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Gholam Azad M, Hussaini M, Russell TM, Richardson V, Kaya B, Dharmasivam M, Richardson DR. Multi-modal mechanisms of the metastasis suppressor, NDRG1: Inhibition of WNT/β-catenin signaling by stabilization of protein kinase Cα. J Biol Chem 2024; 300:107417. [PMID: 38815861 PMCID: PMC11261793 DOI: 10.1016/j.jbc.2024.107417] [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: 02/23/2024] [Revised: 05/14/2024] [Accepted: 05/18/2024] [Indexed: 06/01/2024] Open
Abstract
The metastasis suppressor, N-myc downstream regulated gene-1 (NDRG1), inhibits pro-oncogenic signaling in pancreatic cancer (PC). This investigation dissected a novel mechanism induced by NDRG1 on WNT/β-catenin signaling in multiple PC cell types. NDRG1 overexpression decreased β-catenin and downregulated glycogen synthase kinase-3β (GSK-3β) protein levels and its activation. However, β-catenin phosphorylation at Ser33, Ser37, and Thr41 are classically induced by GSK-3β was significantly increased after NDRG1 overexpression, suggesting a GSK-3β-independent mechanism. Intriguingly, NDRG1 overexpression upregulated protein kinase Cα (PKCα), with PKCα silencing preventing β-catenin phosphorylation at Ser33, Ser37, and Thr41, and decreasing β-catenin expression. Further, NDRG1 and PKCα were demonstrated to associate, with PKCα stabilization occurring after NDRG1 overexpression. PKCα half-life increased from 1.5 ± 0.8 h (3) in control cells to 11.0 ± 2.5 h (3) after NDRG1 overexpression. Thus, NDRG1 overexpression leads to the association of NDRG1 with PKCα and PKCα stabilization, resulting in β-catenin phosphorylation at Ser33, Ser37, and Thr41. The association between PKCα, NDRG1, and β-catenin was identified, with the formation of a potential metabolon that promotes the latter β-catenin phosphorylation. This anti-oncogenic activity of NDRG1 was multi-modal, with the above mechanism accompanied by the downregulation of the nucleo-cytoplasmic shuttling protein, p21-activated kinase 4 (PAK4), which is involved in β-catenin nuclear translocation, inhibition of AKT phosphorylation (Ser473), and decreased β-catenin phosphorylation at Ser552 that suppresses its transcriptional activity. These mechanisms of NDRG1 activity are important to dissect to understand the marked anti-cancer efficacy of NDRG1-inducing thiosemicarbazones that upregulate PKCα and inhibit WNT signaling.
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Affiliation(s)
- Mahan Gholam Azad
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Brisbane, Queensland, Australia
| | - Mohammed Hussaini
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Brisbane, Queensland, Australia
| | - Tiffany M Russell
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Brisbane, Queensland, Australia
| | - Vera Richardson
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Brisbane, Queensland, Australia
| | - Busra Kaya
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Brisbane, Queensland, Australia
| | - Mahendiran Dharmasivam
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Brisbane, Queensland, Australia
| | - Des R Richardson
- Centre for Cancer Cell Biology and Drug Discovery, Griffith University, Brisbane, Queensland, Australia; Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan.
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Du F, Li J, Zhang S, Zeng X, Nie J, Li Z. Oxidative stress in hair follicle development and hair growth: Signalling pathways, intervening mechanisms and potential of natural antioxidants. J Cell Mol Med 2024; 28:e18486. [PMID: 38923380 PMCID: PMC11196958 DOI: 10.1111/jcmm.18486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 05/02/2024] [Accepted: 05/28/2024] [Indexed: 06/28/2024] Open
Abstract
Hair follicle development and hair growth are regulated by multiple factors and multiple signalling pathways. The hair follicle, as an important skin appendage, is the basis for hair growth, and it has the functions of safeguarding the body, perceiving the environment and regulating body temperature. Hair growth undergoes a regular hair cycle, including anagen, catagen and telogen. A small amount of physiological shedding of hair occurs under normal conditions, always in a dynamic equilibrium. Hair loss occurs when the skin or hair follicles are stimulated by oxidative stress, inflammation or hormonal disorders that disrupt the homeostasis of the hair follicles. Numerous researches have indicated that oxidative stress is an important factor causing hair loss. Here, we summarize the signalling pathways and intervention mechanisms by which oxidative stress affects hair follicle development and hair growth, discuss existing treatments for hair loss via the antioxidant pathway and provide our own insights. In addition, we collate antioxidant natural products promoting hair growth in recent years and discuss the limitations and perspectives of current hair loss prevention and treatment.
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Affiliation(s)
- Fanpan Du
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of EducationZunyi Medical UniversityZunyiChina
- Key Laboratory of Basic Pharmacology of Guizhou ProvinceZunyi Medical UniversityZunyiChina
- Department of Pharmacology, School of PharmacyZunyi Medical UniversityZunyiChina
| | - Jingjie Li
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of EducationZunyi Medical UniversityZunyiChina
- Key Laboratory of Basic Pharmacology of Guizhou ProvinceZunyi Medical UniversityZunyiChina
- Department of Pharmacology, School of PharmacyZunyi Medical UniversityZunyiChina
| | - Shiqian Zhang
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of EducationZunyi Medical UniversityZunyiChina
- Key Laboratory of Basic Pharmacology of Guizhou ProvinceZunyi Medical UniversityZunyiChina
- Department of Pharmacology, School of PharmacyZunyi Medical UniversityZunyiChina
| | - Xuemei Zeng
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of EducationZunyi Medical UniversityZunyiChina
- Key Laboratory of Basic Pharmacology of Guizhou ProvinceZunyi Medical UniversityZunyiChina
- Department of Pharmacology, School of PharmacyZunyi Medical UniversityZunyiChina
| | - Jing Nie
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of EducationZunyi Medical UniversityZunyiChina
- Key Laboratory of Basic Pharmacology of Guizhou ProvinceZunyi Medical UniversityZunyiChina
- Department of Pharmacology, School of PharmacyZunyi Medical UniversityZunyiChina
| | - Zheng Li
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of EducationZunyi Medical UniversityZunyiChina
- Key Laboratory of Basic Pharmacology of Guizhou ProvinceZunyi Medical UniversityZunyiChina
- Department of Pharmacology, School of PharmacyZunyi Medical UniversityZunyiChina
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Baxi AB, Li J, Quach VM, Pade LR, Moody SA, Nemes P. Cell lineage-guided mass spectrometry reveals increased energy metabolism and reactive oxygen species in the vertebrate organizer. Proc Natl Acad Sci U S A 2024; 121:e2311625121. [PMID: 38300871 PMCID: PMC10861879 DOI: 10.1073/pnas.2311625121] [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: 07/13/2023] [Accepted: 12/12/2023] [Indexed: 02/03/2024] Open
Abstract
Molecular understanding of the vertebrate Organizer, a tissue center critical for inductive signaling during gastrulation, has so far been mostly limited to transcripts and a few proteins, the latter due to limitations in detection and sensitivity. The Spemann-Mangold Organizer (SMO) in the South African Clawed Frog (X. laevis), a popular model of development, has long been known to be the origin of signals that pattern the mesoderm and central nervous system. Molecular screens of the SMO have identified several genes responsible for the ability of the SMO to establish the body axis. Nonetheless, a comprehensive study of proteins and metabolites produced specifically in the SMO and their functional roles has been lacking. Here, we pioneer a deep discovery proteomic and targeted metabolomic screen of the SMO in comparison to the remainder of the embryo using high-resolution mass spectrometry (HRMS). Quantification of ~4,600 proteins and a panel of targeted metabolites documented differential expression for 460 proteins and multiple intermediates of energy metabolism in the SMO. Upregulation of oxidative phosphorylation and redox regulatory proteins gave rise to elevated oxidative stress and an accumulation of reactive oxygen species in the SMO. Imaging experiments corroborated these findings, discovering enrichment of hydrogen peroxide in the SMO. Chemical perturbation of the redox gradient perturbed mesoderm involution during early gastrulation. HRMS expands the bioanalytical toolbox of cell and developmental biology, providing previously unavailable information on molecular classes to challenge and refine our classical understanding of the Organizer and its function during early patterning of the embryo.
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Affiliation(s)
- Aparna B. Baxi
- Department of Chemistry and Biochemistry, University of Maryland, College Park, MD20742
- Department of Anatomy and Cell Biology,School of Medical and Health Sciences,The George Washington University, Washington, DC20037
| | - Jie Li
- Department of Chemistry and Biochemistry, University of Maryland, College Park, MD20742
| | - Vi M. Quach
- Department of Chemistry and Biochemistry, University of Maryland, College Park, MD20742
| | - Leena R. Pade
- Department of Chemistry and Biochemistry, University of Maryland, College Park, MD20742
| | - Sally A. Moody
- Department of Anatomy and Cell Biology,School of Medical and Health Sciences,The George Washington University, Washington, DC20037
| | - Peter Nemes
- Department of Chemistry and Biochemistry, University of Maryland, College Park, MD20742
- Department of Anatomy and Cell Biology,School of Medical and Health Sciences,The George Washington University, Washington, DC20037
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Baxi AB, Li J, Quach VM, Nemes P. Cell Lineage-Guided Microanalytical Mass Spectrometry Reveals Increased Energy Metabolism and Reactive Oxygen Species in the Vertebrate Organizer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.07.548174. [PMID: 37461553 PMCID: PMC10350060 DOI: 10.1101/2023.07.07.548174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2024]
Abstract
Molecular understanding of the vertebrate Organizer, a tissue center critical for inductive signaling during gastrulation, has so far been limited to transcripts and some proteins due to limitations in detection and sensitivity. The Spemann-Mangold Organizer (SMO) in the South African Clawed Frog ( X. laevis ), a popular model of development, has long been discovered to induce the patterning of the central nervous system. Molecular screens on the tissue have identified several genes, such as goosecoid, chordin, and noggin, with independent ability to establish a body axis. A comprehensive study of proteins and metabolites produced in the SMO and their functional roles has been lacking. Here, we pioneer a deep discovery proteomic and targeted metabolomic screen of the SMO in comparison to the rest of the embryo using liquid chromatography high-resolution mass spectrometry (HRMS). Quantification of ∼4,600 proteins and a panel of metabolites documented differential expression for ∼450 proteins and multiple intermediates of energy metabolism in the SMO. Upregulation of oxidative phosphorylation (OXPHOS) and redox regulatory proteins gave rise to elevated oxidative stress and an accumulation of reactive oxygen species in the Organizer. Imaging experiments corroborated these findings, discovering enrichment of hydrogen peroxide in the SMO tissue. Chemical perturbation of the redox gradient affected mesoderm involution during early tissue movements of gastrulation. HRMS expands the bioanalytical toolbox of cell and developmental biology, providing previously unavailable information on molecular classes to challenge and refine our classical understanding of the Organizer and its function during early patterning of the embryo.
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Prutton KM, Marentette JO, Maclean KN, Roede JR. Characterization of mitochondrial and metabolic alterations induced by trisomy 21 during neural differentiation. Free Radic Biol Med 2023; 196:11-21. [PMID: 36638900 PMCID: PMC9898228 DOI: 10.1016/j.freeradbiomed.2023.01.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 01/03/2023] [Accepted: 01/08/2023] [Indexed: 01/11/2023]
Abstract
Cellular redox state directs differentiation of induced pluripotent stem cells (iPSC) by energy metabolism control and ROS generation. As oxidative stress and mitochondrial dysfunction have been extensively reported in Down syndrome (DS), we evaluated mitochondrial phenotypes and energy metabolism during neural differentiation of DS iPSCs to neural progenitor cells (NPCs). Our results indicate early maturation of mitochondrial networks and elevated NADPH oxidase 4 (NOX4) expression in DS iPSCs. DS cells also fail to transition from glycolysis to oxidative phosphorylation during differentiation. Specifically, DS NPCs show an increased energetic demand that is limited in their mitochondrial and glycolytic response to mitochondrial distress. Additionally, DS iPSC and NPC non-mitochondrial oxygen consumption was significantly impacted by NOX inhibition. Together, these data build upon previous evidence of accelerated neural differentiation in DS that correlates with cellular redox state. We demonstrate the potential for mitochondrial and non-mitochondrial ROS sources to impact differentiation timing in the context of DS, which could contribute to developmental deficits in this condition.
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Affiliation(s)
- Kendra M Prutton
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA; Linda Crnic Institute for Down Syndrome, Aurora, CO, USA
| | - John O Marentette
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA; Linda Crnic Institute for Down Syndrome, Aurora, CO, USA
| | - Kenneth N Maclean
- Linda Crnic Institute for Down Syndrome, Aurora, CO, USA; Department of Pediatrics, School of Medicine, University of Colorado, Aurora, CO, USA
| | - James R Roede
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA; Linda Crnic Institute for Down Syndrome, Aurora, CO, USA.
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Zhu M, Wang Q, Gu T, Han Y, Zeng X, Li J, Dong J, Huang H, Qian P. Hydrogel-based microenvironment engineering of haematopoietic stem cells. Cell Mol Life Sci 2023; 80:49. [PMID: 36690903 PMCID: PMC11073069 DOI: 10.1007/s00018-023-04696-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 11/06/2022] [Accepted: 01/08/2023] [Indexed: 01/25/2023]
Abstract
Haematopoietic Stem cells (HSCs) have the potential for self-renewal and multilineage differentiation, and their behaviours are finely tuned by the microenvironment. HSC transplantation (HSCT) is widely used in the treatment of haematologic malignancies while limited by the quantity of available HSCs. With the development of tissue engineering, hydrogels have been deployed to mimic the HSC microenvironment in vitro. Engineered hydrogels influence HSC behaviour by regulating mechanical strength, extracellular matrix microstructure, cellular ligands and cytokines, cell-cell interaction, and oxygen concentration, which ultimately facilitate the acquisition of sufficient HSCs. Here, we review recent advances in the application of hydrogel-based microenvironment engineering of HSCs, and provide future perspectives on challenges in basic research and clinical practice.
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Affiliation(s)
- Meng Zhu
- Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China
- Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, 310058, China
| | - Qiwei Wang
- Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China
- Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, 310058, China
| | - Tianning Gu
- Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China
- Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, 310058, China
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yingli Han
- Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China
- Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, 310058, China
| | - Xin Zeng
- Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China
- Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, 310058, China
| | - Jinxin Li
- Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China
- Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, 310058, China
| | - Jian Dong
- Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China
- Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, 310058, China
| | - He Huang
- Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.
- Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, 310058, China.
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
| | - Pengxu Qian
- Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
- Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.
- Institute of Hematology, Zhejiang University and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, 310058, China.
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Heredia-García G, Gómez-Oliván LM, Elizalde-Velázquez GA, Cardoso-Vera JD, Orozco-Hernández JM, Rosales-Pérez KE, García-Medina S, Islas-Flores H, Galar-Martínez M, Dublán-García O. Multi-biomarker approach and IBR index to evaluate the effects of bisphenol A on embryonic stages of zebrafish (Danio rerio). ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2022; 94:103925. [PMID: 35835282 DOI: 10.1016/j.etap.2022.103925] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 06/23/2022] [Accepted: 06/29/2022] [Indexed: 06/15/2023]
Abstract
This study assessed the effects of Bisphenol A in embryonic stages of zebrafish, applying an IBR multi-biomarker approach that included alterations in growth and oxidative status and relates it with the expression of Nrf1, Nrf2, Wnt3a, Wnt8a, COX-2, Qdpra, and DKK1 genes. For this purpose, we exposed zebrafish embryos to eight environmentally relevant concentrations of BPA (220, 380, 540, 700, 860, 1180, 1340, and 1500 ng L-1) until 96 h post-fertilization. Our results show that BPA induces several malformations in embryos (developmental delay, hypopigmentation, tail malformations, and on), leading to their death. The LC50, EC50 of malformations, and teratogenic index (TI) were 1234.60 ng L-1, 987.77 ng L-1, and 1.25, respectively; thus, this emerging contaminant is teratogenic. Regarding oxidative stress and gene expression, we demonstrated BPA altered oxidative status and the gene expression in embryos of Danio rerio.
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Affiliation(s)
- Gerardo Heredia-García
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón intersección Paseo Tollocan, Colonia Residencial Colón, 50120 Toluca, Estado de México, Mexico
| | - Leobardo Manuel Gómez-Oliván
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón intersección Paseo Tollocan, Colonia Residencial Colón, 50120 Toluca, Estado de México, Mexico.
| | - Gustavo Axel Elizalde-Velázquez
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón intersección Paseo Tollocan, Colonia Residencial Colón, 50120 Toluca, Estado de México, Mexico
| | - Jesús Daniel Cardoso-Vera
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón intersección Paseo Tollocan, Colonia Residencial Colón, 50120 Toluca, Estado de México, Mexico
| | - José Manuel Orozco-Hernández
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón intersección Paseo Tollocan, Colonia Residencial Colón, 50120 Toluca, Estado de México, Mexico
| | - Karina Elisa Rosales-Pérez
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón intersección Paseo Tollocan, Colonia Residencial Colón, 50120 Toluca, Estado de México, Mexico
| | - Sandra García-Medina
- Laboratorio de Toxicología Acuática, Departamento de Farmacia, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Unidad Profesional Adolfo López Mateos, Av. Wilfrido Massieu s/n y cerrada Manuel Stampa, Col. Industrial Vallejo, 07700 Ciudad de México, Mexico
| | - Hariz Islas-Flores
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón intersección Paseo Tollocan, Colonia Residencial Colón, 50120 Toluca, Estado de México, Mexico
| | - Marcela Galar-Martínez
- Laboratorio de Toxicología Acuática, Departamento de Farmacia, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Unidad Profesional Adolfo López Mateos, Av. Wilfrido Massieu s/n y cerrada Manuel Stampa, Col. Industrial Vallejo, 07700 Ciudad de México, Mexico
| | - Octavio Dublán-García
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón intersección Paseo Tollocan, Colonia Residencial Colón, 50120 Toluca, Estado de México, Mexico
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Guo CL. Self-Sustained Regulation or Self-Perpetuating Dysregulation: ROS-dependent HIF-YAP-Notch Signaling as a Double-Edged Sword on Stem Cell Physiology and Tumorigenesis. Front Cell Dev Biol 2022; 10:862791. [PMID: 35774228 PMCID: PMC9237464 DOI: 10.3389/fcell.2022.862791] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 04/29/2022] [Indexed: 12/19/2022] Open
Abstract
Organ development, homeostasis, and repair often rely on bidirectional, self-organized cell-niche interactions, through which cells select cell fate, such as stem cell self-renewal and differentiation. The niche contains multiplexed chemical and mechanical factors. How cells interpret niche structural information such as the 3D topology of organs and integrate with multiplexed mechano-chemical signals is an open and active research field. Among all the niche factors, reactive oxygen species (ROS) have recently gained growing interest. Once considered harmful, ROS are now recognized as an important niche factor in the regulation of tissue mechanics and topology through, for example, the HIF-YAP-Notch signaling pathways. These pathways are not only involved in the regulation of stem cell physiology but also associated with inflammation, neurological disorder, aging, tumorigenesis, and the regulation of the immune checkpoint molecule PD-L1. Positive feedback circuits have been identified in the interplay of ROS and HIF-YAP-Notch signaling, leading to the possibility that under aberrant conditions, self-organized, ROS-dependent physiological regulations can be switched to self-perpetuating dysregulation, making ROS a double-edged sword at the interface of stem cell physiology and tumorigenesis. In this review, we discuss the recent findings on how ROS and tissue mechanics affect YAP-HIF-Notch-PD-L1 signaling, hoping that the knowledge can be used to design strategies for stem cell-based and ROS-targeting therapy and tissue engineering.
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Affiliation(s)
- Chin-Lin Guo
- Institute of Physics, Academia Sinica, Taipei, Taiwan
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9
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Prutton KM, Marentette JO, Leifheit BA, Esquer H, LaBarbera DV, Anderson CC, Maclean KN, Roede JR. Oxidative stress as a candidate mechanism for accelerated neuroectodermal differentiation due to trisomy 21. Free Radic Biol Med 2022; 186:32-42. [PMID: 35537597 DOI: 10.1016/j.freeradbiomed.2022.04.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 04/21/2022] [Accepted: 04/27/2022] [Indexed: 11/17/2022]
Abstract
The ubiquity of cognitive deficits and early onset Alzheimer's disease in Down syndrome (DS) has focused much DS iPSC-based research on neuron degeneration and regeneration. Despite reports of elevated oxidative stress in DS brains, few studies assess the impact of this oxidative burden on iPSC differentiation. Here, we evaluate cellular specific redox differences in DS and euploid iPSCs and neural progenitor cells (NPCs) during critical intermediate stages of differentiation. Despite successful generation of NPCs, our results indicate accelerated neuroectodermal differentiation of DS iPSCs compared to isogenic, euploid controls. Specifically, DS embryoid bodies (EBs) and neural rosettes prematurely develop with distinct morphological differences from controls. Additionally, we observed developmental stage-specific alterations in mitochondrial superoxide production and SOD1/2 abundance, coupled with modulations in thioredoxin, thioredoxin reductase, and peroxiredoxin isoforms. Disruption of intracellular redox state and its associated signaling has the potential to disrupt cellular differentiation and development in DS lending to DS-specific phenotypes.
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Affiliation(s)
- Kendra M Prutton
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, 80045, USA; Linda Crnic Institute for Down Syndrome, Aurora, CO, 80045, USA
| | - John O Marentette
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, 80045, USA; Linda Crnic Institute for Down Syndrome, Aurora, CO, 80045, USA
| | - Brice A Leifheit
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, 80045, USA
| | - Hector Esquer
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, 80045, USA; Center for Drug Discovery, University of Colorado, Aurora, CO, 80045, USA
| | - Daniel V LaBarbera
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, 80045, USA; Center for Drug Discovery, University of Colorado, Aurora, CO, 80045, USA
| | - Colin C Anderson
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, 80045, USA; Linda Crnic Institute for Down Syndrome, Aurora, CO, 80045, USA
| | - Kenneth N Maclean
- Linda Crnic Institute for Down Syndrome, Aurora, CO, 80045, USA; Department of Pediatrics, School of Medicine, University of Colorado, Aurora, CO, 80045, USA
| | - James R Roede
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, 80045, USA; Linda Crnic Institute for Down Syndrome, Aurora, CO, 80045, USA.
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10
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Zhu L, Yang X, Feng J, Mao J, Zhang Q, He M, Mi Y, Mei Y, Jin G, Zhang H. CYP2E1 plays a suppressive role in hepatocellular carcinoma by regulating Wnt/Dvl2/β-catenin signaling. J Transl Med 2022; 20:194. [PMID: 35509083 PMCID: PMC9066941 DOI: 10.1186/s12967-022-03396-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 04/18/2022] [Indexed: 01/02/2023] Open
Abstract
Objective Knowledge of the role of CYP2E1 in hepatocarcinogenesis is largely based on epidemiological and animal studies, with a primary focus on the role of CYP2E1 in metabolic activation of procarcinogens. Few studies have directly assessed the effects of CYP2E1 on HCC malignant phenotypes. Methods The expression of CYP2E1 in HCC tissues was determined by qRT-PCR, western blotting and immunohistochemistry. Overexpression of CYP2E1 in HCC cell was achieved by lentivirus transfection. The function of CYP2E1 were detected by CCK-8, wound healing, transwell assays, xenograft models and pulmonary metastasis model. TOP/FOPFlash reporter assay, western blotting, functional rescue experiments, Co-immunoprecipitation and reactive oxygen species detection were conducted to reveal the underlying mechanism of the tumor suppressive role of CYP2E1. Results CYP2E1 expression is down-regulated in HCC tissues, and this downregulation was associated with large tumor diameter, vascular invasion, poor differentiation, and shortened patient survival time. Ectopic expression of CYP2E1 inhibits the proliferation, invasion and migration and epithelial-to-mesenchymal transition of HCC cells in vitro, and inhibits tumor formation and lung metastasis in nude mice. Mechanistic investigations show that CYP2E1 overexpression significantly inhibited Wnt/β-catenin signaling activity and decreased Dvl2 expression in HCC cells. An increase in Dvl2 expression restored the malignant phenotype of HCC cells. Notably, CYP2E1 promoted the ubiquitin-mediated degradation of Dvl2 by strengthening the interaction between Dvl2 and the E3 ubiquitin ligase KLHL12 in CYP2E1-stable HCC cells. CYP2E1-induced ROS accumulation was a critical upstream event in the Wnt/β-Catenin pathway in CYP2E1-overexpressing HCC cells. Conclusions These results provide novel insight into the role of CYP2E1 in HCC and the tumor suppressor role of CYP2E1 can be attributed to its ability to manipulate Wnt/Dvl2/β-catenin pathway via inducing ROS accumulation, which provides a potential target for the prevention and treatment of HCC. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03396-6.
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Affiliation(s)
- Lili Zhu
- Department of Biochemistry & Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, 100 Kexue Road, Zhengzhou, 450001, Henan, China
| | - Xiaobei Yang
- Department of Biochemistry & Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, 100 Kexue Road, Zhengzhou, 450001, Henan, China
| | - Jingyu Feng
- Department of Biochemistry & Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, 100 Kexue Road, Zhengzhou, 450001, Henan, China
| | - Jian Mao
- Zhengzhou Tobacco Research Institute of China National Tobacco Company, Zhengzhou, 450001, China
| | - Qidong Zhang
- Zhengzhou Tobacco Research Institute of China National Tobacco Company, Zhengzhou, 450001, China
| | - Mengru He
- Department of Biochemistry & Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, 100 Kexue Road, Zhengzhou, 450001, Henan, China
| | - Yang Mi
- Department of Biochemistry & Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, 100 Kexue Road, Zhengzhou, 450001, Henan, China
| | - Yingwu Mei
- Department of Biochemistry & Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, 100 Kexue Road, Zhengzhou, 450001, Henan, China
| | - Ge Jin
- Department of Biochemistry & Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, 100 Kexue Road, Zhengzhou, 450001, Henan, China
| | - Haifeng Zhang
- Department of Biochemistry & Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, 100 Kexue Road, Zhengzhou, 450001, Henan, China.
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11
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Maes M, Kubera M, Kotańska M. Aberrations in the Cross-Talks Among Redox, Nuclear Factor-κB, and Wnt/β-Catenin Pathway Signaling Underpin Myalgic Encephalomyelitis and Chronic Fatigue Syndrome. Front Psychiatry 2022; 13:822382. [PMID: 35599774 PMCID: PMC9120845 DOI: 10.3389/fpsyt.2022.822382] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 03/23/2022] [Indexed: 01/07/2023] Open
Abstract
There is evidence that chronic fatigue spectrum disorders (CFAS-Ds), including myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS), and chronic fatigue with physiosomatic symptoms including when due to comorbid medical disease, are characterized by neuroimmune and neuro-oxidative biomarkers. This study was performed to delineate the protein-protein interaction (PPI) network of CFAS-D and to discover the pathways, molecular patterns, and domains enriched in their PPI network. We performed network, enrichment, and annotation analyses using differentially expressed proteins and metabolics, which were established in patients with CFAS-D. The PPI network analysis revealed that the backbone of the highly connective CFAS-D network comprises NFKB1, CTNNB1, ALB, peroxides, NOS2, tumor necrosis factor (TNF), and interleukin-6 (IL-6) and that the network comprises interconnected immune-oxidative-nitrosative and Wnt/β-catenin subnetworks. Multiomics enrichment analysis shows that the CFAS-D network is highly significantly associated with cellular (antioxidant) detoxification, hydrogen peroxide metabolic process, peroxidase and oxidoreductase activity, interleukin-10 (IL-10) anti-inflammatory signaling and neurodegenerative canonical Wnt, the β-catenin complex, cadherin domains, cell-cell junctions and TLR2/4 pathways, and the transcription factors nuclear factor kappa B (NF-κB) and RELA. The top 10 DOID annotations of the CFAS-D network include four intestinal, three immune system disorders, cancer, and infectious disease. The custom Gene Ontology (GO) term annotation analysis revealed that the CFAS-D network is associated with a response to a toxic substance, lipopolysaccharides, bacterium, or virus. In conclusion, CFAS-D may be triggered by a variety of stimuli and their effects are mediated by aberrations in the cross-talks between redox, NF-κB, and Wnt/β-catenin signaling pathways leading to dysfunctions in multicellular organismal homeostatic processes.
