investigación, Facultad de Odontología, Universidad Nacional Autónoma de México, Ciudad de México 04510, México
| | - Ángel Escamilla-Ramírez
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía, Ciudad de México 14269, Tlalpan, México.,Hospital Regional de Alta Especialidad de Oaxaca, Secretaria de Salud, C.P. 71256 Oaxaca, México
| | - Sergio Zavala-Vega
- Departamento de Patología, Instituto Nacional de Neurología y Neurocirugía, Ciudad de México 14269, Tlalpan, México
| | - Arturo Cruz-Salgado
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía, Ciudad de México 14269, Tlalpan, México
| | | | - Isabel Gracia-Mora
- Departamento de Química Inorgánica y Nuclear, Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, Investigación Científica 70, Ciudad de México 04510, México
| | - Lena Ruiz-Azuara
- Facultad de Química, Departamento de Química Inorgánica y Nuclear, Universidad Nacional Autónoma de México, Ciudad de México 04510, México
| | - Cristina Trejo-Solis
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía, Ciudad de México 14269, Tlalpan, México
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Patriarca EJ, Cermola F, D’Aniello C, Fico A, Guardiola O, De Cesare D, Minchiotti G. The Multifaceted Roles of Proline in Cell Behavior. Front Cell Dev Biol 2021; 9:728576. [PMID: 34458276 PMCID: PMC8397452 DOI: 10.3389/fcell.2021.728576] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 07/23/2021] [Indexed: 12/13/2022] Open
Abstract
Herein, we review the multifaceted roles of proline in cell biology. This peculiar cyclic imino acid is: (i) A main precursor of extracellular collagens (the most abundant human proteins), antimicrobial peptides (involved in innate immunity), salivary proteins (astringency, teeth health) and cornifins (skin permeability); (ii) an energy source for pathogenic bacteria, protozoan parasites, and metastatic cancer cells, which engage in extracellular-protein degradation to invade their host; (iii) an antistress molecule (an osmolyte and chemical chaperone) helpful against various potential harms (UV radiation, drought/salinity, heavy metals, reactive oxygen species); (iv) a neural metabotoxin associated with schizophrenia; (v) a modulator of cell signaling pathways such as the amino acid stress response and extracellular signal-related kinase pathway; (vi) an epigenetic modifier able to promote DNA and histone hypermethylation; (vii) an inducer of proliferation of stem and tumor cells; and (viii) a modulator of cell morphology and migration/invasiveness. We highlight how proline metabolism impacts beneficial tissue regeneration, but also contributes to the progression of devastating pathologies such as fibrosis and metastatic cancer.
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Affiliation(s)
| | | | | | | | | | | | - Gabriella Minchiotti
- Stem Cell Fate Laboratory, Institute of Genetics and Biophysics “A. Buzzati Traverso”, Consiglio Nazionale delle Ricerche, Naples, Italy
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28
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Abstract
PURPOSE OF REVIEW Disorders of glucose metabolism, including insulin resistance, prediabetes, and diabetes, have been identified as risk factors for worsened asthma. This review summarizes emerging evidence for their role as modifiable risk factors in asthma, including the potential benefit of diabetes medications on asthma outcomes. RECENT FINDINGS Experimental studies show that hyperinsulinemia associated with insulin resistance is associated with airway smooth muscle proliferation and promotes contractility. Epidemiologic studies have identified a higher prevalence of glycemic dysfunction among those with severe and uncontrolled asthma, and longitudinal studies have associated prediabetes and diabetes with higher risk of asthma exacerbations. The potential benefits of thiazolidinediones (TZDs), glucagon-like peptide-1 agonists, and metformin being investigated in asthma, but thus far interventional studies of TZDs have reported null results. On the contrary, observational studies have inconsistently controlled for relevant confounders which leaves conclusions vulnerable to misattribution of relationships due to corelated metabolic disorders, including dyslipidemia. SUMMARY Developing evidence suggests that disorders of glucose metabolism may be associated with worsening asthma. However, these conditions arise within a network of obesity-related metabolic diseases that may themselves worsen asthma. Few interventional trials have not identified a benefit, but data have been limited. Additional research is needed to define the potential independent impact of disorders of glucose metabolism in asthma.
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29
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Chen J, Debebe A, Zeng N, Kopp J, He L, Sander M, Stiles BL. Transformation of SOX9 + cells by Pten deletion synergizes with steatotic liver injury to drive development of hepatocellular and cholangiocarcinoma. Sci Rep 2021; 11:11823. [PMID: 34083580 PMCID: PMC8175600 DOI: 10.1038/s41598-021-90958-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 05/19/2021] [Indexed: 01/07/2023] Open
Abstract
SOX9 (Sex-determining region Y Box 9) is a well-characterized transcription factor that is a marker for progenitor cells in various tissues. In the liver, cells delineated by SOX9 are responsible for regenerating liver parenchyma when cell proliferation is impaired following chronic injury. However, whether these SOX9+ cells play a role in liver carcinogenesis has not been fully understood, although high SOX9 expression has been linked to poor survival outcome in liver cancer patients. To address this question, we developed a liver cancer mouse model (PtenloxP/loxP; Sox9-CreERT+; R26RYFP) where tumor suppressor Pten (phosphatase and tensin homolog deleted on chromosome ten) is deleted in SOX9+ cells following tamoxifen injection. In this paper, we employ lineage-tracing to demonstrate the tumorigenicity potential of the Pten-, SOX9+ cells. We show that these cells are capable of giving rise to mixed-lineage tumors that manifest features of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA). Our results suggest that PTEN loss induces the transformation of SOX9+ cells. We further show that to activate these transformed SOX9+ cells, the presence of liver injury is crucial. Liver injury, induced by hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or high-fat diet (HFD), substantially increases tumor incidence and accelerates liver carcinogenesis from SOX9+ cells in Pten null mice but not in control mice. We further examine the mechanisms underlying tumor formation in this model to show that concurrent with the induction of niche signal (i.e., Wnt signaling), liver injury significantly stimulates the expansion of tumor-initiating cells (TICs). Together, these data show that (1) SOX9+ cells have the potential to become TICs following the primary transformation (i.e. Pten deletion) and that (2) liver injury is necessary for promoting the activation and proliferation of transformed SOX9+ cells, resulting in the genesis of mixed-lineage liver tumors.
