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Alasmar A, Al-Alami Z, Zein S, Al-Smadi A, Al Bashir S, Alorjani MS, Al-Zoubi RM, Al Zoubi M. Novel Mutations in AKT1 Gene in Prostate Cancer Patients in Jordan. Curr Issues Mol Biol 2024; 46:9856-9866. [PMID: 39329938 PMCID: PMC11430622 DOI: 10.3390/cimb46090586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 08/28/2024] [Accepted: 09/03/2024] [Indexed: 09/28/2024] Open
Abstract
The AKT1 oncogene is related to various cancers due to its critical role in the PIC3CA/AKT1 pathway; however, most of the studies screened the hotspot mutation AKT1 (E17K) with various incidences. Low frequency or lack of AKT1 (E17K) mutation was reported in prostate cancer (PC) patients. This study aims to explore genetic alterations in the AKT1 PH domain by extending the sequencing to include AKT1 gene exons 3 and 4. Genomic DNA was extracted from 84 Formalin-Fixed Paraffin-Embedded samples of PC patients in Jordan, and then subjected to PCR and sequencing for the targeted exons. This study revealed the presence of two novel mutations (N53Y and Q59K) and a high frequency of mutations in exon 4, with a lack of mutations in the E17K hotspot. Nine missense and two synonymous mutations were detected in exon 4 (Phe27Tyr, Phe27Leu, Ala58Thr, Ser56Phe, Arg41Trp, Phe35Leu, Asp32Glu, Phe35Tyr, and Gln43Lys) and (Ser56 and Glu40), respectively. Two synonymous mutations were detected in exon 3 (Leu12 and Ser2). It is concluded that there is a high frequency of AKT1 mutation in PC patients in Jordan with two novel missense mutations in the Pleckstrin homology (PH) domain. E17K hotspot mutation was not detected in any tested samples, which underlined the significant role of mutations in other AKT1 exons in PC development.
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Affiliation(s)
- Ala’a Alasmar
- Department of Medical Laboratory Sciences, Faculty of Allied Medical Sciences, Al-Ahliyya Amman University, Amman 19328, Jordan;
| | - Zina Al-Alami
- Department of Basic Laboratory Sciences, Faculty of Allied Medical Sciences, Al-Ahliyya Amman University, Amman 19328, Jordan;
| | - Sima Zein
- Department of Pharmaceutical Biotechnology, Faculty of Allied Medical Sciences, Al-Ahliyya Amman University, Amman 19328, Jordan;
| | - Asmaa Al-Smadi
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan;
| | - Samir Al Bashir
- Department of Pathology and Microbiology, Faculty of Medicine, Jordan University of Science and Technology, Irbid 22110, Jordan; (S.A.B.); (M.S.A.)
| | - Mohammed S. Alorjani
- Department of Pathology and Microbiology, Faculty of Medicine, Jordan University of Science and Technology, Irbid 22110, Jordan; (S.A.B.); (M.S.A.)
| | - Raed M. Al-Zoubi
- Surgical Research Section, Department of Surgery, Hamad Medical Corporation, Doha P.O. Box 3050, Qatar;
- Department of Biomedical Sciences, QU-Health, College of Health Sciences, Qatar University, Doha 2713, Qatar
| | - Mazhar Al Zoubi
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan;
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2
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Wen X, Li P, Ma Y, Wang D, Jia R, Xia Y, Li W, Li Y, Li G, Sun T, Lu F, Ye J, Ji C. RHOF activation of AKT/β-catenin signaling pathway drives acute myeloid leukemia progression and chemotherapy resistance. iScience 2024; 27:110221. [PMID: 39021805 PMCID: PMC11253531 DOI: 10.1016/j.isci.2024.110221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 04/29/2024] [Accepted: 06/05/2024] [Indexed: 07/20/2024] Open
Abstract
Acute myeloid leukemia (AML) is a clonal malignancy originating from leukemia stem cells, characterized by a poor prognosis, underscoring the necessity for novel therapeutic targets and treatment methodologies. This study focuses on Ras homolog family member F, filopodia associated (RHOF), a Rho guanosine triphosphatase (GTPase) family member. We found that RHOF is overexpressed in AML, correlating with an adverse prognosis. Our gain- and loss-of-function experiments revealed that RHOF overexpression enhances proliferation and impedes apoptosis in AML cells in vitro. Conversely, genetic suppression of RHOF markedly reduced the leukemia burden in a human AML xenograft mouse model. Furthermore, we investigated the synergistic effect of RHOF downregulation and chemotherapy, demonstrating significant therapeutic efficacy in vivo. Mechanistically, RHOF activates the AKT/β-catenin signaling pathway, thereby accelerating the progression of AML. Our findings elucidate the pivotal role of RHOF in AML pathogenesis and propose RHOF inhibition as a promising therapeutic approach for AML management.
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Affiliation(s)
- Xin Wen
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, People’s Republic of China
| | - Peng Li
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, People’s Republic of China
| | - Yuechan Ma
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, People’s Republic of China
| | - Dongmei Wang
- Shandong Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan 250012, People’s Republic of China
| | - Ruinan Jia
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, People’s Republic of China
| | - Yuan Xia
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, People’s Republic of China
| | - Wei Li
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, People’s Republic of China
| | - Yongjian Li
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, People’s Republic of China
| | - Guosheng Li
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, People’s Republic of China
- Shandong Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan 250012, People’s Republic of China
| | - Tao Sun
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, People’s Republic of China
- Shandong Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan 250012, People’s Republic of China
| | - Fei Lu
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, People’s Republic of China
| | - Jingjing Ye
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, People’s Republic of China
- Shandong Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan 250012, People’s Republic of China
| | - Chunyan Ji
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, People’s Republic of China
- Shandong Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan 250012, People’s Republic of China
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3
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Nadel G, Yao Z, Hacohen-Lev-Ran A, Wainstein E, Maik-Rachline G, Ziv T, Naor Z, Admon A, Seger R. Phosphorylation of PP2Ac by PKC is a key regulatory step in the PP2A-switch-dependent AKT dephosphorylation that leads to apoptosis. Cell Commun Signal 2024; 22:154. [PMID: 38419089 PMCID: PMC10900696 DOI: 10.1186/s12964-024-01536-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 02/17/2024] [Indexed: 03/02/2024] Open
Abstract
BACKGROUND Although GqPCR activation often leads to cell survival by activating the PI3K/AKT pathway, it was previously shown that in several cell types AKT activity is reduced and leads to JNK activation and apoptosis. The mechanism of AKT inactivation in these cells involves an IGBP1-coupled PP2Ac switch that induces the dephosphorylation and inactivation of both PI3K and AKT. However, the machinery involved in the initiation of PP2A switch is not known. METHODS We used phospho-mass spectrometry to identify the phosphorylation site of PP2Ac, and raised specific antibodies to follow the regulation of this phosphorylation. Other phosphorylations were monitored by commercial antibodies. In addition, we used coimmunoprecipitation and proximity ligation assays to follow protein-protein interactions. Apoptosis was detected by a TUNEL assay as well as PARP1 cleavage using SDS-PAGE and Western blotting. RESULTS We identified Ser24 as a phosphorylation site in PP2Ac. The phosphorylation is mediated mainly by classical PKCs (PKCα and PKCβ) but not by novel PKCs (PKCδ and PKCε). By replacing the phosphorylated residue with either unphosphorylatable or phosphomimetic residues (S24A and S24E), we found that this phosphorylation event is necessary and sufficient to mediate the PP2A switch, which ultimately induces AKT inactivation, and a robust JNK-dependent apoptosis. CONCLUSION Our results show that the PP2A switch is induced by PKC-mediated phosphorylation of Ser24-PP2Ac and that this phosphorylation leads to apoptosis upon GqPCR induction of various cells. We propose that this mechanism may provide an unexpected way to treat some cancer types or problems in the endocrine machinery.
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Affiliation(s)
- Guy Nadel
- Department of Immunology and Regenerative Biology, the Weizmann Institute of Science, Rehovot, Israel
| | - Zhong Yao
- Department of Immunology and Regenerative Biology, the Weizmann Institute of Science, Rehovot, Israel
| | - Avital Hacohen-Lev-Ran
- Department of Immunology and Regenerative Biology, the Weizmann Institute of Science, Rehovot, Israel
| | - Ehud Wainstein
- Department of Immunology and Regenerative Biology, the Weizmann Institute of Science, Rehovot, Israel
| | - Galia Maik-Rachline
- Department of Immunology and Regenerative Biology, the Weizmann Institute of Science, Rehovot, Israel
| | - Tamar Ziv
- Smoler Proteomic Center, Technion-Israel Institute of Technology, Haifa, Israel
| | - Zvi Naor
- Department of Biochemistry and Molecular Biology, Tel Aviv University, Tel Aviv, Israel
| | - Arie Admon
- Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel
| | - Rony Seger
- Department of Immunology and Regenerative Biology, the Weizmann Institute of Science, Rehovot, Israel.
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4
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Peters XQ, Elamin G, Aljoundi A, Alahmdi MI, Abo-Dya NE, Sidhom PA, Tawfeek AM, Ibrahim MAA, Soremekun O, Soliman MES. Therapeutic Path to Triple Knockout: Investigating the Pan-inhibitory Mechanisms of AKT, CDK9, and TNKS2 by a Novel 2-phenylquinazolinone Derivative in Cancer Therapy- An In-silico Investigation Therapy. Curr Pharm Biotechnol 2024; 25:1288-1303. [PMID: 37581526 DOI: 10.2174/1389201024666230815145001] [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: 02/27/2023] [Revised: 06/18/2023] [Accepted: 06/26/2023] [Indexed: 08/16/2023]
Abstract
BACKGROUND Blocking the oncogenic Wnt//β-catenin pathway has of late been investigated as a viable therapeutic approach in the treatment of cancer. This involves the multi-targeting of certain members of the tankyrase-kinase family; Tankyrase 2 (TNKS2), Protein Kinase B (AKT), and Cyclin- Dependent Kinase 9 (CDK9), which propagate the oncogenic Wnt/β-catenin signalling pathway. METHODS During a recent investigation, the pharmacological activity of 2-(4-aminophenyl)-7-chloro- 3H-quinazolin-4-one was repurposed to serve as a 'triple-target' inhibitor of TNKS2, AKT and CDK9. Yet, the molecular mechanism that surrounds its multi-targeting activity remains unanswered. As such, this study aims to explore the pan-inhibitory mechanism of 2-(4-aminophenyl)-7-chloro-3H-quinazolin- 4-one towards AKT, CDK9, and TNKS2, using in silico techniques. RESULTS Results revealed favourable binding affinities of -34.17 kcal/mol, -28.74 kcal/mol, and -27.30 kcal/mol for 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one towards TNKS2, CDK9, and AKT, respectively. Pan-inhibitory binding of 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one is illustrated by close interaction with specific residues on tankyrase-kinase. Structurally, 2-(4-aminophenyl)-7-chloro- 3H-quinazolin-4-one had an impact on the flexibility, solvent-accessible surface area, and stability of all three proteins, which was illustrated by numerous modifications observed in the unbound as well as the bound states of the structures, which evidenced the disruption of their biological function. Prediction of the pharmacokinetics and physicochemical properties of 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4- one further established its inhibitory potential, evidenced by the favourable absorption, metabolism, excretion, and minimal toxicity properties. CONCLUSION The following structural insights provide a starting point for understanding the paninhibitory activity of 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one. Determining the criticality of the interactions that exist between the pyrimidine ring and catalytic residues could offer insight into the structure-based design of innovative tankyrase-kinase inhibitors with enhanced therapeutic effects.
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Affiliation(s)
- Xylia Q Peters
- Department of Pharmaceutical Science, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa
| | - Ghazi Elamin
- Department of Pharmaceutical Science, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa
| | - Aimen Aljoundi
- Department of Pharmaceutical Science, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa
| | - Mohamed Issa Alahmdi
- Department of Pharmaceutical Science, University of Tabuk, Tabuk, 7149, Saudi Arabia
| | - Nader E Abo-Dya
- Department of Pharmaceutical Science, University of Tabuk, Tabuk, 7149, Saudi Arabia
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Peter A Sidhom
- Department of Pharmacy, Tanta University, Tanta, 31527, Egypt
| | - Ahmed M Tawfeek
- Chemistry Department, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Mahmoud A A Ibrahim
- Department of Pharmaceutical Science, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa
- Chemistry Department, Computational Chemistry Laboratory, Faculty of Science, Minia University, Minia, 61519, Egypt
| | - Opeyemi Soremekun
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Mahmoud E S Soliman
- Department of Pharmaceutical Science, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa
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5
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Zhang K, An X, Zhu Y, Huang L, Yao X, Zeng X, Liang S, Yu J. Netrin-1 inducing antiapoptotic effect of acute myeloid leukemia cells in a concentration-dependent manner through the Unc-5 netrin receptor B-focal adhesion kinase axis. Cancer Biol Ther 2023; 24:2200705. [PMID: 37038247 PMCID: PMC10088980 DOI: 10.1080/15384047.2023.2200705] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/12/2023] Open
Abstract
Acute myeloid leukemia (AML) is a hematological malignancy that commonly occurs in children. The prognosis of pediatric AML is relatively poor, thus threatening the patient's survival. The aberrant expression of the axon guidance factor, netrin-1, is observed in various types of malignancies, and it participates in the proliferation and apoptosis of tumor cells. Herein, we aimed to explore the role of netrin-1 in AML cells. Netrin-1 is highly expressed in AML patients. Proliferation and anti-apoptosis were observed in AML cells treated with netrin-1. The interaction between netrin-1 and Unc-5 netrin receptor B (UNC5B) was detected through coimmunoprecipitation, and UNC5B ribonucleic acid interference restrained the influence of netrin-1 on the AML cells. The phosphorylation of focal adhesion kinase-protein kinase B (FAK-Akt) was upregulated in AML cells treated with netrin-1. Both FAK and Akt inhibitors abrogated the effects of netrin-1 on the proliferation and apoptosis of AML cells. In conclusion, netrin-1 could promote the growth and reduce the apoptosis of AML cells in a concentration-dependent manner, and that these effects were mediated by activating the FAK-Akt signaling pathway via the UNC5B.
