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Kim YA, Oh S, Park G, Park S, Park Y, Choi H, Kim M, Choi J. Characteristics of bovine muscle satellite cell from different breeds for efficient production of cultured meat. JOURNAL OF ANIMAL SCIENCE AND TECHNOLOGY 2024; 66:1257-1272. [PMID: 39691610 PMCID: PMC11647411 DOI: 10.5187/jast.2023.e115] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 10/11/2023] [Accepted: 10/17/2023] [Indexed: 12/19/2024]
Abstract
The purpose of this study was comparing in vitro performances of three breeds of donor satellite cells for cultured meat and selecting the optimal donor and providing insight into the selection of donors for cultured meat production. Cattle muscle satellite cells were isolated from the muscle tissue of Hanwoo, Holstein, and Jeju black cattle, and then sorted by fluorescence activated cell sorting (FACS). Regarding proliferation of satellite cells, all three breeds showed similar trends. The myogenic potential, based on PAX7 and MYOD mRNA expression levels, was similar or significantly higher for Holstein than other breeds. When the area, width, and fusion index of the myotube were calculated through immunofluorescence staining of myosin, it was expressed upward for Holstein in all experiments except myotube area at passage 8. In addition, it was confirmed that Holstein's muscle satellite cells showed an upward expression in the amount of gene and protein expression related to myogenic. In the case of gene expression of MYOG, DES, and MYH4 known to play a key role in differentiation into muscles, it was confirmed that Holstein's muscle satellite cells expressed higher levels. CAV3, IGF1 and TNNT1, which contribute to hypertrophy and differentiation of muscle cells, showed high expression in Holstein. Our results suggest using cells from Holstein cattle can increase the efficiency of cultured meat production, compared to Hanwoo and Jeju breeds, because the cells exhibit superior differentiation behavior which would lead to greater yields during the maturation phase of bioprocessing.
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Affiliation(s)
- Yun-a Kim
- Department of Animal Science, Chungbuk National University, Cheongju 28644, Korea
| | - Sehyuk Oh
- Department of Animal Science, Chungbuk National University, Cheongju 28644, Korea
| | - Gyutae Park
- Department of Animal Science, Chungbuk National University, Cheongju 28644, Korea
| | - Sanghun Park
- Department of Animal Science, Chungbuk National University, Cheongju 28644, Korea
| | - Yunhwan Park
- Department of Animal Science, Chungbuk National University, Cheongju 28644, Korea
| | - Hyunsoo Choi
- Department of Animal Science, Chungbuk National University, Cheongju 28644, Korea
| | - Minjung Kim
- Food Functionality Research Division, Korea Food Research Institute, Wanju 55365, Korea
| | - Jungseok Choi
- Department of Animal Science, Chungbuk National University, Cheongju 28644, Korea
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Patritti-Cram J, Rahrmann EP, Rizvi TA, Scheffer KC, Phoenix TN, Largaespada DA, Ratner N. NF1-dependent disruption of the blood-nerve-barrier is improved by blockade of P2RY14. iScience 2024; 27:110294. [PMID: 39100928 PMCID: PMC11294707 DOI: 10.1016/j.isci.2024.110294] [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: 06/10/2022] [Revised: 12/17/2023] [Accepted: 06/14/2024] [Indexed: 08/06/2024] Open
Abstract
The blood-nerve-barrier (BNB) that regulates peripheral nerve homeostasis is formed by endoneurial capillaries and perineurial cells surrounding the Schwann cell (SC)-rich endoneurium. Barrier dysfunction is common in human tumorigenesis, including in some nerve tumors. We identify barrier disruption in human NF1 deficient neurofibromas, which were characterized by reduced perineurial cell glucose transporter 1 (GLUT1) expression and increased endoneurial fibrin(ogen) deposition. Conditional Nf1 loss in murine SCs recapitulated these alterations and revealed decreased tight junctions and decreased caveolin-1 (Cav1) expression in mutant nerves and in tumors, implicating reduced Cav1-mediated transcytosis in barrier disruption and tumorigenesis. Additionally, elevated receptor tyrosine kinase activity and genetic deletion of Cav1 increased endoneurial fibrin(ogen), and promoted SC tumor formation. Finally, when SC lacked Nf1, genetic loss or pharmacological inhibition of P2RY14 rescued Cav1 expression and barrier function. Thus, loss of Nf1 in SC causes dysfunction of the BNB via P2RY14-mediated G-protein coupled receptor (GPCR) signaling.
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Affiliation(s)
- Jennifer Patritti-Cram
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
- Neuroscience Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0713, USA
| | - Eric P. Rahrmann
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Tilat A. Rizvi
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Katherine C. Scheffer
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Timothy N. Phoenix
- Division of Pharmaceutical Sciences, James L. Wrinkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45229, USA
| | - David A. Largaespada
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Nancy Ratner
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
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Han Q, Qiu S, Hu H, Li W, Li X. Role of Caveolae family-related proteins in the development of breast cancer. Front Mol Biosci 2023; 10:1242426. [PMID: 37828916 PMCID: PMC10565104 DOI: 10.3389/fmolb.2023.1242426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 09/14/2023] [Indexed: 10/14/2023] Open
Abstract
Breast cancer has become the most significant malignant tumor threatening women's lives. Caveolae are concave pits formed by invagination of the plasma membrane that participate in many biological functions of the cell membrane, such as endocytosis, cell membrane assembly, and signal transduction. In recent years, Caveolae family-related proteins have been found to be closely related to the occurrence and development of breast cancer. The proteins associated with the Caveolae family-related include Caveolin (Cav) and Cavins. The Cav proteins include Cav-1, Cav-2 and Cav-3, among which Cav-1 has attracted the most attention as a tumor suppressor and promoting factor affecting the proliferation, apoptosis, migration, invasion and metastasis of breast cancer cells. Cav-2 also has dual functions of inhibiting and promoting cancer and can be expressed in combination with Cav-1 or play a regulatory role alone. Cav-3 has been less studied in breast cancer, and the loss of its expression can form an antitumor microenvironment. Cavins include Cavin-1, Cavin-2, Cavin-3 and Cavin-4. Cavin-1 inhibits Cav-1-induced cell membrane tubule formation, and its specific role in breast cancer remains controversial. Cavin-2 acts as a breast cancer suppressor, inhibiting breast cancer progression by blocking the transforming growth factor (TGF-β) signaling pathway. Cavin-3 plays an anticancer role in breast cancer, but its specific mechanism of action is still unclear. The relationship between Cavin-4 and breast cancer is unclear. In this paper, the role of Caveolae family-related proteins in the occurrence and development of breast cancer and their related mechanisms are discussed in detail to provide evidence supporting the further study of Caveolae family-related proteins as potential targets for the diagnosis and treatment of breast cancer.
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Affiliation(s)
- Qinyu Han
- Department of Breast Center, The Second Affiliated Hospital of Shandong First Medical University, Tai’an, Shandong, Chinaa
| | - Shi Qiu
- Department of Breast Center, The Second Affiliated Hospital of Shandong First Medical University, Tai’an, Shandong, Chinaa
| | - Huiwen Hu
- Department of the First Clinical Medical School, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Wenjing Li
- Department of Breast Center, The Second Affiliated Hospital of Shandong First Medical University, Tai’an, Shandong, Chinaa
| | - Xiangqi Li
- Department of Breast Center, The Second Affiliated Hospital of Shandong First Medical University, Tai’an, Shandong, Chinaa
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Bakonyi P, Kolonics A, Aczel D, Zhou L, Mozaffaritabar S, Molnár K, László L, Kutasi B, Tanisawa K, Park J, Gu Y, Pinho RA, Radak Z. Voluntary exercise does not increase gastrointestinal motility but increases spatial memory, intestinal eNOS, Akt levels, and Bifidobacteria abundance in the microbiome. Front Physiol 2023; 14:1173636. [PMID: 37664431 PMCID: PMC10468588 DOI: 10.3389/fphys.2023.1173636] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 07/03/2023] [Indexed: 09/05/2023] Open
Abstract
The interaction between the gut and brain is a great puzzle since it is mediated by very complex mechanisms. Therefore, the possible interactions of the brain-exercise-intestine-microbiome axis were investigated in a control (C, N = 6) and voluntarily exercised (VE, N = 8) middle-aged rats. The endurance capacity was assessed by VO2max on the treadmill, spatial memory by the Morris maze test, gastrointestinal motility by EMG, the microbiome by 16S RNA gene amplicon sequencing, caveolae by electron microscopy, and biochemical assays were used to measure protein levels and production of reactive oxygen species (ROS). Eight weeks of voluntary running increased VO2max, and spatial memory was assessed by the Morris maze test but did not significantly change the motility of the gastrointestinal tract or production of ROS in the intestine. The protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS) protein levels significantly increased in the intestine, while peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), mitochondrial transcription factor A (TFAM), nuclear respiratory factor 1 (NFR1), SIRT1, SIRT3, nicotinamide phosphoribosyl transferase (NAMPT), and nuclear factor κB (NF-κB) did not change. On the other hand, voluntary exercise increased the number of caveolae in the smooth muscles of the intestine and relative abundance of Bifidobacteria in the microbiome, which correlated with the Akt levels in the intestine. Voluntary exercise has systemic effects and the relationship between intestinal Akt and the microbiome of the gastrointestinal tract could be an important adaptive response.
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Affiliation(s)
- Peter Bakonyi
- Research Institute of Sport Science, Hungarian University of Sport Science, Budapest, Hungary
| | - Attila Kolonics
- Research Institute of Sport Science, Hungarian University of Sport Science, Budapest, Hungary
| | - Dora Aczel
- Research Institute of Sport Science, Hungarian University of Sport Science, Budapest, Hungary
| | - Lei Zhou
- Research Institute of Sport Science, Hungarian University of Sport Science, Budapest, Hungary
| | - Soroosh Mozaffaritabar
- Research Institute of Sport Science, Hungarian University of Sport Science, Budapest, Hungary
| | - Kinga Molnár
- Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University of Sciences, Budapest, Hungary
| | - Lajos László
- Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University of Sciences, Budapest, Hungary
| | - Balazs Kutasi
- Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, Hungary
| | - Kumpei Tanisawa
- Faculty of Sport Sciences, Waseda University, Tokorozawa, Japan
| | - Jonguk Park
- Artificial Intelligence Center for Health and Biomedical Research, Osaka, Japan
| | - Yaodong Gu
- Faculty of Sports Science, Ningbo University, Ningbo, China
| | - Ricardo A. Pinho
- Laboratory of Exercise Biochemistry in Health, Graduate Program in Health Sciences, School of Medicine, Pontifícia Universidade Católica Do Paraná, Curitiba, Brazil
| | - Zsolt Radak
- Research Institute of Sport Science, Hungarian University of Sport Science, Budapest, Hungary
- Faculty of Sport Sciences, Waseda University, Tokorozawa, Japan
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Batori RK, Chen F, Bordan Z, Haigh S, Su Y, Verin AD, Barman SA, Stepp DW, Chakraborty T, Lucas R, Fulton DJR. Protective role of Cav-1 in pneumolysin-induced endothelial barrier dysfunction. Front Immunol 2022; 13:945656. [PMID: 35967431 PMCID: PMC9363592 DOI: 10.3389/fimmu.2022.945656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 07/04/2022] [Indexed: 01/16/2023] Open
Abstract
Pneumolysin (PLY) is a bacterial pore forming toxin and primary virulence factor of Streptococcus pneumonia, a major cause of pneumonia. PLY binds cholesterol-rich domains of the endothelial cell (EC) plasma membrane resulting in pore assembly and increased intracellular (IC) Ca2+ levels that compromise endothelial barrier integrity. Caveolae are specialized plasmalemma microdomains of ECs enriched in cholesterol. We hypothesized that the abundance of cholesterol-rich domains in EC plasma membranes confers cellular susceptibility to PLY. Contrary to this hypothesis, we found increased PLY-induced IC Ca2+ following membrane cholesterol depletion. Caveolin-1 (Cav-1) is an essential structural protein of caveolae and its regulation by cholesterol levels suggested a possible role in EC barrier function. Indeed, Cav-1 and its scaffolding domain peptide protected the endothelial barrier from PLY-induced disruption. In loss of function experiments, Cav-1 was knocked-out using CRISPR-Cas9 or silenced in human lung microvascular ECs. Loss of Cav-1 significantly enhanced the ability of PLY to disrupt endothelial barrier integrity. Rescue experiments with re-expression of Cav-1 or its scaffolding domain peptide protected the EC barrier against PLY-induced barrier disruption. Dynamin-2 (DNM2) is known to regulate caveolar membrane endocytosis. Inhibition of endocytosis, with dynamin inhibitors or siDNM2 amplified PLY induced EC barrier dysfunction. These results suggest that Cav-1 protects the endothelial barrier against PLY by promoting endocytosis of damaged membrane, thus reducing calcium entry and PLY-dependent signaling.