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Affiliation(s)
- Michael Maes
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.,Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria.,IMPACT Strategic Research Center, Deakin University, Geelong, VIC, Australia
| | - Marta Kubera
- Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
| | - Magdalena Kotańska
- Department of Pharmacological Screening, Medical College, Jagiellonian University, Kraków, Poland
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12
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D’Aloia A, Arrigoni E, Costa B, Berruti G, Martegani E, Sacco E, Ceriani M. RalGPS2 Interacts with Akt and PDK1 Promoting Tunneling Nanotubes Formation in Bladder Cancer and Kidney Cells Microenvironment. Cancers (Basel) 2021; 13:cancers13246330. [PMID: 34944949 PMCID: PMC8699646 DOI: 10.3390/cancers13246330] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/01/2021] [Accepted: 12/14/2021] [Indexed: 12/30/2022] Open
Abstract
Simple Summary Cell-to-cell communication in the tumor microenvironment is a crucial process to orchestrate the different components of the tumoral infrastructure. Among the mechanisms of cellular interplay in cancer cells, tunneling nanotubes (TNTs) are dynamic connections that play an important role. The mechanism of the formation of TNTs among cells and the molecules involved in the process remain to be elucidated. In this study, we analyze several bladder cancer cell lines, representative of tumors at different stages and grades. We demonstrate that TNTs are formed only by mid or high-stage cell lines that show muscle-invasive properties and that they actively transport mitochondria and proteins. The formation of TNTs is triggered by stressful conditions and starts with the assembly of a specific multimolecular complex. In this study, we characterize some of the protein components of the TNTs complex, as they are potential novel molecular targets for future therapies aimed at counteracting tumor progression. Abstract RalGPS2 is a Ras-independent Guanine Nucleotide Exchange Factor for RalA GTPase that is involved in several cellular processes, including cytoskeletal organization. Previously, we demonstrated that RalGPS2 also plays a role in the formation of tunneling nanotubes (TNTs) in bladder cancer 5637 cells. In particular, TNTs are a novel mechanism of cell–cell communication in the tumor microenvironment, playing a central role in cancer progression and metastasis formation. However, the molecular mechanisms involved in TNTs formation still need to be fully elucidated. Here we demonstrate that mid and high-stage bladder cancer cell lines have functional TNTs, which can transfer mitochondria. Moreover, using confocal fluorescence time-lapse microscopy, we show in 5637 cells that TNTs mediate the trafficking of RalA protein and transmembrane MHC class III protein leukocyte-specific transcript 1 (LST1). Furthermore, we show that RalGPS2 is essential for nanotubes generation, and stress conditions boost its expression both in 5637 and HEK293 cell lines. Finally, we prove that RalGPS2 interacts with Akt and PDK1, in addition to LST1 and RalA, leading to the formation of a complex that promotes nanotubes formation. In conclusion, our findings suggest that in the tumor microenvironment, RalGPS2 orchestrates the assembly of multimolecular complexes that drive the formation of TNTs.
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Affiliation(s)
- Alessia D’Aloia
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy; (A.D.); (E.A.); (B.C.); (E.M.); (E.S.)
| | - Edoardo Arrigoni
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy; (A.D.); (E.A.); (B.C.); (E.M.); (E.S.)
| | - Barbara Costa
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy; (A.D.); (E.A.); (B.C.); (E.M.); (E.S.)
| | - Giovanna Berruti
- Department of Biosciences, University of Milan, Via Celoria 26, 20133 Milan, Italy;
| | - Enzo Martegani
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy; (A.D.); (E.A.); (B.C.); (E.M.); (E.S.)
- SYSBIO-ISBE-IT-Candidate National Node of Italy for ISBE, Research Infrastructure for Systems Biology Europe, 20126 Milan, Italy
| | - Elena Sacco
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy; (A.D.); (E.A.); (B.C.); (E.M.); (E.S.)
- SYSBIO-ISBE-IT-Candidate National Node of Italy for ISBE, Research Infrastructure for Systems Biology Europe, 20126 Milan, Italy
| | - Michela Ceriani
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy; (A.D.); (E.A.); (B.C.); (E.M.); (E.S.)
- Milan Center for Neuroscience (NeuroMI), University of Milano-Bicocca, Piazza dell’Ateneo Nuovo 1, 20126 Milano, Italy
- Correspondence: ; Tel.: +39-0264483544
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13
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Apatinib suppresses lung cancer stem-like cells by complex interplay between β-catenin signaling and mitochondrial ROS accumulation. Cell Death Discov 2021; 7:102. [PMID: 33980809 PMCID: PMC8115647 DOI: 10.1038/s41420-021-00480-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/21/2021] [Accepted: 04/13/2021] [Indexed: 02/07/2023] Open
Abstract
The abnormal activation of Wnt/β-catenin signaling plays a critical role in the development of lung cancer, which is also important in the generation and maintenance of lung cancer stem cell (CSC). CSCs have unique capabilities to resist anticancer therapy, seed recurrent tumors, and disseminate to and colonize distant tissues. Apatinib, a small-molecule VEGFR2-tyrosine kinase inhibitor, shows highly efficient antitumor activity in heavily treated, chemoresistant, and metastatic lung cancer. We speculated that inhibition of Wnt/β-catenin signaling and targeting lung CSCs could be one of the anti-tumor mechanisms of apatinib. In the present study we demonstrated that apatinib repressed lung CSC-like traits by hindering sphere formation ability, lung CSC-related marker expression and decreasing chemoresistance derived stemness. Mechanistically, apatinib exerted its anti-CSC effects by inhibiting β-catenin and its downstream targets. Moreover, apatinib induced the production of reactive oxyen species (ROS), which participated in the inhibitory effects of apatinib on lung CSCs. It was found that β-catenin regulated apatinib-induced production of ROS. Inhibition or promotion of ROS production with N-acetyl-L-cysteine or H2O2 not only upregulated or downregulated β-catenin expression, but also prevented or promoted DNA damage, rescued or impeded sphere formation, respectively. Collectively, our findings reveal that apatinib directly inhibits β-catenin signaling and promotes ROS generation to suppress lung CSC-like characteristics. A clearer understanding of the anti-cancer mechanisms of apatinib is required for its better application in combating advanced and refractory/recurrent lung cancer when combined with conventional chemotherapy.
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14
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Chandrasekharan B, Montllor-Albalate C, Colin AE, Andersen JL, Jang YC, Reddi AR. Cu/Zn Superoxide Dismutase (Sod1) regulates the canonical Wnt signaling pathway. Biochem Biophys Res Commun 2021; 534:720-726. [PMID: 33218686 PMCID: PMC7785591 DOI: 10.1016/j.bbrc.2020.11.011] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Accepted: 11/04/2020] [Indexed: 01/20/2023]
Abstract
Cu/Zn Superoxide Dismutase (Sod1) catalyzes the disproportionation of cytotoxic superoxide radicals (O2•-) into oxygen (O2) and hydrogen peroxide (H2O2), a key signaling molecule. In Saccharomyces cerevisiae, we previously discovered that Sod1 participates in an H2O2-mediated redox signaling circuit that links nutrient availability to the control of energy metabolism. In response to glucose and O2, Sod1-derived H2O2 stabilizes a pair of conserved plasma membrane kinases - yeast casein kinase 1 and 2 (Yck1/2) - that signal glycolytic growth and the repression of respiration. The Yck1/2 homolog in humans, casein kinase 1-γ (CK1γ), is an integral component of the Wingless and Int-1 (Wnt) signaling pathway, which is essential for regulating cell fate and proliferation in early development and adult tissue and is dysregulated in many cancers. Herein, we establish the conservation of the SOD1/YCK1 redox signaling axis in humans by finding that SOD1 regulates CK1γ expression in human embryonic kidney 293 (HEK293) cells and is required for canonical Wnt signaling and Wnt-dependent cell proliferation.
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Affiliation(s)
- Bindu Chandrasekharan
- School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, 30332, USA
| | | | - Alyson E Colin
- School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, 30332, USA
| | - Joshua L Andersen
- Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT, 84602, USA
| | - Young C Jang
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, 30332, USA; Parker Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, 30332, USA
| | - Amit R Reddi
- School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, 30332, USA; School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, 30332, USA; Parker Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, 30332, USA.
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15
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Bellei B, Papaccio F, Filoni A, Caputo S, Lopez G, Migliano E, Picardo M. Extracellular fraction of adipose tissue as an innovative regenerative approach for vitiligo treatment. Exp Dermatol 2020; 28:695-703. [PMID: 31066942 DOI: 10.1111/exd.13954] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Revised: 04/15/2019] [Accepted: 04/29/2019] [Indexed: 12/26/2022]
Abstract
Vitiligo is a common, disfiguring autoimmune disease that negatively affects patients' self-esteem and quality of life. Current treatments are moderately effective in reversing disease and promoting melanocyte regeneration. Thus, therapeutic advanced strategies are emerging from regenerative medicine. It has recently emerged that adipose tissue secretome may be used as a cell-free therapy in skin regeneration since paracrine functions of adipose-derived stem cells alone are responsible for most of the therapeutic effect of stem cells in several animal disease models. In this study, we tested the effect of adipose tissue extracellular fraction (AT-Ex) isolated from lipoaspirates on dermal and epidermal vitiligo cells in vitro. Using this experimental model, we demonstrated that molecules secreted by adipose tissue ameliorate the capability to counteract oxidative stress by a physiological stimulation of intracellular antioxidant enzymes and positively impact on cell proliferation. Due to the presence of Wnt-secreted factors, AT-Ex treatment promotes glycogen synthase kinase 3β inactivation and consequently Wnt/β-catenin pathway activation. Collectively, our findings show that AT-Ex could be useful as a natural approach to improve treatment of vitiligo.
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Affiliation(s)
- Barbara Bellei
- Laboratory of Cutaneous Physiopathology and Integrated Center for Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Rome, Italy.,Department of Plastic and Reconstructive Surgery, San Gallicano Dermatological Institute, IRCCS, Rome, Italy
| | - Federica Papaccio
- Laboratory of Cutaneous Physiopathology and Integrated Center for Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Rome, Italy.,Department of Plastic and Reconstructive Surgery, San Gallicano Dermatological Institute, IRCCS, Rome, Italy
| | - Angela Filoni
- Laboratory of Cutaneous Physiopathology and Integrated Center for Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Rome, Italy.,Department of Plastic and Reconstructive Surgery, San Gallicano Dermatological Institute, IRCCS, Rome, Italy
| | - Silvia Caputo
- Laboratory of Cutaneous Physiopathology and Integrated Center for Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Rome, Italy.,Department of Plastic and Reconstructive Surgery, San Gallicano Dermatological Institute, IRCCS, Rome, Italy
| | - Gianluca Lopez
- Laboratory of Cutaneous Physiopathology and Integrated Center for Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Rome, Italy.,Department of Plastic and Reconstructive Surgery, San Gallicano Dermatological Institute, IRCCS, Rome, Italy
| | - Emilia Migliano
- Laboratory of Cutaneous Physiopathology and Integrated Center for Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Rome, Italy.,Department of Plastic and Reconstructive Surgery, San Gallicano Dermatological Institute, IRCCS, Rome, Italy
| | - Mauro Picardo
- Laboratory of Cutaneous Physiopathology and Integrated Center for Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Rome, Italy.,Department of Plastic and Reconstructive Surgery, San Gallicano Dermatological Institute, IRCCS, Rome, Italy
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16
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Haval GA, Pekhale KD, Perween NA, Ghaskadbi SM, Ghaskadbi SS. Excess hydrogen peroxide inhibits head and foot regeneration in hydra by affecting DNA repair and expression of essential genes. J Biochem Mol Toxicol 2020; 34:e22577. [PMID: 32627281 DOI: 10.1002/jbt.22577] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 06/11/2020] [Accepted: 06/23/2020] [Indexed: 11/07/2022]
Abstract
Reactive oxygen species (ROS) are necessary for various cellular processes. However, excess ROS cause damage to many biological molecules and therefore must be tightly regulated in time and space. Hydrogen peroxide (H2 O2 ) is the most commonly used ROS as second messenger in the cell. It is a relatively long-lived freely diffusible signaling molecule during early events of injury. In the Cnidarian hydra, injury-induced ROS production is essential for regeneration to proceed. In the present study, we have examined influence of varying exposure to H2 O2 on head and foot regeneration in the middlepieces of trisected hydra. We find that longer (4 hours) exposure to 1 mM H2 O2 inhibits both head and foot regeneration while shorter exposure (2 hours) does not. Longer exposure to H2 O2 resulted in extensive damage to DNA that could not be repaired, probably due to suboptimal induction of APE1, an enzyme necessary for base excision repair (BER). Concomitantly, genes involved in activation of Wnt pathway, necessary for head regeneration, were significantly downregulated. This appeared to be due to failure of both stabilization and transient nuclear localization of β-catenin. Similarly, genes involved in foot regeneration were also downregulated on longer exposure to H2 O2 . Thus, exposure to excess ROS inhibits regenerative processes in hydra through reduced expression of genes involved in regeneration and diminished DNA repair.
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Affiliation(s)
- Gauri A Haval
- Department of Zoology, Savitribai Phule Pune University, Pune, India.,Department of Zoology, Abasaheb Garware College, Pune, India
| | - Komal D Pekhale
- Department of Zoology, Savitribai Phule Pune University, Pune, India
| | - Nusrat A Perween
- Department of Zoology, Savitribai Phule Pune University, Pune, India.,Department of Zoology, Abeda Inamdar Senior College, Pune, India
| | - Surendra M Ghaskadbi
- Developmental Biology Group, MACS-Agharkar Research Institute, Savitribai Phule Pune University, Pune, India
| | - Saroj S Ghaskadbi
- Department of Zoology, Savitribai Phule Pune University, Pune, India
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17
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Li Y, He M, Zhang W, Yang M, Ding Y, Xu S, Gu J, Li Y, Yin J, Gao Y. Antioxidant Small Molecule Compound Chrysin Promotes the Self-Renewal of Hematopoietic Stem Cells. Front Pharmacol 2020; 11:399. [PMID: 32300303 PMCID: PMC7142222 DOI: 10.3389/fphar.2020.00399] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Accepted: 03/16/2020] [Indexed: 12/11/2022] Open
Abstract
There is an increasing demand for the expansion of functional human hematopoietic stem cells (hHSCs) for various clinical applications. Based on our primary screening of antioxidant small molecule compounds library, a small molecule compound C2968 (chrysin) was identificated to expand cord blood CD34+ cells in vitro. Then we further verified the optimum concentration and explored its effect on hHSCs phenotype and biological function. C2968 could significantly increase the proportion and absolute number of CD34+CD38−CD49f+ and CD34+CD38−CD45RA−CD90+ cells under 2.5 μM. Furthermore, the total number of colony-forming units and the frequency of LT-HSCs in C2968-treated group were significantly higher than control, indicating the multipotency and long-term activity of hematopoietic stem and progenitor cells were sustained. Additionally, C2968 treatment could maintain transplantable HSCs that preserve balanced multilineage potential and promote rapid engraftment after transplantation in immunodeficient (NOG) mice. Mechanistically, the activity of chrysin might be mediated through multiple mechanisms namely delaying HSC differentiation, inhibiting ROS-activated apoptosis, and modulating of cyclin-dependent kinase inhibitors. Overall, chrysin showed good ex vivo expansion effect on hHSCs, which could maintain the self-renewal and multilineage differentiation potential of hHSCs. Through further research on its antioxidant mechanism, it may become a promising tool for further fundamental research and clinical umbilical cord blood transplantation of hHSCs.