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Affiliation(s)
- Kainan Zhang
- Department of Hematology and Oncology, Children's Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Pediatrics, Chongqing, China
- Pediatric research institute, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Xizhou An
- Department of Hematology and Oncology, Children's Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Yao Zhu
- Department of Hematology and Oncology, Children's Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Pediatrics, Chongqing, China
- Pediatric research institute, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Lan Huang
- Department of Hematology and Oncology, Children's Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Pediatrics, Chongqing, China
- Pediatric research institute, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Xinyuan Yao
- Department of Hematology and Oncology, Children's Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Xing Zeng
- Department of Hematology and Oncology, Children's Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Shaoyan Liang
- Pediatric research institute, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Jie Yu
- Department of Hematology and Oncology, Children's Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Pediatrics, Chongqing, China
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6
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Zhou JC, Li HL, Zhou Y, Li XT, Yang ZY, Tohda C, Komatsu K, Piao XH, Ge YW. The roles of natural triterpenoid saponins against Alzheimer's disease. Phytother Res 2023; 37:5017-5040. [PMID: 37491018 DOI: 10.1002/ptr.7967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/23/2023] [Accepted: 07/07/2023] [Indexed: 07/27/2023]
Abstract
The aging of the world population and increasing stress levels in life are the major cause of the increased incidence of neurological disorders. Alzheimer's disease (AD) creates a huge burden on the lives and health of individuals and has become a big concern for society. Triterpenoid saponins (TS), representative natural product components, have a wide range of pharmacological bioactivities such as anti-inflammation, antioxidation, antiapoptosis, hormone-like, and gut microbiota regulation. Notably, some natural TS exhibited promising neuroprotective activity that can intervene in AD progress, especially in the early stage. Recently, studies have indicated that TS play a pronounced positive role in the prevention and treatment of AD. This review discusses the recent research on the neuroprotection of TS and proceeds to detail the action mechanisms of TS against AD, hoping to provide a reference for drug development for anti-AD.
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Affiliation(s)
- Jie-Chun Zhou
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM, Innovative team of research on effective substances of traditional Chinese medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Hui-Lin Li
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM, Innovative team of research on effective substances of traditional Chinese medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yu Zhou
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM, Innovative team of research on effective substances of traditional Chinese medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xi-Tao Li
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM, Innovative team of research on effective substances of traditional Chinese medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Zhi-You Yang
- College of Food Science and Technology, Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, Institute of Nutrition and Marine Drugs, Guangdong Ocean University, Zhanjiang, China
| | - Chihiro Tohda
- Division of Neuromedical Science, Institute of Natural Medicine, University of Toyama, Toyama, Japan
| | - Katsuko Komatsu
- Division of Neuromedical Science, Institute of Natural Medicine, University of Toyama, Toyama, Japan
| | - Xiu-Hong Piao
- School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yue-Wei Ge
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, China
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM, Innovative team of research on effective substances of traditional Chinese medicine, Guangdong Pharmaceutical University, Guangzhou, China
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7
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Kostes WW, Brafman DA. The Multifaceted Role of WNT Signaling in Alzheimer's Disease Onset and Age-Related Progression. Cells 2023; 12:1204. [PMID: 37190113 PMCID: PMC10136584 DOI: 10.3390/cells12081204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 04/12/2023] [Accepted: 04/17/2023] [Indexed: 05/17/2023] Open
Abstract
The evolutionary conserved WNT signaling pathway orchestrates numerous complex biological processes during development and is critical to the maintenance of tissue integrity and homeostasis in the adult. As it relates to the central nervous system, WNT signaling plays several roles as it relates to neurogenesis, synaptic formation, memory, and learning. Thus, dysfunction of this pathway is associated with multiple diseases and disorders, including several neurodegenerative disorders. Alzheimer's disease (AD) is characterized by several pathologies, synaptic dysfunction, and cognitive decline. In this review, we will discuss the various epidemiological, clinical, and animal studies that demonstrate a precise link between aberrant WNT signaling and AD-associated pathologies. In turn, we will discuss the manner in which WNT signaling influences multiple molecular, biochemical, and cellular pathways upstream of these end-point pathologies. Finally, we will discuss how merging tools and technologies can be used to generate next generation cellular models to dissect the relationship between WNT signaling and AD.
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Affiliation(s)
| | - David A. Brafman
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ 85287, USA
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8
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Cameron VA, Jones GT, Horwood LJ, Pilbrow AP, Martin J, Frampton C, Ip WT, Troughton RW, Greer C, Yang J, Epton MJ, Harris SL, Darlow BA. DNA methylation patterns at birth predict health outcomes in young adults born very low birthweight. Clin Epigenetics 2023; 15:47. [PMID: 36959629 PMCID: PMC10035230 DOI: 10.1186/s13148-023-01463-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 03/07/2023] [Indexed: 03/25/2023] Open
Abstract
Background Individuals born very low birthweight (VLBW) are at increased risk of impaired cardiovascular and respiratory function in adulthood. To identify markers to predict future risk for VLBW individuals, we analyzed DNA methylation at birth and at 28 years in the New Zealand (NZ) VLBW cohort (all infants born < 1500 g in NZ in 1986) compared with age-matched, normal birthweight controls. Associations between neonatal methylation and cardiac structure and function (echocardiography), vascular function and respiratory outcomes at age 28 years were documented. Results Genomic DNA from archived newborn heel-prick blood (n = 109 VLBW, 51 controls) and from peripheral blood at ~ 28 years (n = 215 VLBW, 96 controls) was analyzed on Illumina Infinium MethylationEPIC 850 K arrays. Following quality assurance and normalization, methylation levels were compared between VLBW cases and controls at both ages by linear regression, with genome-wide significance set to p < 0.05 adjusted for false discovery rate (FDR, Benjamini-Hochberg). In neonates, methylation at over 16,400 CpG methylation sites differed between VLBW cases and controls and the canonical pathway most enriched for these CpGs was Cardiac Hypertrophy Signaling (p = 3.44E−11). The top 20 CpGs that differed most between VLBW cases and controls featured clusters in ARID3A, SPATA33, and PLCH1 and these 3 genes, along with MCF2L, TRBJ2-1 and SRC, led the list of 15,000 differentially methylated regions (DMRs) reaching FDR-adj significance. Fifteen of the 20 top CpGs in the neonate EWAS showed associations between methylation at birth and adult cardiovascular traits (particularly LnRHI). In 28-year-old adults, twelve CpGs differed between VLBW cases and controls at FDR-adjusted significance, including hypermethylation in EBF4 (four CpGs), CFI and UNC119B and hypomethylation at three CpGs in HIF3A and one in KCNQ1. DNA methylation GrimAge scores at 28 years were significantly greater in VLBW cases versus controls and weakly associated with cardiovascular traits. Four CpGs were identified where methylation differed between VLBW cases and controls in both neonates and adults, three reversing directions with age (two CpGs in EBF4, one in SNAI1 were hypomethylated in neonates, hypermethylated in adults). Of these, cg16426670 in EBF4 at birth showed associations with several cardiovascular traits in adults. Conclusions These findings suggest that methylation patterns in VLBW neonates may be informative about future adult cardiovascular and respiratory outcomes and have value in guiding early preventative care to improve adult health. Supplementary Information The online version contains supplementary material available at 10.1186/s13148-023-01463-3.
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Affiliation(s)
- Vicky A. Cameron
- grid.29980.3a0000 0004 1936 7830Christchurch Heart Institute, Department of Medicine, University of Otago, Christchurch, PO Box 4345, Christchurch, 8140 New Zealand
| | - Gregory T. Jones
- grid.29980.3a0000 0004 1936 7830Department of Surgical Sciences, University of Otago, Dunedin, New Zealand
| | - L. John Horwood
- grid.29980.3a0000 0004 1936 7830Christchurch Health and Development Study, Department of Psychological Medicine, University of Otago, Christchurch, New Zealand
| | - Anna P. Pilbrow
- grid.29980.3a0000 0004 1936 7830Christchurch Heart Institute, Department of Medicine, University of Otago, Christchurch, PO Box 4345, Christchurch, 8140 New Zealand
| | - Julia Martin
- grid.29980.3a0000 0004 1936 7830Department of Paediatrics, University of Otago, Christchurch, New Zealand
| | - Chris Frampton
- grid.29980.3a0000 0004 1936 7830Christchurch Heart Institute, Department of Medicine, University of Otago, Christchurch, PO Box 4345, Christchurch, 8140 New Zealand
| | - Wendy T. Ip
- grid.29980.3a0000 0004 1936 7830Christchurch Heart Institute, Department of Medicine, University of Otago, Christchurch, PO Box 4345, Christchurch, 8140 New Zealand
| | - Richard W. Troughton
- grid.29980.3a0000 0004 1936 7830Christchurch Heart Institute, Department of Medicine, University of Otago, Christchurch, PO Box 4345, Christchurch, 8140 New Zealand
| | - Charlotte Greer
- grid.29980.3a0000 0004 1936 7830Christchurch Heart Institute, Department of Medicine, University of Otago, Christchurch, PO Box 4345, Christchurch, 8140 New Zealand
| | - Jun Yang
- grid.414299.30000 0004 0614 1349Respiratory Physiology Laboratory, Christchurch Hospital, Christchurch, New Zealand
| | - Michael J. Epton
- grid.414299.30000 0004 0614 1349Respiratory Physiology Laboratory, Christchurch Hospital, Christchurch, New Zealand
| | - Sarah L. Harris
- grid.29980.3a0000 0004 1936 7830Department of Paediatrics, University of Otago, Christchurch, New Zealand
| | - Brian A. Darlow
- grid.29980.3a0000 0004 1936 7830Department of Paediatrics, University of Otago, Christchurch, New Zealand
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9
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AKT inhibitor Hu7691 induces differentiation of neuroblastoma cells. Acta Pharm Sin B 2023; 13:1522-1536. [PMID: 37139432 PMCID: PMC10150122 DOI: 10.1016/j.apsb.2023.01.024] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 11/22/2022] [Accepted: 01/08/2023] [Indexed: 02/05/2023] Open
Abstract
While neuroblastoma accounts for 15% of childhood tumor-related deaths, treatments against neuroblastoma remain scarce and mainly consist of cytotoxic chemotherapeutic drugs. Currently, maintenance therapy of differentiation induction is the standard of care for neuroblastoma patients in clinical, especially high-risk patients. However, differentiation therapy is not used as a first-line treatment for neuroblastoma due to low efficacy, unclear mechanism, and few drug options. Through compound library screening, we accidently found the potential differentiation-inducing effect of AKT inhibitor Hu7691. The protein kinase B (AKT) pathway is an important signaling pathway for regulating tumorigenesis and neural differentiation, yet the relation between the AKT pathway and neuroblastoma differentiation remains unclear. Here, we reveal the anti-proliferation and neurogenesis effect of Hu7691 on multiple neuroblastoma cell lines. Further evidence including neurites outgrowth, cell cycle arrest, and differentiation mRNA marker clarified the differentiation-inducing effect of Hu7691. Meanwhile, with the introduction of other AKT inhibitors, it is now clear that multiple AKT inhibitors can induce neuroblastoma differentiation. Furthermore, silencing AKT was found to have the effect of inducing neuroblastoma differentiation. Finally, confirmation of the therapeutic effects of Hu7691 is dependent on inducing differentiation in vivo, suggesting that Hu7691 is a potential molecule against neuroblastoma. Through this study, we not only define the key role of AKT in the progression of neuroblastoma differentiation but also provide potential drugs and key targets for the application of differentiation therapies for neuroblastoma clinically.
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10
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Das A, Bhattacharya B, Roy S. Decrypting a path based approach for identifying the interplay between PI3K and GSK3 signaling cascade from the perspective of cancer. Genes Dis 2022; 9:868-888. [PMID: 35685456 PMCID: PMC9170611 DOI: 10.1016/j.gendis.2021.12.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/21/2021] [Accepted: 12/29/2021] [Indexed: 11/27/2022] Open
Abstract
Cancer is one of those leading diseases worldwide, which takes millions of lives every year. Researchers are continuously looking for specific approaches to eradicate the deadly disease, ensuring minimal adverse effects along with more therapeutic significance. Targeting of different aberrantly regulated signaling pathways, involved in cancer, is surely one of the revolutionary chemotherapeutic approach. In this instance, GSK3 and PI3K signaling cascades are considered as important role player for both the oncogenic activation and inactivation which further leads to cancer proliferation and metastasis. In this review, we have discussed the potential role of GSK3 and PI3K signaling in cancer, and we further established the crosstalk between PI3K and GSK3 signaling, through showcasing their cross activation, cross inhibition and convergence pathways in association with cancer. We also exhibited the effect of GSK3 on the efficacy of PI3K inhibitors to overcome the drug resistance and preventing the cell proliferation, metastasis in a combinatorial way with GSK3 inhibitors for a better treatment strategy in clinical settings.