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Affiliation(s)
- Jingyu Chen
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90033, USA
| | - Anketse Debebe
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90033, USA
| | - Ni Zeng
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90033, USA
| | - Janel Kopp
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada
| | - Lina He
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90033, USA
| | - Maike Sander
- Department of Pediatrics and Cellar and Molecular Medicine, UCSD, La Jolla, CA, 92093, USA
| | - Bangyan L Stiles
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90033, USA.
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
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El Sabeh M, Saha SK, Afrin S, Islam MS, Borahay MA. Wnt/β-catenin signaling pathway in uterine leiomyoma: role in tumor biology and targeting opportunities. Mol Cell Biochem 2021; 476:3513-3536. [PMID: 33999334 DOI: 10.1007/s11010-021-04174-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 04/28/2021] [Indexed: 02/06/2023]
Abstract
Uterine leiomyoma is the most common tumor of the female reproductive system and originates from a single transformed myometrial smooth muscle cell. Despite the immense medical, psychosocial, and financial impact, the exact underlying mechanisms of leiomyoma pathobiology are poorly understood. Alterations of signaling pathways are thought to be instrumental in leiomyoma biology. Wnt/β-catenin pathway appears to be involved in several aspects of the genesis of leiomyomas. For example, Wnt5b is overexpressed in leiomyoma, and the Wnt/β-catenin pathway appears to mediate the role of MED12 mutations, the most common mutations in leiomyoma, in tumorigenesis. Moreover, Wnt/β-catenin pathway plays a paracrine role where estrogen/progesterone treatment of mature myometrial or leiomyoma cells leads to increased expression of Wnt11 and Wnt16, which induces proliferation of leiomyoma stem cells and tumor growth. Constitutive activation of β-catenin leads to myometrial hyperplasia and leiomyoma-like lesions in animal models. Wnt/β-catenin signaling is also closely involved in mechanotransduction and extracellular matrix regulation and relevant alterations in leiomyoma, and crosstalk is noted between Wnt/β-catenin signaling and other pathways known to regulate leiomyoma development and growth such as estrogen, progesterone, TGFβ, PI3K/Akt/mTOR, Ras/Raf/MEK/ERK, IGF, Hippo, and Notch signaling. Finally, evidence suggests that inhibition of the canonical Wnt pathway using β-catenin inhibitors inhibits leiomyoma cell proliferation. Understanding the molecular mechanisms of leiomyoma development is essential for effective treatment. The specific Wnt/β-catenin pathway molecules discussed in this review constitute compelling candidates for therapeutic targeting.
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Affiliation(s)
- Malak El Sabeh
- Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA
| | - Subbroto Kumar Saha
- Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA
| | - Sadia Afrin
- Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA
| | - Md Soriful Islam
- Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA
| | - Mostafa A Borahay
- Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA.
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CHIR99021 Augmented the Function of Late Endothelial Progenitor Cells by Preventing Replicative Senescence. Int J Mol Sci 2021; 22:ijms22094796. [PMID: 33946516 PMCID: PMC8124445 DOI: 10.3390/ijms22094796] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 04/27/2021] [Indexed: 12/12/2022] Open
Abstract
Endothelial progenitor cells (EPCs) are specialized cells in circulating blood, well known for their ability to form new vascular structures. Aging and various ailments such as diabetes, atherosclerosis and cardiovascular disease make EPCs vulnerable to decreasing in number, which affects their migration, proliferation and angiogenesis. Myocardial ischemia is also linked to a reduced number of EPCs and their endothelial functional role, which hinders proper blood circulation to the myocardium. The current study shows that an aminopyrimidine derivative compound (CHIR99021) induces the inhibition of GSK-3β in cultured late EPCs. GSK-3β inhibition subsequently inhibits mTOR by blocking the phosphorylation of TSC2 and lysosomal localization of mTOR. Furthermore, suppression of GSK-3β activity considerably increased lysosomal activation and autophagy. The activation of lysosomes and autophagy by GSK-3β inhibition not only prevented replicative senescence of the late EPCs but also directed their migration, proliferation and angiogenesis. To conclude, our results demonstrate that lysosome activation and autophagy play a crucial role in blocking the replicative senescence of EPCs and in increasing their endothelial function. Thus, the findings provide an insight towards the treatment of ischemia-associated cardiovascular diseases based on the role of late EPCs.
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Nikhil Kumar Tej J, Johnson P, Krishna K, Kaushik K, Gupta PSP, Nandi S, Mondal S. Copper and Selenium stimulates CYP19A1 expression in caprine ovarian granulosa cells: possible involvement of AKT and WNT signalling pathways. Mol Biol Rep 2021; 48:3515-3527. [PMID: 33881728 DOI: 10.1007/s11033-021-06346-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Accepted: 04/07/2021] [Indexed: 11/29/2022]
Abstract
The role of copper and selenium on activation of estradiol synthesis pathways viz. PKA/AKT/WNT is not clearly elucidated. On this background we attempt to elcuiated the role of copper and selenium on mRNA expression of genes associated with estradiol synthesis in caprine ovarian granulose cell models. Ovarian granulosa cells from medium (3-5 mm) sized follicles were aspirated and distributed separately to different groups. Group I: control, Group II: cupric chloride (Cu: 0.5 mM), Group III: sodium selenite (Se: 100 ng/ml), Group IV: Cu + Se. The cells (105/well) were cultured in 96 well plate in the base culture medium of MEMα comprising of nonessential amino acids (1.1 mM), FSH (10 ng/mL), transferrin (5 µg/mL), IGF-I (2 ng/mL), androstenedione (10-6 M), penicillin (100 IU/mL), streptomycin (0.1 mg/mL) and fungizone (0.625 µl/mL) and insulin (1 ng/mL). The cells were incubated in a carbondioxide incubator (38 °C, 5% CO2, 95% RH). The medium was changed on alternate days and cells were harvested on day 6. Day 6 media was used for estimation of estradiol. The RNA isolated form harvested cells was used for qPCR assay. There was no significant (p > 0.05) difference in estradiol concentration between groups. The mRNA expression of AKT1, CYP19A1, WNT2 & 4, FZD6 and APC2 were significantly (p < 0.05) higher in Cu and Cu + Se groups compared to control. Whereas, the mRNA transcript of DVL1 and CSNK1 was significantly (p < 0.05) higher in Cu + Se group compared to control. Incontrast, no significant difference in mRNA expression of PRKAR1A and CTNNB1 was noticed. Our study support a key role of copper and selenium in activation of AKT and WNT signalling pathway that further lead to increase in the mRNA expression of CYP19A1.