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Affiliation(s)
- Robert K. Batori
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Feng Chen
- Department of Forensic Medicine, Nanjing Medical University, Nanjing, China
| | - Zsuzsanna Bordan
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Stephen Haigh
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Yunchao Su
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Alexander D. Verin
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States
- Division of Critical Care and Pulmonary Medicine, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Scott A. Barman
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - David W. Stepp
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States
- Department of Phyiology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Trinad Chakraborty
- Institute of Human Microbiology, Justus-Liebig University, Giessen, Germany
| | - Rudolf Lucas
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States
- Division of Critical Care and Pulmonary Medicine, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - David J. R. Fulton
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States
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Zhou Y, Guo Y, Wang Y. Identification and validation of a seven-gene prognostic marker in colon cancer based on single-cell transcriptome analysis. IET Syst Biol 2022; 16:72-83. [PMID: 35352485 PMCID: PMC8965382 DOI: 10.1049/syb2.12041] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 11/06/2021] [Accepted: 12/04/2021] [Indexed: 11/25/2022] Open
Abstract
Colon cancer (CC) is one of the most commonly diagnosed tumours worldwide. Single-cell RNA sequencing (scRNA-seq) can accurately reflect the heterogeneity within and between tumour cells and identify important genes associated with cancer development and growth. In this study, scRNA-seq was used to identify reliable prognostic biomarkers in CC. ScRNA-seq data of CC before and after 5-fluorouracil treatment were first downloaded from the Gene Expression Omnibus database. The data were pre-processed, and dimensionality reduction was performed using principal component analysis and t-distributed stochastic neighbour embedding algorithms. Additionally, the transcriptome data, somatic variant data, and clinical reports of patients with CC were obtained from The Cancer Genome Atlas database. Seven key genes were identified using Cox regression analysis and the least absolute shrinkage and selection operator method to establish signatures associated with CC prognoses. The identified signatures were validated on independent datasets, and somatic mutations and potential oncogenic pathways were further explored. Based on these features, gene signatures, and other clinical variables, a more effective predictive model nomogram for patients with CC was constructed, and a decision curve analysis was performed to assess the utility of the nomogram. A prognostic signature consisting of seven prognostic-related genes, including CAV2, EREG, NGFRAP1, WBSCR22, SPINT2, CCDC28A, and BCL10, was constructed and validated. The proficiency and credibility of the signature were verified in both internal and external datasets, and the results showed that the seven-gene signature could effectively predict the prognosis of patients with CC under various clinical conditions. A nomogram was then constructed based on features such as the RiskScore, patients' age, neoplasm stage, and tumor (T), nodes (N), and metastases (M) classification, and the nomogram had good clinical utility. Higher RiskScores were associated with a higher tumour mutational burden, which was confirmed to be a prognostic risk factor. Gene set enrichment analysis showed that high-score groups were enriched in 'cytoplasmic DNA sensing', 'Extracellular matrix receptor interactions', and 'focal adhesion', and low-score groups were enriched in 'natural killer cell-mediated cytotoxicity', and 'T-cell receptor signalling pathways', among other pathways. A robust seven-gene marker for CC was identified based on scRNA-seq data and was validated in multiple independent cohort studies. These findings provide a new potential marker to predict the prognosis of patients with CC.
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Affiliation(s)
- Yang Zhou
- Medical Oncology Department of Gastrointestinal CancerLiaoning Cancer Hospital & InstituteCancer Hospital of China Medical UniversityLiaoning ProvinceChina
| | - Yang Guo
- Shenyang Tenth People's Hospital (Shenyang Chest Hospital)ShenyangLiaoningP. R. China
| | - Yuanhe Wang
- Medical Oncology Department of Gastrointestinal CancerLiaoning Cancer Hospital & InstituteCancer Hospital of China Medical UniversityLiaoning ProvinceChina
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Kim JH, Yu SH, Kim SO. Decreased urothelial expression of caveolin 1 and 2 in aging rats showing detrusor overactivity: Potential association with aging bladder. Investig Clin Urol 2021; 62:690-696. [PMID: 34729968 PMCID: PMC8566782 DOI: 10.4111/icu.20210284] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/29/2021] [Accepted: 09/14/2021] [Indexed: 11/18/2022] Open
Abstract
PURPOSE The purpose of this study was to investigate the effect of aging on bladder function and caveolin protein expression in rat urothelium. MATERIALS AND METHODS Female Sprague-Dawley rats were divided into the following two groups: young age control group (12 weeks) and old-aged group of rats (80 weeks). Urodynamic measurements were taken to compare the contraction interval and the contraction pressure between the two groups. The expression and cellular localization of caveolin 1 and 2 in the urothelium of the rat urinary bladder were determined by Western blot and immunofluorescence microscopy. RESULTS In cystometrograms, the contraction interval (min) was significantly shorter in the old-aged group (3.7±0.5 min) than in the young age control group (6.2±0.8 min). Also, the average contraction pressure (mmHg) was lower in the old-aged group (8.4±0.6 mmHg) than in the young age control group (13.2±1.3 mmHg). Caveolin 1 and 2 were expressed in the subepithelial area in the urothelium. The protein expression of both caveolin 1 and 2 was significantly lower in the old-aged group than in the young age control group. CONCLUSIONS Aging caused a significant change in the expression of caveolin 1 and 2 in the urothelium of the rat urinary bladder. These findings suggest that these molecules might have specific roles in the functional change of the urinary bladder that occurs in association with aging.
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Affiliation(s)
- Jae Hyeon Kim
- Department of Urology, Chonnam National University Medical School, Research Institute of Medical Sciences, Gwangju, Korea
| | - Seong Hyeon Yu
- Department of Urology, Chonnam National University Medical School, Research Institute of Medical Sciences, Gwangju, Korea
| | - Sun-Ouck Kim
- Department of Urology, Chonnam National University Medical School, Research Institute of Medical Sciences, Gwangju, Korea.
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Li M, Zhang YJ, Liu DX, Liu Z, Fu M, Yang QR, Sun HS. Expression of caveolin family proteins in serum of patients with systemic lupus erythematosus. Lupus 2021; 30:1819-1828. [PMID: 34569384 DOI: 10.1177/09612033211035508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVES Caveolin family proteins, including caveolin-1 (Cav-1), caveolin-2 (Cav-2), and caveolin-3 (Cav-3), are identified as the principal protein components of caveolae in mammalian cells. Circulating form of caveolin family proteins can be used as a good potential biomarker for predicting disease. METHODS To investigate the clinical significance of the serological levels of caveolin family proteins in patients with systemic lupus erythematosus (SLE), we evaluated the soluble serum levels of caveolin family proteins in patients with SLE by enzyme-linked immunosorbent assay (ELISA) and assessed their associations with various known clinical variables. RESULTS The major findings of our study are as follows: Cav-2 was not detected in serum of SLE patients and normal controls (NCs). Serum Cav-1 and Cav-3 levels were higher in SLE patients compared with NCs. There were no significant correlations between serum Cav-1 and Cav-3 levels and SLE disease activity. Further analysis showed that serum Cav-3 may be more valuable as a marker than serum Cav-1 in SLE patients. CONCLUSION Serum levels of Cav-1 and Cav-3 might have a diagnostic role in patients with SLE. However, their predictive and prognostic value was not determined. Further studies are necessary to determine the potential clinical significance of these assays in SLE.
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Affiliation(s)
- Ming Li
- Department of Rheumatology and Immunology, 34708Shandong Provincial Hospital Affiliated to Shandong First Medical University (Shandong Provincial Hospital), Jinan, P.R. China
| | - Yi-Jing Zhang
- Department of Geriatric Gastroenterology, 34708Shandong Provincial Hospital Affiliated to Shandong First Medical University (Shandong Provincial Hospital), Jinan, P.R. China
| | - Dong-Xia Liu
- Department of Rheumatology and Immunology, 34708Shandong Provincial Hospital Affiliated to Shandong First Medical University (Shandong Provincial Hospital), Jinan, P.R. China
| | - Zhi Liu
- Department of Clinical Laboratory, 34708Shandong Provincial Hospital Affiliated to Shandong First Medical University (Shandong Provincial Hospital), Jinan, P.R. China
| | - Min Fu
- Department of Rheumatology and Immunology, 34708Shandong Provincial Hospital Affiliated to Shandong First Medical University (Shandong Provincial Hospital), Jinan, P.R. China
| | - Qing-Rui Yang
- Department of Rheumatology and Immunology, 34708Shandong Provincial Hospital Affiliated to Shandong First Medical University (Shandong Provincial Hospital), Jinan, P.R. China
| | - Hong-Sheng Sun
- Department of Rheumatology and Immunology, 34708Shandong Provincial Hospital Affiliated to Shandong First Medical University (Shandong Provincial Hospital), Jinan, P.R. China
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de Souza GM, de Albuquerque Borborema ME, de Lucena TMC, da Silva Santos AF, de Lima BR, de Oliveira DC, de Azevêdo Silva J. Caveolin-1 (CAV-1) up regulation in metabolic syndrome: all roads leading to the same end. Mol Biol Rep 2020; 47:9245-9250. [PMID: 33123955 DOI: 10.1007/s11033-020-05945-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 10/22/2020] [Indexed: 01/02/2023]
Abstract
Metabolic syndrome (MS) is a set of clinical conditions such as insulin resistance, hyperglycemia, systemic arterial hypertension (SAH), dyslipidemia, obesity and high abdominal circumference. Some of these clinical characteristics have been associated with caveolin-1, a caveolae structural protein, responsible for insulin activation, storage and degradation of cholesterol, and so on. Herein we assessed CAV-1 mRNA levels in MS patients comparing to healthy controls (HC) and according patients' clinical features. We included 87 patients in the study, 25 patients with MS, 30 patients with at least one clinical condition (diabetes, SAH, dyslipidemia, obesity and high abdominal circumference), 13 with two clinical conditions and 19 HC. CAV-1 mRNA levels from peripheral blood samples were assessed by Real Time qPCR using specific Taqman probe. The analysis was performed using ∆Cq method and the statistical tests Shapiro-Wilk, One-Way ANOVA and Mann-Whitney. We found CAV-1 increased mRNA levels in patients with MS (1.645 FC, p = 9.794 × 10-20) and even higher in patients with only one or two clinical conditions (2.215 FC, p = 1.215 × 10-32 and 1.716 FC, p = 4.197 × 10-05, respectively). When individual clinical conditions were observed, individuals with high abdominal circumference and obesity present a significantly up regulation when compared to HC (2.956 FC, p = 0.0004 and 3.643 FC, p = 0.002, respectively). This work indicates that CAV-1 gene expression from whole blood samples is associated to MS clinical conditions and may become a potential target for MS treatment and prevention.
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Affiliation(s)
- Gabriela Montenegro de Souza
- Laboratório de Genética e Biologia Molecular Humana, Departamento de Genética, Universidade Federal de Pernambuco, Av. Prof. Moraes Rego, 1235, Recife, Pernambuco, CEP 50760-901, Brazil
| | - Maria Eduarda de Albuquerque Borborema
- Laboratório de Genética e Biologia Molecular Humana, Departamento de Genética, Universidade Federal de Pernambuco, Av. Prof. Moraes Rego, 1235, Recife, Pernambuco, CEP 50760-901, Brazil
- Laboratório de Imunopatologia Keizo Asami (LIKA), Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil
| | - Thays Maria Costa de Lucena
- Laboratório de Genética e Biologia Molecular Humana, Departamento de Genética, Universidade Federal de Pernambuco, Av. Prof. Moraes Rego, 1235, Recife, Pernambuco, CEP 50760-901, Brazil
- Laboratório de Imunopatologia Keizo Asami (LIKA), Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil
| | - Ariane Fernandes da Silva Santos
- Laboratório de Genética e Biologia Molecular Humana, Departamento de Genética, Universidade Federal de Pernambuco, Av. Prof. Moraes Rego, 1235, Recife, Pernambuco, CEP 50760-901, Brazil
- Laboratório de Imunopatologia Keizo Asami (LIKA), Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil
| | - Brenda Regina de Lima
- Laboratório de Genética e Biologia Molecular Humana, Departamento de Genética, Universidade Federal de Pernambuco, Av. Prof. Moraes Rego, 1235, Recife, Pernambuco, CEP 50760-901, Brazil
- Laboratório de Imunopatologia Keizo Asami (LIKA), Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil
| | - Dinaldo Cavalcanti de Oliveira
- Divisão de Cardiologia, Departamento de Medicina Clínica, Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil
| | - Jaqueline de Azevêdo Silva
- Laboratório de Genética e Biologia Molecular Humana, Departamento de Genética, Universidade Federal de Pernambuco, Av. Prof. Moraes Rego, 1235, Recife, Pernambuco, CEP 50760-901, Brazil.
- Laboratório de Imunopatologia Keizo Asami (LIKA), Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil.
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The caveolar-mitochondrial interface: regulation of cellular metabolism in physiology and pathophysiology. Biochem Soc Trans 2020; 48:165-177. [PMID: 32010944 DOI: 10.1042/bst20190388] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 01/09/2020] [Accepted: 01/10/2020] [Indexed: 12/15/2022]
Abstract
The plasma membrane is an important cellular organelle that is often overlooked in terms of a primary factor in regulating physiology and pathophysiology. There is emerging evidence to suggest that the plasma membrane serves a greater purpose than a simple barrier or transporter of ions. New paradigms suggest that the membrane serves as a critical bridge to connect extracellular to intracellular communication particularly to regulate energy and metabolism by forming physical and biochemical associations with intracellular organelles. This review will focus on the relationship of a particular membrane microdomain - caveolae - with mitochondria and the particular implication of this to physiology and pathophysiology.
