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Chen J, Wang Z, Wang S, Lyu J, Fang Z, Qi W, Yang X, Gao G, Zhou T. Probing the familial ties between serpin members Kallistatin and PEDF: A comparative analysis review. Life Sci 2025; 362:123333. [PMID: 39719168 DOI: 10.1016/j.lfs.2024.123333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 12/07/2024] [Accepted: 12/19/2024] [Indexed: 12/26/2024]
Abstract
The serine protease inhibitors (Serpins) represent a diverse protein superfamily that holds paramount significance in governing vital pathophysiological processes. Their influence on critical biological pathways renders serpins highly coveted targets for drug discovery endeavors. Among the numerous members of this family, two distinct proteins, Kallistatin (encoded by the SERPINA4 gene) and Pigment Epithelium-Derived Factor (PEDF, encoded by the SERPINF1 gene), stand out as secreted proteins that are abundantly present in peripheral blood. Kallistatin is a serine protease inhibitor that specifically inhibits human tissue kallikrein, while PEDF is a non-inhibitory member of the serine protease inhibitors superfamily (Lin et al., 2015a; Chao and Chao, 1995 [1,2]). Instead, they exhibit notable anti-angiogenic effects and play pivotal roles in the pathogenesis of metabolic disorders. Extensive research, including our own investigations, has revealed intriguing similarities as well as noteworthy differences between these two proteins. Despite their shared characteristics, the distinctive features of Kallistatin and PEDF render them unique in their respective functions and mechanisms of action. However, a comprehensive literature review comparing their similarities and differences remains elusive. Therefore, the present review aims to systematically delve into and summarize the comparable and contrasting aspects of Kallistatin and PEDF. We will delve into their expression patterns, structural features, and mechanisms of expression regulation. Furthermore, this review will delve into their physiological functions and roles in diseases, the signaling pathways they influence, and their potential clinical applications. By comparing and contrasting these two proteins, we hope to provide a comprehensive understanding of their functions and potential in biomedical research and clinical practice.
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Affiliation(s)
- Jingnan Chen
- Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China; Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Zihan Wang
- Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China; Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Simin Wang
- Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China; Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Jiayi Lyu
- Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China; Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Zhenzhen Fang
- Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Weiwei Qi
- Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Xia Yang
- Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Guoquan Gao
- Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China; Guangdong Engineering & Technology Research Center for Gene Manipulation and Biomacromolecular Products, Sun Yat-Sen University, Guangzhou 510080, China.
| | - Ti Zhou
- Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China; China Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou 510080, China; Guangdong Province Key Laboratory of Diabetology, Guangzhou 510080, China.
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Patel MA, Daley M, Van Nynatten LR, Slessarev M, Cepinskas G, Fraser DD. A reduced proteomic signature in critically ill Covid-19 patients determined with plasma antibody micro-array and machine learning. Clin Proteomics 2024; 21:33. [PMID: 38760690 PMCID: PMC11100131 DOI: 10.1186/s12014-024-09488-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 05/06/2024] [Indexed: 05/19/2024] Open
Abstract
BACKGROUND COVID-19 is a complex, multi-system disease with varying severity and symptoms. Identifying changes in critically ill COVID-19 patients' proteomes enables a better understanding of markers associated with susceptibility, symptoms, and treatment. We performed plasma antibody microarray and machine learning analyses to identify novel proteins of COVID-19. METHODS A case-control study comparing the concentration of 2000 plasma proteins in age- and sex-matched COVID-19 inpatients, non-COVID-19 sepsis controls, and healthy control subjects. Machine learning was used to identify a unique proteome signature in COVID-19 patients. Protein expression was correlated with clinically relevant variables and analyzed for temporal changes over hospitalization days 1, 3, 7, and 10. Expert-curated protein expression information was analyzed with Natural language processing (NLP) to determine organ- and cell-specific expression. RESULTS Machine learning identified a 28-protein model that accurately differentiated COVID-19 patients from ICU non-COVID-19 patients (accuracy = 0.89, AUC = 1.00, F1 = 0.89) and healthy controls (accuracy = 0.89, AUC = 1.00, F1 = 0.88). An optimal nine-protein model (PF4V1, NUCB1, CrkL, SerpinD1, Fen1, GATA-4, ProSAAS, PARK7, and NET1) maintained high classification ability. Specific proteins correlated with hemoglobin, coagulation factors, hypertension, and high-flow nasal cannula intervention (P < 0.01). Time-course analysis of the 28 leading proteins demonstrated no significant temporal changes within the COVID-19 cohort. NLP analysis identified multi-system expression of the key proteins, with the digestive and nervous systems being the leading systems. CONCLUSIONS The plasma proteome of critically ill COVID-19 patients was distinguishable from that of non-COVID-19 sepsis controls and healthy control subjects. The leading 28 proteins and their subset of 9 proteins yielded accurate classification models and are expressed in multiple organ systems. The identified COVID-19 proteomic signature helps elucidate COVID-19 pathophysiology and may guide future COVID-19 treatment development.