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Affiliation(s)
- Abhijit Das
- Department of Pharmacology, NSHM Knowledge Campus, Kolkata- Group of Institutions, Kolkata 700053, India
| | - Barshana Bhattacharya
- Department of Pharmacology, NSHM Knowledge Campus, Kolkata- Group of Institutions, Kolkata 700053, India
| | - Souvik Roy
- Department of Pharmacology, NSHM Knowledge Campus, Kolkata- Group of Institutions, Kolkata 700053, India
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11
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Chen X, Yang M, Yin J, Li P, Zeng S, Zheng G, He Z, Liu H, Wang Q, Zhang F, Chen D. Tumor-associated macrophages promote epithelial-mesenchymal transition and the cancer stem cell properties in triple-negative breast cancer through CCL2/AKT/β-catenin signaling. Cell Commun Signal 2022; 20:92. [PMID: 35715860 PMCID: PMC9205034 DOI: 10.1186/s12964-022-00888-2] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 04/23/2022] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with poor prognosis and limited treatment. As a major component of the tumor microenvironment, tumor-associated macrophages (TAMs) play an important role in facilitating the aggressive behavior of TNBC. This study aimed to explore the novel mechanism of TAMs in the regulation of epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) properties in TNBC. METHODS Expression of the M2-like macrophage marker CD163 was evaluated by immunohistochemistry in human breast cancer tissues. The phenotype of M2 macrophages polarized from Tohoku-Hospital-Pediatrics-1 (THP1) cells was verified by flow cytometry. Transwell assays, wound healing assays, western blotting, flow cytometry, ELISA, quantitative polymerase chain reaction (qPCR), luciferase reporter gene assays, and immunofluorescence assays were conducted to investigate the mechanism by which TAMs regulate EMT and CSC properties in BT549 and HCC1937 cells. RESULTS Clinically, we observed a high infiltration of M2-like tumor-associated macrophages in TNBC tissues and confirmed that TAMs were associated with unfavorable prognosis in TNBC patients. Moreover, we found that conditioned medium from M2 macrophages (M2-CM) markedly promoted EMT and CSC properties in BT549 and HCC1937 cells. Mechanistically, we demonstrated that chemokine (C-C motif) ligand 2 (CCL2) secretion by TAMs activated Akt signaling, which in turn increased the expression and nuclear localization of β-catenin. Furthermore, β-catenin knockdown reversed TAM-induced EMT and CSC properties. CONCLUSIONS This study provides a novel mechanism by which TAMs promote EMT and enhance CSC properties in TNBC via activation of CCL2/AKT/β-catenin signaling, which may offer new strategies for the diagnosis and treatment of TNBC. Video Abstract.
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Affiliation(s)
- Xiangzhou Chen
- Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Affiliated Cancer Hospital & Institute of Guangzhou Medical University, No.78 Hengzhigang Road, Guangzhou, 510095, Guangdong, China
| | - Mingqiang Yang
- Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Affiliated Cancer Hospital & Institute of Guangzhou Medical University, No.78 Hengzhigang Road, Guangzhou, 510095, Guangdong, China
| | - Jiang Yin
- Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Affiliated Cancer Hospital & Institute of Guangzhou Medical University, No.78 Hengzhigang Road, Guangzhou, 510095, Guangdong, China
| | - Pan Li
- Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Affiliated Cancer Hospital & Institute of Guangzhou Medical University, No.78 Hengzhigang Road, Guangzhou, 510095, Guangdong, China
| | - Shanshan Zeng
- Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Affiliated Cancer Hospital & Institute of Guangzhou Medical University, No.78 Hengzhigang Road, Guangzhou, 510095, Guangdong, China
| | - Guopei Zheng
- Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Affiliated Cancer Hospital & Institute of Guangzhou Medical University, No.78 Hengzhigang Road, Guangzhou, 510095, Guangdong, China
| | - Zhimin He
- Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Affiliated Cancer Hospital & Institute of Guangzhou Medical University, No.78 Hengzhigang Road, Guangzhou, 510095, Guangdong, China
| | - Hao Liu
- Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Affiliated Cancer Hospital & Institute of Guangzhou Medical University, No.78 Hengzhigang Road, Guangzhou, 510095, Guangdong, China
| | - Qian Wang
- Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Affiliated Cancer Hospital & Institute of Guangzhou Medical University, No.78 Hengzhigang Road, Guangzhou, 510095, Guangdong, China.
| | - Fan Zhang
- Department of Pharmacy, Renmin Hospital of Wuhan University, No.99 Zhangzhidong Road, Wuhan, 430000, Hubei, China.
| | - Danyang Chen
- Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Affiliated Cancer Hospital & Institute of Guangzhou Medical University, No.78 Hengzhigang Road, Guangzhou, 510095, Guangdong, China.
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12
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Wang Q, Wu S, Gu Y, Liang H, He F, Wang X, He D, Wu K. RASAL2 regulates the cell cycle and cyclin D1 expression through PI3K/AKT signalling in prostate tumorigenesis. Cell Death Dis 2022; 8:275. [PMID: 35668070 PMCID: PMC9170709 DOI: 10.1038/s41420-022-01069-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 04/30/2022] [Accepted: 05/25/2022] [Indexed: 12/14/2022]
Abstract
Prostate cancer (PCa) growth and progression are uniquely dependent on androgens, making the androgen receptor pathway a prime target for therapy; however, cancer progression to androgen independence leads to treatment failure and poor prognosis. In recent years, alternative therapeutic pathways for PCa have been extensively explored, such as the PTEN/PI3K/AKT pathway, cell cycle, and DNA repair. In the present study, we discovered that RASAL2, a RAS-GTPase-activating protein, acted as an oncogene to regulate cancer cell proliferation and the cell cycle and contributed to tumorigenesis via the PI3K/AKT/cyclin D1 pathway. First, RASAL2 expression was higher in PCa tumour and metastatic lymph node tissues than in matched adjacent nontumor tissues and was associated with higher PCa tumour stage, Gleason score and poorer prognosis. Mechanistically, we found that RASAL2 promoted tumour cell proliferation, the transition from G1 to S phase in vitro and tumour growth in vivo. Furthermore, we demonstrated that RASAL2 facilitated phosphorylation of AKT, which in turn increased the expression of cyclin D1 encoded by the CCND1 gene. In addition, there was a positive correlation between the expression of RASAL2 and cyclin D1 in subcutaneous xenografts and clinical specimens. Taken together, these findings indicate that RASAL2 plays an oncogenic role in prostate cancer and may promote PCa tumorigenesis through PI3K/AKT signalling and cyclin D1 expression.
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Affiliation(s)
- Qi Wang
- Department of Urology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Shiqi Wu
- Department of Urology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Yanan Gu
- Department of Urology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Hua Liang
- Department of Pathology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Fei He
- Department of Urology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Xinyang Wang
- Department of Urology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Dalin He
- Department of Urology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Kaijie Wu
- Department of Urology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
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13
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Deng C, Zhang L, Ma X, Cai S, Jia Y, Zhao L. RFTN1 facilitates gastric cancer progression by modulating AKT/p38 signaling pathways. Pathol Res Pract 2022; 234:153902. [DOI: 10.1016/j.prp.2022.153902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 04/06/2022] [Accepted: 04/15/2022] [Indexed: 10/18/2022]
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14
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Nadel G, Yao Z, Wainstein E, Cohen I, Ben-Ami I, Schajnovitz A, Maik-Rachline G, Naor Z, Horwitz BA, Seger R. GqPCR-stimulated dephosphorylation of AKT is induced by an IGBP1-mediated PP2A switch. Cell Commun Signal 2022; 20:5. [PMID: 34998390 PMCID: PMC8742922 DOI: 10.1186/s12964-021-00805-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 11/18/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND G protein-coupled receptors (GPCRs) usually regulate cellular processes via activation of intracellular signaling pathways. However, we have previously shown that in several cell lines, GqPCRs induce immediate inactivation of the AKT pathway, which leads to JNK-dependent apoptosis. This apoptosis-inducing AKT inactivation is essential for physiological functions of several GqPCRs, including those for PGF2α and GnRH. METHODS Here we used kinase activity assays of PI3K and followed phosphorylation state of proteins using specific antibodies. In addition, we used coimmunoprecipitation and proximity ligation assays to follow protein-protein interactions. Apoptosis was detected by TUNEL assay and PARP1 cleavage. RESULTS We identified the mechanism that allows the unique stimulated inactivation of AKT and show that the main regulator of this process is the phosphatase PP2A, operating with the non-canonical regulatory subunit IGBP1. In resting cells, an IGBP1-PP2Ac dimer binds to PI3K, dephosphorylates the inhibitory pSer608-p85 of PI3K and thus maintains its high basal activity. Upon GqPCR activation, the PP2Ac-IGBP1 dimer detaches from PI3K and thus allows the inhibitory dephosphorylation. At this stage, the free PP2Ac together with IGBP1 and PP2Aa binds to AKT, causing its dephosphorylation and inactivation. CONCLUSION Our results show a stimulated shift of PP2Ac from PI3K to AKT termed "PP2A switch" that represses the PI3K/AKT pathway, providing a unique mechanism of GPCR-stimulated dephosphorylation. Video Abstract.
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Affiliation(s)
- Guy Nadel
- Departments of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel
| | - Zhong Yao
- Departments of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel
| | - Ehud Wainstein
- Departments of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel
| | - Izel Cohen
- Departments of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel
| | - Ido Ben-Ami
- Departments of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.,IVF and Fertility Unit, Department of OB/GYN, Shaare Zedek Medical Center and The Hebrew University Medical School, Jerusalem, Israel
| | - Amir Schajnovitz
- Departments of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel
| | - Galia Maik-Rachline
- Departments of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel
| | - Zvi Naor
- Department of Biochemistry and Molecular Biology, Tel Aviv University, Tel Aviv, Israel
| | - Benjamin A Horwitz
- Departments of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.,Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel
| | - Rony Seger
- Departments of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
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15
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Yeoh Y, Low TY, Abu N, Lee PY. Regulation of signal transduction pathways in colorectal cancer: implications for therapeutic resistance. PeerJ 2021; 9:e12338. [PMID: 34733591 PMCID: PMC8544255 DOI: 10.7717/peerj.12338] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 09/28/2021] [Indexed: 12/13/2022] Open
Abstract
Resistance to anti-cancer treatments is a critical and widespread health issue that has brought serious impacts on lives, the economy and public policies. Mounting research has suggested that a selected spectrum of patients with advanced colorectal cancer (CRC) tend to respond poorly to both chemotherapeutic and targeted therapeutic regimens. Drug resistance in tumours can occur in an intrinsic or acquired manner, rendering cancer cells insensitive to the treatment of anti-cancer therapies. Multiple factors have been associated with drug resistance. The most well-established factors are the emergence of cancer stem cell-like properties and overexpression of ABC transporters that mediate drug efflux. Besides, there is emerging evidence that signalling pathways that modulate cell survival and drug metabolism play major roles in the maintenance of multidrug resistance in CRC. This article reviews drug resistance in CRC as a result of alterations in the MAPK, PI3K/PKB, Wnt/β-catenin and Notch pathways.
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Affiliation(s)
- Yeelon Yeoh
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Teck Yew Low
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Nadiah Abu
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Pey Yee Lee
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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16
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O'Reilly CL, Uranga S, Fluckey JD. Culprits or consequences: Understanding the metabolic dysregulation of muscle in diabetes. World J Biol Chem 2021; 12:70-86. [PMID: 34630911 PMCID: PMC8473417 DOI: 10.4331/wjbc.v12.i5.70] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 06/21/2021] [Accepted: 08/03/2021] [Indexed: 02/06/2023] Open
Abstract
The prevalence of type 2 diabetes (T2D) continues to rise despite the amount of research dedicated to finding the culprits of this debilitating disease. Skeletal muscle is arguably the most important contributor to glucose disposal making it a clear target in insulin resistance and T2D research. Within skeletal muscle there is a clear link to metabolic dysregulation during the progression of T2D but the determination of culprits vs consequences of the disease has been elusive. Emerging evidence in skeletal muscle implicates influential cross talk between a key anabolic regulatory protein, the mammalian target of rapamycin (mTOR) and its associated complexes (mTORC1 and mTORC2), and the well-described canonical signaling for insulin-stimulated glucose uptake. This new understanding of cellular signaling crosstalk has blurred the lines of what is a culprit and what is a consequence with regard to insulin resistance. Here, we briefly review the most recent understanding of insulin signaling in skeletal muscle, and how anabolic responses favoring anabolism directly impact cellular glucose disposal. This review highlights key cross-over interactions between protein and glucose regulatory pathways and the implications this may have for the design of new therapeutic targets for the control of glucoregulatory function in skeletal muscle.