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11
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Jiao F, Han T, Yuan C, Liang Y, Cui J, Zhuo M, Wang L. Caveolin-2 is regulated by BRD4 and contributes to cell growth in pancreatic cancer. Cancer Cell Int 2020; 20:55. [PMID: 32099528 PMCID: PMC7029443 DOI: 10.1186/s12935-020-1135-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 02/04/2020] [Indexed: 02/07/2023] Open
Abstract
Background The bromodomain and extra-terminal domain (BET) family of proteins, especially BRD4 play an important role in epigenetic regulation, and are essential for cell survival and also are promising anticancer targets. This study aims to analyze the effect of BRD4 on the cell growth and progression of pancreatic cancer and novel mechanisms involved. Methods Expression of BRD4 in pancreatic cancer and paired adjacent noncancerous tissues from 76 patients was analyzed by western blotting, immunohistochemistry, and real time PCR. Its correlation with the clinicopathological characteristics and prognosis of pancreatic cancer patients was analyzed. The effects of BRD4 on the cell proliferation were detected by colony formation assay and sulforhodamine B assay. Migration and invasion were determined by Transwell assays, and the effect of BRD4 on subcutaneous tumor formation was verified in nude mice. Cell cycle analysis was detected by flow cytometry. The potential downstream targets of BRD4 and related molecular mechanisms were clarified by RNA sequencing, chromatin immunoprecipitation and dual luciferase reporter assay. Results BRD4 was overexpressed in pancreatic cancer. Biological results showed that BRD4 functioned as tumor promoter, facilitated cell proliferation, migration and invasion in vitro and in vivo. Further, caveolin-2 was selected as the downstream gene of BRD4 by RNA sequencing. Caveolin-2 overexpression can partially reverse the decreased cell growth ability caused by BRD4 knockdown, but did not affect cell migration and invasion. Chromatin immunoprecipitation assay and dual luciferase reporter assay revealed BRD4 could bind to the promoter region of caveolin-2 and upregulate caveolin-2 expression. Clinical data further indicated a positive correlation between BRD4 and caveolin-2 expression. BRD4 (high)/caveolin-2 (high) correlated with shorter overall survival of patients with pancreatic cancer. Multivariate analysis revealed that both BRD4 and caveolin-2 were independent factors. Conclusions Our findings reveal the oncogenic effects of BRD4 in pancreatic cancer and elucidate a possible mechanism by which BRD4 and caveolin-2 act to enhance cell growth. Targeting the BRD4-caveolin-2 interaction by development of BET inhibitors will be a therapeutic strategy for pancreatic cancer.
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Affiliation(s)
- Feng Jiao
- 1Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai, 200127 China
| | - Ting Han
- 1Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai, 200127 China
| | - Cuncun Yuan
- 2Department of Pathology, Fudan University Eye Ear Nose and Throat Hospital, 83 Fenyang Road, Shanghai, 201114 China
| | - Yiyi Liang
- 1Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai, 200127 China
| | - Jiujie Cui
- 1Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai, 200127 China
| | - Meng Zhuo
- 1Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai, 200127 China
| | - Liwei Wang
- 1Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai, 200127 China
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12
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Caveolin-1 Expression in Benign and Malignant Breast Lesions and Its Correlation with Expression of Estrogen Receptor (ER), Progesterone Receptor (PR), and Human Epidermal Growth Factor Receptor 2 (HER2), Lymph Node Metastasis, Tumor Grade, and Survival of the Patients. INTERNATIONAL JOURNAL OF CANCER MANAGEMENT 2020. [DOI: 10.5812/ijcm.97468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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13
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Haddad D, Al Madhoun A, Nizam R, Al-Mulla F. Role of Caveolin-1 in Diabetes and Its Complications. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:9761539. [PMID: 32082483 PMCID: PMC7007939 DOI: 10.1155/2020/9761539] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 12/10/2019] [Accepted: 12/26/2019] [Indexed: 12/25/2022]
Abstract
It is estimated that in 2017 there were 451 million people with diabetes worldwide. These figures are expected to increase to 693 million by 2045; thus, innovative preventative programs and treatments are a necessity to fight this escalating pandemic disorder. Caveolin-1 (CAV1), an integral membrane protein, is the principal component of caveolae in membranes and is involved in multiple cellular functions such as endocytosis, cholesterol homeostasis, signal transduction, and mechanoprotection. Previous studies demonstrated that CAV1 is critical for insulin receptor-mediated signaling, insulin secretion, and potentially the development of insulin resistance. Here, we summarize the recent progress on the role of CAV1 in diabetes and diabetic complications.
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Affiliation(s)
- Dania Haddad
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Ashraf Al Madhoun
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Rasheeba Nizam
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Fahd Al-Mulla
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait
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14
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Blochet C, Buscemi L, Clément T, Gehri S, Badaut J, Hirt L. Involvement of caveolin-1 in neurovascular unit remodeling after stroke: Effects on neovascularization and astrogliosis. J Cereb Blood Flow Metab 2020; 40:163-176. [PMID: 30354902 PMCID: PMC6928561 DOI: 10.1177/0271678x18806893] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Complex cellular and molecular events occur in the neurovascular unit after stroke, such as blood-brain barrier (BBB) dysfunction and inflammation that contribute to neuronal death, neurological deterioration and mortality. Caveolin-1 (Cav-1) has distinct physiological functions such as caveolae formation associated with endocytosis and transcytosis as well as in signaling pathways. Cav-1 has been proposed to be involved in BBB dysfunction after brain injury; however, its precise role is poorly understood. The goal of this study was to characterize the expression and effect of Cav-1 deletion on outcome in the first week in a transient Middle Cerebral Artery Occlusion stroke model. We found increased Cav-1 expression in new blood vessels in the lesion and in reactive astrocytes in the peri-lesion areas. In Cav-1 KO mice, the lesion volume was larger and the behavioral outcome worse than in WT mice. Cav-1 KO mice exhibited reduced neovascularization and modified astrogliosis, without formation of a proper glial scar around the lesion at three days post injury, coinciding with aggravated outcomes. Altogether, these results point towards a potential protective role of endogenous Cav-1 in the first days after ischemia by promoting neovascularization, astrogliosis and scar formation.
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Affiliation(s)
- Camille Blochet
- Department of Clinical Neurosciences, CHUV, Lausanne, Switzerland.,Brain Molecular Imaging Lab, CNRS UMR 5287, INCIA, University of Bordeaux, Bordeaux, France
| | - Lara Buscemi
- Department of Clinical Neurosciences, CHUV, Lausanne, Switzerland
| | - Tifenn Clément
- Brain Molecular Imaging Lab, CNRS UMR 5287, INCIA, University of Bordeaux, Bordeaux, France
| | - Sabrina Gehri
- Department of Clinical Neurosciences, CHUV, Lausanne, Switzerland
| | - Jérôme Badaut
- Brain Molecular Imaging Lab, CNRS UMR 5287, INCIA, University of Bordeaux, Bordeaux, France.,Basic Science Department, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Lorenz Hirt
- Department of Clinical Neurosciences, CHUV, Lausanne, Switzerland
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15
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Lifelong n-3 Polyunsaturated Fatty Acid Exposure Modulates Size of Mammary Epithelial Cell Populations and Expression of Caveolae Resident Proteins in Fat-1 Mice. Nutrients 2019; 11:nu11102477. [PMID: 31619022 PMCID: PMC6835466 DOI: 10.3390/nu11102477] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 09/30/2019] [Accepted: 10/05/2019] [Indexed: 01/26/2023] Open
Abstract
Omega-3 polyunsaturated fatty acids (n-3 PUFA) have been associated with reduced breast cancer risk; however, the exact mechanism remains elusive. Female wildtype (WT) and fat-1 mice were fed a 10% safflower diet until 6 weeks of age. Mammary gland epithelial cells (EC) were isolated and EC populations were determined by CD24 surface expression. Fat-1 mice expressed 65%, 20%, and 15% while WT mice expressed 65%, 26% and 9% for non-, myo- and luminal ECs, respectively. The luminal EC population was significantly greater in fat-1 mice (p ≤ 0.05), while the total number of mammary ECs were similar between groups (p = 0.79). Caveolae was isolated from ECs and Her-2/neu, ER-α and cav-1 protein expression was determined by Western blotting. Fat-1 mice had a two-fold greater ER-α (p ≤ 0.05) and a 1.5-fold greater cav-1 (p ≤ 0.05) expression than WT with a similar amount of Her-2/neu protein (p = 0.990) between groups. Overall, this study provides novel mechanistic evidence by which n-3 PUFA modifies early mammary gland development that may potentially reduce breast cancer risk later in life.
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16
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Forte A, Balistreri CR, De Feo M, Della Corte A, Hellstrand P, Persson L, Nilsson BO. Polyamines and microbiota in bicuspid and tricuspid aortic valve aortopathy. J Mol Cell Cardiol 2019; 129:179-187. [PMID: 30825483 DOI: 10.1016/j.yjmcc.2019.02.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 02/25/2019] [Indexed: 02/07/2023]
Abstract
Polyamines are small aliphatic cationic molecules synthesized via a highly regulated pathway and involved in general molecular and cellular phenomena. Both mammalian cells and microorganisms synthesize polyamines, and both sources may contribute to the presence of polyamines in the circulation. The dominant location for microorganisms within the body is the gut. Accordingly, the gut microbiota probably synthesizes most of the polyamines in the circulation in addition to those produced by the mammalian host cells. Polyamines are mandatory for cellular growth and proliferation. Established evidence suggests that the polyamine spermidine prolongs lifespan and improves cardiovascular health in animal models and humans through both local mechanisms, involving improved cardiomyocyte function, and systemic mechanisms, including increased NO bioavailability and reduced systemic inflammation. Higher levels of polyamines have been detected in non-dilated aorta of patients affected by bicuspid aortic valve congenital malformation, an aortopathy associated with an increased risk for thoracic ascending aorta aneurysm. In this review, we discuss metabolism of polyamines and their potential effects on vascular smooth muscle and endothelial cell function in vascular pathology of the thoracic ascending aorta associated with bicuspid or tricuspid aortic valve.
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Affiliation(s)
- Amalia Forte
- Department of Translational Medical Sciences, Università degli Studi della Campania "L. Vanvitelli", Naples, Italy
| | - Carmela Rita Balistreri
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), University of Palermo, Palermo, Italy
| | - Marisa De Feo
- Department of Translational Medical Sciences, Università degli Studi della Campania "L. Vanvitelli", Naples, Italy
| | - Alessandro Della Corte
- Department of Translational Medical Sciences, Università degli Studi della Campania "L. Vanvitelli", Naples, Italy
| | - Per Hellstrand
- Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Lo Persson
- Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Bengt-Olof Nilsson
- Department of Experimental Medical Science, Lund University, Lund, Sweden.
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Pérez-Verdaguer M, Capera J, Ortego-Domínguez M, Bielanska J, Comes N, Montoro RJ, Camps M, Felipe A. Caveolar targeting links Kv1.3 with the insulin-dependent adipocyte physiology. Cell Mol Life Sci 2018; 75:4059-4075. [PMID: 29947924 PMCID: PMC11105548 DOI: 10.1007/s00018-018-2851-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 05/14/2018] [Accepted: 06/05/2018] [Indexed: 12/23/2022]
Abstract
The voltage-dependent potassium channel Kv1.3 participates in peripheral insulin sensitivity. Genetic ablation of Kv1.3 triggers resistance to diet-induced weight gain, thereby pointing to this protein as a pharmacological target for obesity and associated type II diabetes. However, this role is under intense debate because Kv1.3 expression in adipose tissue raises controversy. We demonstrated that Kv1.3 is expressed in white adipose tissue from humans and rodents. Moreover, other channels, such as Kv1.1, Kv1.2, Kv1.4 and especially Kv1.5, from the same Shaker family are also present. Although elevated insulin levels and adipogenesis remodel the Kv phenotype, which could lead to multiple heteromeric complexes, Kv1.3 markedly participates in the insulin-dependent regulation of glucose uptake in mature adipocytes. Adipocyte differentiation increased the expression of Kv1.3, which is targeted to caveolae by molecular interactions with caveolin 1. Using a caveolin 1-deficient 3T3-L1 adipocyte cell line, we demonstrated that the localization of Kv1.3 in caveolar raft structures is important for proper insulin signaling. Insulin-dependent phosphorylation of the channel occurs at the onset of insulin-mediated signaling. However, when Kv1.3 was spatially outside of these lipid microdomains, impaired phosphorylation was exhibited. Our data shed light on the putative role of Kv1.3 in weight gain and insulin-dependent responses contributing to knowledge about adipocyte physiology.