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Affiliation(s)
- Maitray A Patel
- Epidemiology and Biostatistics, Western University, London, ON, N6A 3K7, Canada
| | - Mark Daley
- Epidemiology and Biostatistics, Western University, London, ON, N6A 3K7, Canada
- Computer Science, Western University, London, ON, N6A 3K7, Canada
| | | | - Marat Slessarev
- Medicine, Western University, London, ON, N6A 3K7, Canada
- Lawson Health Research Institute, London, ON, N6C 2R5, Canada
| | - Gediminas Cepinskas
- Lawson Health Research Institute, London, ON, N6C 2R5, Canada
- Medical Biophysics, Western University, London, ON, N6A 3K7, Canada
| | - Douglas D Fraser
- Lawson Health Research Institute, London, ON, N6C 2R5, Canada.
- Children's Health Research Institute, London, ON, N6C 4V3, Canada.
- Pediatrics, Western University, London, ON, N6A 3K7, Canada.
- Clinical Neurological Sciences, Western University, London, ON, N6A 3K7, Canada.
- Physiology & Pharmacology, Western University, London, ON, N6A 3K7, Canada.
- London Health Sciences Centre, 800 Commissioners Road East, London, ON, N6A 5W9, Canada.
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Sandforth L, Brachs S, Reinke J, Willmes D, Sancar G, Seigner J, Juarez-Lopez D, Sandforth A, McBride JD, Ma JX, Haufe S, Jordan J, Birkenfeld AL. Role of human Kallistatin in glucose and energy homeostasis in mice. Mol Metab 2024; 82:101905. [PMID: 38431218 PMCID: PMC10937158 DOI: 10.1016/j.molmet.2024.101905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 02/20/2024] [Accepted: 02/21/2024] [Indexed: 03/05/2024] Open
Abstract
OBJECTIVE Kallistatin (KST), also known as SERPIN A4, is a circulating, broadly acting human plasma protein with pleiotropic properties. Clinical studies in humans revealed reduced KST levels in obesity. The exact role of KST in glucose and energy homeostasis in the setting of insulin resistance and type 2 diabetes is currently unknown. METHODS Kallistatin mRNA expression in human subcutaneous white adipose tissue (sWAT) of 47 people with overweight to obesity of the clinical trial "Comparison of Low Fat and Low Carbohydrate Diets With Respect to Weight Loss and Metabolic Effects (B-SMART)" was measured. Moreover, we studied transgenic mice systemically overexpressing human KST (hKST-TG) and wild type littermate control mice (WT) under normal chow (NCD) and high-fat diet (HFD) conditions. RESULTS In sWAT of people with overweight to obesity, KST mRNA increased after diet-induced weight loss. On NCD, we did not observe differences between hKST-TG and WT mice. Under HFD conditions, body weight, body fat and liver fat content did not differ between genotypes. Yet, during intraperitoneal glucose tolerance tests (ipGTT) insulin excursions and HOMA-IR were lower in hKST-TG (4.42 ± 0.87 AU, WT vs. 2.20 ± 0.27 AU, hKST-TG, p < 0.05). Hyperinsulinemic euglycemic clamp studies with tracer-labeled glucose infusion confirmed improved insulin sensitivity by higher glucose infusion rates in hKST-TG mice (31.5 ± 1.78 mg/kg/min, hKST-TG vs. 18.1 ± 1.67 mg/kg/min, WT, p < 0.05). Improved