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Affiliation(s)
- Yinghui Li
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Mei He
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Wenshan Zhang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Ming Yang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Yahui Ding
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, China
| | - Shiqi Xu
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Jiali Gu
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Yafang Li
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Jingjing Yin
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Yingdai Gao
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
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18
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Bellei B, Picardo M. Premature cell senescence in human skin: Dual face in chronic acquired pigmentary disorders. Ageing Res Rev 2020; 57:100981. [PMID: 31733332 DOI: 10.1016/j.arr.2019.100981] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 10/16/2019] [Accepted: 11/07/2019] [Indexed: 01/10/2023]
Abstract
Although senescence was originally described as an in vitro acquired cellular characteristic, it was recently recognized that senescence is physiologically and pathologically involved in aging and age-related diseases in vivo. The definition of cellular senescence has expanded to include the growth arrest caused by various cellular stresses, including DNA damage, inadequate mitochondria function, activated oncogene or tumor suppressor genes and oxidative stress. While senescence in normal aging involves various tissues over time and contributes to a decline in tissue function even with healthy aging, disease-induced premature senescence may be restricted to one or a few organs triggering a prolonged and more intense rate of accumulation of senescent cells than in normal aging. Organ-specific high senescence rate could lead to chronic diseases, especially in post-mitotic rich tissue. Recently, two opposite acquired pathological conditions related to skin pigmentation were described to be associated with premature senescence: vitiligo and melasma. In both cases, it was demonstrated that pathological dysfunctions are not restricted to melanocytes, the cell type responsible for melanin production and transport to surrounding keratinocytes. Similar to physiological melanogenesis, dermal and epidermal cells contribute directly and indirectly to deregulate skin pigmentation as a result of complex intercellular communication. Thus, despite senescence usually being reported as a uniform phenotype sharing the expression of characteristic markers, skin senescence involving mainly the dermal compartment and its paracrine function could be associated with the disappearance of melanocytes in vitiligo lesions and with the exacerbated activity of melanocytes in the hyperpigmentation spots of melasma. This suggests that the difference may arise in melanocyte intrinsic differences and/or in highly defined microenvironment peculiarities poorly explored at the current state of the art. A similar dualistic phenotype has been attributed to intratumoral stromal cells as cancer-associated fibroblasts presenting a senescent-like phenotype which influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. Here, we present a framework dissecting senescent-related molecular alterations shared by vitiligo and melasma patients and we also discuss disease-specific differences representing new challenges for treatment.
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Affiliation(s)
- Barbara Bellei
- Laboratory of Cutaneous Physiopathology and Integrated Center for Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Rome, Italy.
| | - Mauro Picardo
- Laboratory of Cutaneous Physiopathology and Integrated Center for Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Rome, Italy
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19
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Cheng YH, Dong JC, Bian Q. Small molecules for mesenchymal stem cell fate determination. World J Stem Cells 2019; 11:1084-1103. [PMID: 31875870 PMCID: PMC6904864 DOI: 10.4252/wjsc.v11.i12.1084] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 09/13/2019] [Accepted: 10/14/2019] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are adult stem cells harboring self-renewal and multilineage differentiation potential that are capable of differentiating into osteoblasts, adipocytes, or chondrocytes in vitro, and regulating the bone marrow microenvironment and adipose tissue remodeling in vivo. The process of fate determination is initiated by signaling molecules that drive MSCs into a specific lineage. Impairment of MSC fate determination leads to different bone and adipose tissue-related diseases, including aging, osteoporosis, and insulin resistance. Much progress has been made in recent years in discovering small molecules and their underlying mechanisms control the cell fate of MSCs both in vitro and in vivo. In this review, we summarize recent findings in applying small molecules to the trilineage commitment of MSCs, for instance, genistein, medicarpin, and icariin for the osteogenic cell fate commitment; isorhamnetin, risedronate, and arctigenin for pro-adipogenesis; and atractylenolides and dihydroartemisinin for chondrogenic fate determination. We highlight the underlying mechanisms, including direct regulation, epigenetic modification, and post-translational modification of signaling molecules in the AMPK, MAPK, Notch, PI3K/AKT, Hedgehog signaling pathways etc. and discuss the small molecules that are currently being studied in clinical trials. The target-based manipulation of lineage-specific commitment by small molecules offers substantial insights into bone marrow microenvironment regulation, adipose tissue homeostasis, and therapeutic strategies for MSC-related diseases.
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Affiliation(s)
- Yu-Hao Cheng
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
| | - Jing-Cheng Dong
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Qin Bian
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China.
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Expansion of primitive human hematopoietic stem cells by culture in a zwitterionic hydrogel. Nat Med 2019; 25:1566-1575. [DOI: 10.1038/s41591-019-0601-5] [Citation(s) in RCA: 107] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 08/29/2019] [Indexed: 01/12/2023]
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Kim U, Kim CY, Lee JM, Oh H, Ryu B, Kim J, Park JH. Phloretin Inhibits the Human Prostate Cancer Cells Through the Generation of Reactive Oxygen Species. Pathol Oncol Res 2019; 26:977-984. [PMID: 30937835 DOI: 10.1007/s12253-019-00643-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 03/18/2019] [Indexed: 02/07/2023]
Abstract
Phloretin is a flavonoid with known anticancer activities. However, we do not fully understand how phloretin mitigates prostate cancer on the molecular level. In the present study, we examined changes in proliferation, colony formation, and migration after phloretin treatment in human prostate cancer cells PC3 and DU145. We measured reactive oxygen species (ROS) and gene expression. Phloretin increased ROS and suppressed cell proliferation, migration, and colony formation in both cell lines. Additionally, phloretin treatment increased oxidative stress, as demonstrated through lower antioxidant enzymes (catalase, SOD2, Gpx1, Gpx3). In addition, their regulator CISD2 decreased in expression. We also found that increased ROS significantly downregulated multiple components of the Wnt/β-catenin signaling pathway (β-catenin, TCF4, FoxA2, c-Myc) and Twist1. Thus, anticancer activity of phloretin against human prostate cancer cells occurs through generating ROS to influence Wnt/β-catenin signaling. The results of this study suggest that phloretin has a therapeutic effect on prostate cancer in vitro, inhibiting the proliferation and migration of cancer cell lines PC3 and DU145. The mechanism of phloretin appears to be increasing ROS production. We thus recommend phloretin as a promising anticancer therapeutic agent.
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Affiliation(s)
- Ukjin Kim
- Department of Laboratory Animal Medicine, Research Institute for Veterinary Science, BK21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - C-Yoon Kim
- Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul, 05029, Republic of Korea
| | - Ji Min Lee
- Department of Laboratory Animal Medicine, Research Institute for Veterinary Science, BK21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Hanseul Oh
- Department of Laboratory Animal Medicine, Research Institute for Veterinary Science, BK21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea.,National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Chungcheongbuk, Republic of Korea
| | - Bokyeong Ryu
- Department of Laboratory Animal Medicine, Research Institute for Veterinary Science, BK21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Jin Kim
- Department of Laboratory Animal Medicine, Research Institute for Veterinary Science, BK21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Jae-Hak Park
- Department of Laboratory Animal Medicine, Research Institute for Veterinary Science, BK21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea.
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Li Z, Zhou L, Jiang T, Fan L, Liu X, Qiu X. Proteasomal deubiquitinase UCH37 inhibits degradation of β-catenin and promotes cell proliferation and motility. Acta Biochim Biophys Sin (Shanghai) 2019; 51:277-284. [PMID: 30726867 DOI: 10.1093/abbs/gmy176] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 12/27/2018] [Indexed: 11/13/2022] Open
Abstract
The ubiquitin-proteasome system degrades most cellular proteins in eukaryotes. UCH37, also known as UCH-L5, is a deubiquitinase binding to Rpn13, a receptor for ubiquitinated substrates in the 26 S proteasome. But, it remains unclear how UCH37 influences the proteasomal degradation of the ubiquitinated substrates. Because deletion of UCH37 is embryonically lethal in mice, this study aims to investigate the role of UCH37 in proteasomal degradation by constructing the UCH37-deficient cell lines using CRISPR/Cas9 technology. Our results demonstrated that deletion of UCH37 decreased the levels of proteasomal Rpn13, implying that UCH37 might facilitate incorporation of Rpn13 into the proteasome. Meanwhile, deletion of UCH37 decreased the levels of β-catenin and the early endosomal protein Rab8. β-Catenin interacts with TCF/LEF to control transcription, and is involved in development, tissue homeostasis and tumorigenesis. We further found that deletion of UCH37 increased the levels of the ubiquitinated β-catenin and accelerated the hydrogen peroxide-stimulated degradation of β-catenin. Deletion of UCH37 also down-regulated the transcription of c-Myc, a downstream effector of β-catenin, and inhibited cell proliferation and motility. These results raise the possibility that UCH37 maintains the homeostasis of proteasomal degradation reciprocally by assisting the recruitment of the ubiquitin receptor Rpn13 into the proteasome and by reversing ubiquitination of certain critical substrates of the 26 S proteasome.
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Affiliation(s)
- Zijian Li
- College of Life Sciences, Anhui Medical University, Hefei, China
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, and College of Life Sciences, Beijing Normal University, Beijing, China
| | - Luming Zhou
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, and College of Life Sciences, Beijing Normal University, Beijing, China
| | - Tianxia Jiang
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, and College of Life Sciences, Beijing Normal University, Beijing, China
| | - Libin Fan
- College of Life Sciences, Anhui Medical University, Hefei, China
| | - Xiaoying Liu
- College of Life Sciences, Anhui Medical University, Hefei, China
| | - Xiaobo Qiu
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, and College of Life Sciences, Beijing Normal University, Beijing, China
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Sharma N, Tramutola A, Lanzillotta C, Arena A, Blarzino C, Cassano T, Butterfield DA, Di Domenico F, Perluigi M, Barone E. Loss of biliverdin reductase-A favors Tau hyper-phosphorylation in Alzheimer's disease. Neurobiol Dis 2019; 125:176-189. [PMID: 30738142 DOI: 10.1016/j.nbd.2019.02.003] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 01/31/2019] [Accepted: 02/04/2019] [Indexed: 01/16/2023] Open
Abstract
Hyper-active GSK-3β favors Tau phosphorylation during the progression of Alzheimer's disease (AD). Akt is one of the main kinases inhibiting GSK-3β and its activation occurs in response to neurotoxic stimuli including, i.e., oxidative stress. Biliverdin reductase-A (BVR-A) is a scaffold protein favoring the Akt-mediated inhibition of GSK-3β. Reduced BVR-A levels along with increased oxidative stress were observed early in the hippocampus of 3xTg-AD mice (at 6 months), thus suggesting that loss of BVR-A could be a limiting factor in the oxidative stress-induced Akt-mediated inhibition of GSK-3β in AD. We evaluated changes of BVR-A, Akt, GSK-3β, oxidative stress and Tau phosphorylation levels: (a) in brain from young (6-months) and old (12-months) 3xTg-AD mice; and (b) in post-mortem inferior parietal lobule (IPL) samples from amnestic mild cognitive impairment (MCI), from AD and from age-matched controls. Furthermore, similar analyses were performed in vitro in cells lacking BVR-A and treated with H2O2. Reduced BVR-A levels along with: (a) increased oxidative stress; (b) reduced GSK-3β inhibition; and (c) increased Tau Ser404 phosphorylation (target of GSK-3β activity) without changes of Akt activation in young mice, were observed. Similar findings were obtained in MCI, consistent with the notion that this is a molecular mechanism disrupted in humans. Interestingly, cells lacking BVR-A and treated with H2O2 showed reduced GSK-3β inhibition and increased Tau Ser404 phosphorylation, which resulted from a defect of Akt and GSK-3β physical interaction. Reduced levels of Akt/GSK-3β complex were confirmed in both young 3xTg-AD and MCI brain. We demonstrated that loss of BVR-A impairs the neuroprotective Akt-mediated inhibition of GSK-3β in response to oxidative stress, thus contributing to Tau hyper-phosphorylation in early stage AD. Such changes potential provide promising therapeutic targets for this devastating disorder.
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Affiliation(s)
- Nidhi Sharma
- Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, Roma 00185, Italy
| | - Antonella Tramutola
- Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, Roma 00185, Italy
| | - Chiara Lanzillotta
- Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, Roma 00185, Italy
| | - Andrea Arena
- Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, Roma 00185, Italy
| | - Carla Blarzino
- Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, Roma 00185, Italy
| | - Tommaso Cassano
- Department of Clinical and Experimental Medicine, University of Foggia, Via L. Pinto, Foggia 71122, Italy
| | - D Allan Butterfield
- Department of Chemistry, Markey Cancer Center, and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA
| | - Fabio Di Domenico
- Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, Roma 00185, Italy
| | - Marzia Perluigi
- Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, Roma 00185, Italy
| | - Eugenio Barone
- Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, Roma 00185, Italy.
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Abstract
PURPOSE OF REVIEW Substantial advances have been made in understanding the biological basis of fracture healing. Yet, it is unclear whether the presence of osteoporosis or prior or current osteoporosis therapy influences the healing process or is associated with impaired healing. This review discusses the normal process of fracture healing and the role of osteoporosis and patient-specific factors in relation to fracture repair. RECENT FINDINGS The definitive association of osteoporosis to impaired fracture healing remains inconclusive because of limited evidence addressing this point. eStudies testing anabolic agents in preclinical models of ovariectomized animals with induced fractures have produced mostly positive findings showing enhanced fracture repair. Prospective human clinical trials, although few in number and limited in design and to testing only one anabolic agent, have similarly yielded modestly favorable results. Interest is high for exploring currently available osteoporosis therapies for efficacy in fracture repair. Definitive data supporting their efficacy are essential in achieving approval for this indication.