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Affiliation(s)
- J Nikhil Kumar Tej
- ICAR-National Dairy Research Institute (NDRI), Karnal, Haryana, 132001, India.
| | - P Johnson
- Animal Biotechnology Lab, ICAR-National Institute of Animal Nutrition and Physiology (NIANP), Bengaluru, Karnataka, India
| | - Kavya Krishna
- Animal Biotechnology Lab, ICAR-National Institute of Animal Nutrition and Physiology (NIANP), Bengaluru, Karnataka, India
| | - Kalpana Kaushik
- Animal Biotechnology Lab, ICAR-National Institute of Animal Nutrition and Physiology (NIANP), Bengaluru, Karnataka, India
| | - P S P Gupta
- Animal Biotechnology Lab, ICAR-National Institute of Animal Nutrition and Physiology (NIANP), Bengaluru, Karnataka, India
| | - S Nandi
- Animal Biotechnology Lab, ICAR-National Institute of Animal Nutrition and Physiology (NIANP), Bengaluru, Karnataka, India
| | - S Mondal
- Animal Biotechnology Lab, ICAR-National Institute of Animal Nutrition and Physiology (NIANP), Bengaluru, Karnataka, India
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Abstract
Osteoarthritis (OA) is considered the most frequent degenerative disease and is characterized by cartilage degradation and synovial inflammation. Fibroblast-like synoviocytes (FLSs) are vital to synovial inflammation in OA. Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance and hyperinsulinemia (HINS) and has been demonstrated to be an independent risk factor for OA. Autophagy is involved in the processes of various inflammatory diseases, and autophagy inhibition can stimulate OA development. Thus, we aimed to investigate the role of insulin in the inflammatory phenotype and autophagy of FLSs in OA. The data showed that cell viability and proinflammatory cytokine production in FLSs were both increased after insulin stimulation. We also found that high insulin could promote macrophage infiltration and chemokine production but inhibited autophagy in FLSs. To further explore the potential mechanisms, the effects of insulin on PI3K/Akt/mTOR and NF-ĸB signaling activation were evaluated. The results indicated that insulin activated PI3K/Akt/mTOR/NF-ĸB signaling, and the above-mentioned inflammatory responses, including autophagy inhibition, were notably attenuated by specific signaling inhibitors in the presence of high insulin. Moreover, the data showed that a positive feedback loop existed between proinflammatory cytokines (e.g., IL-1β, IL-6, and TNF-α) and PI3K/mTOR/Akt/NF-ĸB signaling in FLSs, and insulin enhanced this feedback loop to accelerate OA progression. Our study suggests that insulin may be a novel therapeutic strategy for OA prevention and treatment in the future.
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Affiliation(s)
- Li Qiao
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China
| | - Yi Li
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China
| | - Shui Sun
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China.
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Gao Y, Wang J, Zhu DC, Miao Y, Hu ZQ. Dermal macrophage and its potential in inducing hair follicle regeneration. Mol Immunol 2021; 134:25-33. [PMID: 33706040 DOI: 10.1016/j.molimm.2021.02.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 02/18/2021] [Accepted: 02/23/2021] [Indexed: 10/22/2022]
Abstract
Hair follicle (HF) is an excellent mini-model to study adult tissue regeneration, since it can regenerate itself under appropriate stress settings via interaction with niche components. Dermal macrophages, a group of heterogeneous cell populations, serve as key regulators in this microenvironment. Recent advances in phenotype identification and lineage tracing have unveiled various dermal macrophage subsets involved in stress-induced hair regeneration through different mechanisms, where HF structural integrity is impaired to varying degrees. This review summarized current knowledge regarding the distribution, sources, phenotypes of dermal macrophages in association with HF, as well as the mechanisms underlying macrophage-mediated hair regeneration in response to different internal-stress settings. Further investigation on macrophage dynamics will provide novel cell-targeting therapies for HF engineering and hair loss.
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Affiliation(s)
- Yuan Gao
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, 510515, China
| | - Jin Wang
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, 510515, China
| | - De-Cong Zhu
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, 510515, China
| | - Yong Miao
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, 510515, China.
| | - Zhi-Qi Hu
- Department of Plastic and Aesthetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, 510515, China.
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Jarabo P, de Pablo C, Herranz H, Martín FA, Casas-Tintó S. Insulin signaling mediates neurodegeneration in glioma. Life Sci Alliance 2021; 4:4/3/e202000693. [PMID: 33526430 PMCID: PMC7898663 DOI: 10.26508/lsa.202000693] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 01/07/2021] [Accepted: 01/08/2021] [Indexed: 12/18/2022] Open
Abstract
Tumoral cells secrete an antagonist that attenuates insulin signaling in neurons. It induces mitochondrial defects and synapse loss; restoring neuronal insulin activity rescues neurodegeneration. Cell to cell communication facilitates tissue development and physiology. Under pathological conditions, brain tumors disrupt glia-neuron communication signals that in consequence, promote tumor expansion at the expense of surrounding healthy tissue. The glioblastoma is one of the most aggressive and frequent primary brain tumors. This type of glioma expands and infiltrates into the brain, causing neuronal degeneration and neurological decay, among other symptoms. Here, we describe in a Drosophila model how glioblastoma cells produce ImpL2, an antagonist of the insulin pathway, which targets neighboring neurons and causes mitochondrial disruption as well as synapse loss, both early symptoms of neurodegeneration. Furthermore, glioblastoma progression requires insulin pathway attenuation in neurons. Restoration of neuronal insulin activity is sufficient to rescue synapse loss and to delay the premature death caused by glioma. Therefore, signals from glioblastoma to neuron emerge as a potential field of study to prevent neurodegeneration and to develop anti-tumoral strategies.