insulin sensitivity was driven by reduced hepatic insulin resistance (clamp hepatic glucose output: 7.7 ± 1.9 mg/kg/min, hKST-TG vs 12.2 ± 0.8 mg/kg/min, WT, p < 0.05), providing evidence for direct insulin sensitizing effects of KST for the first time. Insulin sensitivity was differentially affected in skeletal muscle and adipose tissue. Mechanistically, we observed reduced Wnt signaling in the liver but not in skeletal muscle, which may explain the effect. CONCLUSIONS KST expression increases after weight loss in sWAT from people with obesity. Furthermore, human KST ameliorates diet-induced hepatic insulin resistance in mice, while differentially affecting skeletal muscle and adipose tissue insulin sensitivity. Thus, KST may be an interesting, yet challenging, therapeutic target for patients with obesity and insulin resistance.
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Affiliation(s)
- Leontine Sandforth
- Internal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital of Tuebingen, Tuebingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Sebastian Brachs
- Department of Endocrinology and Metabolism, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany
| | - Julia Reinke
- Department of Endocrinology and Metabolism, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Section of Metabolic Vascular Medicine, Department of Medicine III, University Clinic Dresden, TU Dresden, Germany
| | - Diana Willmes
- Department of Endocrinology and Metabolism, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Section of Metabolic Vascular Medicine, Department of Medicine III, University Clinic Dresden, TU Dresden, Germany
| | - Gencer Sancar
- Internal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital of Tuebingen, Tuebingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Judith Seigner
- Internal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital of Tuebingen, Tuebingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - David Juarez-Lopez
- Internal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital of Tuebingen, Tuebingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Arvid Sandforth
- Internal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital of Tuebingen, Tuebingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Jeffrey D McBride
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Jian-Xing Ma
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Sven Haufe
- Department of Rehabilitation and Sports Medicine, Hannover Medical School (MHH), Hannover, Germany
| | - Jens Jordan
- Institute of Aerospace Medicine, German Aerospace Center (DLR), Cologne, Germany; Medical Faculty, University of Cologne, Cologne, Germany
| | - Andreas L Birkenfeld
- Internal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital of Tuebingen, Tuebingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Section of Metabolic Vascular Medicine, Department of Medicine III, University Clinic Dresden, TU Dresden, Germany; Department of Diabetes, Life Sciences & Medicine, Cardiovascular Medicine & Life Sciences, King's College London, UK.