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Affiliation(s)
| | - Selina Uranga
- Health and Kinesiology, Texas A&M University, TX 77843, United States
| | - James D Fluckey
- Health and Kinesiology, Texas A&M University, TX 77843, United States
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17
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Two Sides to Every Story: Herpes Simplex Type-1 Viral Glycoproteins gB, gD, gH/gL, gK, and Cellular Receptors Function as Key Players in Membrane Fusion. Viruses 2021; 13:v13091849. [PMID: 34578430 PMCID: PMC8472851 DOI: 10.3390/v13091849] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 09/02/2021] [Accepted: 09/04/2021] [Indexed: 12/21/2022] Open
Abstract
Herpes simplex virus type-1 (HSV-1) and type-2 (HSV-2) are prototypical alphaherpesviruses that are characterized by their unique properties to infect trigeminal and dorsal root ganglionic neurons, respectively, and establish life-long latent infections. These viruses initially infect mucosal epithelial tissues and subsequently spread to neurons. They are associated with a significant disease spectrum, including orofacial and ocular infections for HSV-1 and genital and neonatal infections for HSV-2. Viral glycoproteins within the virion envelope bind to specific cellular receptors to mediate virus entry into cells. This is achieved by the fusion of the viral envelope with the plasma membrane. Similarly, viral glycoproteins expressed on cell surfaces mediate cell-to-cell fusion and facilitate virus spread. An interactive complex of viral glycoproteins gB, gD/gH/gL, and gK and other proteins mediate these membrane fusion phenomena with glycoprotein B (gB), the principal membrane fusogen. The requirement for the virion to enter neuronal axons suggests that the heterodimeric protein complex of gK and membrane protein UL20, found only in alphaherpesviruses, constitute a critical determinant for neuronal entry. This hypothesis was substantiated by the observation that a small deletion in the amino terminus of gK prevents entry into neuronal axons while allowing entry into other cells via endocytosis. Cellular receptors and receptor-mediated signaling synergize with the viral membrane fusion machinery to facilitate virus entry and intercellular spread. Unraveling the underlying interactions among viral glycoproteins, envelope proteins, and cellular receptors will provide new innovative approaches for antiviral therapy against herpesviruses and other neurotropic viruses.
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18
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Prostate Cancer Biomarkers: From diagnosis to prognosis and precision-guided therapeutics. Pharmacol Ther 2021; 228:107932. [PMID: 34174272 DOI: 10.1016/j.pharmthera.2021.107932] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/10/2021] [Accepted: 05/12/2021] [Indexed: 12/23/2022]
Abstract
Prostate cancer (PCa) is one of the most commonly diagnosed malignancies and among the leading causes of cancer-related death worldwide. It is a highly heterogeneous disease, ranging from remarkably slow progression or inertia to highly aggressive and fatal disease. As therapeutic decision-making, clinical trial design and outcome highly depend on the appropriate stratification of patients to risk groups, it is imperative to differentiate between benign versus more aggressive states. The incorporation of clinically valuable prognostic and predictive biomarkers is also potentially amenable in this process, in the timely prevention of metastatic disease and in the decision for therapy selection. This review summarizes the progress that has so far been made in the identification of the genomic events that can be used for the classification, prediction and prognostication of PCa, and as major targets for clinical intervention. We include an extensive list of emerging biomarkers for which there is enough preclinical evidence to suggest that they may constitute crucial targets for achieving significant advances in the management of the disease. Finally, we highlight the main challenges that are associated with the identification of clinically significant PCa biomarkers and recommend possible ways to overcome such limitations.
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TRIM21 and PHLDA3 negatively regulate the crosstalk between the PI3K/AKT pathway and PPP metabolism. Nat Commun 2020; 11:1880. [PMID: 32312982 PMCID: PMC7170963 DOI: 10.1038/s41467-020-15819-3] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 03/30/2020] [Indexed: 12/13/2022] Open
Abstract
PI3K/AKT signaling is known to regulate cancer metabolism, but whether metabolic feedback regulates the PI3K/AKT pathway is unclear. Here, we demonstrate the important reciprocal crosstalk between the PI3K/AKT signal and pentose phosphate pathway (PPP) branching metabolic pathways. PI3K/AKT activation stabilizes G6PD, the rate-limiting enzyme of the PPP, by inhibiting the newly identified E3 ligase TIRM21 and promotes the PPP. PPP metabolites, in turn, reinforce AKT activation and further promote cancer metabolic reprogramming by blocking the expression of the AKT inhibitor PHLDA3. Knockout of TRIM21 or PHLDA3 promotes crosstalk and cell proliferation. Importantly, PTEN null human cancer cells and in vivo murine models are sensitive to anti-PPP treatments, suggesting the importance of the PPP in maintaining AKT activation even in the presence of a constitutively activated PI3K pathway. Our study suggests that blockade of this reciprocal crosstalk mechanism may have a therapeutic benefit for cancers with PTEN loss or PI3K/AKT activation.
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20
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Li K, Deng Y, Deng G, Chen P, Wang Y, Wu H, Ji Z, Yao Z, Zhang X, Yu B, Zhang K. High cholesterol induces apoptosis and autophagy through the ROS-activated AKT/FOXO1 pathway in tendon-derived stem cells. Stem Cell Res Ther 2020; 11:131. [PMID: 32197645 PMCID: PMC7082977 DOI: 10.1186/s13287-020-01643-5] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 02/27/2020] [Accepted: 03/10/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Hypercholesterolemia increases the risk of tendon pain and tendon rupture. Tendon-derived stem cells (TDSCs) play a vital role in the development of tendinopathy. Our previous research found that high cholesterol inhibits tendon-related gene expression in TDSCs. Whether high cholesterol has other biological effects on TDSCs remains unknown. METHODS TDSCs isolated from female SD rats were exposed to 10 mg/dL cholesterol for 24 h. Then, cell apoptosis was assessed using flow cytometry and fluorescence microscope. RFP-GFP-LC3 adenovirus transfection was used for measuring autophagy. Signaling transduction was measured by immunofluorescence and immunoblotting. In addition, Achilles tendons from ApoE -/- mice fed with a high-fat diet were histologically assessed using HE staining and immunohistochemistry. RESULTS In this work, we verified that 10 mg/dL cholesterol suppressed cell proliferation and migration and induced G0/G1 phase arrest. Additionally, cholesterol induced apoptosis and autophagy simultaneously in TDSCs. Apoptosis induction was related to increased expression of cleaved caspase-3 and BAX and decreased expression of Bcl-xL. The occurrence of autophagic flux and accumulation of LC3-II demonstrated the induction of autophagy by cholesterol. Compared with the effects of cholesterol treatment alone, the autophagy inhibitor 3-methyladenine (3-MA) enhanced apoptosis, while the apoptosis inhibitor Z-VAD-FMK diminished cholesterol-induced autophagy. Moreover, cholesterol triggered reactive oxygen species (ROS) generation and activated the AKT/FOXO1 pathway, while the ROS scavenger NAC blocked cholesterol-induced activation of the AKT/FOXO1 pathway. NAC and the FOXO1 inhibitor AS1842856 rescued the apoptosis and autophagy induced by cholesterol. Finally, high cholesterol elevated the expression of cleaved caspase-3, Bax, LC3-II, and FOXO1 in vivo. CONCLUSION The present study indicated that high cholesterol induced apoptosis and autophagy through ROS-activated AKT/FOXO1 signaling in TDSCs, providing new insights into the mechanism of hypercholesterolemia-induced tendinopathy. High cholesterol induces apoptosis and autophagy through the ROS-activated AKT/FOXO1 pathway in tendon-derived stem cells.
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Affiliation(s)
- Kaiqun Li
- Department of Orthopaedics, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, China
| | - Ye Deng
- Department of Orthopaedics, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, China
| | - Ganming Deng
- Department of Orthopaedics, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, China.,Baoan District People's Hospital of Shenzhen, Shenzhen, 518100, China
| | - Pengyu Chen
- Department of Orthopaedics, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, China
| | - Yutian Wang
- Department of Orthopaedics, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, China
| | - Hangtian Wu
- Department of Orthopaedics, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, China
| | - Zhiguo Ji
- Department of Orthopaedics, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, China
| | - Zilong Yao
- Department of Orthopaedics, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, China
| | - Xianrong Zhang
- Department of Orthopaedics, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, China.,Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Bin Yu
- Department of Orthopaedics, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, China. .,Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - Kairui Zhang
- Department of Orthopaedics, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, 510515, China.
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21
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Human insulin modulates α-synuclein aggregation via DAF-2/DAF-16 signalling pathway by antagonising DAF-2 receptor in C. elegans model of Parkinson's disease. Oncotarget 2020; 11:634-649. [PMID: 32110282 PMCID: PMC7021237 DOI: 10.18632/oncotarget.27366] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Accepted: 09/29/2017] [Indexed: 01/11/2023] Open
Abstract
Insulin-signalling is an important pathway in multiple cellular functions and organismal ageing across the taxa. A strong association of insulin-signalling with Parkinson’s disease (PD) has been proposed but the exact nature of molecular events and genetic associations are yet to be understood. We employed transgenic C. elegans strain harboring human α-synuclein::YFP transgene, towards studying the aggregation pattern of α-synuclein, a PD-associated endpoint, under human insulin (Huminsulin®) treatment and DAF-16/DAF-2 knockdown conditions, independently and in combination. The aggregation was increased when DAF-16 was knocked-down independently or alongwith a co-treatment of Human insulin (HumINS) and decreased when DAF-2 was knocked-down independently or alongwith a co-treatment of HumINS; whereas HumINS treatment per se, reduced the aggregation. Our results depicted that HumINS decreases α-synuclein aggregation via DAF-2/DAF-16 pathway by acting as an antagonist for DAF-2 receptor. Knockdown of reported DAF-2 agonist (INS-6) and antagonists (INS-17 and INS-18) also resulted in a similar effect on α-synuclein aggregation. Further by utilizing bioinformatics tools, we compared the differences between the binding sites of probable agonists and antagonists on DAF-2 including HumINS. Our results suggest that HumINS treatment and DAF-16 expression play a protective role against α-synuclein aggregation and its associated effects.
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Functionalized Upconversion Nanoparticles for Targeted Labelling of Bladder Cancer Cells. Biomolecules 2019; 9:biom9120820. [PMID: 31816991 PMCID: PMC6995529 DOI: 10.3390/biom9120820] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 11/29/2019] [Accepted: 12/02/2019] [Indexed: 01/22/2023] Open
Abstract
Bladder cancer is the ninth most common cancer worldwide. Due to a high risk of recurrence and progression of bladder cancer, every patient needs long-term surveillance, which includes regular cystoscopy, sometimes followed by a biopsy of suspicious lesions or resections of recurring tumours. This study addresses the development of novel biohybrid nanocomplexes representing upconversion nanoparticles (UCNP) coupled to antibodies for photoluminescent (PL) detection of bladder cancer cells. Carrying specific antibodies, these nanoconjugates selectively bind to urothelial carcinoma cells and make them visible by emitting visible PL upon excitation with deeply penetrating near-infrared light. UCNP were coated with a silica layer and linked to anti-Glypican-1 antibody MIL38 via silica-specific solid-binding peptide. Conjugates have been shown to specifically attach to urothelial carcinoma cells with high expression of Glypican-1. This result highlights the potential of produced conjugates and conjugation technology for further studies of their application in the tumour detection and fluorescence-guided resection.
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Wang W, Han P, Xie R, Yang M, Zhang C, Mi Q, Sun B, Zhang Z. TAT-mGluR1 Attenuation of Neuronal Apoptosis through Prevention of MGluR1α Truncation after Experimental Subarachnoid Hemorrhage. ACS Chem Neurosci 2019; 10:746-756. [PMID: 30339347 DOI: 10.1021/acschemneuro.8b00531] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Excessive glutamate-mediated overactivation of metabotropic glutamate receptor 1 (mGluR1) plays a leading role in neuronal apoptosis following subarachnoid hemorrhage (SAH). TAT-mGluR1, a fusion peptide consisting of a peptide spanning the calpain cleavage site of mGluR1α and the trans-activating regulatory protein (TAT) of HIV, effectively blocks mGluR1α truncation and protects neurons against excitotoxic damage. This study investigated the effects of TAT-mGluR1 on neuronal apoptosis in the rat SAH model. Here, we report that SAH caused activation of calpain and truncation of mGluR1α; intraperitoneally administered TAT-mGluR1 did not affect calpain activity, while it blocked truncation of mGluR1α after SAH. Intraperitoneally administered FITC-labeled TAT-mGluR1 was colocalized with mGluR1α in thecortex after SAH. Furthermore, TAT-mGluR1 significantly improved the neurological deficit, increased p-PI3K, p-Akt, and p-GSK3β, downregulated Bax, upregulated Bcl-2, and reduced cortical apoptosis in the basal cortex at 24 h after SAH. These findings indicated that TAT-mGluR1 acted against SAH-induced cell apoptosis through preventing mGluR1α truncation.