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Affiliation(s)
- Patricia Jarabo
- Instituto Cajal, Consejo Superior de Investigaciones Cientificas (CSIC), Madrid, Spain
| | - Carmen de Pablo
- Instituto Cajal, Consejo Superior de Investigaciones Cientificas (CSIC), Madrid, Spain
| | | | | | - Sergio Casas-Tintó
- Instituto Cajal, Consejo Superior de Investigaciones Cientificas (CSIC), Madrid, Spain
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Guevara-Aguirre J, Torres C, Peña G, Palacios M, Bautista C, Guevara A, Gavilanes AW. IGF-I deficiency and enhanced insulin sensitivity due to a mutated growth hormone receptor gene in humans. Mol Cell Endocrinol 2021; 519:111044. [PMID: 33053393 DOI: 10.1016/j.mce.2020.111044] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 09/25/2020] [Accepted: 09/28/2020] [Indexed: 12/19/2022]
Abstract
Human size is achieved by the coordinated expression of many genes. From conception to adulthood, a given genomic endowment is modified by highly variable environmental circumstances. During each stage of a person's life, distinct nutritional and hormonal influences continuously shape growing physical features until mature characteristics are attained. Underlying processes depend on precise provision of substrates and energy extracted by insulin action from nutrients, which allows cell proliferation, differentiation, and survival, under the concerted actions of growth hormone and insulin-like growth factor-I (IGF-I). It should be noted that growth and metabolic signaling pathways are interdependent and superimposed at multiple levels. Attainment of a fully developed human phenotype should be considered as a harmonious increment in body size rather than a simple increase in height. From this perspective we herein analyze adult features of individuals with an inactive growth hormone receptor, who consequently have severely diminished concentrations of serum insulin and endocrine IGF-I.
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Affiliation(s)
- Jaime Guevara-Aguirre
- Colegio de Ciencias de La Salud, Universidad San Francisco de Quito, Diego de Robles s/n y Pampite, Cumbayá, Quito, Ecuador; Maastricht University, Maastricht, the Netherlands; Instituto de Endocrinología IEMYR, Quito, Ecuador.
| | - Carlos Torres
- Colegio de Ciencias de La Salud, Universidad San Francisco de Quito, Diego de Robles s/n y Pampite, Cumbayá, Quito, Ecuador
| | - Gabriela Peña
- Colegio de Ciencias de La Salud, Universidad San Francisco de Quito, Diego de Robles s/n y Pampite, Cumbayá, Quito, Ecuador
| | - María Palacios
- Colegio de Ciencias de La Salud, Universidad San Francisco de Quito, Diego de Robles s/n y Pampite, Cumbayá, Quito, Ecuador
| | - Camila Bautista
- Colegio de Ciencias de La Salud, Universidad San Francisco de Quito, Diego de Robles s/n y Pampite, Cumbayá, Quito, Ecuador
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Catellani C, Ravegnini G, Sartori C, Angelini S, Street ME. GH and IGF System: The Regulatory Role of miRNAs and lncRNAs in Cancer. Front Endocrinol (Lausanne) 2021; 12:701246. [PMID: 34484116 PMCID: PMC8415755 DOI: 10.3389/fendo.2021.701246] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 07/13/2021] [Indexed: 12/13/2022] Open
Abstract
Growth hormone (GH) and the insulin-like growth factor (IGF) system are involved in many biological processes and have growth-promoting actions regulating cell proliferation, differentiation, apoptosis and angiogenesis. A recent chapter in epigenetics is represented by microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) which regulate gene expression. Dysregulated miRNAs and lncRNAs have been associated with several diseases including cancer. Herein we report the most recent findings concerning miRNAs and lncRNAs regulating GH and the IGF system in the context of pituitary adenomas, osteosarcoma and colorectal cancer, shedding light on new possible therapeutic targets. Pituitary adenomas are increasingly common intracranial tumors and somatotroph adenomas determine supra-physiological GH secretion and cause acromegaly. Osteosarcoma is the most frequent bone tumor in children and adolescents and was reported in adults who were treated with GH in childhood. Colorectal cancer is the third cancer in the world and has a higher prevalence in acromegalic patients.
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Affiliation(s)
- Cecilia Catellani
- Department of Mother and Child, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
- PhD Program in Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Gloria Ravegnini
- Department of Pharmacy & Biotechnology, University of Bologna, Bologna, Italy
| | - Chiara Sartori
- Department of Mother and Child, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Sabrina Angelini
- Department of Pharmacy & Biotechnology, University of Bologna, Bologna, Italy
| | - Maria E. Street
- Department of Mother and Child, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
- *Correspondence: Maria E. Street,
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Khodabandehloo F, Taleahmad S, Aflatoonian R, Rajaei F, Zandieh Z, Nassiri-Asl M, Eslaminejad MB. Microarray analysis identification of key pathways and interaction network of differential gene expressions during osteogenic differentiation. Hum Genomics 2020; 14:43. [PMID: 33234152 PMCID: PMC7687700 DOI: 10.1186/s40246-020-00293-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 11/13/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Adult bone marrow-derived mesenchymal stem cells (BM-MSCs) are multipotent stem cells that can differentiate into three lineages. They are suitable sources for cell-based therapy and regenerative medicine applications. This study aims to evaluate the hub genes and key pathways of differentially expressed genes (DEGs) related to osteogenesis by bioinformatics analysis in three different days. The DEGs were derived from the three different days compared with day 0. RESULTS Gene expression profiles of GSE37558 were obtained from the Gene Expression Omnibus (GEO) database. A total of 4076 DEGs were acquired on days 8, 12, and 25. Gene ontology (GO) enrichment analysis showed that the non-canonical Wnt signaling pathway and lipopolysaccharide (LPS)-mediated signaling pathway were commonly upregulated DEGs for all 3 days. KEGG pathway analysis indicated that the PI3K-Akt and focal adhesion were also commonly upregulated DEGs for all 3 days. Ten hub genes were identified by CytoHubba on days 8, 12, and 25. Then, we focused on the association of these hub genes with the Wnt pathways that had been enriched from the protein-protein interaction (PPI) by the Cytoscape plugin MCODE. CONCLUSIONS These findings suggested further insights into the roles of the PI3K/AKT and Wnt pathways and their association with osteogenesis. In addition, the stem cell microenvironment via growth factors, extracellular matrix (ECM), IGF1, IGF2, LPS, and Wnt most likely affect osteogenesis by PI3K/AKT.