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Shahbazi B, Mafakher L, Arab SS, Teimoori-Toolabi L. Kallistatin as an inhibitory protein against colorectal cancer cells through binding to LRP6. J Biomol Struct Dyn 2024; 42:918-934. [PMID: 37114408 DOI: 10.1080/07391102.2023.2196704] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 03/22/2023] [Indexed: 04/29/2023]
Abstract
Kallistatin (KL) is a member of the serine proteinase inhibitor (serpin) family regulating oxidative stress, vascular relaxation, inflammation, angiogenesis, cell proliferation, and invasion. The heparin-binding site of Kallistatin has an important role in the interaction with LRP6 leading to the blockade of the Wnt signaling pathway. In this study, we aimed to explore the structural basis of the Kallistatin-LRP6E1E4 complex using in silico approaches and evaluating the anti-proliferative, apoptotic, and cell cycle arrest activities of Kallistatin in colon cancer lines. The molecular docking showed Kallistatin could bind to the LRP6E3E4 much stronger than LRP6E1E2. The Kallistatin-LRP6E1E2 and Kallistatin-LRP6E3E4 complexes were stable during Molecular Dynamics (MD) simulation. The Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) showed that the Kallistatin-LRP6E3E4 has a higher binding affinity compared to Kallistatin-LRP6E1E2. Kallistatin induced higher cytotoxicity and apoptosis in HCT116 compared to the SW480 cell line. This protein-induced cell-cycle arrest in both cell lines at the G1 phase. The B-catenin, cyclin D1, and c-Myc expression levels were decreased in response to treatment with Kallistatin in both cell lines while the LRP6 expression level was decreased in the HCT116 cell line. Kallistatin has a greater effect on the HCT116 cell line compared to the SW480 cell line. Kallistatin can be used as a cytotoxic and apoptotic-inducing agent in colorectal cancer cell lines.
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Affiliation(s)
- Behzad Shahbazi
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Ladan Mafakher
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Seyed Shahriar Arab
- Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ladan Teimoori-Toolabi
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
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Ferreira MM, Santos AS, Santos AS, Zugaib M, Pirovani CP. Plant Serpins: Potential Inhibitors of Serine and Cysteine Proteases with Multiple Functions. PLANTS (BASEL, SWITZERLAND) 2023; 12:3619. [PMID: 37896082 PMCID: PMC10609998 DOI: 10.3390/plants12203619] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 06/23/2023] [Accepted: 06/26/2023] [Indexed: 10/29/2023]
Abstract
Plant serpins are a superfamily of protein inhibitors that have been continuously studied in different species and have great biotechnological potential. However, despite ongoing studies with these inhibitors, the biological role of this family in the plant kingdom has not yet been fully clarified. In order to obtain new insights into the potential of plant serpins, this study presents the first systematic review of the topic, whose main objective was to scrutinize the published literature to increase knowledge about this superfamily. Using keywords and the eligibility criteria defined in the protocol, we selected studies from the Scopus, PubMed, and Web of Science databases. According to the eligible studies, serpins inhibit different serine and non-serine proteases from plants, animals, and pathogens, and their expression is affected by biotic and abiotic stresses. Moreover, serpins like AtSerpin1, OSP-LRS, MtSer6, AtSRP4, AtSRP5, and MtPiI4, act in resistance and are involved in stress-induced cell death in the plant. Also, the system biology analysis demonstrates that serpins are related to proteolysis control, cell regulation, pollen development, catabolism, and protein dephosphorylation. The information systematized here contributes to the design of new studies of plant serpins, especially those aimed at exploring their biotechnological potential.
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Affiliation(s)
- Monaliza Macêdo Ferreira
- Center for Biotechnology and Genetics, Department of Biological Sciences, Santa Cruz State University, Ilhéus 45662-900, BA, Brazil; (A.S.S.); (M.Z.); (C.P.P.)
| | - Ariana Silva Santos
- Center for Biotechnology and Genetics, Department of Biological Sciences, Santa Cruz State University, Ilhéus 45662-900, BA, Brazil; (A.S.S.); (M.Z.); (C.P.P.)
| | | | - Maria Zugaib
- Center for Biotechnology and Genetics, Department of Biological Sciences, Santa Cruz State University, Ilhéus 45662-900, BA, Brazil; (A.S.S.); (M.Z.); (C.P.P.)
| | - Carlos Priminho Pirovani
- Center for Biotechnology and Genetics, Department of Biological Sciences, Santa Cruz State University, Ilhéus 45662-900, BA, Brazil; (A.S.S.); (M.Z.); (C.P.P.)