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Affiliation(s)
- Cheng Cheng
- Endocrine Research Unit, Department of Medicine, San Francisco Veterans Affairs Medical Center, 1700 Owens Street, Room 369, San Francisco, CA, 94158, USA
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, USA
| | - Dolores Shoback
- Endocrine Research Unit, Department of Medicine, San Francisco Veterans Affairs Medical Center, 1700 Owens Street, Room 369, San Francisco, CA, 94158, USA.
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, USA.
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Li B, Cao Y, Meng G, Qian L, Xu T, Yan C, Luo O, Wang S, Wei J, Ding Y, Yu D. Targeting glutaminase 1 attenuates stemness properties in hepatocellular carcinoma by increasing reactive oxygen species and suppressing Wnt/beta-catenin pathway. EBioMedicine 2019; 39:239-254. [PMID: 30555042 PMCID: PMC6355660 DOI: 10.1016/j.ebiom.2018.11.063] [Citation(s) in RCA: 153] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 11/29/2018] [Accepted: 11/29/2018] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is an aggressive malignant disease with poor prognosis. Recent advances suggest the existence of cancer stem cells (CSCs) within liver cancer, which are considered to be responsible for tumor relapse, metastasis, and chemoresistance. However, novel therapeutic approaches for eradicating CSCs are yet to be established. Here, we aimed to identify the role of glutaminase 1 (GLS1) in stemness, and the feasibility that GLS1 serves as a therapeutic target for elimination CSCs as well as the possible mechanism. METHODS Publicly-available data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) was mined to unearth the association between GLS1 and stemness phenotype. Using big data, human tissues and multiple cell lines, we gained a general picture of GLS1 expression in HCC progression. We generated stable cell lines by lentiviral-mediated overexpression or CRISPR/Cas9-based knockout. Sphere formation assays and colony formation assays were employed to analyze the relationship between GLS1 and stemness. A series of bioinformatics analyses and molecular experiments including qRT-PCR, immunoblotting, flow cytometry, and immunofluorescence were employed to investigate the role of GLS1 in regulating stemness in vitro and in vivo. FINDINGS We observed GLS1 (both KGA and GAC isoform) is highly expressed in HCC, and that high expression of GAC predicts a poor prognosis. GLS1 is exclusively expressed in the mitochondrial matrix. Upregulation of GLS1 is positively associated with advanced clinicopathological features and stemness phenotype. Targeting GLS1 reduced the expression of stemness-related genes and suppressed CSC properties in vitro. We further found GLS1 regulates stemness properties via ROS/Wnt/β-catenin signaling and that GLS1 knockout inhibits tumorigenicity in vivo. INTERPRETATION Targeting GLS1 attenuates stemness properties in HCC by increasing ROS accumulation and suppressing Wnt/β-catenin pathway, which implied that GLS1 could serve as a therapeutic target for elimination of CSCs.
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Affiliation(s)
- Binghua Li
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China
| | - Yajuan Cao
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China
| | - Gang Meng
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China; Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, China
| | - Liyuan Qian
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China
| | - Tiancheng Xu
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China
| | - Chen Yan
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China
| | - Ouyang Luo
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China
| | - Shaohe Wang
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China
| | - Jiwu Wei
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, China.
| | - Yitao Ding
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China.
| | - Decai Yu
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China.
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Shen M, Bai D, Liu B, Lu X, Hou R, Zeng C, Li N, Fu Z, Li C, Tao L, Wang H, Yin T. Dysregulated Txnip-ROS-Wnt axis contributes to the impaired ischemic heart repair in diabetic mice. Biochim Biophys Acta Mol Basis Dis 2018; 1864:3735-3745. [PMID: 30261287 DOI: 10.1016/j.bbadis.2018.09.029] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 08/08/2018] [Accepted: 09/20/2018] [Indexed: 01/15/2023]
Abstract
Hyperglycemia-induced impairment of angiogenesis contributes to the unfavorable prognosis of myocardial ischemia in long-standing diabetes mellitus. The underlying mechanism remains largely unknown and therapeutic strategies thereby limited. In the present study, we investigated the possible involvement of thioredoxin-interacting protein (TXNIP) and Wnt/β-catenin signaling in the context, and their possible relation was also explored. STZ induced diabetic mice were subjected to myocardial infarction (MI). Adenovirus expressing shTXNIP, shCtnnb1 (β-catenin) driven by VE-Cadherin promoter was administered intramyocardially immediately after MI. Cardiac function, histology, and molecular analyses were performed at predetermined time points. Increased endothelial expression of TXNIP was found in diabetic hearts, which correlated well with reduced nuclear β-catenin expression, insufficient angiogenesis, aggravated cardiac remodeling, and poor survival. Endothelial-specific knockdown of TXNIP significantly rescued β-catenin activity, together with increased angiogenesis, preserved cardiac function, and improved survival rate. Moreover, additional knockdown of β-catenin essentially reversed the beneficial effects of TXNIP downregulation. In vitro, high glucose treatment of human umbilical vein endothelial cells (HUVECs) increased TXNIP levels and ROS concentration, while it reduced β-catenin activity. Silencing TXNIP or ROS scavenger restored the high glucose induced reduction of Wnt/β-catenin activity in HUVECs. In addition, either reduction of TXNIP expression or supplementation of exogenous Wnt3a improved the HUVECs quantity and migration under high glucose conditions. Diabetes-induced increase of TXNIP expression in the endothelium contributes to impaired angiogenesis after MI, especially via the elevation of ROS and the impaired Wnt/β-catenin signaling. Targeting TXNIP-ROS-Wnt is a promising strategy in improving the prognosis.
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Affiliation(s)
- Mingzhi Shen
- Department of Cardiology, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, PR China; Department of Cardiology and National Clinical Research Center of Geriatrics Disease, Hainan Branch of PLA General Hospital, Sanya, Hainan, PR China
| | - Danna Bai
- Department of Physiology, Fourth Military Medical University, Xi'an, Shaanxi, PR China
| | - Bei Liu
- Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, PR China
| | - Xiaozhao Lu
- Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi, PR China
| | - Rongrong Hou
- Department of Endocrinology, the Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Chao Zeng
- Department of Cardiology, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, PR China
| | - Na Li
- Department of Cardiology, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, PR China
| | - Zhenhong Fu
- Department of Cardiology, PLA General Hospital, Beijing, PR China
| | - Congye Li
- Department of Cardiology, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, PR China
| | - Ling Tao
- Department of Cardiology, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, PR China
| | - Haichang Wang
- Department of Cardiology, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, PR China.
| | - Tao Yin
- Department of Cardiology, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, PR China.
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β-Catenin gene promoter hypermethylation by reactive oxygen species correlates with the migratory and invasive potentials of colon cancer cells. Cell Oncol (Dordr) 2018; 41:569-580. [DOI: 10.1007/s13402-018-0391-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/11/2018] [Indexed: 12/16/2022] Open
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Zhang S, Huang Q, Wang Q, Wang Q, Cao X, Zhao L, Xu N, Zhuge Z, Mao J, Fu X, Liu R, Wilcox CS, Patzak A, Li L, Lai EY. Enhanced Renal Afferent Arteriolar Reactive Oxygen Species and Contractility to Endothelin-1 Are Associated with Canonical Wnt Signaling in Diabetic Mice. Kidney Blood Press Res 2018; 43:860-871. [PMID: 29870994 PMCID: PMC6050514 DOI: 10.1159/000490334] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 05/24/2018] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND/AIMS Canonical Wnt signaling is involved in oxidative stress, vasculopathy and diabetes mellitus but its role in diabetic renal microvascular dysfunction is unclear. We tested the hypothesis that enhanced canonical Wnt signaling in renal afferent arterioles from diabetic mice increases reactive oxygen species (ROS) and contractions to endothelin-1 (ET-1). METHODS Streptozotocin-induced diabetes or control C57Bl/6 mice received vehicle or sulindac (40 mg·kg-1·day-1) to block Wnt signaling for 4 weeks. ET-1 contractions were measured by changes of afferent arteriolar diameter. Arteriolar H2O2, O2 -, protein expression and enzymatic activity were assessed using sensitive fluorescence probes, immunoblotting and colorimetric assay separately. RESULTS Compared to control, diabetic mouse afferent arteriole had increased O2- (+ 84%) and H2O2 (+ 91%) and enhanced responses to ET-1 at 10-8 mol·l-1 (-72±4% of versus -43±4%, P< 0.05) accompanied by reduced protein expressions and activities for catalase and superoxide dismutase 2 (SOD2). Arteriolar O2 - was increased further by ET-1 and contractions to ET-1 reduced by PEG-SOD in both groups whereas H2O2 unchanged by ET-1 and contractions were reduced by PEG-catalase selectively in diabetic mice. The Wnt signaling protein β-catenin was upregulated (3.3-fold decrease in p-β-catenin/β-catenin) while the glycogen synthase kinase-3β (GSK-3β) was downregulated (2.6-fold increase in p-GSK-3β/ GSK-3β) in preglomerular vessels of diabetic mice. Sulindac normalized the Wnt signaling proteins, arteriolar O2 -, H2O2 and ET-1 contractions while doubling microvascular catalase and SOD2 expression in diabetic mice. CONCLUSION Increased ROS, notably H2O2 contributes to enhanced afferent arteriolar responses to ET-1 in diabetes, which is closely associated with Wnt signaling. Antioxidant pharmacological strategies targeting Wnt signaling may improve vascular function in diabetic nephropathy.
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Affiliation(s)
- Suping Zhang
- Department of Physiology, and the Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qian Huang
- Department of Physiology, and the Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Physiology, Quanzhou Medical College, Quanzhou, China
| | - Qiaoling Wang
- Department of Physiology, and the Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qin Wang
- Department of Physiology, and the Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaoyun Cao
- Department of Physiology, and the Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Liang Zhao
- Department of Physiology, and the Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Physiology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Nan Xu
- Department of Physiology, and the Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhengbing Zhuge
- Department of Physiology, and the Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianhua Mao
- Department of Physiology, and the Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaodong Fu
- Department of Physiology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Ruisheng Liu
- Department of Molecular Pharmacology & Physiology, University of South Florida College of Medicine, Tampa, Florida, USA
| | - Christopher S Wilcox
- Division of Nephrology and Hypertension, and Hypertension Center, Georgetown University, Washington, District of Columbia, USA
| | - Andreas Patzak
- Institute of Vegetative Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Lingli Li
- Division of Nephrology and Hypertension, and Hypertension Center, Georgetown University, Washington, District of Columbia, USA
| | - En Yin Lai
- Department of Physiology, and the Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China,
- Division of Nephrology and Hypertension, and Hypertension Center, Georgetown University, Washington, District of Columbia, USA,
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Ohn J, Kim SJ, Choi SJ, Choe YS, Kwon O, Kim KH. Hydrogen peroxide (H2O2) suppresses hair growth through downregulation of β-catenin. J Dermatol Sci 2018; 89:91-94. [DOI: 10.1016/j.jdermsci.2017.09.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 07/17/2017] [Accepted: 09/22/2017] [Indexed: 11/15/2022]
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30
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XAV939 Inhibits Intima Formation by Decreasing Vascular Smooth Muscle Cell Proliferation and Migration Through Blocking Wnt Signaling. J Cardiovasc Pharmacol 2017; 68:414-424. [PMID: 27525574 DOI: 10.1097/fjc.0000000000000427] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Excessive proliferation, migration, and oxidative stress of vascular smooth muscle cells (VSMCs) are key mechanisms involved in intima formation, which is the basic pathological process of in stent restenosis. This study aims at exploring the role of XAV939 in proliferation, migration, and reactive oxygen species (ROS) generation of VSMCs, and hence evaluating its effects on intima formation. METHODS Carotid artery ligation models for C57BL/6 mice were established and gave them different intervention: saline, XAV939, Axin2 overexpression adenovirus, and negative control adenovirus. The intima formation was assayed by intima area and intima/media ratio. To investigate the underlying mechanisms, primary rat VSMCs were cultured and treated with XAV939 and platelet-derived growth factor-BB. EdU, direct cell counting, cell wound-healing assay, and flow cytometry were used to measure proliferation, migration, cell cycle, apoptosis, and ROS generation of VSMCs, respectively. By Western blot, we examined proliferating cell nuclear antigen, Cyclin D1, Cyclin E, p21, β-actin, JNK, phosphorylated JNK, Axin2 and β-catenin expression. Immunofluorescence staining and confocal microscopy were conducted to detect translocation of β-catenin. RESULTS XAV939 inhibited intima formation, which was exhibited by the loss of intima area and I/M ratio and attenuated proliferation, migration, and ROS generation, as well as promoted cell cycle arrest of VSMCs. Specifically, XAV939 inhibited Wnt pathway. CONCLUSIONS XAV939 attenuates intima formation because of its inhibition of proliferation, migration, and apoptosis of VSMCs through suppression of Wnt signaling pathway.
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Traver G, Mont S, Gius D, Lawson WE, Ding GX, Sekhar KR, Freeman ML. Loss of Nrf2 promotes alveolar type 2 cell loss in irradiated, fibrotic lung. Free Radic Biol Med 2017; 112:578-586. [PMID: 28870520 PMCID: PMC5623074 DOI: 10.1016/j.freeradbiomed.2017.08.026] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 08/28/2017] [Accepted: 08/31/2017] [Indexed: 12/21/2022]
Abstract
The development of radiation-induced pulmonary fibrosis represents a critical clinical issue limiting delivery of therapeutic doses of radiation to non-small cell lung cancer. Identification of the cell types whose injury initiates a fibrotic response and the underlying biological factors that govern that response are needed for developing strategies that prevent or mitigate fibrosis. C57BL/6 mice (wild type, Nrf2 null, Nrf2flox/flox, and Nrf2Δ/Δ; SPC-Cre) were administered a thoracic dose of 12Gy and allowed to recover for 250 days. Whole slide digital and confocal microscopy imaging of H&E, Masson's trichrome and immunostaining were used to assess tissue remodeling, collagen deposition and cell renewal/mobilization during the regenerative process. Histological assessment of irradiated, fibrotic wild type lung revealed significant loss of alveolar type 2 cells 250 days after irradiation. Type 2 cell loss and the corresponding development of fibrosis were enhanced in the Nrf2 null mouse. Yet, conditional deletion of Nrf2 in alveolar type 2 cells in irradiated lung did not impair type 2 cell survival nor yield an increased fibrotic phenotype. Instead, radiation-induced ΔNp63 stem/progenitor cell mobilization was inhibited in the Nrf2 null mouse while the propensity for radiation-induced myofibroblasts derived from alveolar type 2 cells was magnified. In summary, these results indicate that Nrf2 is an important regulator of irradiated lung's capacity to maintain alveolar type 2 cells, whose injury can initiate a fibrotic phenotype. Loss of Nrf2 inhibits ΔNp63 stem/progenitor mobilization, a key event for reconstitution of injured lung, while promoting a myofibroblast phenotype that is central for fibrosis.