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Affiliation(s)
- Weiqi Wang
- Medical College of Qingdao University, Qingdao 266021, Shandong, People’s Republic of China
- Key Lab of Cerebral Microcirculation at the Universities of Shandong, Department of Neurology, Affiliated Hospital of Taishan Medical University, Taian 271016, Shandong, People’s Republic of China
| | - Ping Han
- Key Lab of Cerebral Microcirculation at the Universities of Shandong, Department of Neurology, Affiliated Hospital of Taishan Medical University, Taian 271016, Shandong, People’s Republic of China
| | - Rongxia Xie
- Key Lab of Cerebral Microcirculation at the Universities of Shandong, Department of Neurology, Affiliated Hospital of Taishan Medical University, Taian 271016, Shandong, People’s Republic of China
- Department of Neurology, Central Hospital of Xinwen Mining Group, Taian 271000, People’s Republic of China
| | - Mingfeng Yang
- Key Lab of Cerebral Microcirculation at the Universities of Shandong, Department of Neurology, Affiliated Hospital of Taishan Medical University, Taian 271016, Shandong, People’s Republic of China
| | - Cheng Zhang
- Key Lab of Cerebral Microcirculation at the Universities of Shandong, Department of Neurology, Affiliated Hospital of Taishan Medical University, Taian 271016, Shandong, People’s Republic of China
| | - Qiongjie Mi
- Key Lab of Cerebral Microcirculation at the Universities of Shandong, Department of Neurology, Affiliated Hospital of Taishan Medical University, Taian 271016, Shandong, People’s Republic of China
| | - Baoliang Sun
- Key Lab of Cerebral Microcirculation at the Universities of Shandong, Department of Neurology, Affiliated Hospital of Taishan Medical University, Taian 271016, Shandong, People’s Republic of China
| | - Zongyong Zhang
- Key Lab of Cerebral Microcirculation at the Universities of Shandong, Department of Neurology, Affiliated Hospital of Taishan Medical University, Taian 271016, Shandong, People’s Republic of China
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Grabon A, Bankaitis VA, McDermott MI. The interface between phosphatidylinositol transfer protein function and phosphoinositide signaling in higher eukaryotes. J Lipid Res 2018; 60:242-268. [PMID: 30504233 DOI: 10.1194/jlr.r089730] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 11/12/2018] [Indexed: 12/22/2022] Open
Abstract
Phosphoinositides are key regulators of a large number of diverse cellular processes that include membrane trafficking, plasma membrane receptor signaling, cell proliferation, and transcription. How a small number of chemically distinct phosphoinositide signals are functionally amplified to exert specific control over such a diverse set of biological outcomes remains incompletely understood. To this end, a novel mechanism is now taking shape, and it involves phosphatidylinositol (PtdIns) transfer proteins (PITPs). The concept that PITPs exert instructive regulation of PtdIns 4-OH kinase activities and thereby channel phosphoinositide production to specific biological outcomes, identifies PITPs as central factors in the diversification of phosphoinositide signaling. There are two evolutionarily distinct families of PITPs: the Sec14-like and the StAR-related lipid transfer domain (START)-like families. Of these two families, the START-like PITPs are the least understood. Herein, we review recent insights into the biochemical, cellular, and physiological function of both PITP families with greater emphasis on the START-like PITPs, and we discuss the underlying mechanisms through which these proteins regulate phosphoinositide signaling and how these actions translate to human health and disease.
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Affiliation(s)
- Aby Grabon
- E. L. Wehner-Welch Laboratory, Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, TX 77843-1114
| | - Vytas A Bankaitis
- E. L. Wehner-Welch Laboratory, Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, TX 77843-1114
| | - Mark I McDermott
- E. L. Wehner-Welch Laboratory, Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, TX 77843-1114
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25
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Pharmacologic inhibition of AKT leads to cell death in relapsed multiple myeloma. Cancer Lett 2018; 432:205-215. [DOI: 10.1016/j.canlet.2018.06.020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 06/14/2018] [Accepted: 06/14/2018] [Indexed: 11/18/2022]
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26
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Cunha MP, Pazini FL, Lieberknecht V, Rodrigues ALS. Subchronic administration of creatine produces antidepressant-like effect by modulating hippocampal signaling pathway mediated by FNDC5/BDNF/Akt in mice. J Psychiatr Res 2018; 104:78-87. [PMID: 30005372 DOI: 10.1016/j.jpsychires.2018.07.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 06/18/2018] [Accepted: 07/05/2018] [Indexed: 12/22/2022]
Abstract
Creatine has been shown to play a significant role in the pathophysiology and treatment of major depressive disorder (MDD) in preclinical and clinical studies. However, the biological mechanisms underlying its antidepressant effect is still not fully elucidated. This study investigated the effect of creatine (p.o.) administered for 21 days in the behavior of mice submitted to tail suspension test (TST), a predictive test of antidepressant activity. Creatine reduced the immobility time in the TST (1-10 mg/kg), without affecting locomotor activity, a finding consistent with an antidepressant profile. Creatine administration increased the ubiquitous creatine kinase (uCK) and creatine kinase brain isoform (CK-B) mRNA in the hippocampus of mice. Taking into account that PGC-1α induces FNDC5/irisin expression mediating BDNF-dependent neuroplasticity, the effect of creatine administration (1 mg/kg, p. o.) on the hippocampal PGC-1α, FNDC5 and BDNF gene expression was investigated. Creatine treatment increased PGC-1α, FNDC5 and BDNF mRNA in the hippocampus as well as BDNF immunocontent. The involvement of BDNF downstream intracellular signaling pathway mediated by Akt, proapoptotic proteins BAX and BAD and antiapoptotic proteins Bcl2 and Bcl-xL was also investigated following creatine treatment. Creatine increased Akt phosphorylation (Ser 473), and Bcl2 mRNA and protein levels, and Bcl-xL mRNA, whereas BAD mRNA was decreased following creatine administration in the hippocampus. Altogether these results indicate that creatine antidepressant-like effect may be dependent on Akt activation and increased expression of the neuroprotective proteins in the hippocampus of mice. The obtained data reinforce the antidepressant property of creatine and highlight the role of these molecular targets in the pathophysiology of MDD.
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Affiliation(s)
- Mauricio P Cunha
- Universidade Federal de Santa Catarina, Department of Biochemistry, Florianópolis, Brazil.
| | - Francis L Pazini
- Universidade Federal de Santa Catarina, Department of Biochemistry, Florianópolis, Brazil
| | - Vicente Lieberknecht
- Universidade Federal de Santa Catarina, Department of Biochemistry, Florianópolis, Brazil
| | - Ana Lúcia S Rodrigues
- Universidade Federal de Santa Catarina, Department of Biochemistry, Florianópolis, Brazil
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Musarrat F, Jambunathan N, Rider PJF, Chouljenko VN, Kousoulas KG. The Amino Terminus of Herpes Simplex Virus 1 Glycoprotein K (gK) Is Required for gB Binding to Akt, Release of Intracellular Calcium, and Fusion of the Viral Envelope with Plasma Membranes. J Virol 2018; 92:e01842-17. [PMID: 29321326 PMCID: PMC5827371 DOI: 10.1128/jvi.01842-17] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 12/17/2017] [Indexed: 01/28/2023] Open
Abstract
Previously, we have shown that the amino terminus of glycoprotein K (gK) binds to the amino terminus of gB and that deletion of the amino-terminal 38 amino acids of gK prevents herpes simplex virus 1 (HSV-1) infection of mouse trigeminal ganglia after ocular infection and virus entry into neuronal axons. Recently, it has been shown that gB binds to Akt during virus entry and induces Akt phosphorylation and intracellular calcium release. Proximity ligation and two-way immunoprecipitation assays using monoclonal antibodies against gB and Akt-1 phosphorylated at S473 [Akt-1(S473)] confirmed that HSV-1(McKrae) gB interacted with Akt-1(S473) during virus entry into human neuroblastoma (SK-N-SH) cells and induced the release of intracellular calcium. In contrast, the gB specified by HSV-1(McKrae) gKΔ31-68, lacking the amino-terminal 38 amino acids of gK, failed to interact with Akt-1(S473) and induce intracellular calcium release. The Akt inhibitor miltefosine inhibited the entry of McKrae but not the gKΔ31-68 mutant into SK-N-SH cells. Importantly, the entry of the gKΔ31-68 mutant but not McKrae into SK-N-SH cells treated with the endocytosis inhibitors pitstop-2 and dynasore hydrate was significantly inhibited, indicating that McKrae gKΔ31-68 entered via endocytosis. These results suggest that the amino terminus of gK functions to regulate the fusion of the viral envelope with cellular plasma membranes.IMPORTANCE HSV-1 glycoprotein B (gB) functions in the fusion of the viral envelope with cellular membranes during virus entry. Herein, we show that a deletion in the amino terminus of glycoprotein K (gK) inhibits gB binding to Akt-1(S473), the release of intracellular calcium, and virus entry via fusion of the viral envelope with cellular plasma membranes.
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Affiliation(s)
- Farhana Musarrat
- Division of Biotechnology and Molecular Medicine and Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, USA
| | - Nithya Jambunathan
- Division of Biotechnology and Molecular Medicine and Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, USA
| | - Paul J F Rider
- Division of Biotechnology and Molecular Medicine and Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, USA
| | - V N Chouljenko
- Division of Biotechnology and Molecular Medicine and Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, USA
| | - K G Kousoulas
- Division of Biotechnology and Molecular Medicine and Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, USA
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28
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Surface chemistry induces mitochondria-mediated apoptosis of breast cancer cells via PTEN/PI3K/AKT signaling pathway. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2018; 1865:172-185. [DOI: 10.1016/j.bbamcr.2017.10.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Revised: 09/17/2017] [Accepted: 10/13/2017] [Indexed: 01/31/2023]
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29
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Shobana N, Aruldhas MM, Tochhawng L, Loganathan A, Balaji S, Kumar MK, Banu LAS, Navin AK, Mayilvanan C, Ilangovan R, Balasubramanian K. Transient gestational exposure to drinking water containing excess hexavalent chromium modifies insulin signaling in liver and skeletal muscle of rat progeny. Chem Biol Interact 2017; 277:119-128. [DOI: 10.1016/j.cbi.2017.09.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Revised: 09/03/2017] [Accepted: 09/05/2017] [Indexed: 12/11/2022]
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30
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Ryu M, Nogami A, Kitakaze T, Harada N, Suzuki YA, Yamaji R. Lactoferrin induces tropoelastin expression by activating the lipoprotein receptor-related protein 1-mediated phosphatidylinositol 3-kinase/Akt pathway in human dermal fibroblasts. Cell Biol Int 2017; 41:1325-1334. [DOI: 10.1002/cbin.10845] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 08/12/2017] [Indexed: 12/24/2022]
Affiliation(s)
- Mizuyuki Ryu
- Biochemical Laboratory; Saraya Co. Ltd; Kashiwara Osaka Japan
- Division of Applied Life Sciences; Graduate School of Life and Environmental Sciences; Osaka Prefecture University; Sakai Osaka Japan
| | - Asuka Nogami
- Biochemical Laboratory; Saraya Co. Ltd; Kashiwara Osaka Japan
| | - Tomoya Kitakaze
- Division of Applied Life Sciences; Graduate School of Life and Environmental Sciences; Osaka Prefecture University; Sakai Osaka Japan
| | - Naoki Harada
- Division of Applied Life Sciences; Graduate School of Life and Environmental Sciences; Osaka Prefecture University; Sakai Osaka Japan
| | | | - Ryoichi Yamaji
- Division of Applied Life Sciences; Graduate School of Life and Environmental Sciences; Osaka Prefecture University; Sakai Osaka Japan
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31
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Wang J, Zhou Y, Li D, Sun X, Deng Y, Zhao Q. TSPAN
31 is a critical regulator on transduction of survival and apoptotic signals in hepatocellular carcinoma cells. FEBS Lett 2017; 591:2905-2918. [DOI: 10.1002/1873-3468.12737] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 06/20/2017] [Accepted: 06/21/2017] [Indexed: 12/27/2022]
Affiliation(s)
- Jianglin Wang
- Department of Biochemistry and Molecular Biology GMU‐GIBH Joint School of Life Sciences Guangzhou Medical University China
| | - Yuting Zhou
- Department of Molecular & Cellular Biochemistry College of Medicine University of Kentucky Lexington KY USA
| | - Dan Li
- Department of Biochemistry and Molecular Biology GMU‐GIBH Joint School of Life Sciences Guangzhou Medical University China
| | - Xuemeng Sun
- Department of Biochemistry and Molecular Biology GMU‐GIBH Joint School of Life Sciences Guangzhou Medical University China
| | - Yuanfei Deng
- Department of Biochemistry and Molecular Biology GMU‐GIBH Joint School of Life Sciences Guangzhou Medical University China
| | - Qing Zhao
- Department of Biochemistry and Molecular Biology GMU‐GIBH Joint School of Life Sciences Guangzhou Medical University China
- Sino‐French Hoffmann Institute Guangzhou Medical University China
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32
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Szondy Z, Korponay-Szabó I, Király R, Sarang Z, Tsay GJ. Transglutaminase 2 in human diseases. Biomedicine (Taipei) 2017; 7:15. [PMID: 28840829 PMCID: PMC5571667 DOI: 10.1051/bmdcn/2017070315] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2017] [Accepted: 05/15/2017] [Indexed: 12/30/2022] Open
Abstract
Transglutaminase 2 (TG2) is an inducible transamidating acyltransferase that catalyzes Ca(2+)-dependent protein modifications. In addition to being an enzyme, TG2 also serves as a G protein for several seven transmembrane receptors and acts as a co-receptor for integrin β1 and β3 integrins distinguishing it from other members of the transglutaminase family. TG2 is ubiquitously expressed in almost all cell types and all cell compartments, and is also present on the cell surface and gets secreted to the extracellular matrix via non-classical mechanisms. TG2 has been associated with various human diseases including inflammation, cancer, fibrosis, cardiovascular disease, neurodegenerative diseases, celiac disease in which it plays either a protective role, or contributes to the pathogenesis. Thus modulating the biological activities of TG2 in these diseases will have a therapeutic value.