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Affiliation(s)
- Mireia Pérez-Verdaguer
- Molecular Physiology Laboratory, Dpt. de Bioquímica i Biomedicina Molecular, Universitat de Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain
- Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain
| | - Jesusa Capera
- Molecular Physiology Laboratory, Dpt. de Bioquímica i Biomedicina Molecular, Universitat de Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain
- Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain
| | - María Ortego-Domínguez
- Dpto. de Fisiología Médica y Biofísica, Universidad de Sevilla, Av. Dr. Fedriani, s/n., 41009, Seville, Spain
| | - Joanna Bielanska
- Molecular Physiology Laboratory, Dpt. de Bioquímica i Biomedicina Molecular, Universitat de Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain
- Max-Planck-Institute of Experimental Medicine, Molecular Biology of Neuronal Signals, AG Oncophysiology, Hermann-Rein-Str. 3, 37075, Göttingen, Germany
| | - Núria Comes
- Molecular Physiology Laboratory, Dpt. de Bioquímica i Biomedicina Molecular, Universitat de Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain
| | - Rafael J Montoro
- Dpto. de Fisiología Médica y Biofísica, Universidad de Sevilla, Av. Dr. Fedriani, s/n., 41009, Seville, Spain
| | - Marta Camps
- Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain
| | - Antonio Felipe
- Molecular Physiology Laboratory, Dpt. de Bioquímica i Biomedicina Molecular, Universitat de Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain.
- Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain.
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18
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Liu F, Shangli Z, Hu Z. CAV2 promotes the growth of renal cell carcinoma through the EGFR/PI3K/Akt pathway. Onco Targets Ther 2018; 11:6209-6216. [PMID: 30288056 PMCID: PMC6163017 DOI: 10.2147/ott.s172803] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Caveolin-2 (CAV2) is reported to have an important role in cancer. The following study investigated the expression and function of CAV2 in kidney cancer in vitro and in vivo. Materials and methods Real-time PCR, immunohistochemistry and Western blotting analysis were used to determine CAV2, epidermal growth factor receptor (EGFR), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) in kidney cancer cell line OS-RC-2 and clinical specimens. The role of CAV2 in maintaining kidney cancer malignant phenotype was examined by wound healing assay, Matrigel invasion assays and mouse orthotopic xenograft model. Results Higher expression of CAV2 was found in renal cell carcinoma tissue compared to normal tissue. Furthermore, increased expression of CAV2 was associated with cancer progression. Also, silencing of CAV2 inhibited the proliferation, migration and invasion, as well as the expression of EGFR, PI3K and p-Akt in OS-RC-2 cells in vitro, and OS-RC-2 xenograft growth in vivo. Conclusion Our results revealed that CAV2 promotes the growth of renal cell carcinoma through EGFR/PI3K/Akt pathway.
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Affiliation(s)
- Fu Liu
- The First People's Hospital of Ziyang, Sichuan, People's Republic of China,
| | - Zhi Shangli
- The First People's Hospital of Ziyang, Sichuan, People's Republic of China,
| | - Zhili Hu
- The Second Hospital Affiliated to Chongqing Medical University, Chongqing, People's Republic of China
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Abd El-Kaream SA, Abd Elsamie GH, Abd-Alkareem AS. Sono-photodynamic modality for cancer treatment using bio-degradable bio-conjugated sonnelux nanocomposite in tumor-bearing mice: Activated cancer therapy using light and ultrasound. Biochem Biophys Res Commun 2018; 503:1075-1086. [DOI: 10.1016/j.bbrc.2018.06.119] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 06/20/2018] [Indexed: 12/22/2022]
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20
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Nuno DW, Coppey LJ, Yorek MA, Lamping KG. Dietary fats modify vascular fat composition, eNOS localization within lipid rafts and vascular function in obesity. Physiol Rep 2018; 6:e13820. [PMID: 30105819 PMCID: PMC6090220 DOI: 10.14814/phy2.13820] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 07/16/2018] [Indexed: 12/15/2022] Open
Abstract
We tested whether dietary fatty acids alter membrane composition shifting localization of signaling pathways within caveolae to determine their role in vascular function. Wild type (WT) and caveolin-1-deficient mice (cav-1 KO), required for vascular caveolae formation, were fed low fat (LF), high saturated fat (HF, 60% kcal from lard), or high-fat diet with 50:50 lard and n-3 polyunsaturated fatty acid-enriched menhaden oil (MO). HF and MO increased body weight and fat in WT but had less effect in cav-1 KO. MO increased unsaturated fatty acids and the unsaturation index of aorta from WT and cav-1 KO. In LF WT aorta, endothelial nitric oxide synthase (eNOS) was localized to cav-1-enriched low-density fractions which shifted to actin-enriched high-density fractions with acetylcholine (ACh). HF and MO shifted eNOS to high-density fractions in WT aorta which was not affected by ACh. In cav-1 KO aorta, eNOS was localized in low-density non-caveolar fractions but not shifted by ACh or diet. Inducible NOS and cyclooxygenase 1/2 were not localized in low-density fractions or affected by diet, ACh or genotype. ACh-induced dilation of gracilis arteries from HF WT was similar to dilation in LF but the NOS component was reduced. In WT and cav-1 KO, dilation to ACh was enhanced by MO through increased role for NOS and cyclooxygenase. We conclude that dietary fats affect vascular fatty acid composition and membrane localization of eNOS but the contribution of eNOS and cyclooxygenase in ACh-mediated vascular responses is independent of lipid rafts.
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Affiliation(s)
- Daniel W. Nuno
- Department of Internal MedicineRoy J. and Lucille A. Carver College of MedicineUniversity of IowaIowa CityIowa
| | - Lawrence J. Coppey
- Department of Internal MedicineRoy J. and Lucille A. Carver College of MedicineUniversity of IowaIowa CityIowa
| | - Mark A. Yorek
- Department of Internal MedicineRoy J. and Lucille A. Carver College of MedicineUniversity of IowaIowa CityIowa
- Iowa City Veterans Affairs Healthcare SystemIowa CityIowa
| | - Kathryn G. Lamping
- Department of Internal MedicineRoy J. and Lucille A. Carver College of MedicineUniversity of IowaIowa CityIowa
- Iowa City Veterans Affairs Healthcare SystemIowa CityIowa
- Department of PharmacologyRoy J. and Lucille A. Carver College of MedicineUniversity of IowaIowa CityIowa
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Chen HS, Chen X, Li WT, Shen JG. Targeting RNS/caveolin-1/MMP signaling cascades to protect against cerebral ischemia-reperfusion injuries: potential application for drug discovery. Acta Pharmacol Sin 2018; 39:669-682. [PMID: 29595191 PMCID: PMC5943912 DOI: 10.1038/aps.2018.27] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 01/26/2018] [Indexed: 02/07/2023]
Abstract
Reactive nitrogen species (RNS) play important roles in mediating cerebral ischemia-reperfusion injury. RNS activate multiple signaling pathways and participate in different cellular events in cerebral ischemia-reperfusion injury. Recent studies have indicated that caveolin-1 and matrix metalloproteinase (MMP) are important signaling molecules in the pathological process of ischemic brain injury. During cerebral ischemia-reperfusion, the production of nitric oxide (NO) and peroxynitrite (ONOO−), two representative RNS, down-regulates the expression of caveolin-1 (Cav-1) and, in turn, further activates nitric oxide synthase (NOS) to promote RNS generation. The increased RNS further induce MMP activation and mediate disruption of the blood-brain barrier (BBB), aggravating the brain damage in cerebral ischemia-reperfusion injury. Therefore, the feedback interaction among RNS/Cav-1/MMPs provides an amplified mechanism for aggravating ischemic brain damage during cerebral ischemia-reperfusion injury. Targeting the RNS/Cav-1/MMP pathway could be a promising therapeutic strategy for protecting against cerebral ischemia-reperfusion injury. In this mini-review article, we highlight the important role of the RNS/Cav-1/MMP signaling cascades in ischemic stroke injury and review the current progress of studies seeking therapeutic compounds targeting the RNS/Cav-1/MMP signaling cascades to attenuate cerebral ischemia-reperfusion injury. Several representative natural compounds, including calycosin-7-O-β-D-glucoside, baicalin, Momordica charantia polysaccharide (MCP), chlorogenic acid, lutein and lycopene, have shown potential for targeting the RNS/Cav-1/MMP signaling pathway to protect the brain in ischemic stroke. Therefore, the RNS/Cav-1/MMP pathway is an important therapeutic target in ischemic stroke treatment.
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22
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Liang YN, Liu Y, Wang L, Yao G, Li X, Meng X, Wang F, Li M, Tong D, Geng J. Combined caveolin-1 and epidermal growth factor receptor expression as a prognostic marker for breast cancer. Oncol Lett 2018; 15:9271-9282. [PMID: 29805656 DOI: 10.3892/ol.2018.8533] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2015] [Accepted: 07/27/2017] [Indexed: 12/17/2022] Open
Abstract
Previous studies have indicated that caveolin-1 (Cav-1) is able to bind the signal transduction factor epidermal growth factor receptor (EGFR) to regulate its tyrosine kinase activity. The aim of the present study was to evaluate the clinical significance of Cav-1 gene expression in association with the expression of EGFR in patients with breast cancer. Primary breast cancer samples from 306 patients were analyzed for Cav-1 and EGFR expression using immunohistochemistry, and clinical significance was assessed using multivariate Cox regression analysis, Kaplan-Meier estimator curves and the log-rank test. Stromal Cav-1 was downregulated in 38.56% (118/306) of tumor tissues, whereas cytoplasmic EGFR and Cav-1 were overexpressed in 53.92% (165/306) and 44.12% (135/306) of breast cancer tissues, respectively. EGFR expression was positively associated with cytoplasmic Cav-1 and not associated with stromal Cav-1 expression in breast cancer samples; however, low expression of stromal Cav-1 was negatively associated with cytoplasmic Cav-1 expression in total tumor tissues, and analogous results were identified in the chemotherapy group. Multivariate Cox's proportional hazards model analysis revealed that, for patients in the estrogen receptor (ER)(+) group, the expression of stromal Cav-1 alone was a significant prognostic marker of breast cancer. However, in the chemotherapy, human epidermal growth factor receptor 2 (HER-2)(-), HER-2(+) and ER(-) groups, the use of combined markers was more effective prognostic marker. Stromal Cav-1 has a tumor suppressor function, and the combined marker stromal Cav-1/EGFR expression was identified as an improved prognostic marker in the diagnosis of breast cancer. Parenchymal expression of Cav-1 is able to promote EGFR signaling in breast cancer, potentially being required for EGFR-mediated initiation of mitosis.
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Affiliation(s)
- Ya-Nan Liang
- College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.,Department of Pathology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Yu Liu
- Department of Pathology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Letian Wang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Guodong Yao
- Department of Pathology, The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Xiaobo Li
- Department of Pathology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Xiangning Meng
- Department of Medical Genetics, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Fan Wang
- School of Public Health, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Ming Li
- School of Public Health, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Dandan Tong
- Department of Pathology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Jingshu Geng
- Department of Pathology, The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.,Department of Medical Genetics, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
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23
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Qiu B, Wang Q, Liu W, Xu TC, Liu LN, Zong AZ, Jia M, Li J, Du FL. Biological effects of trans fatty acids and their possible roles in the lipid rafts in apoptosis regulation. Cell Biol Int 2018; 42:904-912. [PMID: 29500886 DOI: 10.1002/cbin.10958] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 02/24/2018] [Indexed: 12/25/2022]
Abstract
A large number of recent studies are focused on evaluating the mechanism of action of trans fatty acids (TFAs) on the progression of apoptosis. A strong positive association has been reported between TFA and coronary heart disease (CHD), obesity and nonalcoholic steatohepatitis and so on. The present study reviewed the biological effects of trans fatty acids (TFA) and their possible roles in lipid rafts in regulating apoptosis. The following aspects of TFA were included: the research about TFA and diseases affecting serum lipid levels, inducing system inflammation and immune response, and the correlation between TFA and apoptosis. The primary purpose of the review article was to comprehensively evaluate the potential correlation between lipid rafts and apoptosis induced by different structures of TFA and provide some new research progress and future directions about it.