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Affiliation(s)
- Geri Traver
- Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Stacey Mont
- Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - David Gius
- Department of Radiation Oncology, Driskill Graduate Program in Life Sciences, Department of Pharmacology, Robert Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - William E Lawson
- Division of Pulmonary & Critical Care, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37240, USA
| | - George X Ding
- Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Konjeti R Sekhar
- Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Michael L Freeman
- Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
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Richards CJ, Graf KW, Mashru RP. The Effect of Opioids, Alcohol, and Nonsteroidal Anti-inflammatory Drugs on Fracture Union. Orthop Clin North Am 2017; 48:433-443. [PMID: 28870304 DOI: 10.1016/j.ocl.2017.06.002] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The estimated rate of fracture nonunion is between 5% and 10%, adding significant cost to the health care system. The cause of fracture nonunion is multifactorial, including the severity of the injury, patient factors resulting in aberrancies in the biology of fracture, and the side effects of pain control modalities. Minimizing surgeon-controlled factors causing nonunion is important to reduce the cost of health care and improve patient outcomes. Opioids, alcohol, and nonsteroidal anti-inflammatory drugs have been implicated as risk factors for fracture nonunion. Current literature was reviewed to examine the effects of opioids, alcohol, and nonsteroidal anti-inflammatory drugs on fracture union.
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Affiliation(s)
- Christopher J Richards
- Department of Orthopaedic Surgery, Cooper University Hospital, 3 Cooper Plaza, Camden, NJ 08103, USA.
| | - Kenneth W Graf
- Department of Orthopaedic Surgery, Cooper Medical School of Rowan University, 401 South Broadway, Camden, NJ 08103, USA
| | - Rakesh P Mashru
- Department of Orthopaedic Surgery, Cooper Medical School of Rowan University, 401 South Broadway, Camden, NJ 08103, USA
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Long MJ, Lin HY, Parvez S, Zhao Y, Poganik JR, Huang P, Aye Y. β-TrCP1 Is a Vacillatory Regulator of Wnt Signaling. Cell Chem Biol 2017; 24:944-957.e7. [PMID: 28736239 DOI: 10.1016/j.chembiol.2017.06.009] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Revised: 05/16/2017] [Accepted: 06/17/2017] [Indexed: 12/22/2022]
Abstract
Simultaneous hyperactivation of Wnt and antioxidant response (AR) are often observed during oncogenesis. However, it remains unclear how the β-catenin-driven Wnt and the Nrf2-driven AR mutually regulate each other. The situation is compounded because many players in these two pathways are redox sensors, rendering bolus redox signal-dosing methods uninformative. Herein we examine the ramifications of single-protein target-specific AR upregulation in various knockdown lines. Our data document that Nrf2/AR strongly inhibits β-catenin/Wnt. The magnitude and mechanism of this negative regulation are dependent on the direct interaction between β-catenin N terminus and β-TrCP1 (an antagonist of both Nrf2 and β-catenin), and independent of binding between Nrf2 and β-TrCP1. Intriguingly, β-catenin positively regulates AR. Because AR is a negative regulator of Wnt regardless of β-catenin N terminus, this switch of function is likely sufficient to establish a new Wnt/AR equilibrium during tumorigenesis.
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Affiliation(s)
- Marcus John Long
- Department of Chemistry & Chemical Biology, Cornell University, Ithaca, NY 14853, USA
| | - Hong-Yu Lin
- Department of Chemistry & Chemical Biology, Cornell University, Ithaca, NY 14853, USA
| | - Saba Parvez
- Department of Chemistry & Chemical Biology, Cornell University, Ithaca, NY 14853, USA
| | - Yi Zhao
- Department of Chemistry & Chemical Biology, Cornell University, Ithaca, NY 14853, USA
| | - Jesse Richard Poganik
- Department of Chemistry & Chemical Biology, Cornell University, Ithaca, NY 14853, USA
| | - Paul Huang
- Department of Chemistry & Chemical Biology, Cornell University, Ithaca, NY 14853, USA
| | - Yimon Aye
- Department of Chemistry & Chemical Biology, Cornell University, Ithaca, NY 14853, USA; Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA.
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Perez-Leal O, Barrero CA, Merali S. Pharmacological stimulation of nuclear factor (erythroid-derived 2)-like 2 translation activates antioxidant responses. J Biol Chem 2017; 292:14108-14121. [PMID: 28684421 DOI: 10.1074/jbc.m116.770925] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 07/05/2017] [Indexed: 12/30/2022] Open
Abstract
Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the master regulator of the antioxidant response, and its function is tightly regulated at the transcriptional, translational, and post-translational levels. It is well-known that Nrf2 is regulated at the protein level by proteasomal degradation via Kelch-like ECH-associated protein 1 (Keap1), but how Nrf2 is regulated at the translational level is less clear. Here, we show that pharmacological stimulation increases Nrf2 levels by overcoming basal translational repression. We developed a novel reporter assay that enabled identification of natural compounds that induce Nrf2 translation by a mechanism independent of Keap1-mediated degradation. Apigenin, resveratrol, and piceatannol all induced Nrf2 translation. More importantly, the pharmacologically induced Nrf2 overcomes Keap1 regulation, translocates to the nucleus, and activates the antioxidant response. We conclude that translational regulation controls physiological levels of Nrf2, and this can be modulated by apigenin, resveratrol, and piceatannol. Also, targeting this mechanism with novel compounds could provide new insights into prevention and treatment of multiple diseases in which oxidative stress plays a significant role.
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Affiliation(s)
- Oscar Perez-Leal
- From the Department of Pharmaceutical Sciences, Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, Pennsylvania 19140.
| | - Carlos Alberto Barrero
- From the Department of Pharmaceutical Sciences, Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, Pennsylvania 19140
| | - Salim Merali
- From the Department of Pharmaceutical Sciences, Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, Pennsylvania 19140.
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Yin L, Tagde A, Gali R, Tai YT, Hideshima T, Anderson K, Avigan D, Kufe D. MUC1-C is a target in lenalidomide resistant multiple myeloma. Br J Haematol 2017. [PMID: 28643330 DOI: 10.1111/bjh.14801] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Lenalidomide (LEN) acts directly on multiple myeloma (MM) cells by inducing cereblon-mediated degradation of interferon regulatory factor 4, Ikaros (IKZF)1 and IKZF3, transcription factors that are essential for MM cell survival. The mucin 1 (MUC1) C-terminal transmembrane subunit (MUC1-C) oncoprotein is aberrantly expressed by MM cells and protects against reactive oxygen species (ROS)-mediated MM cell death. The present studies demonstrate that targeting MUC1-C with GO-203, a cell-penetrating peptide inhibitor of MUC1-C homodimerization, is more than additive with LEN in downregulating the WNT/β-catenin pathway, suppressing MYC, and inducing late apoptosis/necrosis. We show that the GO-203/LEN combination acts by synergistically increasing ROS and, in turn, suppressing β-catenin. LEN resistance has been linked to activation of the WNT/β-catenin→CD44 pathway. In this regard, our results further demonstrate that targeting MUC1-C is effective against LEN-resistant MM cells. Moreover, GO-203 resensitized LEN-resistant MM cells to LEN treatment in association with suppression of β-catenin and CD44. Targeting MUC1-C also resulted in downregulation of CD44 on the surface of primary MM cells. These findings, and the demonstration that expression of MUC1 and CD44 significantly correlate in microarrays from primary MM cells, provide support for combining GO-203 with LEN in the treatment of MM and in LEN-resistance.
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Affiliation(s)
- Li Yin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Ashujit Tagde
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Reddy Gali
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Yu-Tzu Tai
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Teru Hideshima
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Kenneth Anderson
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - David Avigan
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Donald Kufe
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
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Yang X, Tang S, Dai C, Li D, Zhang S, Deng S, Zhou Y, Xiao X. Quinocetone induces mitochondrial apoptosis in HepG2 cells through ROS-dependent promotion of VDAC1 oligomerization and suppression of Wnt1/β-catenin signaling pathway. Food Chem Toxicol 2017; 105:161-176. [PMID: 28343033 DOI: 10.1016/j.fct.2017.03.039] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2017] [Revised: 03/12/2017] [Accepted: 03/22/2017] [Indexed: 12/26/2022]
Abstract
Quinocetone (QCT) has been used as an animal feed additive in China since 2003. However, investigations indicate that QCT has potential toxicity due to the fact that it shows cytotoxicity, genotoxicity, hepatotoxicity, nephrotoxicity and immunotoxicity in vitro and animal models. Although QCT-induced mitochondrial apoptosis has been established, the molecular mechanism remains unclear. This study was aimed to investigate the role of voltage-dependent anion channel 1 (VDAC1) oligomerization and Wnt/β-catenin pathway in QCT-induced mitochondrial apoptosis. The results showed VDAC inhibitor 4, 4-diisothiocyano stilbene-2, 2-disulfonic acid (DIDS) partly compromised QCT-induced cell viability decrease (from 34.1% to 68.5%) and mitochondrial apoptosis accompanied by abating VDAC1 oligomerization, cytochrome c (Cyt c) release and the expression levels of cleaved caspase-9, -3 and poly (ADP-ribose) polymerase (PARP). Meanwhile, overexpression VDAC1 exacerbated QCT-induced VDAC1 oligomerization and Cyt c release. In addition, lithium chloride (LiCl), an activator of Wnt/β-catenin pathway, markedly attenuated QCT-induced mitochondrial apoptosis by partly restoring the expression levels of Wnt1 and β-catenin. Finally, reactive oxygen species (ROS) scavenger N-acetyl-l-cysteine (NAC) obviously blocked QCT-induced VDAC1 oligomerization and the inhibition of Wnt1/β-catenin pathway. Taken together, our results reveal that QCT induces mitochondrial apoptosis by ROS-dependent promotion of VDAC1 oligomerization and suppression of Wnt1/β-catenin pathway.
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Affiliation(s)
- Xiayun Yang
- Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Beijing, Haidian District 100193, China
| | - Shusheng Tang
- Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Beijing, Haidian District 100193, China
| | - Chongshan Dai
- Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Beijing, Haidian District 100193, China
| | - Daowen Li
- Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Beijing, Haidian District 100193, China
| | - Shen Zhang
- Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Beijing, Haidian District 100193, China
| | - Sijun Deng
- Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Beijing, Haidian District 100193, China
| | - Yan Zhou
- Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Beijing, Haidian District 100193, China
| | - Xilong Xiao
- Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Beijing, Haidian District 100193, China.
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Liao J, Liu PP, Hou G, Shao J, Yang J, Liu K, Lu W, Wen S, Hu Y, Huang P. Regulation of stem-like cancer cells by glutamine through β-catenin pathway mediated by redox signaling. Mol Cancer 2017; 16:51. [PMID: 28245869 PMCID: PMC5331650 DOI: 10.1186/s12943-017-0623-x] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Accepted: 02/23/2017] [Indexed: 12/11/2022] Open
Abstract
Background Cancer stem cells (CSCs) are thought to play an important role in tumor recurrence and drug resistance, and present a major challenge in cancer therapy. The tumor microenvironment such as growth factors, nutrients and oxygen affect CSC generation and proliferation by providing the necessary energy sources and growth signals. The side population (SP) analysis has been used to detect the stem-like cancer cell populations based on their high expression of ABCG2 that exports Hoechst-33342 and certain cytotoxic drugs from the cells. The purpose of this research is to investigate the effect of a main nutrient molecule, glutamine, on SP cells and the possible underlying mechanism(s). Methods Biochemical assays and flow cytometric analysis were used to evaluate the effect of glutamine on stem-like side population cells in vitro. Molecular analyses including RNAi interfering, qRT-PCR, and immunoblotting were employed to investigate the molecular signaling in response to glutamine deprivation and its influence on tumor formation capacity in vivo. Results We show that glutamine supports the maintenance of the stem cell phenotype by promoting glutathione synthesis and thus maintaining redox balance for SP cells. A deprivation of glutamine in the culture medium significantly reduced the proportion of SP cells. L-asparaginase, an enzyme that catalyzes the hydrolysis of asparagine and glutamine to aspartic acid and glutamate, respectively, mimics the effect of glutamine withdrawal and also diminished the proportion of SP cells. Mechanistically, glutamine deprivation increases intracellular ROS levels, leading to down-regulation of the β-catenin pathway. Conclusion Glutamine plays a significant role in maintaining the stemness of cancer cells by a redox-mediated mechanism mediated by β-catenin. Inhibition of glutamine metabolism or deprivation of glutamine by L-asparaginase may be a new strategy to eliminate CSCs and overcome drug resistance. Electronic supplementary material The online version of this article (doi:10.1186/s12943-017-0623-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jianwei Liao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.,Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Pan-Pan Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Guoxin Hou
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Jiajia Shao
- School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou, 510006, China
| | - Jing Yang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Kaiyan Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.,Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Wenhua Lu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Shijun Wen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Yumin Hu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Peng Huang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China. .,Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
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Wang T, Zhang X, Bikle DD. Osteogenic Differentiation of Periosteal Cells During Fracture Healing. J Cell Physiol 2016; 232:913-921. [PMID: 27731505 DOI: 10.1002/jcp.25641] [Citation(s) in RCA: 156] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 10/07/2016] [Indexed: 12/15/2022]
Abstract
Five to ten percent of fractures fail to heal normally leading to additional surgery, morbidity, and altered quality of life. Fracture healing involves the coordinated action of stem cells primarily coming from the periosteum which differentiate into the chondrocytes and osteoblasts, forming first the soft (cartilage) callus followed by the hard (bone) callus. These stem cells are accompanied by a vascular invasion that appears critical for the differentiation process and which may enable the entry of osteoclasts necessary for the remodeling of the callus into mature bone. However, more research is needed to clarify the signaling events that activate the osteochondroprogenitor cells of periosteum and stimulate their differentiation into chondrocytes and osteoblasts. Ultimately a thorough understanding of the mechanisms for differential regulation of these osteochondroprogenitors will aid in the treatment of bone healing and the prevention of delayed union and nonunion of fractures. In this review, evidence supporting the concept that the periosteal cells are the major cell sources of skeletal progenitors for the fracture callus will be discussed. The osteogenic differentiation of periosteal cells manipulated by Wnt/β-catenin, TGF/BMP, Ihh/PTHrP, and IGF-1/PI3K-Akt signaling in fracture repair will be examined. The effect of physical (hypoxia and hyperoxia) and chemical factors (reactive oxygen species) as well as the potential coordinated regulatory mechanisms in the periosteal progenitor cells promoting osteogenic differentiation will also be discussed. Understanding the regulation of periosteal osteochondroprogenitors during fracture healing could provide insight into possible therapeutic targets and thereby help to enhance future fracture healing and bone tissue engineering approaches. J. Cell. Physiol. 232: 913-921, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Tao Wang
- Center for Musculoskeletal Research, School of Medicine and Dentistry, University of Rochester, Rochester, New York.,Endocrine Unit, VA Medical Center and University of California, San Francisco, California
| | - Xinping Zhang
- Center for Musculoskeletal Research, School of Medicine and Dentistry, University of Rochester, Rochester, New York
| | - Daniel D Bikle
- Endocrine Unit, VA Medical Center and University of California, San Francisco, California
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Zhang Q, Gao M, Luo G, Han X, Bao W, Cheng Y, Tian W, Yan M, Yang G, An J. Enhancement of Radiation Sensitivity in Lung Cancer Cells by a Novel Small Molecule Inhibitor That Targets the β-Catenin/Tcf4 Interaction. PLoS One 2016; 11:e0152407. [PMID: 27014877 PMCID: PMC4807779 DOI: 10.1371/journal.pone.0152407] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Accepted: 03/14/2016] [Indexed: 02/07/2023] Open
Abstract
Radiation therapy is an important treatment choice for unresectable advanced human lung cancers, and a critical adjuvant treatment for surgery. However, radiation as a lung cancer treatment remains far from satisfactory due to problems associated with radiation resistance in cancer cells and severe cytotoxicity to non-cancer cells, which arise at doses typically administered to patients. We have recently identified a promising novel inhibitor of β-catenin/Tcf4 interaction, named BC-23 (C21H14ClN3O4S), which acts as a potent cell death enhancer when used in combination with radiation. Sequential exposure of human p53-null non-small cell lung cancer (NSCLC) H1299 cells to low doses of x-ray radiation, followed 1 hour later by administration of minimally cytotoxic concentrations of BC-23, resulted in a highly synergistic induction of clonogenic cell death (combination index <1.0). Co-treatment with BC-23 at low concentrations effectively inhibits Wnt/β-catenin signaling and down-regulates c-Myc and cyclin D1 expression. S phase arrest and ROS generation are also involved in the enhancement of radiation effectiveness mediated by BC-23. BC-23 therefore represents a promising new class of radiation enhancer.