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Li Q, Zhang Q. MiR-34a and endothelial biology. Life Sci 2023; 330:121976. [PMID: 37495076 DOI: 10.1016/j.lfs.2023.121976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Revised: 07/06/2023] [Accepted: 07/23/2023] [Indexed: 07/28/2023]
Abstract
MicroRNAs (miRNAs) are endogenous ∼22 nt long RNAs that play important gene-regulatory roles in cells by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. Many miRNAs have been identified in endothelial cells and play important roles in endothelial biology. miR-34a is relatively early identified in endothelial cells and has been involved in regulating endothelial functions, angiogenesis, differentiation, senescence, inflammatory response, responses to shear stress, and mitochondrial function. This review outlines the current understanding of miR-34a in endothelial biology and discusses its potential as a therapeutic target to treat vascular diseases.
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Affiliation(s)
- Qiuxia Li
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine and UCLA Health, University of California-Los Angeles, Los Angeles, CA 90095, USA; Division of Cardiovascular Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
| | - Quanjiang Zhang
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine and UCLA Health, University of California-Los Angeles, Los Angeles, CA 90095, USA.
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7
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Marin AM, Batista M, Korte de Azevedo AL, Bombardelli Gomig TH, Soares Caldeira Brant R, Chammas R, Uno M, Dias Araújo D, Zanette DL, Nóbrega Aoki M. Screening of Exosome-Derived Proteins and Their Potential as Biomarkers in Diagnostic and Prognostic for Pancreatic Cancer. Int J Mol Sci 2023; 24:12604. [PMID: 37628784 PMCID: PMC10454563 DOI: 10.3390/ijms241612604] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 07/11/2023] [Accepted: 07/18/2023] [Indexed: 08/27/2023] Open
Abstract
In the oncological area, pancreatic cancer is one of the most lethal diseases, with 5-year survival rising just 10% in high-development countries. This disease is genetically characterized by KRAS as a driven mutation followed by SMAD4, CDKN2, and TP53-associated mutations. In clinical aspects, pancreatic cancer presents unspecific clinical symptoms with the absence of screening and early plasmatic biomarker, being that CA19-9 is the unique plasmatic biomarker having specificity and sensitivity limitations. We analyzed the plasmatic exosome proteomic profile of 23 patients with pancreatic cancer and 10 healthy controls by using Nanoscale liquid chromatography coupled to tandem mass spectrometry (NanoLC-MS/MS). The pancreatic cancer patients were subdivided into IPMN and PDAC. Our findings show 33, 34, and 7 differentially expressed proteins when comparing the IPMN vs. control, PDAC-No treatment vs. control, and PDAC-No treatment vs. IPMN groups, highlighting proteins of the complement system and coagulation, such as C3, APOB, and SERPINA. Additionally, PDAC with no treatment showed 11 differentially expressed proteins when compared to Folfirinox neoadjuvant therapy or Gemcitabine adjuvant therapy. So here, we found plasmatic exosome-derived differentially expressed proteins among cancer patients (IPMN, PDAC) when comparing with healthy controls, which could represent alternative biomarkers for diagnostic and prognostic evaluation, supporting further scientific and clinical studies on pancreatic cancer.
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Affiliation(s)
- Anelis Maria Marin
- Laboratory for Applied Science and Technology in Health, Carlos Chagas Institute, Oswaldo Cruz Foundation (Fiocruz), Curitiba 81350-010, Brazil; (A.M.M.); (M.B.); (D.L.Z.)
| | - Michel Batista
- Laboratory for Applied Science and Technology in Health, Carlos Chagas Institute, Oswaldo Cruz Foundation (Fiocruz), Curitiba 81350-010, Brazil; (A.M.M.); (M.B.); (D.L.Z.)