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Affiliation(s)
| | - Sara Taleahmad
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Reza Aflatoonian
- Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Farzad Rajaei
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Zahra Zandieh
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Marjan Nassiri-Asl
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran.
| | - Mohamadreza Baghaban Eslaminejad
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
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He S, Tang S. WNT/β-catenin signaling in the development of liver cancers. Biomed Pharmacother 2020; 132:110851. [PMID: 33080466 DOI: 10.1016/j.biopha.2020.110851] [Citation(s) in RCA: 212] [Impact Index Per Article: 42.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/27/2020] [Accepted: 10/04/2020] [Indexed: 02/06/2023] Open
Abstract
The WNT/β-catenin signaling pathway is a highly conserved and tightly controlled molecular mechanism that regulates embryonic development, cellular proliferation and differentiation. Of note, accumulating evidence has shown that the aberrant of WNT/β-catenin signaling promotes the development and/or progression of liver cancer, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), the two most prevalent primary liver tumours in adults. There are two different WNT signaling pathways have been identified, which were termed non-canonical and canonical pathways, the latter involving the activation of β-catenin. β-catenin, acting as an intracellular signal transducer in the WNT signaling pathway, is encoded by CTNNB1 and plays a critical role in tumorigenesis. In the past research, most liver tumors have mutations in genes encoding key components of the WNT/β-catenin signaling pathway. In addition, several of other signaling pathways also can crosswalk with β-catenin. In this review, we discuss the most relevant molecular mechanisms of action and regulation of WNT/β-catenin signaling in the development and pathophysiology of liver cancers, as well as in the development of therapeutics.
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Affiliation(s)
- Shuai He
- Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang 110032, China
| | - Shilei Tang
- Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang 110032, China.
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Sun L, Ji X, Wang D, Guan A, Xiao Y, Xu H, Du S, Xu Y, Zhao H, Lu X, Sang X, Zhong S, Yang H, Mao Y. Integrated analysis of serum lipid profile for predicting clinical outcomes of patients with malignant biliary tumor. BMC Cancer 2020; 20:980. [PMID: 33036576 PMCID: PMC7547451 DOI: 10.1186/s12885-020-07496-8] [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: 07/17/2020] [Accepted: 10/05/2020] [Indexed: 11/10/2022] Open
Abstract
Background Serum lipids were reported to be the prognostic factors of various cancers, but their prognostic value in malignant biliary tumor (MBT) patients remains unclear. Thus we aim to assess and compare prognosis values of different serum lipids, and construct a novel prognostic nomogram based on serum lipids. Methods Patients with a confirmed diagnosis of MBT at our institute from 2003 to 2017 were retrospectively reviewed. Prognosis-related factors were identified via univariate and multivariate Cox regression analyses. Then the novel prognostic nomogram and a 3-tier staging system were constructed based on these factors and further compared to the TNM staging system. Results A total of 368 patients were included in this study. Seven optimal survival-related factors—TC/HDL > 10.08, apolipoprotein B > 0.9 g/L, lipoprotein> 72 mg/L, lymph node metastasis, radical cure, CA199 > 37 U/mL, and tumor differentiation —were included to construct the prognostic nomogram. The C-indexes in training and validation sets were 0.738 and 0.721, respectively. Besides, ROC curves, calibration plots, and decision curve analysis all suggested favorable discrimination and predictive ability. The nomogram also performed better predictive ability than the TNM system and nomogram without lipid parameters. And the staging system based on nomogram also presented better discriminative ability than TNM system (P < 0.001). Conclusions The promising prognostic nomogram based on lipid parameters provided an intuitive method for performing survival prediction and facilitating individualized treatment and was a great complement to the TNM staging system in predicting overall survival.
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Affiliation(s)
- Lejia Sun
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Xin Ji
- Peking Union Medical College (PUMC), PUMC & Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Dongyue Wang
- Peking Union Medical College (PUMC), PUMC & Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Ai Guan
- Peking Union Medical College (PUMC), PUMC & Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yao Xiao
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Haifeng Xu
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Shunda Du
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yiyao Xu
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Haitao Zhao
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Xin Lu
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Xinting Sang
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Shouxian Zhong
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Huayu Yang
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Beijing, 100730, China.
| | - Yilei Mao
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Beijing, 100730, China.
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Yoshida T, Delafontaine P. Mechanisms of IGF-1-Mediated Regulation of Skeletal Muscle Hypertrophy and Atrophy. Cells 2020; 9:cells9091970. [PMID: 32858949 PMCID: PMC7564605 DOI: 10.3390/cells9091970] [Citation(s) in RCA: 301] [Impact Index Per Article: 60.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/18/2020] [Accepted: 08/19/2020] [Indexed: 12/18/2022] Open
Abstract
Insulin-like growth factor-1 (IGF-1) is a key growth factor that regulates both anabolic and catabolic pathways in skeletal muscle. IGF-1 increases skeletal muscle protein synthesis via PI3K/Akt/mTOR and PI3K/Akt/GSK3β pathways. PI3K/Akt can also inhibit FoxOs and suppress transcription of E3 ubiquitin ligases that regulate ubiquitin proteasome system (UPS)-mediated protein degradation. Autophagy is likely inhibited by IGF-1 via mTOR and FoxO signaling, although the contribution of autophagy regulation in IGF-1-mediated inhibition of skeletal muscle atrophy remains to be determined. Evidence has suggested that IGF-1/Akt can inhibit muscle atrophy-inducing cytokine and myostatin signaling via inhibition of the NF-κΒ and Smad pathways, respectively. Several miRNAs have been found to regulate IGF-1 signaling in skeletal muscle, and these miRs are likely regulated in different pathological conditions and contribute to the development of muscle atrophy. IGF-1 also potentiates skeletal muscle regeneration via activation of skeletal muscle stem (satellite) cells, which may contribute to muscle hypertrophy and/or inhibit atrophy. Importantly, IGF-1 levels and IGF-1R downstream signaling are suppressed in many chronic disease conditions and likely result in muscle atrophy via the combined effects of altered protein synthesis, UPS activity, autophagy, and muscle regeneration.
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Affiliation(s)
- Tadashi Yoshida
- Heart and Vascular Institute, John W. Deming Department of Medicine, Tulane University School of Medicine, 1430 Tulane Ave SL-48, New Orleans, LA 70112, USA
- Department of Physiology, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA 70112, USA
- Correspondence: (T.Y.); (P.D.)
| | - Patrice Delafontaine
- Heart and Vascular Institute, John W. Deming Department of Medicine, Tulane University School of Medicine, 1430 Tulane Ave SL-48, New Orleans, LA 70112, USA
- Department of Physiology, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA 70112, USA
- Correspondence: (T.Y.); (P.D.)