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Affiliation(s)
- Qinghao Zhang
- Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.,SUNY Upstate Cancer Research Institute, State University of New York, Upstate Medical University, Syracuse, New York, United States of America
| | - Mei Gao
- Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.,SUNY Upstate Cancer Research Institute, State University of New York, Upstate Medical University, Syracuse, New York, United States of America
| | - Guifen Luo
- Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.,SUNY Upstate Cancer Research Institute, State University of New York, Upstate Medical University, Syracuse, New York, United States of America
| | - Xiaofeng Han
- Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.,SUNY Upstate Cancer Research Institute, State University of New York, Upstate Medical University, Syracuse, New York, United States of America
| | - Wenjing Bao
- Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.,SUNY Upstate Cancer Research Institute, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.,Department of Medicine, Liaoning University of Chinese Traditional Medicine, No. 33 Beiling Street, Huanggu District, Shenyang, China
| | - Yanyan Cheng
- Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.,SUNY Upstate Cancer Research Institute, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.,Department of Medicine, Liaoning University of Chinese Traditional Medicine, No. 33 Beiling Street, Huanggu District, Shenyang, China
| | - Wang Tian
- Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.,SUNY Upstate Cancer Research Institute, State University of New York, Upstate Medical University, Syracuse, New York, United States of America
| | - Maocai Yan
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States of America
| | - Guanlin Yang
- Department of Medicine, Liaoning University of Chinese Traditional Medicine, No. 33 Beiling Street, Huanggu District, Shenyang, China
| | - Jing An
- Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.,SUNY Upstate Cancer Research Institute, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.,Department of Medicine, University of California San Diego, La Jolla, California, United States of America
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Ma Y, Lv X, He J, Liu T, Wen S, Wang L. Wnt agonist stimulates liver regeneration after small-for-size liver transplantation in rats. Hepatol Res 2016; 46:E154-64. [PMID: 26176339 DOI: 10.1111/hepr.12553] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Revised: 06/15/2015] [Accepted: 07/06/2015] [Indexed: 01/05/2023]
Abstract
AIM Liver regeneration is inhibited in small-for-size grafts, which plays a role in the failure of partial liver grafts after transplantation. The Wnt/β-catenin signaling pathway plays a critical role in liver development, regeneration and homeostasis. In this study, we investigated whether pharmacological activation of Wnt signaling improves liver regeneration after small-for-size liver transplantation. METHODS The livers of male Sprague-Dawley rats were reduced to approximately 50% and 30% of their original sizes and transplanted. A Wnt agonist (2-amino-4-[3,4-[methylenedioxy]benzylamino]-6-[3-methoxyphenyl] pyrimidine], 5 mg/kg bodyweight) or an equal volume of vehicle was administrated i.p. into the donor 1 h before the transplantation. Tissue and blood samples were collected at various times after transplantation, and a survival study was performed. RESULTS Hepatic expression of active β-catenin and its downstream target gene Axin2 were decreased in 30% of liver grafts after transplantation while the Wnt agonist increased their expression similar to the 50% liver grafts. The Wnt agonist reversed inhibition of cyclin D1 expression and adenosine triphosphate production in the 30% liver grafts compared with the 50% grafts. The Wnt agonist also attenuated hepatocellular injury and increased the hepatocyte proliferation response, liver regeneration rate and survival after transplantation of the 30% liver graft. CONCLUSION Activation of Wnt/β-catenin signaling in liver grafts by pharmacological pretreatment can accelerate regeneration in a partial liver transplant model.
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Affiliation(s)
- Yuefeng Ma
- Department of General Surgery, The Affiliated Zhongshan Hospital of Dalian University, Dalian, China.,Organ Transplantation Center, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xiangwei Lv
- Organ Transplantation Center, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Jinjing He
- Organ Transplantation Center, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Tianqing Liu
- Department of Pathology, Friendship Hospital of Dalian Medical University, Dalian, China
| | - Shuang Wen
- Department of Pathology, Friendship Hospital of Dalian Medical University, Dalian, China
| | - Liming Wang
- Organ Transplantation Center, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
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Visweswaran M, Pohl S, Arfuso F, Newsholme P, Dilley R, Pervaiz S, Dharmarajan A. Multi-lineage differentiation of mesenchymal stem cells - To Wnt, or not Wnt. Int J Biochem Cell Biol 2015; 68:139-47. [PMID: 26410622 DOI: 10.1016/j.biocel.2015.09.008] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Revised: 09/21/2015] [Accepted: 09/22/2015] [Indexed: 01/06/2023]
Abstract
Mesenchymal stem cells (MSCs) are multipotent precursor cells originating from several adult connective tissues. MSCs possess the ability to self-renew and differentiate into several lineages, and are recognized by the expression of unique cell surface markers. Several lines of evidence suggest that various signal transduction pathways and their interplay regulate MSC differentiation. To that end, a critical player in regulating MSC differentiation is a group of proteins encoded by the Wnt gene family, which was previously known for influencing various stages of embryonic development and cell fate determination. As MSCs have gained significant clinical attention for their potential applications in regenerative medicine, it is imperative to unravel the mechanisms by which molecular regulators control differentiation of MSCs for designing cell-based therapeutics. It is rather coincidental that the functional outcome(s) of Wnt-induced signals share similarities with cellular redox-mediated networks from the standpoint of MSC biology. Furthermore, there is evidence for a crosstalk between Wnt and redox signalling, which begs the question whether Wnt-mediated differentiation signals involve the intermediary role of reactive oxygen species. In this review, we summarize the impact of Wnt signalling on multi-lineage differentiation of MSCs, and attempt to unravel the intricate interplay between Wnt and redox signals.
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Affiliation(s)
- Malini Visweswaran
- Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6102, Australia
| | - Sebastian Pohl
- Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6102, Australia
| | - Frank Arfuso
- Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6102, Australia
| | - Philip Newsholme
- School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6102, Australia
| | - Rodney Dilley
- Ear Sciences Centre, University of Western Australia and Ear Science Institute Australia, Perth, Western Australia 6008, Australia
| | - Shazib Pervaiz
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; National University Cancer Institute, National University Health System, Singapore; School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6102, Australia
| | - Arun Dharmarajan
- Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6102, Australia.
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Kook SH, Lee D, Cho ES, Heo JS, Poudel SB, Ahn YH, Hwang JW, Ji H, Kim JG, Lee JC. Activation of canonical Wnt/β-catenin signaling inhibits H2O2-induced decreases in proliferation and differentiation of human periodontal ligament fibroblasts. Mol Cell Biochem 2015; 411:83-94. [PMID: 26369531 DOI: 10.1007/s11010-015-2570-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 09/04/2015] [Indexed: 12/13/2022]
Abstract
Human periodontal ligament fibroblasts (hPLFs) are exposed to oxidative stress during periodontal inflammation and dental treatments. It is hypothesized that hydrogen peroxide (H2O2)-mediated oxidative stress decreases survival and osteogenic differentiation of hPLFs, whereas these decreases are prevented by activation of the Wnt pathway. However, there has been a lack of reports that define the exact roles of canonical Wnt/β-catenin signaling in H2O2-exposed hPLFs. Treatment with H2O2 reduced viability and proliferation in hPLFs in a dose- and time-dependent manner and led to mitochondria-mediated apoptosis. Pretreatment with lithium chloride (LiCl) or Wnt1 inhibited the oxidative damage that occurred in H2O2-exposed hPLFs. However, knockout of β-catenin or treatment with DKK1 facilitated the H2O2-induced decreases in viability, mitochondrial membrane potential, and Bcl-2 induction. Osteoblastic differentiation of hPLFs was also inhibited by combined treatment with 100 μM H2O2, as evidenced by the decreases in alkaline phosphatase (ALP) activity and mineralization. H2O2-mediated inhibition of osteoblast differentiation in hPLFs was significantly attenuated in the presence of 500 ng/ml Wnt1 or 20 mM LiCl. In particular, H2O2 stimulated the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) at protein and mRNA levels in hPLFs, whereas the induction was almost completely suppressed in the presence of Wnt1 or LiCl. Furthermore, siRNA-mediated silencing of Nrf2 blocked H2O2-induced decreases in ALP activity and mineralization of hPLFs with the concomitant restoration of runt-related transcription factor 2 and osteocalcin mRNA expression and ALP activity. Collectively, these results suggest that activation of the Wnt/β-catenin pathway improves proliferation and mineralization in H2O2-exposed hPLFs by downregulating Nrf2.
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Affiliation(s)
- Sung-Ho Kook
- Cluster for Craniofacial Development & Regeneration Research, Chonbuk National University, Jeonju, 561-756, South Korea.,Department of Bioactive Material Sciences, Institute of Oral Biosciences (BK21 program) and School of Dentistry, Chonbuk National University, Jeonju, 561-756, South Korea
| | - Daewoo Lee
- Department of Bioactive Material Sciences, Institute of Oral Biosciences (BK21 program) and School of Dentistry, Chonbuk National University, Jeonju, 561-756, South Korea
| | - Eui-Sic Cho
- Cluster for Craniofacial Development & Regeneration Research, Chonbuk National University, Jeonju, 561-756, South Korea.,Department of Bioactive Material Sciences, Institute of Oral Biosciences (BK21 program) and School of Dentistry, Chonbuk National University, Jeonju, 561-756, South Korea
| | - Jung Sun Heo
- Department of Maxillofacial Biomedical Engineering and Institute of Oral Biology, School of Dentistry, Kyung Hee University, Seoul, 130-701, South Korea
| | - Sher Bahadur Poudel
- Cluster for Craniofacial Development & Regeneration Research, Chonbuk National University, Jeonju, 561-756, South Korea.,Department of Bioactive Material Sciences, Institute of Oral Biosciences (BK21 program) and School of Dentistry, Chonbuk National University, Jeonju, 561-756, South Korea
| | - Yu-Hyeon Ahn
- Cluster for Craniofacial Development & Regeneration Research, Chonbuk National University, Jeonju, 561-756, South Korea.,Department of Bioactive Material Sciences, Institute of Oral Biosciences (BK21 program) and School of Dentistry, Chonbuk National University, Jeonju, 561-756, South Korea
| | - Jae-Won Hwang
- Cluster for Craniofacial Development & Regeneration Research, Chonbuk National University, Jeonju, 561-756, South Korea.,Department of Bioactive Material Sciences, Institute of Oral Biosciences (BK21 program) and School of Dentistry, Chonbuk National University, Jeonju, 561-756, South Korea
| | - Hyeok Ji
- Department of Bioactive Material Sciences, Institute of Oral Biosciences (BK21 program) and School of Dentistry, Chonbuk National University, Jeonju, 561-756, South Korea
| | - Jong-Ghee Kim
- Department of Bioactive Material Sciences, Institute of Oral Biosciences (BK21 program) and School of Dentistry, Chonbuk National University, Jeonju, 561-756, South Korea
| | - Jeong-Chae Lee
- Cluster for Craniofacial Development & Regeneration Research, Chonbuk National University, Jeonju, 561-756, South Korea. .,Department of Bioactive Material Sciences, Institute of Oral Biosciences (BK21 program) and School of Dentistry, Chonbuk National University, Jeonju, 561-756, South Korea.