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Affiliation(s)
- Zsuzsa Szondy
- Dental Biochemistry, Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen 4010, Hungary
| | - Ilma Korponay-Szabó
- Department of Pediatrics and Biochemistry and Molecular Biology, University of Debrecen, Debrecen 4010, Hungary - Celiac Disease Center, Heim Pál Children's Hospital, Budapest 1089, Hungary
| | - Robert Király
- Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen 4010, Hungary
| | - Zsolt Sarang
- Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen 4010, Hungary
| | - Gregory J Tsay
- Division of Immunology and Rheumatology, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan - School of medicine, College of Medicine, China Medical University, Taichung 404, Taiwan
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Kefeli U, Ucuncu Kefeli A, Cabuk D, Isik U, Sonkaya A, Acikgoz O, Ozden E, Uygun K. Netrin-1 in cancer: Potential biomarker and therapeutic target? Tumour Biol 2017; 39:1010428317698388. [PMID: 28443497 DOI: 10.1177/1010428317698388] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Netrin-1, a laminin-related protein, is known to be involved in the nervous system development. Recently, Netrin-1's involvement in other processes such as cell adhesion, motility, proliferation, and differentiation that are important for the development of epithelial tissues has been described. In addition, Netrin-1 and its receptors, deleted in colorectal cancer and uncoordinated-5 homolog, have been linked to apoptosis and angiogenesis. Since these properties are essential for tumor development, Netrin-1 and its receptors have been reported to promote tumorigenesis in many types of cancers. Here, we review the Netrin-1 mediated regulation of cancer, its potential use as a biomarker, and the targeting of the Netrin-1 pathway to treat cancers.
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Affiliation(s)
- Umut Kefeli
- 1 Department of Medical Oncology, Kocaeli University School of Medicine, Kocaeli, Turkey
| | | | - Devrim Cabuk
- 1 Department of Medical Oncology, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Ulas Isik
- 1 Department of Medical Oncology, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Alper Sonkaya
- 1 Department of Medical Oncology, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Ozgur Acikgoz
- 1 Department of Medical Oncology, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Ercan Ozden
- 1 Department of Medical Oncology, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Kazim Uygun
- 1 Department of Medical Oncology, Kocaeli University School of Medicine, Kocaeli, Turkey
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Zhuo MQ, Pan YX, Wu K, Xu YH, Zhang LH, Luo Z. AKTs/PKBs: molecular characterization, tissue expression and transcriptional responses to insulin and/or wortmannin in yellow catfish Pelteobagrus fulvidraco. FISH PHYSIOLOGY AND BIOCHEMISTRY 2017; 43:719-730. [PMID: 28000079 DOI: 10.1007/s10695-016-0327-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Accepted: 12/11/2016] [Indexed: 06/06/2023]
Abstract
In the present study, four AKT isoforms termed AKT1, AKT2, AKT3a and AKT3b were isolated and characterized from yellow catfish. Their molecular characterizations, tissue expressions and transcriptional responses to insulin and/or wortmannin were determined. The validated complementary DNA (cDNA) of yellow catfish AKT1, AKT2, AKT3a and AKT3b were 1422, 1431, 1389 and 1440 bp in length, encoding the peptide of 472, 475, 462 and 479 amino acid residues, respectively. The amino acid sequences of yellow catfish AKTs possessed all the characteristics of AKTs in other species. AKT1, AKT2 and AKT3b contained a conserved domain structure including a specific PH domain, a central catalytic domain and a C-terminal regulatory domain, while AKT3a lacked the C-terminal regulatory domain. All mRNAs of AKTs were expressed at the highest levels in the ovary. Among other tissues, the messenger RNA (mRNA) of AKT1 was widely distributed in all tested tissues, and AKT2 mRNA was more abundant in the muscle, liver and fat and lowest in other tested tissues, while AKT3a mRNA was predominant in the brain and showed no significant difference among other tested tissues, and AKT3b mRNA was highly expressed in the ovary, followed by the brain, muscle and fat and was relatively low in other tissues. Intraperitoneal insulin injection and incubation increased the mRNA expression of AKT1 and AKT2, but not that of AKT3a and AKT3b in the liver and hepatocytes of yellow catfish. Wortmannin reduced the mRNA level of all AKT isoforms and also alleviated the insulin-induced changes of AKT2 expression. The present study cloned full-length cDNA sequences of four AKTs in fish and determined their tissue expression profiles and studied their transcriptional responses to insulin and/or wortmannin, which serves to increase our understanding of their physiological function in lipid metabolism in fish.
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Affiliation(s)
- Mei-Qin Zhuo
- Key Laboratory of Freshwater Animal Breeding Ministry of Agriculture of P.R.C., Fishery College, Huazhong Agricultural University, Wuhan, 430070, China
- Freshwater Aquaculture Collaborative Innovative Centre of Hubei Province, Wuhan, 430070, China
| | - Ya-Xiong Pan
- Key Laboratory of Freshwater Animal Breeding Ministry of Agriculture of P.R.C., Fishery College, Huazhong Agricultural University, Wuhan, 430070, China
- Freshwater Aquaculture Collaborative Innovative Centre of Hubei Province, Wuhan, 430070, China
| | - Kun Wu
- Key Laboratory of Freshwater Animal Breeding Ministry of Agriculture of P.R.C., Fishery College, Huazhong Agricultural University, Wuhan, 430070, China
- Freshwater Aquaculture Collaborative Innovative Centre of Hubei Province, Wuhan, 430070, China
| | - Yi-Huan Xu
- Key Laboratory of Freshwater Animal Breeding Ministry of Agriculture of P.R.C., Fishery College, Huazhong Agricultural University, Wuhan, 430070, China
- Freshwater Aquaculture Collaborative Innovative Centre of Hubei Province, Wuhan, 430070, China
| | - Li-Han Zhang
- Key Laboratory of Freshwater Animal Breeding Ministry of Agriculture of P.R.C., Fishery College, Huazhong Agricultural University, Wuhan, 430070, China
- Freshwater Aquaculture Collaborative Innovative Centre of Hubei Province, Wuhan, 430070, China
| | - Zhi Luo
- Key Laboratory of Freshwater Animal Breeding Ministry of Agriculture of P.R.C., Fishery College, Huazhong Agricultural University, Wuhan, 430070, China.
- Freshwater Aquaculture Collaborative Innovative Centre of Hubei Province, Wuhan, 430070, China.
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35
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Roettger A, Bruchhage KL, Drenckhan M, Ploetze-Martin K, Pries R, Wollenberg B. Inhibitory Effect of 1,8-Cineol on β-Catenin Regulation, WNT11 Expression, and Cellular Progression in HNSCC. Front Oncol 2017; 7:92. [PMID: 28589081 PMCID: PMC5438970 DOI: 10.3389/fonc.2017.00092] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Accepted: 04/24/2017] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES Head and neck squamous cell carcinoma (HNSCC) is one of the most common tumors worldwide. The high mortality rates have not changed during the last three decades, and thus there is an enormous need for innovative therapy approaches. Several recent studies suggest an important role of the Wnt/β-catenin signaling pathway in the tumorigenesis of HNSCC. We analyzed the effect of the monoterpene oxide 1,8-cineol on the regulation of the Wnt/β-catenin signaling pathway and the cellular progression of different HNSCC cell lines. METHODS Permanent HNSCC cell lines were exposed to varying concentrations and times of 1,8-cineol. Regulation and activity profiles of the Wnt/β-catenin signaling cascade were analyzed using Western hybridization experiments, MTT assays, real-time PCR-based epithelial to mesenchymal transition array, and immunohistochemistry. RESULTS Exposure of different cell lines to 1,8-cineol treatment resulted in a dose-dependent inhibition of proliferation and a decreased activity of the WNT/β-catenin pathway. We can show the inhibition of glycogen synthase kinase 3 (GSK-3)α/β (Ser-9/21) as well as a corresponding decreased endolysosomal localization, leading to a decreased β-catenin activity. Furthermore, we can show that exposure to cineol functionally results in a reduced expression of WNT11. CONCLUSION In this work, we demonstrate for the first time that 1,8-cineol acts as an inhibitor of the Wnt/β-catenin activity in HNSCC via a decreased inhibition of GSK-3, which lead to reduced levels of WNT11 and a dose-dependent decrease of the cellular progression. Our data represent a new mechanism of 1,8-cineol activity, which may lead to novel molecular targets and treatment approaches of this natural drug.
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Affiliation(s)
- Anna Roettger
- Clinic for Otorhinolaryngology, Head and Neck Surgery, University Clinic Schleswig Holstein, Lübeck, Germany
| | - Karl-Ludwig Bruchhage
- Clinic for Otorhinolaryngology, Head and Neck Surgery, University Clinic Schleswig Holstein, Lübeck, Germany
| | - Maren Drenckhan
- Clinic for Otorhinolaryngology, Head and Neck Surgery, University Clinic Schleswig Holstein, Lübeck, Germany
| | - Kirsten Ploetze-Martin
- Clinic for Otorhinolaryngology, Head and Neck Surgery, University Clinic Schleswig Holstein, Lübeck, Germany
| | - Ralph Pries
- Clinic for Otorhinolaryngology, Head and Neck Surgery, University Clinic Schleswig Holstein, Lübeck, Germany
| | - Barbara Wollenberg
- Clinic for Otorhinolaryngology, Head and Neck Surgery, University Clinic Schleswig Holstein, Lübeck, Germany
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Lee JS, Ahn C, Kang HY, Jeung EB. Effect of 2-methoxyestradiol on SK-LMS-1 uterine leiomyosarcoma cells. Oncol Lett 2017; 14:103-110. [PMID: 28693141 PMCID: PMC5494911 DOI: 10.3892/ol.2017.6165] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 03/07/2017] [Indexed: 12/22/2022] Open
Abstract
An endogenous metabolite of 17β-estradiol, 2-methoxyestradiol (2-ME), has affinity for estrogen receptors. This compound was reported to be a promising antitumor drug due to its anti-proliferative effects on a wide range of tumor cell types. Numerous previous studies have been performed to evaluate the cytotoxic effects of 2-ME on tumor cell lines in following the induction of G2/M cell cycle arrest and subsequent apoptosis. Uterine leiomyosarcoma (ULMS) is a relatively rare malignant smooth muscle cell tumor that develops in the uterus muscle layer. The aim of the present study was to examine the in vitro anti-proliferative effects of 2-ME on SK-LMS-1 human leiomyosarcoma cells. An MTT assay, terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling assay, immunocytochemistry and western blotting were performed. A high concentration (10−5 M) of 2-ME was identified to have an anti-proliferative effect on SK-LMS-1 cells. Additionally, expression of the apoptosis markers was upregulated in the presence of 10−5 M 2-ME, according to western blot analysis. Furthermore, the expression level of an autophagic marker, light chain 3, was increased by 2-ME treatment in a dose-dependent manner. This was associated with cell death induced by the upregulation of phosphorylated extracellular-signal-regulated kinase 1/2 signaling pathway. The results of the present study demonstrated that 2-ME, which is used as a therapeutic agent for treating solid tumors, exhibits apoptotic and anti-proliferative effects depending on the dose. Therefore, 2-ME may be a potential therapeutic reagent for human ULMS, but the appropriate dose of this compound should be carefully selected.
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Affiliation(s)
- Ji-Sun Lee
- Laboratory of Veterinary Biochemistry and Molecular Biology, Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea
| | - Changhwan Ahn
- Laboratory of Veterinary Biochemistry and Molecular Biology, Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea
| | - Hee Young Kang
- Laboratory of Veterinary Biochemistry and Molecular Biology, Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea
| | - Eui-Bae Jeung
- Laboratory of Veterinary Biochemistry and Molecular Biology, Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea
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Zhang W, Shao X. Isoflurane Promotes Non-Small Cell Lung Cancer Malignancy by Activating the Akt-Mammalian Target of Rapamycin (mTOR) Signaling Pathway. Med Sci Monit 2016; 22:4644-4650. [PMID: 27897153 PMCID: PMC5142580 DOI: 10.12659/msm.898434] [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] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Lung cancer is one of the leading causes of cancer mortalities worldwide, and non-small cell lung cancer (NSCLC) accounts for the majority of all lung cancer cases. Surgery remains one of the front-line treatment options for NSCLC, but events within the perioperative period were found to affect cancer prognosis, such as anesthesia procedures. Isoflurane, a commonly used volatile anesthetic, enhances the malignant potential of renal, prostate, and ovarian cancer cells, but its effects on NSCLC development have not been previously reported. MATERIAL AND METHODS CCK-8 and MTT cell proliferation assays were used to analyze NSCLC cell proliferation. Metastatic ability was examined by wound healing and transwell assays. We used Western blot analysis to study the mechanism of effect of Isoflurane in NSCLC development. RESULTS We demonstrated that isoflurane promotes proliferation, migration and invasiveness of NSCLC cells, as well as upregulation of the Akt-mTOR signaling pathway in NSCLC cells. Pharmacological inhibition of Akt-mTOR signaling abolished the ability of isoflurane to promote proliferation, migration, and invasion of NSCLC cells, indicating that isoflurane promotes NSCLC cell malignancy by activating the Akt-mTOR signaling pathway. CONCLUSIONS Isoflurane promotes NSCLC proliferation, migration and invasion by activating the Akt-mTOR signaling pathway.