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Tepekoy F, Akkoyunlu G. The interaction of Wnt signaling members with growth factors in cultured granulosa cells. Anim Reprod 2020; 17:e20190106. [PMID: 32714449 PMCID: PMC7375871 DOI: 10.1590/1984-3143-ar2019-0106] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Wnt family members have recently been distinguished in the adult ovary with potential roles in ovarian function. Though particular growth factors interact with Wnt signaling members in extraovarian cell types, it is unclear whether this interaction is applicable in the granulosa cells. Therefore, the current study aimed to determine the effect of insulin-like growth factor-1 (IGF-I), epidermal growth factor (EGF) and basic fibroblast growth factor (FGF-β) on Wnt ligands WNT2 and WNT4 and Wnt receptor Frizzled-4 (FZD4) protein levels in cultured mouse granulosa cells. Granulosa cells were isolated from antral follicles of adult Balb/C mice and cultured for 24 hours in the presence of 100 ng/mL of IGF-I, or EGF or FGF-β. WNT2, WNT4 and FZD4 protein levels were evaluated through western blotting after the culture process. IGF-I treated granulosa cells had significantly the highest level of WNT2 and WNT4 as well as FZD4 when compared to FGF-β and EGF groups. FGF-β group had a significantly higher level of WNT2, WNT4 and FZD4 expression when compared to EGF group. FZD4 expression was at the highest level in the IGF-I group and this difference was statistically significant for all groups including uncultured cells and vehicle group. In addition, FGF-β was shown to positively affect the adhesion of granulosa cells. This study demonstrates that IGF-I, FGF-β and EGF have differential effects on the expressions of WNT2, WNT4, and FZD4 in cultured mouse granulosa cells, suggesting that particular growth factors related to ovarian function might conduct their roles in the ovary through Wnt signaling.
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Affiliation(s)
- Filiz Tepekoy
- Department of Histology and Embryology, Faculty of Medicine, Altinbas University, Istanbul, Turkey.,Department of Histology and Embryology, Faculty of Medicine, Akdeniz University, Antalya, Turkey
| | - Gokhan Akkoyunlu
- Department of Histology and Embryology, Faculty of Medicine, Akdeniz University, Antalya, Turkey
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GSK3: A Kinase Balancing Promotion and Resolution of Inflammation. Cells 2020; 9:cells9040820. [PMID: 32231133 PMCID: PMC7226814 DOI: 10.3390/cells9040820] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 03/25/2020] [Accepted: 03/26/2020] [Indexed: 12/11/2022] Open
Abstract
GSK3 has been implicated for years in the regulation of inflammation and addressed in a plethora of scientific reports using a variety of experimental (disease) models and approaches. However, the specific role of GSK3 in the inflammatory process is still not fully understood and controversially discussed. Following a detailed overview of structure, function, and various regulatory levels, this review focusses on the immunoregulatory functions of GSK3, including the current knowledge obtained from animal models. Its impact on pro-inflammatory cytokine/chemokine profiles, bacterial/viral infections, and the modulation of associated pro-inflammatory transcriptional and signaling pathways is discussed. Moreover, GSK3 contributes to the resolution of inflammation on multiple levels, e.g., via the regulation of pro-resolving mediators, the clearance of apoptotic immune cells, and tissue repair processes. The influence of GSK3 on the development of different forms of stimulation tolerance is also addressed. Collectively, the role of GSK3 as a kinase balancing the initiation/perpetuation and the amelioration/resolution of inflammation is highlighted.
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Insulin activates hepatic Wnt/β-catenin signaling through stearoyl-CoA desaturase 1 and Porcupine. Sci Rep 2020; 10:5186. [PMID: 32198362 PMCID: PMC7083857 DOI: 10.1038/s41598-020-61869-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 02/24/2020] [Indexed: 12/15/2022] Open
Abstract
The Wnt/β-catenin pathway plays a pivotal role in liver structural and metabolic homeostasis. Wnt activity is tightly regulated by the acyltransferase Porcupine through the addition of palmitoleate. Interestingly palmitoleate can be endogenously produced by the stearoyl-CoA desaturase 1 (SCD1), a lipogenic enzyme transcriptionally regulated by insulin. This study aimed to determine whether nutritional conditions, and insulin, regulate Wnt pathway activity in liver. An adenoviral TRE-Luciferase reporter was used as a readout of Wnt/β-catenin pathway activity, in vivo in mouse liver and in vitro in primary hepatocytes. Refeeding enhanced TRE-Luciferase activity and expression of Wnt target genes in mice liver, revealing a nutritional regulation of the Wnt/β-catenin pathway. This effect was inhibited in liver specific insulin receptor KO (iLIRKO) mice and upon wortmannin or rapamycin treatment. Overexpression or inhibition of SCD1 expression regulated Wnt/β-catenin activity in primary hepatocytes. Similarly, palmitoleate added exogenously or produced by SCD1-mediated desaturation of palmitate, induced Wnt signaling activity. Interestingly, this effect was abolished in the absence of Porcupine, suggesting that both SCD1 and Porcupine are key mediators of insulin-induced Wnt/β-catenin activity in hepatocytes. Altogether, our findings suggest that insulin and lipogenesis act as potential novel physiological inducers of hepatic Wnt/β-catenin pathway.
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Zhang ZD, Ren H, Wang WX, Shen GY, Huang JJ, Zhan MQ, Tang JJ, Yu X, Zhang YZ, Liang D, Yang ZD, Jiang XB. IGF-1R/β-catenin signaling axis is involved in type 2 diabetic osteoporosis. J Zhejiang Univ Sci B 2020; 20:838-848. [PMID: 31489803 DOI: 10.1631/jzus.b1800648] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Insulin-like growth factor-1 receptor (IGF-1R) is involved in both glucose and bone metabolism. IGF-1R signaling regulates the canonical Wnt/β-catenin signaling pathway. In this study, we investigated whether the IGF-1R/ β-catenin signaling axis plays a role in the pathogenesis of diabetic osteoporosis (DOP). Serum from patients with or without DOP was collected to measure the IGF-1R level using enzyme-linked immunosorbent assay (ELISA). Rats were given streptozotocin following a four-week high-fat diet induction (DOP group), or received vehicle after the same period of a normal diet (control group). Dual energy X-ray absorption, a biomechanics test, and hematoxylin-eosin (HE) staining were performed to evaluate bone mass, bone strength, and histomorphology, respectively, in vertebrae. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were performed to measure the total and phosphorylation levels of IGF-1R, glycogen synthase kinase-3β (GSK-3β), and β-catenin. The serum IGF-1R level was much higher in patients with DOP than in controls. DOP rats exhibited strikingly reduced bone mass and attenuated compression strength of the vertebrae compared with the control group. HE staining showed that the histomorphology of DOP vertebrae was seriously impaired, which manifested as decreased and thinned trabeculae and increased lipid droplets within trabeculae. PCR analysis demonstrated that IGF-1R mRNA expression was significantly up-regulated, and western blotting detection showed that phosphorylation levels of IGF-1R, GSK-3β, and β-catenin were enhanced in DOP rat vertebrae. Our results suggest that the IGF-1R/β-catenin signaling axis plays a role in the pathogenesis of DOP. This may contribute to development of the underlying therapeutic target for DOP.