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Transcriptional Analysis of Vitiligo Skin Reveals the Alteration of WNT Pathway: A Promising Target for Repigmenting Vitiligo Patients. J Invest Dermatol 2015; 135:3105-3114. [PMID: 26322948 DOI: 10.1038/jid.2015.335] [Citation(s) in RCA: 122] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Revised: 07/01/2015] [Accepted: 07/19/2015] [Indexed: 02/06/2023]
Abstract
Vitiligo affects 1% of the worldwide population. Halting disease progression and repigmenting the lesional skin represent the two faces of therapeutic challenge in vitiligo. We performed transcriptome analysis on lesional, perilesional, and non-depigmented skin from vitiligo patients and on matched skin from healthy subjects. We found a significant increase in CXCL10 in non-depigmented and perilesional vitiligo skin compared with levels in healthy control skin; however, neither CXCL10 nor other immune factors were deregulated in depigmented vitiligo skin. Interestingly, the WNT pathway, which is involved in melanocyte differentiation, was altered specifically in vitiligo skin. We demonstrated that oxidative stress decreases WNT expression/activation in keratinocytes and melanocytes. We developed an ex vivo skin model and confirmed the decrease activation of the WNT pathway in human skin subjected to oxidative stress. Finally, using pharmacological agents that activate the WNT pathway, we treated ex vivo depigmented skin from vitiligo patients and successfully induced differentiation of resident stem cells into pre-melanocytes. Our results shed light on the previously unrecognized role of decreased WNT activation in the prevention of melanocyte differentiation in depigmented vitiligo skin. Furthermore, these results support further clinical exploration of WNT agonists to repigment vitiligo lesions.
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Zhao J, Han J, Jiang J, Shi S, Ma X, Liu X, Wang C, Nie X, He Y, Jiang S, Wan C. The downregulation of Wnt/β-catenin signaling pathway is associated with zinc deficiency-induced proliferative deficit of C17.2 neural stem cells. Brain Res 2015; 1615:61-70. [DOI: 10.1016/j.brainres.2015.04.028] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Revised: 03/23/2015] [Accepted: 04/16/2015] [Indexed: 12/29/2022]
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Shen C, Wang D, Liu X, Gu B, Du Y, Wei FZ, Cao LL, Song B, Lu X, Yang Q, Zhu Q, Hou T, Li M, Wang L, Wang H, Zhao Y, Yang Y, Zhu WG. SET7/9 regulates cancer cell proliferation by influencing β-catenin stability. FASEB J 2015; 29:4313-23. [PMID: 26116705 DOI: 10.1096/fj.15-273540] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Accepted: 06/22/2015] [Indexed: 12/19/2022]
Abstract
β-Catenin, which is a key mediator of the wingless-integration site (Wnt)/β-catenin signaling pathway, plays an important role in cell proliferation, cell fate determination, and tumorigenesis, by regulating the expression of a wide range of target genes. Although a variety of posttranslational modifications are involved in β-catenin activity, the role of lysine methylation in β-catenin activity is largely unknown. In this study, su(var)3-9, enhancer-of-zeste, trithorax (SET) domain-containing protein 7 (SET7/9), a lysine methyltransferase, interacted with and methylated β-catenin, as demonstrated both in vitro and in vivo. The interaction and methylation were significantly enhanced in response to H2O2 stimulation. A mutagenesis assay and mass spectrometric analyses revealed that β-catenin was monomethylated by SET7/9 at lysine residue 180. Methylated β-catenin was easily recognized by phosphokinase glycogen synthase kinase (GSK)-3β for degradation. Consistent with this finding, the mutated β-catenin (K180R) that cannot be methylated exhibited a longer half-life than did the methylated β-catenin. The consequent depletion of SET7/9 by shRNA or the mutation of the β-catenin (K180R) significantly enhanced the expression of Wnt/β-catenin target genes such as c-myc and cyclin D1 and promoted the growth of cancer cells. Together, these results provide a novel mechanism by which Wnt/β-catenin signaling is regulated in response to oxidative stress.
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Affiliation(s)
- Changchun Shen
- *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China
| | - Donglai Wang
- *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China
| | - Xiangyu Liu
- *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China
| | - Bo Gu
- *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China
| | - Yipeng Du
- *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China
| | - Fu-Zheng Wei
- *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China
| | - Lin-Lin Cao
- *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China
| | - Boyan Song
- *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China
| | - Xiaopeng Lu
- *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China
| | - Qiaoyan Yang
- *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China
| | - Qian Zhu
- *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China
| | - Tianyun Hou
- *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China
| | - Meiting Li
- *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China
| | - Lina Wang
- *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China
| | - Haiying Wang
- *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China
| | - Ying Zhao
- *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China
| | - Yang Yang
- *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China
| | - Wei-Guo Zhu
- *Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China; and Peking University-Tsinghua University Center for Life Sciences, Beijing, China
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Wei L, Ding L, Mo MS, Lei M, Zhang L, Chen K, Xu P. Wnt3a protects SH-SY5Y cells against 6-hydroxydopamine toxicity by restoration of mitochondria function. Transl Neurodegener 2015; 4:11. [PMID: 26085927 PMCID: PMC4470059 DOI: 10.1186/s40035-015-0033-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2015] [Accepted: 06/09/2015] [Indexed: 01/07/2023] Open
Abstract
Background Wnt/β-catenin signal has been reported to exert cytoprotective effects in cellular models of several diseases, including Parkinson’s disease (PD). This study aimed to investigate the neuroprotective effects of actived Wnt/β-catenin signal by Wnt3a on SH-SY5Y cells treated with 6-hydroxydopamine (6-OHDA). Methods Wnt3a-conditioned medium (Wnt3a-CM) was used to intervene dopaminegic SH-SY5Y cells treated with 6-OHDA. Cell toxicity was determined by cell viability and lactate dehydrogenase leakage (LDH) assay. The mitochondria function was measured by the mitochondrial membrane potential, while oxidative stress was monitored with intracellular reactive oxygen species (ROS). Western blot analysis was used to detect the expression of GSK3β, β-catenin as well as Akt. Results Our results showed that 100 μM 6-OHDA treated for 24 h significantly decreased cell viability and mitochondrial transmembrane potential, reduced the level of β-catenin and p-Akt, increased LDH leakage, ROS production and the ratio of p-GSK3β (Tyr216) to p-GSK3β (Ser9). However, Wnt3a-conditioned medium reversing SH-SY5Y cells against 6-OHDA-induced neurotoxicity by reversing these changes. Conclusions Activating of Wnt/β-catenin pathway by Wnt3a-CM attenuated 6-OHDA-induced neurotoxicity significantly, which related to the inhibition of oxidative stress and maintenance of normal mitochondrial function.
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Affiliation(s)
- Lei Wei
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630 China ; Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080 China
| | - Li Ding
- Department of pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080 China
| | - Ming-Shu Mo
- Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080 China
| | - Ming Lei
- Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080 China
| | - Limin Zhang
- Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080 China
| | - Kang Chen
- Division of Clinical Laboratory, Zhongshan Hospital of Sun Yat-sen University, Zhongshan, 528403 China
| | - Pingyi Xu
- Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080 China ; Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120 China
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Lim KM, An S, Lee OK, Lee MJ, Lee JP, Lee KS, Lee GT, Lee KK, Bae S. Analysis of changes in microRNA expression profiles in response to the troxerutin-mediated antioxidant effect in human dermal papilla cells. Mol Med Rep 2015; 12:2650-60. [PMID: 25955790 PMCID: PMC4464413 DOI: 10.3892/mmr.2015.3717] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2014] [Accepted: 03/26/2015] [Indexed: 01/08/2023] Open
Abstract
Dermal papilla (DP) cells function as important regulators of the hair growth cycle. The loss of these cells is a primary cause of diseases characterized by hair loss, including alopecia, and evidence has revealed significantly increased levels of reactive oxygen species (ROS) in hair tissue and DP cells in the balding population. In the present study, troxerutin, a flavonoid derivative of rutin, was demonstrated to have a protective effect against H2O2-mediated cellular damage in human DP (HDP) cells. Biochemical assays revealed that pretreatment with troxerutin exerted a protective effect against H2O2-induced loss of cell viability and H2O2 induced cell death. Further experiments confirmed that troxerutin inhibited the H2O2-induced production of ROS and upregulation of senescence-associated β-galactosidase activity. Using microRNA (miRNA) microarrays, the present study identified 24 miRNAs, which were differentially expressed in the troxerutin pretreated, H2O2-treated HDP cells. Subsequent prediction using bioinformatics analysis revealed that the altered miRNAs were functionally involved in several cell signaling pathways, including the mitogen-activated protein kinase and WNT pathways. Overall, these results indicated that ROS-mediated cellular damage was inhibited by troxerutin and suggested that the use of troxerutin may be an effective approach in the treatment of alopecia.
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Affiliation(s)
- Kyung Mi Lim
- Molecular‑Targeted Drug Research Center and Korea Institute for Skin and Clinical Sciences, Konkuk University, Seoul 143‑701, Republic of Korea
| | - Sungkwan An
- Molecular‑Targeted Drug Research Center and Korea Institute for Skin and Clinical Sciences, Konkuk University, Seoul 143‑701, Republic of Korea
| | - Ok-Kyu Lee
- Molecular‑Targeted Drug Research Center and Korea Institute for Skin and Clinical Sciences, Konkuk University, Seoul 143‑701, Republic of Korea
| | - Myung Joo Lee
- Molecular‑Targeted Drug Research Center and Korea Institute for Skin and Clinical Sciences, Konkuk University, Seoul 143‑701, Republic of Korea
| | - Jeong Pyo Lee
- Coreana Cosmetics Co., Ltd., Cheonan, Chungcheong 330‑882, Republic of Korea
| | - Kwang Sik Lee
- Coreana Cosmetics Co., Ltd., Cheonan, Chungcheong 330‑882, Republic of Korea
| | - Ghang Tai Lee
- Coreana Cosmetics Co., Ltd., Cheonan, Chungcheong 330‑882, Republic of Korea
| | - Kun Kook Lee
- Coreana Cosmetics Co., Ltd., Cheonan, Chungcheong 330‑882, Republic of Korea
| | - Seunghee Bae
- Molecular‑Targeted Drug Research Center and Korea Institute for Skin and Clinical Sciences, Konkuk University, Seoul 143‑701, Republic of Korea
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Prozorovski T, Schneider R, Berndt C, Hartung HP, Aktas O. Redox-regulated fate of neural stem progenitor cells. Biochim Biophys Acta Gen Subj 2015; 1850:1543-54. [PMID: 25662818 DOI: 10.1016/j.bbagen.2015.01.022] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Accepted: 01/29/2015] [Indexed: 12/31/2022]
Abstract
BACKGROUND Accumulated data indicate that self-renewal, multipotency, and differentiation of neural stem cells are under an intrinsic control mediated by alterations in the redox homeostasis. These dynamic redox changes not only reflect and support the ongoing metabolic and energetic processes, but also serve to coordinate redox-signaling cascades. Controlling particular redox couples seems to have a relevant impact on cell fate decision during development, adult neurogenesis and regeneration. SCOPE OF REVIEW Our own research provided initial evidence for the importance of NAD+-dependent enzymes in neural stem cell fate decision. In this review, we summarize recent knowledge on the active role of reactive oxygen species, redox couples and redox-signaling mechanisms on plasticity and function of neural stem and progenitor cells focusing on NAD(P)+/NAD(P)H-mediated processes. MAJOR CONCLUSIONS The compartmentalized subcellular sources and availability of oxidizing/reducing molecules in particular microenvironment define the specificity of redox regulation in modulating the delicate balance between stemness and differentiation of neural progenitors. The generalization of "reactive oxygen species" as well as the ambiguity of their origin might explain the diametrically-opposed findings in the field of redox-dependent cell fate reflected by the literature. GENERAL SIGNIFICANCE Increasing knowledge of temporary and spatially defined redox regulation is of high relevance for the development of novel approaches in the field of cell-based regeneration of nervous tissue in various pathological states. This article is part of a special issue entitled Redox regulation of differentiation and de-differentiation.
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Affiliation(s)
- Tim Prozorovski
- Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
| | - Reiner Schneider
- Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Carsten Berndt
- Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Hans-Peter Hartung
- Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Orhan Aktas
- Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
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Ludin A, Gur-Cohen S, Golan K, Kaufmann KB, Itkin T, Medaglia C, Lu XJ, Ledergor G, Kollet O, Lapidot T. Reactive oxygen species regulate hematopoietic stem cell self-renewal, migration and development, as well as their bone marrow microenvironment. Antioxid Redox Signal 2014; 21:1605-19. [PMID: 24762207 PMCID: PMC4175025 DOI: 10.1089/ars.2014.5941] [Citation(s) in RCA: 247] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
SIGNIFICANCE Blood forming, hematopoietic stem cells (HSCs) mostly reside in the bone marrow in a quiescent, nonmotile state via adhesion interactions with stromal cells and macrophages. Quiescent, proliferating, and differentiating stem cells have different metabolism, and accordingly different amounts of intracellular reactive oxygen species (ROS). Importantly, ROS is not just a byproduct of metabolism, but also plays a role in stem cell state and function. RECENT ADVANCES ROS levels are dynamic and reversibly dictate enhanced cycling and myeloid bias in ROS(high) short-term repopulating stem cells, and ROS(low) quiescent long-term repopulating stem cells. Low levels of ROS, regulated by intrinsic factors such as cell respiration or nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) activity, or extrinsic factors such as stem cell factor or prostaglandin E2 are required for maintaining stem cell self-renewal. High ROS levels, due to stress and inflammation, induce stem cell differentiation and enhanced motility. CRITICAL ISSUES Stem cells need to be protected from high ROS levels to avoid stem cell exhaustion, insufficient host immunity, and leukemic transformation that may occur during chronic inflammation. However, continuous low ROS production will lead to lack of stem cell function and opportunistic infections. Ultimately, balanced ROS levels are crucial for maintaining the small stem cell pool and host immunity, both in homeostasis and during stress situations. FUTURE DIRECTIONS Deciphering the signaling pathway of ROS in HSC will provide a better understanding of ROS roles in switching HSC from quiescence to activation and vice versa, and will also shed light on the possible roles of ROS in leukemia initiation and development.
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Affiliation(s)
- Aya Ludin
- 1 Department of Immunology, Weizmann Institute of Science , Rehovot, Israel
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Paeng J, Chang JH, Lee SH, Nam BY, Kang HY, Kim S, Oh HJ, Park JT, Han SH, Yoo TH, Kang SW. Enhanced glycogen synthase kinase-3β activity mediates podocyte apoptosis under diabetic conditions. Apoptosis 2014; 19:1678-90. [DOI: 10.1007/s10495-014-1037-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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