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Affiliation(s)
- Wenhua Zhang
- Department of Anesthesiology, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, Heilongjiang, China (mainland)
| | - Xueqian Shao
- Department of Surgical Oncology, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, Heilongjiang, China (mainland)
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Lack of association between genetic polymorphism of FTO, AKT1 and AKTIP in childhood overweight and obesity. JORNAL DE PEDIATRIA (VERSÃO EM PORTUGUÊS) 2016. [DOI: 10.1016/j.jpedp.2016.07.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
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Lack of association between genetic polymorphism of FTO, AKT1 and AKTIP in childhood overweight and obesity. J Pediatr (Rio J) 2016; 92:521-7. [PMID: 27342216 DOI: 10.1016/j.jped.2015.12.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Revised: 12/10/2015] [Accepted: 12/15/2015] [Indexed: 01/10/2023] Open
Abstract
OBJECTIVE Obesity is a chronic disease caused by both environmental and genetic factors. Epidemiological studies have documented that increased energy intake and sedentary lifestyle, as well as a genetic contribution, are forces behind the obesity epidemic. Knowledge about the interaction between genetic and environmental components can facilitate the choice of the most effective and specific measures for the prevention of obesity. The aim of this study was to assess the association between the FTO, AKT1, and AKTIP genes and childhood obesity and insulin resistance. METHODS This was a case-control study in which SNPs in the FTO (rs99396096), AKT1, and AKTIP genes were genotyped in groups of controls and obese/overweight children. The study included 195 obese/overweight children and 153 control subjects. RESULTS As expected, the obese/overweight group subjects had higher body mass index, higher fasting glucose, HOMA-IR index, total cholesterol, low-density lipoprotein, and triglycerides. However, no significant differences were observed in genes polymorphisms genotype or allele frequencies. CONCLUSION The present results suggest that AKT1, FTO, and AKTIP polymorphisms were not associated with obesity/overweight in Brazilians children. Future studies on the genetics of obesity in Brazilian children and their environment interactions are needed.
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Li J, Krishna SM, Golledge J. The Potential Role of Kallistatin in the Development of Abdominal Aortic Aneurysm. Int J Mol Sci 2016; 17:ijms17081312. [PMID: 27529213 PMCID: PMC5000709 DOI: 10.3390/ijms17081312] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 07/29/2016] [Accepted: 08/05/2016] [Indexed: 02/06/2023] Open
Abstract
Abdominal aortic aneurysm (AAA) is a vascular condition that causes permanent dilation of the abdominal aorta, which can lead to death due to aortic rupture. The only treatment for AAA is surgical repair, and there is no current drug treatment for AAA. Aortic inflammation, vascular smooth muscle cell apoptosis, angiogenesis, oxidative stress and vascular remodeling are implicated in AAA pathogenesis. Kallistatin is a serine proteinase inhibitor, which has been shown to have a variety of functions, potentially relevant in AAA pathogenesis. Kallistatin has been reported to have inhibitory effects on tumor necrosis factor alpha (TNF-α) signaling induced oxidative stress and apoptosis. Kallistatin also inhibits vascular endothelial growth factor (VEGF) and Wnt canonical signaling, which promote inflammation, angiogenesis, and vascular remodeling in various pre-clinical experimental models. This review explores the potential protective role of kallistatin in AAA pathogenesis.
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Affiliation(s)
- Jiaze Li
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, 4811 Townsville, Australia.
| | - Smriti Murali Krishna
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, 4811 Townsville, Australia.
| | - Jonathan Golledge
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, 4811 Townsville, Australia.
- Department of Vascular and Endovascular Surgery, The Townsville Hospital, 4811 Townsville, Australia.
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Lack of SIRPα phosphorylation and concomitantly reduced SHP-2-PI3K-Akt2 signaling decrease osteoblast differentiation. Biochem Biophys Res Commun 2016; 478:268-273. [PMID: 27422603 DOI: 10.1016/j.bbrc.2016.07.048] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Accepted: 07/08/2016] [Indexed: 12/27/2022]
Abstract
Normal differentiation of bone forming osteoblasts is a prerequisite for maintenance of skeletal health and is dependent on intricate cellular signaling pathways, including the essential transcription factor Runx2. The cell surface glycoprotein CD47 and its receptor signal regulatory protein alpha (SIRPα) have both been suggested to regulate bone cell differentiation. Here we investigated osteoblastic differentiation of bone marrow stromal cells from SIRPα mutant mice lacking the cytoplasmic signaling domain of SIRPα. An impaired osteoblastogenesis in SIRPα-mutant cell cultures was demonstrated by lower alkaline phosphatase activity and less mineral formation compared to wild-type cultures. This reduced osteoblastic differentiation potential in SIRPα-mutant stromal cells was associated with a significantly reduced expression of Runx2, osterix, osteocalcin, and alkaline phosphatase mRNA, as well as a reduced phosphorylation of SHP-2 and Akt2, as compared with that in wild-type stromal cells. Addition of a PI3K-inhibitor to wild-type stromal cells could mimic the impaired osteoblastogenesis seen in SIRPα-mutant cells. In conclusion, our data suggest that SIRPα signaling through SHP-2-PI3K-Akt2 strongly influences osteoblast differentiation from bone marrow stromal cells.
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Wang G, Liu M, Wang H, Yu S, Jiang Z, Sun J, Han K, Shen J, Zhu M, Lin Z, Jiang C, Guo M. Centrosomal Protein of 55 Regulates Glucose Metabolism, Proliferation and Apoptosis of Glioma Cells via the Akt/mTOR Signaling Pathway. J Cancer 2016; 7:1431-40. [PMID: 27471559 PMCID: PMC4964127 DOI: 10.7150/jca.15497] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 05/18/2016] [Indexed: 01/02/2023] Open
Abstract
Introduction: Glioma is one of the most common and most aggressive brain tumors in humans. The molecular and cellular mechanisms responsible for the onset and the progression of glioma are elusive and controversial. Centrosomal protein of 55 (CEP55) was initially described as a highly coiled-coil protein that plays critical roles in cell division, but was recently identified as being overexpressed in many human cancers. The function of CEP55 has not previously been characterized in glioma. We aim to discover the effect and mechanism of CEP55 in glioma development. Method: qRT-PCR and immunohistochemistry were used to analyze CEP55 expression. Glucose uptake, western blot, MTS, CCK-8, Caspase-3 activity and TUNEL staining assays were performed to investigate the role and mechanism of CEP55 on glioma cell process. Results: We found that the levels of CEP55 expression were upregulated in glioma. In addition, CEP55 appeared to regulate glucose metabolism of glioma cells. Furthermore, knockdown of CEP55 inhibited cell proliferation and induced cell apoptosis in glioma. Finally, we provided preliminary evidence that knockdown of CEP55 inhibited glioma development via suppressing the activity of Akt/mTOR signaling. Conclusions: Our results demonstrated that CEP55 regulates glucose metabolism, proliferation and apoptosis of glioma cells via the Akt/mTOR signaling pathway, and its promotive effect on glioma tumorigenesis can be a potential target for glioma therapy in the future.
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Affiliation(s)
- Guangzhi Wang
- 1. Department of Neurosurgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China;; 2. Department of Medical Service Management, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Mingna Liu
- 3. Department of Gastroenterology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Hongjun Wang
- 1. Department of Neurosurgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Shan Yu
- 4. Department of Pathology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Zhenfeng Jiang
- 5. Department of Neurosurgery, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Jiahang Sun
- 1. Department of Neurosurgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Ke Han
- 6. School of Computer and Information Engineering, Harbin University of Commerce, Harbin, Heilongjiang 150086, China
| | - Jia Shen
- 7. Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, California 90095, USA
| | - Minwei Zhu
- 5. Department of Neurosurgery, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Zhiguo Lin
- 5. Department of Neurosurgery, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Chuanlu Jiang
- 1. Department of Neurosurgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Mian Guo
- 1. Department of Neurosurgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China
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Yanagimoto Y, Takiguchi S, Miyazaki Y, Makino T, Takahashi T, Kurokawa Y, Yamasaki M, Miyata H, Nakajima K, Hosoda H, Kangawa K, Mori M, Doki Y. Improvement of cisplatin-related renal dysfunction by synthetic ghrelin: a prospective randomised phase II trial. Br J Cancer 2016; 114:1318-25. [PMID: 27253174 PMCID: PMC4984476 DOI: 10.1038/bjc.2016.160] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Revised: 04/12/2016] [Accepted: 05/06/2016] [Indexed: 12/22/2022] Open
Abstract
Background: Ghrelin, a 28-amino acid peptide predominantly produced by the stomach, exerts powerful renal protective effects by increasing levels of insulin-like growth factor-1 (IGF-1). The aim of this study was to evaluate the effects of ghrelin on the incidence of renal dysfunction in patients receiving cisplatin-based chemotherapy. Methods: Forty patients with oesophageal cancer receiving cisplatin-based chemotherapy were assigned to either the ghrelin group (n=20), which received ghrelin (0.5 μg kg−1 h−1) for 5 days, or a placebo group (n=20). The primary endpoint was serum creatinine. Secondary endpoints were serum cystatin C, chemotherapy-related adverse events, changes in serum ghrelin-related hormone levels, correlation between markers of renal injury and hormone concentrations, and effects on the second cycle of chemotherapy. Results: Blood acyl ghrelin, total ghrelin, and IGF-1 concentrations on day 4 were significantly higher in the ghrelin group. The renal dysfunction, serum creatinine and cystatin C levels, dose reduction, and delay in the initiation of the second cycle of chemotherapy were lower in the ghrelin group than in the control group. Serum creatinine levels were significantly correlated with serum IGF-1 levels. Conclusion: Continuous synthetic ghrelin administration during cisplatin-based chemotherapy attenuated renal dysfunction and harmful effects on subsequent chemotherapy, possibly by increasing IGF-1 levels.
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Affiliation(s)
- Yoshitomo Yanagimoto
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, E-2, Yamadaoka, Suita 565-0871, Japan
| | - Shuji Takiguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, E-2, Yamadaoka, Suita 565-0871, Japan
| | - Yasuhiro Miyazaki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, E-2, Yamadaoka, Suita 565-0871, Japan
| | - Tomoki Makino
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, E-2, Yamadaoka, Suita 565-0871, Japan
| | - Tsuyoshi Takahashi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, E-2, Yamadaoka, Suita 565-0871, Japan
| | - Yukinori Kurokawa
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, E-2, Yamadaoka, Suita 565-0871, Japan
| | - Makoto Yamasaki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, E-2, Yamadaoka, Suita 565-0871, Japan
| | - Hiroshi Miyata
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, E-2, Yamadaoka, Suita 565-0871, Japan
| | - Kiyokazu Nakajima
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, E-2, Yamadaoka, Suita 565-0871, Japan
| | - Hiroshi Hosoda
- Department of Biochemistry, National Cardiovascular Center Research Institute, 5-7-1, Fujishirodai, Suita 565-8565, Japan
| | - Kenji Kangawa
- Department of Biochemistry, National Cardiovascular Center Research Institute, 5-7-1, Fujishirodai, Suita 565-8565, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, E-2, Yamadaoka, Suita 565-0871, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, E-2, Yamadaoka, Suita 565-0871, Japan
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Yanagimoto Y, Takiguchi S, Miyazaki Y, Makino T, Takahashi T, Kurokawa Y, Yamasaki M, Miyata H, Nakajima K, Mori M, Doki Y. Plasma ghrelin levels as a predictor of adverse renal events due to cisplatin-based chemotherapy in patients with esophageal cancer. Jpn J Clin Oncol 2016; 46:421-6. [DOI: 10.1093/jjco/hyw004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Accepted: 01/04/2016] [Indexed: 12/15/2022] Open
Affiliation(s)
- Yoshitomo Yanagimoto
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-city, Osaka, Japan
| | - Shuji Takiguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-city, Osaka, Japan
| | - Yasuhiro Miyazaki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-city, Osaka, Japan
| | - Tomoki Makino
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-city, Osaka, Japan
| | - Tsuyoshi Takahashi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-city, Osaka, Japan
| | - Yukinori Kurokawa
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-city, Osaka, Japan
| | - Makoto Yamasaki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-city, Osaka, Japan
| | - Hiroshi Miyata
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-city, Osaka, Japan
| | - Kiyokazu Nakajima
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-city, Osaka, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-city, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-city, Osaka, Japan
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Jiang Z, Guo M, Zhang X, Yao L, Shen J, Ma G, Liu L, Zhao L, Xie C, Liang H, Wang H, Zhu M, Hu L, Song Y, Shen H, Lin Z. TUSC3 suppresses glioblastoma development by inhibiting Akt signaling. Tumour Biol 2016; 37:12039-12047. [PMID: 27177902 DOI: 10.1007/s13277-016-5072-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 05/05/2016] [Indexed: 11/29/2022] Open
Abstract
Glioblastoma multiform is one of the most common and most aggressive brain tumors in humans. The molecular and cellular mechanisms responsible for the onset and progression of GBM are elusive and controversial. The function of tumor suppressor candidate 3 (TUSC3) has not been previously characterized in GBM. TUSC3 was originally identified as part of an enzyme complex involved in N-glycosylation of proteins, but was recently implicated as a potential tumor suppressor gene in a variety of cancer types. In this study, we demonstrated that the expression levels of TUSC3 were downregulated in both GBM tissues and cells, and also found that overexpression of TUSC3 inhibits GBM cell proliferation and invasion. In addition, the effects of increased levels of methylation on the TUSC3 promoter were responsible for decreased expression of TUSC3 in GBM. Finally, we determined that TUSC3 regulates proliferation and invasion of GBM cells by inhibiting the activity of the Akt signaling pathway.