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Affiliation(s)
- Zhi-Da Zhang
- The First Clinical School, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Hui Ren
- Department of Spinal Surgery, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Wei-Xi Wang
- The First Clinical School, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Geng-Yang Shen
- Department of Spinal Surgery, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Jin-Jing Huang
- The First Clinical School, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Mei-Qi Zhan
- The First Clinical School, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Jing-Jing Tang
- Department of Spinal Surgery, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Xiang Yu
- The First Clinical School, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Yu-Zhuo Zhang
- School of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - De Liang
- Department of Spinal Surgery, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Zhi-Dong Yang
- Department of Spinal Surgery, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Xiao-Bing Jiang
- Department of Spinal Surgery, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China.,Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou 510405, China
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Akhtar A, Dhaliwal J, Saroj P, Uniyal A, Bishnoi M, Sah SP. Chromium picolinate attenuates cognitive deficit in ICV-STZ rat paradigm of sporadic Alzheimer's-like dementia via targeting neuroinflammatory and IRS-1/PI3K/AKT/GSK-3β pathway. Inflammopharmacology 2020; 28:385-400. [PMID: 31898080 DOI: 10.1007/s10787-019-00681-7] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 12/16/2019] [Indexed: 02/05/2023]
Abstract
Alzheimer's disease (AD) is prevalent in old age people and is one of the most common brain diseases. Brain insulin resistance, neuroinflammation, oxidative stress, and mitochondrial and cholinergic dysfunction are key features of the disease. In our study, streptozotocin (STZ) in a dose of 3 mg/kg was injected in male Wistar rats bilaterally through the intracerebroventricular (ICV) route on stereotaxic apparatus. Chromium picolinate (CrPic) was tested at doses of 1 mg/kg, 2 mg/kg, and 4 mg/kg, while rivastigmine (2 mg/kg) was used as reference standard drug. Cognitive dysfunction induced by STZ was assessed by behavioral tests like Morris water maze and novel object recognition test. Treatment with CrPic revealed attenuation of cognitive deficit. This was confirmed by behavioral tests, biochemical estimations of antioxidant enzymes, oxidative stress, nitrosative stress, and cholinergic and mitochondrial activity. CrPic did not change AchE activity significantly. STZ-induced neuroinflammation evident by increased TNF-α, IL-6, and CRP levels was also significantly decreased by CrPic. Dysfunctional insulin signaling after ICV-STZ was demonstrated by reduced IRS-1, PI3K, AKT, BDNF gene expression, and increased GSK-3β, NF-κB gene expression with the help of qRT-PCR. CrPic treatment produced an improvement in insulin signaling revealed by increased gene expression of IRS-1, PI3-K, AKT, BDNF, and decreased gene expression of GSK-3β and NF-κB. It was concluded that CrPic reversed AD pathology revealed by improved memory, reduced oxidative stress, neuroinflammation, mitochondrial dysfunction, and upregulated insulin signaling.
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Affiliation(s)
- Ansab Akhtar
- Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India
| | - Jatinder Dhaliwal
- Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India
| | - Priyanka Saroj
- Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India
| | - Ankit Uniyal
- Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India
| | - Mahendra Bishnoi
- National Agri-Food Biotechnology Institute (NABI), Sector-81, SAS Nagar, Mohali, Punjab, 140306, India
| | - Sangeeta Pilkhwal Sah
- Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India.
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Chen KC, Chen PH, Ho KH, Shih CM, Chou CM, Cheng CH, Lee CC. IGF-1-enhanced miR-513a-5p signaling desensitizes glioma cells to temozolomide by targeting the NEDD4L-inhibited Wnt/β-catenin pathway. PLoS One 2019; 14:e0225913. [PMID: 31805126 PMCID: PMC6894868 DOI: 10.1371/journal.pone.0225913] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 11/14/2019] [Indexed: 12/20/2022] Open
Abstract
Temozolomide (TMZ) is a first-line alkylating agent for glioblastoma multiforme (GBM). Clarifying the mechanisms inducing TMZ insensitivity may be helpful in improving its therapeutic effectiveness against GBM. Insulin-like growth factor (IGF)-1 signaling and micro (mi)RNAs are relevant in mediating GBM progression. However, their roles in desensitizing GBM cells to TMZ are still unclear. We aimed to identify IGF-1-mediated miRNA regulatory networks that elicit TMZ insensitivity for GBM. IGF-1 treatment attenuated TMZ cytotoxicity via WNT/β-catenin signaling, but did not influence glioma cell growth. By miRNA array analyses, 93 upregulated and 148 downregulated miRNAs were identified in IGF-1-treated glioma cells. miR-513a-5p from the miR-513a-2 gene locus was upregulated by IGF-1-mediated phosphoinositide 3-kinase (PI3K) signaling. Its elevated levels were also observed in gliomas versus normal cells, in array data of The Cancer Genome Atlas (TCGA), and the GSE61710, GSE37366, and GSE41032 datasets. In addition, lower levels of neural precursor cell-expressed developmentally downregulated 4-like (NEDD4L), an E3 ubiquitin protein ligase that inhibits WNT signaling, were found in gliomas by analyzing cells, arrays, and RNA sequencing data of TCGA glioma patients. Furthermore, a negative correlation was identified between miR-513a-5p and NEDD4L in glioma. NEDD4L was also validated as a direct target gene of miR-513a-5p, and it was reduced by IGF-1 treatment. Overexpression of NEDD4L inhibited glioma cell viability and reversed IGF-1-repressed TMZ cytotoxicity. In contrast, miR-513a-5p significantly affected NEDD4L-inhibited WNT signaling and reduced TMZ cytotoxicity. These findings demonstrate a distinct role of IGF-1 signaling through miR-513a-5p-inhibited NEDD4L networks in influencing GBM's drug sensitivity to TMZ.