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Affiliation(s)
- Bin Qiu
- Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, 202, Gongye North Road, Jinan, 250100, PR China.,Key Laboratory of Agro-Products Processing Technology of Shandong Province, 202, Gongye North Road, Jinan, 250100, PR China.,Key Laboratory of Novel Food Resources Processing, Ministry of Agriculture, 202 Gongye North Road, Jinan, 250100, PR China
| | - Qing Wang
- Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, 202, Gongye North Road, Jinan, 250100, PR China.,Key Laboratory of Agro-Products Processing Technology of Shandong Province, 202, Gongye North Road, Jinan, 250100, PR China.,Key Laboratory of Novel Food Resources Processing, Ministry of Agriculture, 202 Gongye North Road, Jinan, 250100, PR China
| | - Wei Liu
- Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, 202, Gongye North Road, Jinan, 250100, PR China.,Key Laboratory of Agro-Products Processing Technology of Shandong Province, 202, Gongye North Road, Jinan, 250100, PR China.,Key Laboratory of Novel Food Resources Processing, Ministry of Agriculture, 202 Gongye North Road, Jinan, 250100, PR China
| | - Tong-Cheng Xu
- Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, 202, Gongye North Road, Jinan, 250100, PR China.,Key Laboratory of Agro-Products Processing Technology of Shandong Province, 202, Gongye North Road, Jinan, 250100, PR China.,Key Laboratory of Novel Food Resources Processing, Ministry of Agriculture, 202 Gongye North Road, Jinan, 250100, PR China
| | - Li-Na Liu
- Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, 202, Gongye North Road, Jinan, 250100, PR China.,Key Laboratory of Agro-Products Processing Technology of Shandong Province, 202, Gongye North Road, Jinan, 250100, PR China.,Key Laboratory of Novel Food Resources Processing, Ministry of Agriculture, 202 Gongye North Road, Jinan, 250100, PR China
| | - Ai-Zhen Zong
- Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, 202, Gongye North Road, Jinan, 250100, PR China.,Key Laboratory of Agro-Products Processing Technology of Shandong Province, 202, Gongye North Road, Jinan, 250100, PR China.,Key Laboratory of Novel Food Resources Processing, Ministry of Agriculture, 202 Gongye North Road, Jinan, 250100, PR China
| | - Min Jia
- Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, 202, Gongye North Road, Jinan, 250100, PR China.,Key Laboratory of Agro-Products Processing Technology of Shandong Province, 202, Gongye North Road, Jinan, 250100, PR China.,Key Laboratory of Novel Food Resources Processing, Ministry of Agriculture, 202 Gongye North Road, Jinan, 250100, PR China
| | - Jing Li
- State Key Lab of Food Science and Technology, Nanchang University, Nanchang, Jiangxi, 330047, PR China
| | - Fang-Ling Du
- Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, 202, Gongye North Road, Jinan, 250100, PR China.,Key Laboratory of Agro-Products Processing Technology of Shandong Province, 202, Gongye North Road, Jinan, 250100, PR China.,Key Laboratory of Novel Food Resources Processing, Ministry of Agriculture, 202 Gongye North Road, Jinan, 250100, PR China
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24
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Decoding resistant hypertension signalling pathways. Clin Sci (Lond) 2017; 131:2813-2834. [PMID: 29184046 DOI: 10.1042/cs20171398] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Revised: 10/16/2017] [Accepted: 10/23/2017] [Indexed: 01/01/2023]
Abstract
Resistant hypertension (RH) is a clinical condition in which the hypertensive patient has become resistant to drug therapy and is often associated with increased cardiovascular morbidity and mortality. Several signalling pathways have been studied and related to the development and progression of RH: modulation of sympathetic activity by leptin and aldosterone, primary aldosteronism, arterial stiffness, endothelial dysfunction and variations in the renin-angiotensin-aldosterone system (RAAS). miRNAs comprise a family of small non-coding RNAs that participate in the regulation of gene expression at post-transcriptional level. miRNAs are involved in the development of both cardiovascular damage and hypertension. Little is known of the molecular mechanisms that lead to development and progression of this condition. This review aims to cover the potential roles of miRNAs in the mechanisms associated with the development and consequences of RH, and explore the current state of the art of diagnostic and therapeutic tools based on miRNA approaches.
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25
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Fang X, Li X, Yin Z, Xia L, Quan X, Zhao Y, Zhou B. Genetic variation at the microRNA binding site of CAV1 gene is associated with lung cancer susceptibility. Oncotarget 2017; 8:92943-92954. [PMID: 29190968 PMCID: PMC5696234 DOI: 10.18632/oncotarget.21687] [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: 04/27/2017] [Accepted: 09/05/2017] [Indexed: 01/09/2023] Open
Abstract
Single nucleotide polymorphism (SNP) may influence the genesis and development of cancer in a variety of ways depending on their location. Here we conducted a study in Chinese female non-smokers to investigate the relationship between rs1049337, rs926198 and the risk or survival of lung cancer. Further, we explored whether rs1049337 could alter the binding affinity between the mRNA of CAV1 and the corresponding microRNAs. Finally, we evaluated the relationship between expression level of CAV1 and prognosis of lung cancer. The results showed that the rs1049337-C allele and rs926198-C allele were the protective alleles of lung cancer risk. Haplotype analysis indicated that the C-C haplotype (constructed by rs1049337 and rs926198) was a protective haplotype for lung cancer risk. The result of luciferase reporter assay showed that rs1049337 can affect the binding affinity of CAV1 mRNA to the corresponding microRNAs both in A549 cell line and H1299 cell line. Compared with C allele, T allele had a relatively decreased luciferase activity. Compared with paired normal adjacent tissue or normal lung tissue, lung cancer tissue showed a relatively low level of CAV1. Refer to those patients at early stage of lung cancer, the expression level of CAV1 in patients at late stage of lung cancer was relatively low. In conclusion, the results indicated that rs1049337, it's a SNP located at 3′UTR region of CAV1 may affect lung cancer risk by altering the binding affinity between the mRNA of CAV1 and the corresponding microRNAs.
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Affiliation(s)
- Xue Fang
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China.,Liaoning Provincial Department of Education, Key Laboratory of Cancer Etiology and Prevention, China Medical University, Liaoning, China.,Department of Epidemiology, School of Public Health, Shenyang Medical College, Shenyang, China
| | - Xuelian Li
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China.,Liaoning Provincial Department of Education, Key Laboratory of Cancer Etiology and Prevention, China Medical University, Liaoning, China
| | - Zhihua Yin
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China.,Liaoning Provincial Department of Education, Key Laboratory of Cancer Etiology and Prevention, China Medical University, Liaoning, China
| | - Lingzi Xia
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China.,Liaoning Provincial Department of Education, Key Laboratory of Cancer Etiology and Prevention, China Medical University, Liaoning, China
| | - Xiaowei Quan
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China.,Liaoning Provincial Department of Education, Key Laboratory of Cancer Etiology and Prevention, China Medical University, Liaoning, China
| | - Yuxia Zhao
- Department of Radiotherapy, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Baosen Zhou
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China.,Liaoning Provincial Department of Education, Key Laboratory of Cancer Etiology and Prevention, China Medical University, Liaoning, China
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26
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Prognostic Value of Metastatic Tumoral Caveolin-1 Expression in Patients with Resected Gastric Cancer. Gastroenterol Res Pract 2017; 2017:5905173. [PMID: 28828003 PMCID: PMC5554552 DOI: 10.1155/2017/5905173] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 06/08/2017] [Accepted: 06/15/2017] [Indexed: 01/01/2023] Open
Abstract
OBJECTIVE Caveolin-1 (Cav-1), as the main component of caveolae, has complex roles in tumourigenesis in human malignancies. We investigated Cav-1 in primary and metastatic tumor cells of gastric cancer (GC) and its association with clinical outcomes. METHODS We retrieved 145 cases of GC who had undergone curative gastrectomy. The expression levels of Cav-1 was evaluated by immunohistochemistry, and its association with clinicopathological parameters and patient survival was analyzed. RESULTS High expression of Cav-1 protein of the GC in the stomach and metastatic lymph node was 12.4% (18/145) and 16.5% (15/91). In the multivariate analysis, tumoral Cav-1 protein in metastatic lymph node showed prognostic significance for relapse-free survival (RFS, HR, 3.934; 95% CI, 1.882-8.224; P = 0.001) and cancer-specific survival outcome (CSS, HR, 2.681; 95% CI, 1.613-8.623; P = 0.002). Among the GCs with metastatic lymph node, it remained as a strong indicator of poor prognosis for RFS (HR, 3.136; 95% CI, 1.444-6.810; P = 0.004) and CSS (HR, 2.509; 95% CI, 1.078-5.837; P = 0.032). CONCLUSION High expression of tumoral Cav-1 protein in metastatic lymph node is associated with unfavorable prognosis of curative resected GC, indicating the potential of novel prognostic markers.
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27
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Motloch LJ, Larbig R, Darabi T, Reda S, Motloch KA, Wernly B, Lichtenauer M, Gebing T, Schwaiger A, Zagidullin N, Wolny M, Hoppe UC. Long-QT syndrome-associated caveolin-3 mutations differentially regulate the hyperpolarization-activated cyclic nucleotide gated channel 4. Physiol Int 2017. [DOI: 10.1556/2060.104.2017.2.6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Background
Caveolin-3 (cav-3) mutations are linked to the long-QT syndrome (LQTS) causing distinct clinical symptoms. Hyperpolarization-activated cyclic nucleotide channel 4 (HCN4) underlies the pacemaker current If. It associates with cav-3 and both form a macromolecular complex.
Methods
To examine the effects of human LQTS-associated cav-3 mutations on HCN4-channel function, HEK293-cells were cotransfected with HCN4 and wild-type (WT) cav-3 or a LQTS-associated cav-3 mutant (T78M, A85T, S141R, or F97C). HCN4 currents were recorded using the whole-cell patch-clamp technique.
Results
WT cav-3 significantly decreased HCN4 current density and shifted midpoint of activation into negative direction. HCN4 current properties were differentially modulated by LQTS-associated cav-3 mutations. When compared with WT cav-3, A85T, F97C, and T78M did not alter the specific effect of cav-3, but S141R significantly increased HCN4 current density. Compared with WT cav-3, no significant modifications of voltage dependence of steady-state activation curves were observed. However, while WT cav-3 alone had no significant effect on HCN4 current activation, all LQTS-associated cav-3 mutations significantly accelerated HCN4 activation kinetics.
Conclusions
Our results indicate that HCN4 channel function is modulated by cav-3. LQTS-associated mutations of cav-3 differentially influence pacemaker current properties indicating a pathophysiological role in clinical manifestations.
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Affiliation(s)
- LJ Motloch
- 1Department of Internal Medicine II, Paracelsus Medical University, Salzburg, Austria
| | - R Larbig
- 2Division of Electrophysiology, Department of Cardiovascular Medicine, University Hospital Muenster, Muenster, Germany
| | - T Darabi
- 1Department of Internal Medicine II, Paracelsus Medical University, Salzburg, Austria
| | - S Reda
- 1Department of Internal Medicine II, Paracelsus Medical University, Salzburg, Austria
| | - KA Motloch
- 3Research Program for Ophthalmology and Glaucoma Research, University Clinic of Ophthalmology and Optometry, Paracelsus Medical University/SALK, Salzburg, Austria
| | - B Wernly
- 1Department of Internal Medicine II, Paracelsus Medical University, Salzburg, Austria
| | - M Lichtenauer
- 1Department of Internal Medicine II, Paracelsus Medical University, Salzburg, Austria
| | - T Gebing
- 1Department of Internal Medicine II, Paracelsus Medical University, Salzburg, Austria
| | - A Schwaiger
- 1Department of Internal Medicine II, Paracelsus Medical University, Salzburg, Austria
| | - N Zagidullin
- 4Department of Internal Diseases, Bashkir State Medical University, Ufa, Russia
| | - M Wolny
- 1Department of Internal Medicine II, Paracelsus Medical University, Salzburg, Austria
| | - UC Hoppe
- 1Department of Internal Medicine II, Paracelsus Medical University, Salzburg, Austria
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28
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Pineda RH, Nedumaran B, Hypolite J, Pan XQ, Wilson S, Meacham RB, Malykhina AP. Altered expression and modulation of the two-pore-domain (K 2P) mechanogated potassium channel TREK-1 in overactive human detrusor. Am J Physiol Renal Physiol 2017; 313:F535-F546. [PMID: 28539337 DOI: 10.1152/ajprenal.00638.2016] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 05/10/2017] [Accepted: 05/18/2017] [Indexed: 01/25/2023] Open
Abstract
Detrusor overactivity (DO) is the abnormal response of the urinary bladder to physiological stretch during the filling phase of the micturition cycle. The mechanisms of bladder smooth muscle compliance upon the wall stretch are poorly understood. We previously reported that the function of normal detrusor is regulated by TREK-1, a member of the mechanogated subfamily of two-pore-domain potassium (K2P) channels. In the present study, we aimed to identify the changes in expression and function of TREK-1 channels under pathological conditions associated with DO, evaluate the potential relationship between TREK-1 channels and cytoskeletal proteins in the human bladder, and test the possibility of modulation of TREK-1 channel expression by small RNAs. Expression of TREK-1 channels in DO specimens was 2.7-fold decreased compared with control bladders and was associated with a significant reduction of the recorded TREK-1 currents. Isolated DO muscle strips failed to relax when exposed to a TREK-1 channel opener. Immunocytochemical labeling revealed close association of TREK-1 channels with cell cytoskeletal proteins and caveolins, with caveolae microdomains being severely disrupted in DO specimens. Small activating RNA (saRNA) tested in vitro provided evidence that expression of TREK-1 protein could be partially upregulated. Our data confirmed a significant downregulation of TREK-1 expression in human DO specimens and provided evidence of close association between the channel, cell cytoskeleton, and caveolins. Upregulation of TREK-1 expression by saRNA could be a future step for the development of in vivo pharmacological and genetic approaches to treat DO in humans.