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Affiliation(s)
- Zhenfeng Jiang
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, Heilongjiang Province, 150001, China
| | - Mian Guo
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiangtong Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, Heilongjiang Province, 150001, China
| | - Lifen Yao
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jia Shen
- Orthopaedic Hospital Research Center, University of California, Los Angeles, CA, USA
| | - Guizhen Ma
- Department of Operating Rooms, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Li Liu
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, Heilongjiang Province, 150001, China
| | - Liwei Zhao
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, Heilongjiang Province, 150001, China
| | - Chuncheng Xie
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, Heilongjiang Province, 150001, China
| | - Hongsheng Liang
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, Heilongjiang Province, 150001, China
| | - Haiyang Wang
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, Heilongjiang Province, 150001, China
| | - Minwei Zhu
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, Heilongjiang Province, 150001, China
| | - Li Hu
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, Heilongjiang Province, 150001, China
| | - Yuanyuan Song
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, Heilongjiang Province, 150001, China
| | - Hong Shen
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, Heilongjiang Province, 150001, China
| | - Zhiguo Lin
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, Heilongjiang Province, 150001, China.
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Yu F, Li G, Gao J, Sun Y, Liu P, Gao H, Li P, Lei T, Chen Y, Cheng Y, Zhai X, Sayari AJ, Huang H, Mu Q. SPOCK1 is upregulated in recurrent glioblastoma and contributes to metastasis and Temozolomide resistance. Cell Prolif 2016; 49:195-206. [PMID: 26923184 DOI: 10.1111/cpr.12241] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 11/11/2015] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES Glioblastoma multiforme (GBM) is the most aggressive brain tumour type in humans. Its poor prognosis is largely attributed to its invasiveness and high rate of recurrence. Recurring GBM is commonly resistant to chemotherapeutic drugs, making it specially difficult to treat. Recent studies have revealed that matricellular glycoprotein SPOCK1 to be upregulated in several cancer types and to be specifically expressed in invasive GBM, but not in other types of non-invasive brain tumour, which prompted us to study the mechanism of action of SPOCK1 in invasion, recurrence and drug resistance of GBM cells. MATERIALS AND METHODS SPOCK1 expression in GBM tissues was evaluated using qPCR, Western blotting and immunohistochemical staining. Cell migration was tested by the wound healing method and cell invasion was assessed using transwell plates with Matrigel coating. Western blotting was performed for E-cadherin, vimentin, N-cadherin, p-Akt and Akt. Cell viability was examined using the MTT assay. RESULTS We found that the expression of SPOCK1 was significantly upregulated in recurrent GBM. We also demonstrated that SPOCK1 positively regulated migration, invasion and EMT process of GBM cells. Furthermore, SPOCK1 mediated TMZ resistance in GBM, as knockdown of SPOCK1 expression in TMZ-resistant GBM cells substantially sensitized these cells to TMZ. CONCLUSION SPOCK1 results were positive and it mediated TMZ resistance in GBM. In addition, SPOCK1 regulated invasion and TMZ resistance in GBM cells via the Akt signalling pathway.
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Affiliation(s)
- Fengbo Yu
- School of Pharmacy, Mudanjiang Medical University, Mudanjiang, Heilongjiang Province, 157011, China
| | - Guihong Li
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, Jilin Province, 130021, China
| | - Junxia Gao
- Department of Emergency, Hongqi hospital of Mudanjiang Medical University, Mudanjiang, Heilongjiang Province, 157011, China
| | - Yuxue Sun
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, Jilin Province, 130021, China
| | - Pengfei Liu
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, Jilin Province, 130021, China
| | - Haijun Gao
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, Jilin Province, 130021, China
| | - Peiwen Li
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, Jilin Province, 130021, China
| | - Ting Lei
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, Jilin Province, 130021, China
| | - Yong Chen
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, Jilin Province, 130021, China
| | - Ye Cheng
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, Jilin Province, 130021, China
| | - Xiao Zhai
- Department of Orthopaedics, Changhai Hospital Affiliated to the Second Military Medical University, Shanghai, 200433, China
| | - Arash J Sayari
- Department of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, 90033, USA
| | - Haiyan Huang
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, Jilin Province, 130021, China
| | - Qingchun Mu
- Department of Neurosurgery, Hongqi Hospital of Mudanjiang Medical University, Mudanjiang, Heilongjiang Province, 157011, China
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Liao CT, Chen SJ, Lee LY, Hsueh C, Yang LY, Lin CY, Fan KH, Wang HM, Ng SH, Lin CH, Tsao CK, Chen IH, Chang KP, Huang SF, Kang CJ, Chen HC, Yen TC. An Ultra-Deep Targeted Sequencing Gene Panel Improves the Prognostic Stratification of Patients With Advanced Oral Cavity Squamous Cell Carcinoma. Medicine (Baltimore) 2016; 95:e2751. [PMID: 26937903 PMCID: PMC4779000 DOI: 10.1097/md.0000000000002751] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
An improved prognostic stratification of patients with oral cavity squamous cell carcinoma (OSCC) and pathologically positive (pN+) nodes is urgently needed. Here, we sought to examine whether an ultra-deep targeted sequencing (UDT-Seq) gene panel may improve the prognostic stratification in this patient group.A mutation-based signature affecting 10 genes (including genetic mutations in 6 oncogenes and 4 tumor suppressor genes) was devised to predict disease-free survival (DFS) in 345 primary tumor specimens obtained from pN+ OSCC patients. Of the 345 patients, 144 were extracapsular spread (ECS)-negative and 201 were ECS-positive. The 5-year locoregional control, distant metastases, disease-free, disease-specific, and overall survival (OS) rates served as outcome measures.The UDT-Seq panel was an independent risk factor (RF) for 5-year locoregional control (P = 0.0067), distant metastases (P = 0.0001), DFS (P < 0.0001), disease-specific survival (DSS, P < 0.0001), and OS (P = 0.0003) in pN+ OSCC patients. The presence of ECS and pT3-4 disease were also independent RFs for DFS, DSS, and OS. A prognostic scoring system was formulated by summing up the significant covariates (UDT-Seq, ECS, pT3-4) separately for each survival endpoint. The presence of a positive UDT-Seq panel (n = 77) significantly improved risk stratification for all the survival endpoints as compared with traditional AJCC staging (P < 0.0001). Among ECS-negative patients, those with a UDT-Seq-positive panel (n = 31) had significantly worse DFS (P = 0.0005) and DSS (P = 0.0002). Among ECS-positive patients, those with a UDT-Seq-positive panel (n = 46) also had significantly worse DFS (P = 0.0032) and DSS (P = 0.0098).Our UDT-Seq gene panel consisting of clinically actionable genes was significantly associated with patient outcomes and provided better prognostic stratification than traditional AJCC staging. It was also able to predict prognosis in OSCC patients regardless of ECS presence.
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Affiliation(s)
- Chun-Ta Liao
- From the Department of Otorhinolaryngology, Head and Neck Surgery (C-TL, I-HC, K-PC, S-FH, C-JK), Department of Biomedical Sciences, School of Medicine (S-JC, H-CC), Department of Genomic Core Laboratory, Molecular Medicine Research Center (S-JC, H-CC), Department of Pathology (L-YL, CH), Department of Biostatistics and Informatics Unit, Clinical Trial Center (L-YY), Department of Radiation Oncology (C-YL, K-HF), Department of Medical Oncology (H-MW), Department of Diagnostic Radiology (S-HN), Department of Plastic and Reconstructive Surgery (C-HL, C-KT), Department of Nuclear Medicine and Molecular Imaging Center (T-CY), Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, ROC
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Ohkawara H, Ikeda K, Ogawa K, Takeishi Y. MEMBRANE TYPE 1-MATRIX METALLOPROTEINASE (MT1-MMP) IDENTIFIED AS A MULTIFUNCTIONAL REGULATOR OF VASCULAR RESPONSES. Fukushima J Med Sci 2015; 61:91-100. [PMID: 26370683 DOI: 10.5387/fms.2015-15] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Membrane type 1-matrix metalloproteinase (MT1-MMP) functions as a signaling molecules in addition to a transmembrane metalloprotease, which degrades interstitial collagens and extracellular matrix components. This review focuses on the multifunctional roles of MT1-MMP as a signaling molecule in vascular responses to pro-atherosclerotic stimuli in the pathogenesis of cardiovascular diseases. First, the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1)-MT1-MMP signaling axis contributes to endothelial dysfunction, which is mediated via small GTP-binding protein RhoA and Rac1 activation. Second, MT1-MMP plays a crucial role in reactive oxygen species (ROS) generation through the activation of receptor for advanced glycation end products (AGEs) in smooth muscle cells, indicating that MT1-MMP may be a therapeutic target for diabetic vascular complications. Third, MT1-MMP is involved in RhoA/Rac1 activation and Ca(2+) signaling in the mechanism of thrombin-stimulated endothelial dysfunction and oxidant stress. Fourth, the inhibition of the MT1-MMP/Akt signaling pathway may be an attractive strategy for treating endothelial disordered hemostasis in the development of vascular diseases linked to TNF-α-induced inflammation. Fifth, MT1-MMP through RAGE induced RhoA/Rac1 activation and tissue factor protein upregulation through NF-κB phosphorylation in endothelial cells stimulated by high-mobility group box-1, which plays a key role in the systemic inflammation. These findings suggest that the MT1-MMP-mediated signaling axis may be a promising target for treating atherosclerosis and subsequent cardiovascular diseases.
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Affiliation(s)
- Hiroshi Ohkawara
- Department of Cardiology and Hematology, Fukushima Medical University
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Piao Y, Li Y, Xu Q, Liu JW, Xing CZ, Xie XD, Yuan Y. Association of MTOR and AKT Gene Polymorphisms with Susceptibility and Survival of Gastric Cancer. PLoS One 2015; 10:e0136447. [PMID: 26317520 PMCID: PMC4552869 DOI: 10.1371/journal.pone.0136447] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Accepted: 08/03/2015] [Indexed: 12/16/2022] Open
Abstract
Background The phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB, AKT)/mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in angiogenesis and cell growth, proliferation, metabolism, migration, differentiation, and apoptosis. Genetic diversity in key factors of this pathway may influence protein function and signal transduction, contributing to disease initiation and progression. Studies suggest that MTOR rs1064261 and AKT rs1130233 polymorphisms are associated with risk and/or prognosis of multiple cancer types. However, this relationship with gastric cancer (GC) remains unclear. The aim of this study was to investigate the role of MTOR and AKT polymorphisms in the risk and prognosis of GC. Methods The Sequenom MassARRAY platform was used to genotype 1842 individuals for MTOR rs1064261 T→C and AKT rs1130233 G→A polymorphisms. ELISA was used to detect Helicobacter pylori antibodies in serum. Immunohistochemical analysis was used to detect total and phosphorylated MTOR and AKT proteins. Results The MTOR rs1064261 (TC+CC) genotype and the AKT rs1130233 (GA+AA) genotype were associated with increased risk of GC in men (P = 0.049, P = 0.030). In H. pylori-negative individuals, the AKT rs1130233 GA and (GA+AA) genotypes were related to increased risk of atrophic gastritis (AG; P = 0.012, P = 0.024). Notably, the AKT rs1130233 (GA+AA) genotype demonstrated significant interactions with H. pylori in disease progression from healthy controls (CON) to AG (P = 0.013) and from AG to GC (P = 0.049). Additionally, for individuals with the AKT rs1130233 variant, those in the H. pylori-positive group had higher levels of phosphorylated AKT (p-AKT) expression. The AKT rs1130233 genotype was found to be associated with clinicopathological parameters including lymph node metastasis and alcohol drinking (P<0.05). Conclusion MTOR rs1064261and AKT rs1130233 polymorphisms were associated with increased GC risk in males and increased AG risk in H. pylori-negative individuals. A significant interaction existed between the AKT rs1130233 genotype and H. pylori infection in CON→AG→GC disease progression. The AKT rs1130233 genotype influenced p-AKT protein expression in H. pylori-infected individuals.
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Affiliation(s)
- Ying Piao
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, People’s Republic of China
- Oncology Department, General Hospital of Shenyang Military Region, Shenyang, Liaoning, People’s Republic of China
| | - Ying Li
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, People’s Republic of China
| | - Qian Xu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, People’s Republic of China
| | - Jing-wei Liu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, People’s Republic of China
| | - Cheng-zhong Xing
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, People’s Republic of China
| | - Xiao-dong Xie
- Oncology Department, General Hospital of Shenyang Military Region, Shenyang, Liaoning, People’s Republic of China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, People’s Republic of China
- * E-mail:
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Abstract
Early brain injury (EBI) plays a crucial role in the pathological progress of subarachnoid hemorrhage (SAH). This study was designed to determine whether rosiglitazone protects the brain against EBI in rats, and discuss the role of the anti-apoptotic mechanism mediated by Bcl-2 family proteins in this neuroprotection. 86 male Sprague-Dawley rats were divided into the sham group, the SAH+ vehicle group and the SAH+ rosiglitazone group. SAH was induced via an endovascular perforation technique and rosiglitazone (3mg/kg) or vehicle was administered. Mortality, neurological scores, brain water content, Evans blue dye assay, TUNEL stain assay, Gelatin zymography, and western blot analysis were performed. Rosiglitazone significantly improved mortality, neurological scores, brain water content, blood brain barrier (BBB) and apoptosis compared with the vehicle group within 24h after SAH. The TUNEL staining assay demonstrated that apoptosis was ameliorated. Cleaved Caspase-3 and MMP-9 expression was reduced, whereas Bcl-2 and p-Bad was markedly preserved by rosiglitazone. A significant elevation of p-Akt was detected after rosiglitazone treatment. Our study demonstrated that rosiglitazone plays a neuroprotective role in EBI after SAH via attenuation of BBB disruption, brain edema and apoptosis.
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