- Mass Spectrometry Facility RPT02H, Carlos Chagas Institute, Oswaldo Cruz Foundation (Fiocruz), Curitiba 81350-010, Brazil
| | - Alexandre Luiz Korte de Azevedo
- Laboratory of Human Cytogenetics and Oncogenetics, Genetic Department, University of Parana State (UFPR), Curitiba 80060-000, Brazil; (A.L.K.d.A.); (T.H.B.G.)
| | - Talita Helen Bombardelli Gomig
- Laboratory of Human Cytogenetics and Oncogenetics, Genetic Department, University of Parana State (UFPR), Curitiba 80060-000, Brazil; (A.L.K.d.A.); (T.H.B.G.)
| | - Rodrigo Soares Caldeira Brant
- Mass Spectrometry Facility RPT02H, Carlos Chagas Institute, Oswaldo Cruz Foundation (Fiocruz), Curitiba 81350-010, Brazil
| | - Roger Chammas
- Center for Translational Research in Oncology (LIM24), Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (HCFMUSP), Comprehensive Center for Precision Oncology (C2PO), Universidade de São Paulo, São Paulo 05508-220, Brazil; (R.C.); (M.U.); (D.D.A.)
| | - Miyuki Uno
- Center for Translational Research in Oncology (LIM24), Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (HCFMUSP), Comprehensive Center for Precision Oncology (C2PO), Universidade de São Paulo, São Paulo 05508-220, Brazil; (R.C.); (M.U.); (D.D.A.)
| | - Diogo Dias Araújo
- Center for Translational Research in Oncology (LIM24), Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (HCFMUSP), Comprehensive Center for Precision Oncology (C2PO), Universidade de São Paulo, São Paulo 05508-220, Brazil; (R.C.); (M.U.); (D.D.A.)
| | - Dalila Luciola Zanette
- Laboratory for Applied Science and Technology in Health, Carlos Chagas Institute, Oswaldo Cruz Foundation (Fiocruz), Curitiba 81350-010, Brazil; (A.M.M.); (M.B.); (D.L.Z.)
| | - Mateus Nóbrega Aoki
- Laboratory for Applied Science and Technology in Health, Carlos Chagas Institute, Oswaldo Cruz Foundation (Fiocruz), Curitiba 81350-010, Brazil; (A.M.M.); (M.B.); (D.L.Z.)
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Perico D, Tong Y, Chen L, Imamichi S, Sanada Y, Ishiai M, Suzuki M, Masutani M, Mauri P. Proteomic Characterization of SAS Cell-Derived Extracellular Vesicles in Relation to Both BPA and Neutron Irradiation Doses. Cells 2023; 12:1562. [PMID: 37371031 PMCID: PMC10296566 DOI: 10.3390/cells12121562] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 05/22/2023] [Accepted: 06/01/2023] [Indexed: 06/29/2023] Open
Abstract
Boron neutron capture therapy (BNCT) is a selective radiotherapy based on nuclear reaction that occurs when 10B atoms accumulated in cancer cells are irradiated by thermal neutrons, triggering a nuclear fission response leading to cell death. Despite its growing importance in cancer treatment, molecular characterization of its effects is still lacking. In this context, proteomics investigation can be useful to study BNCT effect and identify potential biomarkers. Hence, we performed proteomic analysis with nanoLC-MS/MS (liquid chromatography coupled to tandem mass spectrometry) on extracellular vesicles (EVs) isolated from SAS cultures treated or not with 10B-boronophenylalanine (BPA) and different doses of neutron irradiation, to study the cellular response related to both boron administration and neutrons action. Despite the interference of fetal bovine serum in the medium, we were able to stratify BPA- and BPA+ conditions and to identify EVs-derived proteins characterizing pathways potentially related to a BNCT effect such as apoptosis, DNA repair and inflammatory response. In particular, KLF11, SERPINA1 and SERPINF2 were up-regulated in BPA+, while POLE and SERPINC1 were up-regulated in BPA-. These results provide the first proteomic investigation of EVs treated with BNCT in different conditions and highlight the potentiality of proteomics for improving biomarkers identification and mechanisms understanding of BNCT.