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Affiliation(s)
- Ricardo H Pineda
- Division of Urology, Department of Surgery, University of Colorado Denver, Aurora, Colorado; and
| | - Balachandar Nedumaran
- Division of Urology, Department of Surgery, University of Colorado Denver, Aurora, Colorado; and
| | - Joseph Hypolite
- Division of Urology, Department of Surgery, University of Colorado Denver, Aurora, Colorado; and
| | - Xiao-Qing Pan
- Division of Urology, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Shandra Wilson
- Division of Urology, Department of Surgery, University of Colorado Denver, Aurora, Colorado; and
| | - Randall B Meacham
- Division of Urology, Department of Surgery, University of Colorado Denver, Aurora, Colorado; and
| | - Anna P Malykhina
- Division of Urology, Department of Surgery, University of Colorado Denver, Aurora, Colorado; and
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Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis. Proc Natl Acad Sci U S A 2017; 114:E1168-E1177. [PMID: 28137846 DOI: 10.1073/pnas.1609905114] [Citation(s) in RCA: 119] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Disruption of the blood-brain barrier (BBB) is a defining and early feature of multiple sclerosis (MS) that directly damages the central nervous system (CNS), promotes immune cell infiltration, and influences clinical outcomes. There is an urgent need for new therapies to protect and restore BBB function, either by strengthening endothelial tight junctions or suppressing endothelial vesicular transcytosis. Although wingless integrated MMTV (Wnt)/β-catenin signaling plays an essential role in BBB formation and maintenance in healthy CNS, its role in BBB repair in neurologic diseases such as MS remains unclear. Using a Wnt/β-catenin reporter mouse and several downstream targets, we demonstrate that the Wnt/β-catenin pathway is up-regulated in CNS endothelial cells in both human MS and the mouse model experimental autoimmune encephalomyelitis (EAE). Increased Wnt/β-catenin activity in CNS blood vessels during EAE progression correlates with up-regulation of neuronal Wnt3 expression, as well as breakdown of endothelial cell junctions. Genetic inhibition of the Wnt/β-catenin pathway in CNS endothelium before disease onset exacerbates the clinical presentation of EAE, CD4+ T-cell infiltration into the CNS, and demyelination by increasing expression of vascular cell adhesion molecule-1 and the transcytosis protein Caveolin-1 and promoting endothelial transcytosis. However, Wnt signaling attenuation does not affect the progressive degradation of tight junction proteins or paracellular BBB leakage. These results suggest that reactivation of Wnt/β-catenin signaling in CNS vessels during EAE/MS partially restores functional BBB integrity and limits immune cell infiltration into the CNS.
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30
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Abstract
Cardiac arrhythmias can follow disruption of the normal cellular electrophysiological processes underlying excitable activity and their tissue propagation as coherent wavefronts from the primary sinoatrial node pacemaker, through the atria, conducting structures and ventricular myocardium. These physiological events are driven by interacting, voltage-dependent, processes of activation, inactivation, and recovery in the ion channels present in cardiomyocyte membranes. Generation and conduction of these events are further modulated by intracellular Ca2+ homeostasis, and metabolic and structural change. This review describes experimental studies on murine models for known clinical arrhythmic conditions in which these mechanisms were modified by genetic, physiological, or pharmacological manipulation. These exemplars yielded molecular, physiological, and structural phenotypes often directly translatable to their corresponding clinical conditions, which could be investigated at the molecular, cellular, tissue, organ, and whole animal levels. Arrhythmogenesis could be explored during normal pacing activity, regular stimulation, following imposed extra-stimuli, or during progressively incremented steady pacing frequencies. Arrhythmic substrate was identified with temporal and spatial functional heterogeneities predisposing to reentrant excitation phenomena. These could arise from abnormalities in cardiac pacing function, tissue electrical connectivity, and cellular excitation and recovery. Triggering events during or following recovery from action potential excitation could thereby lead to sustained arrhythmia. These surface membrane processes were modified by alterations in cellular Ca2+ homeostasis and energetics, as well as cellular and tissue structural change. Study of murine systems thus offers major insights into both our understanding of normal cardiac activity and its propagation, and their relationship to mechanisms generating clinical arrhythmias.
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Affiliation(s)
- Christopher L-H Huang
- Physiological Laboratory and the Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
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31
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Ross NL, Sullivan MO. Overexpression of caveolin-1 in inflammatory breast cancer cells enables IBC-specific gene delivery and prodrug conversion using histone-targeted polyplexes. Biotechnol Bioeng 2016; 113:2686-2697. [PMID: 27241022 PMCID: PMC5268818 DOI: 10.1002/bit.26022] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Revised: 04/18/2016] [Accepted: 05/27/2016] [Indexed: 12/11/2022]
Abstract
Gene therapy platforms offer a variety of potentially effective solutions for development of targeted agents that can be exploited for cancer treatment. The physicochemical properties of nanocarriers can be tuned to enhance their localization in tumors, and cell specificity can also be increased by appropriate selection of gene targets. A relatively underexploited approach to enhance therapeutic selectivity in cancer tissues is the use of nanocarriers whose nuclear targeting and uptake are triggered by the altered expression of specific endomembrane trafficking proteins in cancer cells. Previously, we showed that histone 3 (H3) peptide-targeted DNA polyplexes traffic to the nucleus efficiently through caveolar endocytosis followed by transfer through the Golgi and endoplasmic reticulum (ER). We hypothesized that these polyplexes would exhibit enhanced activity in inflammatory breast cancer (IBC) cells, which overexpress caveolin-1 as part of their invasive phenotype, and we also posited that this targeting effect could be exploited to facilitate IBC-specific transfection and prodrug conversion in the presence of normal breast epithelial cells. Using cellular transfection experiments, function-blocking assays, and confocal imaging in both IBC SUM149 cell monocultures and IBC SUM149 co-cultures with MCF10A normal breast epithelial cells, we found that our H3-targeted polyplexes selectively transfected IBC SUM149 cells at a 4-fold higher level than normal breast epithelial cells. This selectivity and increased transfection were caused by a 2.2-fold overexpression of caveolin-1 in IBC SUM149 cells, which led to increased polyplex trafficking to the nucleus through the Golgi and ER. We also saw similar enhancements in cell selectivity and transfection when cells were transfected with a suicide gene/prodrug combination, as the increased expression of the suicide gene in IBC SUM149 cells led to a 55% decrease in viability in IBC SUM149 cells as compared to a 25% decrease in MCF10A cells. These findings demonstrate that differences in the expression of the endocytic membrane protein caveolin-1 can be exploited for cell-selective gene delivery, and ultimately, these gene-based targeting approaches may be useful in potential treatments for aggressive cancer types. Biotechnol. Bioeng. 2016;113: 2686-2697. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Nikki L Ross
- Department of Chemical and Biomolecular Engineering, University of Delaware, 150 Academy St., Newark, Delaware 19716
| | - Millicent O Sullivan
- Department of Chemical and Biomolecular Engineering, University of Delaware, 150 Academy St., Newark, Delaware 19716.
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32
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Caveolin-1/-3: therapeutic targets for myocardial ischemia/reperfusion injury. Basic Res Cardiol 2016; 111:45. [PMID: 27282376 DOI: 10.1007/s00395-016-0561-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 05/05/2016] [Accepted: 05/06/2016] [Indexed: 01/20/2023]
Abstract
Myocardial ischemia/reperfusion (I/R) injury is a major cause of morbidity and mortality worldwide. Caveolae, caveolin-1 (Cav-1), and caveolin-3 (Cav-3) are essential for the protective effects of conditioning against myocardial I/R injury. Caveolins are membrane-bound scaffolding proteins that compartmentalize and modulate signal transduction. In this review, we introduce caveolae and caveolins and briefly describe the interactions of caveolins in the cardiovascular diseases. We also review the roles of Cav-1/-3 in protection against myocardial ischemia and I/R injury, and in conditioning. Finally, we suggest several potential research avenues that may be of interest to clinicians and basic scientists. The information included, herein, is potentially useful for the design of future studies and should advance the investigation of caveolins as therapeutic targets.
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33
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Oliveira RL, Parent A, Cyr DG, Gregory M, Mandato CA, Smith CE, Hermo L. Implications of caveolae in testicular and epididymal myoid cells to sperm motility. Mol Reprod Dev 2016; 83:526-40. [PMID: 27088550 DOI: 10.1002/mrd.22649] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 04/08/2016] [Indexed: 12/25/2022]
Abstract
Seminiferous tubules of the testis and epididymal tubules in adult rodents are enveloped by contractile myoid cells, which move sperm and fluids along the male reproductive tract. Myoid cells in the testis influence Sertoli cells by paracrine signaling, but their role in the epididymis is unknown. Electron microscopy revealed that elongated myoid cells formed several concentric layers arranged in a loose configuration. The edges of some myoid cells in a given layer closely approximated one another, and extended small foot-like processes to cells of overlying layers. Gap junction proteins, connexins 32 and 43, were detected within the myoid cell layers by immunohistochemistry. These myoid cells also had caveolae that contained caveolin-1 and cavin-1 (also known as PTRF). The number of caveolae per unit area of plasma membrane was significantly reduced in caveolin-1-deficient mice (Cav1(-/-) ). Morphometric analyses of Cav1-null testes revealed an enlargement in whole-tubule and epithelial profile areas, whereas these parameters were slightly reduced in the epididymis. Although sperm are non-motile as they pass through the proximal epididymis, statistical analyses of cauda epididymidis sperm concentrations revealed no significant differences between wild-type and Cav1(-/-) mice. Motility analyses, however, indicated that sperm velocity parameters were reduced while beat cross frequency was higher in gametes of Cav1(-/-) mice. Thus while caveolae and their associated proteins are not necessary for myoid cell contractility, they appear to be crucial for signaling with the epididymal epithelium to regulate the proper acquisition of sperm motility. Mol. Reprod. Dev. 83: 526-540, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Regiana L Oliveira
- Department of Anatomy and Cell Biology, McGill University, Montreal, Canada
| | - Adam Parent
- Department of Anatomy and Cell Biology, McGill University, Montreal, Canada
| | - Daniel G Cyr
- Department of Anatomy and Cell Biology, McGill University, Montreal, Canada
- INRS-Institut Armand Frappier, Université du Québec, Laval, Quebec, Canada
| | - Mary Gregory
- INRS-Institut Armand Frappier, Université du Québec, Laval, Quebec, Canada
| | - Craig A Mandato
- Department of Anatomy and Cell Biology, McGill University, Montreal, Canada
| | - Charles E Smith
- Department of Anatomy and Cell Biology, McGill University, Montreal, Canada
| | - Louis Hermo
- Department of Anatomy and Cell Biology, McGill University, Montreal, Canada
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34
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Miller H, Castro-Gomes T, Corrotte M, Tam C, Maugel TK, Andrews NW, Song W. Lipid raft-dependent plasma membrane repair interferes with the activation of B lymphocytes. J Cell Biol 2016; 211:1193-205. [PMID: 26694840 PMCID: PMC4687878 DOI: 10.1083/jcb.201505030] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Repair of plasma membrane wounds in B lymphocytes that lack caveolin requires lysosome exocytosis and lipid raft–mediated endocytosis and inhibits activation of the B cell receptor by sequestering lipid rafts. Cells rapidly repair plasma membrane (PM) damage by a process requiring Ca2+-dependent lysosome exocytosis. Acid sphingomyelinase (ASM) released from lysosomes induces endocytosis of injured membrane through caveolae, membrane invaginations from lipid rafts. How B lymphocytes, lacking any known form of caveolin, repair membrane injury is unknown. Here we show that B lymphocytes repair PM wounds in a Ca2+-dependent manner. Wounding induces lysosome exocytosis and endocytosis of dextran and the raft-binding cholera toxin subunit B (CTB). Resealing is reduced by ASM inhibitors and ASM deficiency and enhanced or restored by extracellular exposure to sphingomyelinase. B cell activation via B cell receptors (BCRs), a process requiring lipid rafts, interferes with PM repair. Conversely, wounding inhibits BCR signaling and internalization by disrupting BCR–lipid raft coclustering and by inducing the endocytosis of raft-bound CTB separately from BCR into tubular invaginations. Thus, PM repair and B cell activation interfere with one another because of competition for lipid rafts, revealing how frequent membrane injury and repair can impair B lymphocyte–mediated immune responses.
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Affiliation(s)
- Heather Miller
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742
| | - Thiago Castro-Gomes
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742
| | - Matthias Corrotte
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742
| | - Christina Tam
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742
| | - Timothy K Maugel
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742
| | - Norma W Andrews
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742
| | - Wenxia Song
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742
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35
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Caveolin interaction governs Kv1.3 lipid raft targeting. Sci Rep 2016; 6:22453. [PMID: 26931497 PMCID: PMC4773814 DOI: 10.1038/srep22453] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 02/15/2016] [Indexed: 12/22/2022] Open
Abstract
The spatial localization of ion channels at the cell surface is crucial for their functional role. Many channels localize in lipid raft microdomains, which are enriched in cholesterol and sphingolipids. Caveolae, specific lipid rafts which concentrate caveolins, harbor signaling molecules and their targets becoming signaling platforms crucial in cell physiology. However, the molecular mechanisms involved in such spatial localization are under debate. Kv1.3 localizes in lipid rafts and participates in the immunological response. We sought to elucidate the mechanisms of Kv1.3 surface targeting, which govern leukocyte physiology. Kv1 channels share a putative caveolin-binding domain located at the intracellular N-terminal of the channel. This motif, lying close to the S1 transmembrane segment, is situated near the T1 tetramerization domain and the determinants involved in the Kvβ subunit association. The highly hydrophobic domain (FQRQVWLLF) interacts with caveolin 1 targeting Kv1.3 to caveolar rafts. However, subtle variations of this cluster, putative ancillary associations and different structural conformations can impair the caveolin recognition, thereby altering channel’s spatial localization. Our results identify a caveolin-binding domain in Kv1 channels and highlight the mechanisms that govern the regulation of channel surface localization during cellular processes.