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Affiliation(s)
- Ku-Chung Chen
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Peng-Hsu Chen
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Kuo-Hao Ho
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chwen-Ming Shih
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chih-Ming Chou
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chia-Hsiung Cheng
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chin-Cheng Lee
- Department of Pathology and Laboratory Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
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48
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Safian D, Bogerd J, Schulz RW. Regulation of spermatogonial development by Fsh: The complementary roles of locally produced Igf and Wnt signaling molecules in adult zebrafish testis. Gen Comp Endocrinol 2019; 284:113244. [PMID: 31415728 DOI: 10.1016/j.ygcen.2019.113244] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 08/07/2019] [Accepted: 08/09/2019] [Indexed: 12/28/2022]
Abstract
Spermatogenesis is a cellular developmental process characterized by the coordinated proliferation and differentiation activities of somatic and germ cells in order to produce a large number of spermatozoa, the cellular basis of male fertility. Somatic cells in the testis, such as Leydig, peritubular myoid and Sertoli cells, provide structural and metabolic support and contribute to the regulatory microenvironment required for proper germ cell survival and development. The pituitary follicle-stimulating hormone (Fsh) is a major endocrine regulator of vertebrate spermatogenesis, targeting somatic cell functions in the testes. In fish, Fsh regulates Leydig and Sertoli cell functions, such as sex steroid and growth factor production, processes that also control the development of spermatogonia, the germ cell stages at the basis of the spermatogenic process. Here, we summarize recent advances in our understanding of mechanisms used by Fsh to regulate the development of spermatogonia. This involves discussing the roles of insulin-like growth factor (Igf) 3 and canonical and non-canonical Wnt signaling pathways. We will also discuss how these locally active regulatory systems interact to maintain testis tissue homeostasis.
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Affiliation(s)
- Diego Safian
- Reproductive Biology Group, Division Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology, Faculty of Science, University of Utrecht, 3584 CH Utrecht, The Netherlands
| | - Jan Bogerd
- Reproductive Biology Group, Division Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology, Faculty of Science, University of Utrecht, 3584 CH Utrecht, The Netherlands
| | - Rüdiger W Schulz
- Reproductive Biology Group, Division Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology, Faculty of Science, University of Utrecht, 3584 CH Utrecht, The Netherlands; Reproduction and Developmental Biology Group, Institute of Marine Research, P.O. Box 1870, Nordnes, 5817 Bergen, Norway.
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49
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Wier EM, Garza LA. Through the lens of hair follicle neogenesis, a new focus on mechanisms of skin regeneration after wounding. Semin Cell Dev Biol 2019; 100:122-129. [PMID: 31607627 DOI: 10.1016/j.semcdb.2019.10.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 09/26/2019] [Accepted: 10/01/2019] [Indexed: 12/31/2022]
Abstract
Wound-induced hair follicle neogenesis (WIHN) is a phenomenon that occurs in adult mammalian skin, where fully functional hair follicles are regenerated in the center of large full-thickness excisional wounds. Although originally discovered over 50 years ago in mice and rabbits, within the last decade it has received renewed interest, as the molecular mechanism has begun to be defined. This de novo regeneration of hair follicles largely recapitulates embryonic hair development, requiring canonical Wnt signaling in the epidermis, however, important differences between the two are beginning to come to light. TLR3 mediated double stranded RNA sensing is critical for the regeneration, activating retinoic acid signaling following wounding. Inflammatory cells, including Fgf9-producing γ-δ T cells and macrophages, are also emerging as important mediators of WIHN. Additionally, while dispensable in embryonic hair follicle development, Shh signaling plays a major role in WIHN and may be able to redirect cells fated to scarring wounds into a regenerative phenotype. The cellular basis of WIHN is also becoming clearer, with increasing evidence suggesting an incredible level of cellular plasticity. Multiple stem cell populations, along with lineage switching of differentiated cells all contribute towards the regeneration present in WIHN. Further study of WIHN will uncover key steps in mammalian development and regeneration, potentially leading to new clinical treatments for hair-related disorders or fibrotic scarring.
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Affiliation(s)
- Eric M Wier
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, United States.
| | - Luis A Garza
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, United States.
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50
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Wen J, Min X, Shen M, Hua Q, Han Y, Zhao L, Liu L, Huang G, Liu J, Zhao X. ACLY facilitates colon cancer cell metastasis by CTNNB1. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:401. [PMID: 31511060 PMCID: PMC6740040 DOI: 10.1186/s13046-019-1391-9] [Citation(s) in RCA: 141] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Accepted: 08/26/2019] [Indexed: 02/06/2023]
Abstract
Background Colon cancer is the second leading cancer worldwide. Recurrent disease and chemotherapeutic drug resistance are very common in the advanced stage of colon cancer. ATP-citrate lyase (ACLY), the first-step rate-controlling enzyme in lipid synthesis, is elevated in colon cancer. However, it remains unclear about the exact role of ACLY in the development of colon cancer metastasis. Methods To evaluate the role of ACLY in colon cancer metastasis, we performed cell migration and invasion assays in two ACLY-deficient colon cancer cell lines. Colon cancer mouse model is used to examine ACLY’s effects on colon metastasis potentials in vivo. We analyzed the correlation between ACLY and CTNNB1 protein in 78 colon cancer patients by Pearson correlation. To finally explore the relationship of ACLY and CTNNB1, we used western blots, migration and invasion assays to confirm that ACLY may regulate metastasis by CTNNB1. Results Our data showed that the abilities of cell migration and invasion were attenuated in ACLY-deficient HCT116 and RKO cell lines. Furthermore, we describe the mechanism of ACLY in promoting colon cancer metastasis in vitro and in vivo. ACLY could stabilize CTNNB1 (beta-catenin 1) protein by interacting, and the complex might promote CTNNB1 translocation through cytoplasm to nucleus, subsequently promote the CTNNB1 transcriptional activity and migration and invasion abilities of colon cancer cells. Immunohistochemical analysis of 78 colon cancer patients showed that the high expression levels of ACLY and CTNNB1 protein was positively correlated with metastasis of colon cancer. Conclusions These results shed new light on the molecular mechanism underlying colon cancer metastasis, which might help in improving therapeutic efficacy. Electronic supplementary material The online version of this article (10.1186/s13046-019-1391-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jun Wen
- Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xuejie Min
- The First Affiliated Hospital of Nanyang Medical College, Nanyang, Henan Province, China
| | - Mengqin Shen
- Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qian Hua
- Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yuan Han
- Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Li Zhao
- Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Liu Liu
- Department of Nuclear Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Gang Huang
- Shanghai University of Medicine & Health Sciences, Shanghai, China.
| | - Jianjun Liu
- Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Xiaoping Zhao
- Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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