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Is Postpartum Urinary Retention a Neurogenic Phenomenon? CURRENT BLADDER DYSFUNCTION REPORTS 2015. [DOI: 10.1007/s11884-015-0321-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Wan X, Chen Z, Choi WI, Gee HY, Hildebrandt F, Zhou W. Loss of Epithelial Membrane Protein 2 Aggravates Podocyte Injury via Upregulation of Caveolin-1. J Am Soc Nephrol 2015; 27:1066-75. [PMID: 26264854 DOI: 10.1681/asn.2014121197] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 06/23/2015] [Indexed: 11/03/2022] Open
Abstract
Nephrotic syndrome is a CKD defined by proteinuria with subsequent hypoalbuminemia, hyperlipidemia, and edema caused by impaired renal glomerular filtration barrier function. We previously identified mutations in epithelial membrane protein 2 (EMP2) as a monogenic cause of this disease. Here, we generated an emp2-knockout zebrafish model using transcription activator-like effector nuclease-based genome editing. We found that loss of emp2 in zebrafish upregulated caveolin-1 (cav1), a major component of caveolae, in embryos and adult mesonephric glomeruli and exacerbated podocyte injury. This phenotype was partially rescued by glucocorticoids. Furthermore, overexpression of cav1 in zebrafish podocytes was sufficient to induce the same phenotype observed in emp2 homozygous mutants, which was also treatable with glucocorticoids. Similarly, knockdown of EMP2 in cultured human podocytes resulted in increased CAV1 expression and decreased podocyte survival in the presence of puromycin aminonucleoside, whereas glucocorticoid treatment ameliorated this phenotype. Taken together, we have established excessive CAV1 as a mediator of the predisposition to podocyte injury because of loss of EMP2, suggesting CAV1 could be a novel therapeutic target in nephrotic syndrome and podocyte injury.
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Affiliation(s)
- Xiaoyang Wan
- Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan
| | - Zhaohong Chen
- Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan; Jinling Hospital, Nanjing, China
| | - Won-Il Choi
- Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; and
| | - Heon Yung Gee
- Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; and
| | - Friedhelm Hildebrandt
- Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; and Howard Hughes Medical Institute, Chevy Chase, Maryland
| | - Weibin Zhou
- Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan;
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Faggi F, Codenotti S, Poliani PL, Cominelli M, Chiarelli N, Colombi M, Vezzoli M, Monti E, Bono F, Tulipano G, Fiorentini C, Zanola A, Lo HP, Parton RG, Keller C, Fanzani A. MURC/cavin-4 Is Co-Expressed with Caveolin-3 in Rhabdomyosarcoma Tumors and Its Silencing Prevents Myogenic Differentiation in the Human Embryonal RD Cell Line. PLoS One 2015; 10:e0130287. [PMID: 26086601 PMCID: PMC4472524 DOI: 10.1371/journal.pone.0130287] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Accepted: 05/19/2015] [Indexed: 12/28/2022] Open
Abstract
The purpose of this study was to investigate whether MURC/cavin-4, a plasma membrane and Z-line associated protein exhibiting an overlapping distribution with Caveolin-3 (Cav-3) in heart and muscle tissues, may be expressed and play a role in rhabdomyosarcoma (RMS), an aggressive myogenic tumor affecting childhood. We found MURC/cavin-4 to be expressed, often concurrently with Cav-3, in mouse and human RMS, as demonstrated through in silico analysis of gene datasets and immunohistochemical analysis of tumor samples. In vitro expression studies carried out using human cell lines and primary mouse tumor cultures showed that expression levels of both MURC/cavin-4 and Cav-3, while being low or undetectable during cell proliferation, became robustly increased during myogenic differentiation, as detected via semi-quantitative RT-PCR and immunoblotting analysis. Furthermore, confocal microscopy analysis performed on human RD and RH30 cell lines confirmed that MURC/cavin-4 mostly marks differentiated cell elements, colocalizing at the cell surface with Cav-3 and labeling myosin heavy chain (MHC) expressing cells. Finally, MURC/cavin-4 silencing prevented the differentiation in the RD cell line, leading to morphological cell impairment characterized by depletion of myogenin, Cav-3 and MHC protein levels. Overall, our data suggest that MURC/cavin-4, especially in combination with Cav-3, may play a consistent role in the differentiation process of RMS.
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Affiliation(s)
- Fiorella Faggi
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy
- Interuniversity Institute of Myology (IIM), Rome, Italy
| | - Silvia Codenotti
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy
- Interuniversity Institute of Myology (IIM), Rome, Italy
| | - Pietro Luigi Poliani
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy
| | - Manuela Cominelli
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy
| | - Nicola Chiarelli
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy
| | - Marina Colombi
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy
| | - Marika Vezzoli
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy
| | - Eugenio Monti
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy
| | - Federica Bono
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy
| | - Giovanni Tulipano
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy
| | - Chiara Fiorentini
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy
| | - Alessandra Zanola
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy
| | - Harriet P. Lo
- Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia
| | - Robert G. Parton
- Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia
| | - Charles Keller
- Department of Pediatrics, Oregon Health & Science University, Portland, OR, United States of America
- Children’s Cancer Therapy Development Institute, Fort Collins, CO, United States of America
| | - Alessandro Fanzani
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy
- Interuniversity Institute of Myology (IIM), Rome, Italy
- * E-mail:
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Ponce-Cusi R, Calaf GM. Antitumor activity of pamidronate in breast cancer cells transformed by low doses of α-particles and estrogen in vitro. Int J Oncol 2015; 46:2663-9. [PMID: 25873070 DOI: 10.3892/ijo.2015.2955] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Accepted: 03/02/2015] [Indexed: 11/06/2022] Open
Abstract
Human breast cancer is a major cause of global morbidity and mortality in women and it is a process that involves numerous molecular and cellular alterations attributed to environmental substances and agents such as hormones. Bisphosphonates, such as pamidronate, are potent antiresorptive drugs used to the treatment of metabolic bone disease, exerting anti-proliferative, anti-migratory and apoptotic effects. The aim of this study was to evaluate gene and protein expression involved in these processes. An in vitro model was developed with the MCF-10F immortalized breast epithelial cell line exposed to low radiation doses of high LET (linear energy transfer) α-particles (150 keV/µm) and cultured in the presence of 17β-estradiol (estrogen). This model consisted of the following cell lines: i) MCF-10F, normal; ii) Alpha3, non-malignant; iii) Alpha5, pre-tumorigenic, and iv) Tumor2, derived from Alpha5 injected into the nude mice. Our previous results have shown that Alpha5 and Tumor2 increased cell proliferation, anchorage independency, invasive capabilities and tumor formation in nude mice in comparison to control. Expression of the gene (RT-qPCR) and protein (western blotting, flow cyto-metry) was measured. The results indicated that pamidronate decreased invasion, migration and Rho-A, c-Ha-ras, p53, Serpin-1, Caveolin-1, Bcl-xL and NFκB gene and protein expression. Thus, it seems that pamidronate may impinge upon cellular proliferation, invasion, metastasis and apoptosis and it may exert antitumor activity in breast cancer cells transformed by low doses of α-particles and estrogen in vitro.
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Affiliation(s)
| | - Gloria M Calaf
- Instituto de Alta Investigación, Universidad de Tarapacá, Arica, Chile
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40
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Yang G, Dong Z, Xu H, Wang C, Li H, Li Z, Li F. Structural study of caveolin-1 intramembrane domain by circular dichroism and nuclear magnetic resonance. Biopolymers 2015; 104:11-20. [DOI: 10.1002/bip.22597] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Revised: 10/22/2014] [Accepted: 11/30/2014] [Indexed: 01/08/2023]
Affiliation(s)
- Guanhua Yang
- State Key Laboratory of Supramolecular Structure and Materials; Jilin University; Changchun 130012 People's Republic of China
| | - Zhe Dong
- State Key Laboratory of Supramolecular Structure and Materials; Jilin University; Changchun 130012 People's Republic of China
| | - Haoran Xu
- Key Laboratory for Molecular Enzymology & Engineering; The Ministry of Education, Jilin University; Changchun 130012 People's Republic of China
| | - Chunyu Wang
- State Key Laboratory of Supramolecular Structure and Materials; Jilin University; Changchun 130012 People's Republic of China
| | - Haichao Li
- Key Laboratory for Molecular Enzymology & Engineering; The Ministry of Education, Jilin University; Changchun 130012 People's Republic of China
| | - Zhengqiang Li
- Key Laboratory for Molecular Enzymology & Engineering; The Ministry of Education, Jilin University; Changchun 130012 People's Republic of China
| | - Fei Li
- State Key Laboratory of Supramolecular Structure and Materials; Jilin University; Changchun 130012 People's Republic of China
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Navarro G, Borroto-Escuela DO, Fuxe K, Franco R. Potential of caveolae in the therapy of cardiovascular and neurological diseases. Front Physiol 2014; 5:370. [PMID: 25324780 PMCID: PMC4179688 DOI: 10.3389/fphys.2014.00370] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Accepted: 09/08/2014] [Indexed: 12/25/2022] Open
Abstract
Caveolae are membrane micro-domains enriched in cholesterol, sphingolipids and caveolins, which are transmembrane proteins with a hairpin-like structure. Caveolae participate in receptor-mediated trafficking of cell surface receptors and receptor-mediated signaling. Furthermore, caveolae participate in clathrin-independent endocytosis of membrane receptors. On the one hand, caveolins are involved in vascular and cardiac dysfunction. Also, neurological abnormalities in caveolin-1 knockout mice and a link between caveolin-1 gene haplotypes and neurodegenerative diseases have been reported. The aim of this article is to present the rationale for considering caveolae as potential targets in cardiovascular and neurological diseases.
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Affiliation(s)
- Gemma Navarro
- Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona Barcelona, Spain
| | | | - Kjell Fuxe
- Department of Neuroscience, Karolinska Institutet Stockholm, Sweden
| | - Rafael Franco
- Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona Barcelona, Spain
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42
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Gupta R, Toufaily C, Annabi B. Caveolin and cavin family members: dual roles in cancer. Biochimie 2014; 107 Pt B:188-202. [PMID: 25241255 DOI: 10.1016/j.biochi.2014.09.010] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Accepted: 09/04/2014] [Indexed: 12/16/2022]
Abstract
Caveolae are specialized plasma membrane subdomains with distinct lipid and protein compositions, which play an essential role in cell physiology through regulation of trafficking and signaling functions. The structure and functions of caveolae have been shown to require the proteins caveolins. Recently, members of the cavin protein family were found to be required, in concert with caveolins, for the formation and function of caveolae. Caveolins have a paradoxical role in the development of cancer formation. They have been involved in both tumor suppression and oncogenesis, depending on tumor type and progress stage. High expression of caveolins and cavins leads to inhibition of cancer-related pathways, such as growth factor signaling pathways. However, certain cancer cells that express caveolins and cavins have been shown to be more aggressive and metastatic because of their increased potential for anchorage-independent growth. Here, we will survey the functional roles of caveolins and of different cavin family members in cancer regulation.
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Affiliation(s)
- Reshu Gupta
- Laboratoire d'Oncologie Moléculaire, Centre de Recherche BioMed, Département de Chimie, Université du Québec à Montréal, Québec H3C 3P8, Canada.
| | - Chirine Toufaily
- Laboratoire d'Oncologie Moléculaire, Centre de Recherche BioMed, Département de Chimie, Université du Québec à Montréal, Québec H3C 3P8, Canada
| | - Borhane Annabi
- Laboratoire d'Oncologie Moléculaire, Centre de Recherche BioMed, Département de Chimie, Université du Québec à Montréal, Québec H3C 3P8, Canada
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Guerrero-Hernandez A, Gallegos-Gomez ML, Sanchez-Vazquez VH, Lopez-Mendez MC. Acidic intracellular Ca(2+) stores and caveolae in Ca(2+) signaling and diabetes. Cell Calcium 2014; 56:323-31. [PMID: 25182518 DOI: 10.1016/j.ceca.2014.08.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Accepted: 08/07/2014] [Indexed: 12/19/2022]
Abstract
Acidic Ca(2+) stores, particularly lysosomes, are newly discovered players in the well-orchestrated arena of Ca(2+) signaling and we are at the verge of understanding how lysosomes accumulate Ca(2+) and how they release it in response to different chemical, such as NAADP, and physical signals. Additionally, it is now clear that lysosomes play a key role in autophagy, a process that allows cells to recycle components or to eliminate damaged structures to ensure cellular well-being. Moreover, lysosomes are being unraveled as hubs that coordinate both anabolism via insulin signaling and catabolism via AMPK. These acidic vesicles have close contact with the ER and there is a bidirectional movement of information between these two organelles that exquisitely regulates cell survival. Lysosomes also connect with plasma membrane where caveolae are located as specialized regions involved in Ca(2+) and insulin signaling. Alterations of all these signaling pathways are at the core of insulin resistance and diabetes.
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Palacios-Ortega S, Varela-Guruceaga M, Milagro FI, Martínez JA, de Miguel C. Expression of Caveolin 1 is enhanced by DNA demethylation during adipocyte differentiation. status of insulin signaling. PLoS One 2014; 9:e95100. [PMID: 24751908 PMCID: PMC3994010 DOI: 10.1371/journal.pone.0095100] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2014] [Accepted: 03/23/2014] [Indexed: 12/14/2022] Open
Abstract
Caveolin 1 (Cav-1) is an essential constituent of adipocyte caveolae which binds the beta subunit of the insulin receptor (IR) and is implicated in the regulation of insulin signaling. We have found that, during adipocyte differentiation of 3T3-L1 cells the promoter, exon 1 and first intron of the Cav-1 gene undergo a demethylation process that is accompanied by a strong induction of Cav-1 expression, indicating that epigenetic mechanisms must have a pivotal role in this differentiation process. Furthermore, IR, PKB-Akt and Glut-4 expression are also increased during the differentiation process suggesting a coordinated regulation with Cav-1. Activation of Cav-1 protein by phosphorylation arises during the differentiation process, yet in fully mature adipocytes insulin is no longer able to significantly increase Cav-1 phosphorylation. However, these long-term differentiated cells are still able to respond adequately to insulin, increasing IR and PKB-Akt phosphorylation and glucose uptake. The activation of Cav-1 during the adipocyte differentiation process could facilitate the maintenance of insulin sensitivity by these fully mature adipocytes isolated from additional external stimuli. However, under the influence of physiological conditions associated to obesity, such as chronic inflammation and hypoxia, insulin sensitivity would finally be compromised.
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Affiliation(s)
| | | | - Fermín Ignacio Milagro
- Department of Nutrition Food Science and Physiology, University of Navarra, Pamplona, Spain
- Physiopathology of Obesity and Nutrition CIBERobn, Carlos III Health Research Institute, Madrid, Spain
| | - José Alfredo Martínez
- Department of Nutrition Food Science and Physiology, University of Navarra, Pamplona, Spain
- Physiopathology of Obesity and Nutrition CIBERobn, Carlos III Health Research Institute, Madrid, Spain
| | - Carlos de Miguel
- Department of Biochemistry and Genetics, University of Navarra, Pamplona, Spain
- Physiopathology of Obesity and Nutrition CIBERobn, Carlos III Health Research Institute, Madrid, Spain
- * E-mail:
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45
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Liang CC, Lin YH, Chen TC, Chang SD. How antepartum and postpartum acute urinary retention affects the function and structure of the rat bladder. Int Urogynecol J 2014; 25:1105-13. [PMID: 24515542 DOI: 10.1007/s00192-013-2320-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2013] [Accepted: 12/25/2013] [Indexed: 12/17/2022]
Abstract
INTRODUCTION AND HYPOTHESIS To examine the effect of acute urinary retention (AUR) on the urodynamic function and molecular structure of rat bladders in pregnancy and after parturition. METHODS Forty-eight nulliparous rats were distributed into AUR and non-AUR groups. AUR was induced by clamping the distal urethra of each rat after infusing 3 ml of saline for 60 min. Plasma progesterone levels and cystometric data were evaluated on the 14th day of gestation, 3 and 10 days postpartum, and in virgin rats. The immunoreactivity of caveolins and nerve growth factor (NGF) was analyzed. The number of caveolae in bladder muscle cells was evaluated by electron microscopy. RESULTS Progesterone levels significantly increased during pregnancy and 3 days postpartum. In cystometric results, the AUR group has significantly shorter intercontraction interval, lower void volume and greater residual volume compared with the non-AUR. AUR rats exhibited higher NGF immunoreactivity, lower caveolin-1 immunoreactivity, and less caveolae in the bladder compared with the non-AUR. The caveolin-1 and NGF immunoreactivity and the number of caveolae in the bladder decreased during pregnancy and 3 days postpartum compared with virgin rats. By using Pearson correlations, we found significant correlations between urodynamic variables (residual volumes and intercontraction intervals) and the expressions of caveolin-1, caveolae and NGF in the AUR rats on the 14th day of gestation and 3 days postpartum. CONCLUSIONS Bladder dysfunction in pregnancy and immediately postpartum in a rat model caused by AUR is associated with the plasma progesterone level change and the expressions of caveolin, caveolae, and NGF in bladder muscle cells.
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Affiliation(s)
- Ching-Chung Liang
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Linkou Medical Center, 5, Fu-Shin Street, Kweishan, Taoyuan, Taiwan, Republic of China, 333,
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Banin Hirata BK, Oda JMM, Losi Guembarovski R, Ariza CB, de Oliveira CEC, Watanabe MAE. Molecular markers for breast cancer: prediction on tumor behavior. DISEASE MARKERS 2014; 2014:513158. [PMID: 24591761 PMCID: PMC3925609 DOI: 10.1155/2014/513158] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/24/2013] [Revised: 10/04/2013] [Accepted: 11/12/2013] [Indexed: 12/11/2022]
Abstract
Breast cancer is one of the most common cancers with greater than 1,300,000 cases and 450,000 deaths each year worldwide. The development of breast cancer involves a progression through intermediate stages until the invasive carcinoma and finally into metastatic disease. Given the variability in clinical progression, the identification of markers that could predict the tumor behavior is particularly important in breast cancer. The determination of tumor markers is a useful tool for clinical management in cancer patients, assisting in diagnostic, staging, evaluation of therapeutic response, detection of recurrence and metastasis, and development of new treatment modalities. In this context, this review aims to discuss the main tumor markers in breast carcinogenesis. The most well-established breast molecular markers with prognostic and/or therapeutic value like hormone receptors, HER-2 oncogene, Ki-67, and p53 proteins, and the genes for hereditary breast cancer will be presented. Furthermore, this review shows the new molecular targets in breast cancer: CXCR4, caveolin, miRNA, and FOXP3, as promising candidates for future development of effective and targeted therapies, also with lower toxicity.
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Affiliation(s)
- Bruna Karina Banin Hirata
- Laboratory of Polymorphism and Application Study of DNA, Department of Pathological Sciences, Biological Sciences Center, State University of Londrina, 86057-970 Londrina, Brazil
| | - Julie Massayo Maeda Oda
- Laboratory of Polymorphism and Application Study of DNA, Department of Pathological Sciences, Biological Sciences Center, State University of Londrina, 86057-970 Londrina, Brazil
| | - Roberta Losi Guembarovski
- Laboratory of Polymorphism and Application Study of DNA, Department of Pathological Sciences, Biological Sciences Center, State University of Londrina, 86057-970 Londrina, Brazil
| | - Carolina Batista Ariza
- Laboratory of Polymorphism and Application Study of DNA, Department of Pathological Sciences, Biological Sciences Center, State University of Londrina, 86057-970 Londrina, Brazil
| | - Carlos Eduardo Coral de Oliveira
- Laboratory of Polymorphism and Application Study of DNA, Department of Pathological Sciences, Biological Sciences Center, State University of Londrina, 86057-970 Londrina, Brazil
| | - Maria Angelica Ehara Watanabe
- Laboratory of Polymorphism and Application Study of DNA, Department of Pathological Sciences, Biological Sciences Center, State University of Londrina, 86057-970 Londrina, Brazil
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Kaushik G, Engler AJ. From stem cells to cardiomyocytes: the role of forces in cardiac maturation, aging, and disease. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2014; 126:219-42. [PMID: 25081620 DOI: 10.1016/b978-0-12-394624-9.00009-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Stem cell differentiation into a variety of lineages is known to involve signaling from the extracellular niche, including from the physical properties of that environment. What regulates stem cell responses to these cues is there ability to activate different mechanotransductive pathways. Here, we will review the structures and pathways that regulate stem cell commitment to a cardiomyocyte lineage, specifically examining proteins within muscle sarcomeres, costameres, and intercalated discs. Proteins within these structures stretch, inducing a change in their phosphorylated state or in their localization to initiate different signals. We will also put these changes in the context of stem cell differentiation into cardiomyocytes, their subsequent formation of the chambered heart, and explore negative signaling that occurs during disease.
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Affiliation(s)
- Gaurav Kaushik
- Department of Bioengineering, University of California, San Diego, La Jolla, California, USA
| | - Adam J Engler
- Department of Bioengineering, University of California, San Diego, La Jolla, California, USA
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48
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Thompson MA, Prakash YS, Pabelick CM. The role of caveolae in the pathophysiology of lung diseases. Expert Rev Respir Med 2013; 8:111-22. [PMID: 24308657 DOI: 10.1586/17476348.2014.855610] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Caveolae are flask-shaped plasma membrane invaginations formed by constitutive caveolin proteins and regulatory cavin proteins. Caveolae harbor a range of signaling components such as receptors, ion channels and regulatory molecules. There is now increasing evidence that caveolins and cavins play an important role in a variety of diseases. However, the mechanisms by which these caveolar proteins affect lung health and disease are still under investigation, with emerging data suggesting complex roles in disease pathophysiology. This review summarizes the current state of understanding of how caveolar proteins contribute to lung structure and function and how their altered expression and/or function can influence lung diseases.
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49
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Suzuki Y, Yamamura H, Ohya S, Imaizumi Y. Caveolin-1 facilitates the direct coupling between large conductance Ca2+-activated K+ (BKCa) and Cav1.2 Ca2+ channels and their clustering to regulate membrane excitability in vascular myocytes. J Biol Chem 2013; 288:36750-61. [PMID: 24202214 DOI: 10.1074/jbc.m113.511485] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
L-type voltage-dependent Ca(2+) channels (LVDCC) and large conductance Ca(2+)-activated K(+) channels (BKCa) are the major factors defining membrane excitability in vascular smooth muscle cells (VSMCs). The Ca(2+) release from sarcoplasmic reticulum through ryanodine receptor significantly contributes to BKCa activation in VSMCs. In this study direct coupling between LVDCC (Cav1.2) and BKCa and the role of caveoline-1 on their interaction in mouse mesenteric artery SMCs were examined. The direct activation of BKCa by Ca(2+) influx through coupling LVDCC was demonstrated by patch clamp recordings in freshly isolated VSMCs. Using total internal reflection fluorescence microscopy, it was found that a large part of yellow fluorescent protein-tagged BKCa co-localized with the cyan fluorescent protein-tagged Cav1.2 expressed in the plasma membrane of primary cultured mouse VSMCs and that the two molecules often exhibited FRET. It is notable that each BKα subunit of a tetramer in BKCa can directly interact with Cav1.2 and promotes Cav1.2 cluster in the molecular complex. Furthermore, caveolin-1 deficiency in knock-out (KO) mice significantly reduced not only the direct coupling between BKCa and Cav1.2 but also the functional coupling between BKCa and ryanodine receptor in VSMCs. The measurement of single cell shortening by 40 mm K(+) revealed enhanced contractility in VSMCs from KO mice than wild type. Taken together, caveolin-1 facilitates the accumulation/clustering of BKCa-LVDCC complex in caveolae, which effectively regulates spatiotemporal Ca(2+) dynamics including the negative feedback, to control the arterial excitability and contractility.
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Affiliation(s)
- Yoshiaki Suzuki
- From the Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan and
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Abstract
Traumatic brain injury (TBI) has been associated with various neurological disorders. However, the role of cerebrovascular dysfunction and its mechanisms associated with TBI are still not well understood. Inflammation is the main cause of vascular dysfunction. It affects properties of blood components and the vascular wall leading to changes in blood flow and in interaction of blood components and vascular endothelium exacerbating microcirculatory complications during inflammatory diseases. One of the markers of inflammation is a plasma adhesion protein, fibrinogen (Fg). At elevated levels, Fg can also cause inflammatory responses. One of the manifestations of inflammatory responses is an increase in microvascular permeability leading to accumulation of plasma proteins in the subendothelial matrix and causing vascular remodelling. This has a most devastating effect on cerebral circulation after TBI that is accompanied with an elevation of plasma level of Fg and with an increased cerebrovascular permeability in injury penumbra impairing the normal healing process. This study reviews cerebrovascular alterations after TBI, considers the consequences of increased blood-brain barrier permeability, defines the role of elevated level of Fg and discusses the potential mechanisms of its action leading to vascular dysfunction, which subsequently can cause impairment in neuronal function. Thus, possible mechanisms of vasculo-neuronal dysfunction after TBI are considered.
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Affiliation(s)
- Nino Muradashvili
- Department of Physiology and Biophysics, University of Louisville, School of Medicine , Louisville, KY , USA
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