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Affiliation(s)
- Davide Perico
- Institute of Biomedical Technologies ITB-CNR, Via Fratelli Cervi 93, 20054 Segrate, Italy;
| | - Ying Tong
- Department of Molecular and Genomic Biomedicine, Center for Bioinformatics & Molecular Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523, Japan; (Y.T.); (S.I.)
| | - Lichao Chen
- Central Radioisotope Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan; (L.C.); (M.I.)
| | - Shoji Imamichi
- Department of Molecular and Genomic Biomedicine, Center for Bioinformatics & Molecular Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523, Japan; (Y.T.); (S.I.)
- Central Radioisotope Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan; (L.C.); (M.I.)
- Institute for Integrated Radiation and Nuclear Science, Kyoto University, Osaka 590-0494, Japan; (Y.S.); (M.S.)
| | - Yu Sanada
- Institute for Integrated Radiation and Nuclear Science, Kyoto University, Osaka 590-0494, Japan; (Y.S.); (M.S.)
| | - Masamichi Ishiai
- Central Radioisotope Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan; (L.C.); (M.I.)
| | - Minoru Suzuki
- Institute for Integrated Radiation and Nuclear Science, Kyoto University, Osaka 590-0494, Japan; (Y.S.); (M.S.)
| | - Mitsuko Masutani
- Department of Molecular and Genomic Biomedicine, Center for Bioinformatics & Molecular Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523, Japan; (Y.T.); (S.I.)
- Central Radioisotope Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan; (L.C.); (M.I.)
| | - Pierluigi Mauri
- Institute of Biomedical Technologies ITB-CNR, Via Fratelli Cervi 93, 20054 Segrate, Italy;
- Institute of Life Sciences, Sant’Anna School of Advanced Studies, 56127 Pisa, Italy
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9
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Wang X, Huang X, Gao P, Ren Y, Li X, Diao Y. Kallistatin attenuates inflammatory response in rheumatoid arthritis via the NF-κB signaling pathway. Eur J Pharmacol 2023; 943:175530. [PMID: 36690053 DOI: 10.1016/j.ejphar.2023.175530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 01/18/2023] [Accepted: 01/19/2023] [Indexed: 01/22/2023]
Abstract
Cartilage degeneration and inflammation are important features of rheumatoid arthritis (RA). Chondrocyte inflammation and apoptosis have been increasingly demonstrated to be related to cartilage decomposition. In this study, we analyzed the protective role of kallistatin against RA and its associated mechanisms. We obtained in vitro and in vivo RA models using IL-1β and heat-inactivated Mycobacterium tuberculosis, respectively. Our results showed that kallistatin mitigated IL-1β-mediated chondrocyte apoptosis and inhibited the synthesis of ECM-degrading generation, like matrix metalloproteinase (MMP)-3/13 and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4/5, in IL-1β-mediated chondrocytes. Furthermore, kallistatin markedly suppressed IL-1β-mediated inflammation while decreasing the levels of inflammatory factors and mediators via the NF-κB pathway. Daily administration of kallistatin reduced the expression levels of PGE2, TNF-α, IL-1β, and IL-6. Histochemical analysis revealed that the kallistatin-treated rats exhibited reduced RA severity compared with control mice. In summary, kallistatin suppressed IL-1β-mediated inflammation in chondrocytes via the NF-κB pathway. Administration of kallistatin remarkably inhibited RA development, accompanied by reduced inflammation and apoptosis. Therefore, kallistatin administration can be used as a candidate therapeutic strategy for RA.
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Affiliation(s)
- Xiao Wang
- School of Medicine, Huaqiao University, Quanzhou, 362021, China
| | - Xiaoping Huang
- College of Chemical Engineering and Materials Sciences, Quanzhou Normal University, Quanzhou, 326000, China
| | - Pingzhang Gao
- College of Chemical Engineering and Materials Sciences, Quanzhou Normal University, Quanzhou, 326000, China
| | - Yanxuan Ren
- School of Medicine, Huaqiao University, Quanzhou, 362021, China
| | - Xiaokun Li
- School of Medicine, Huaqiao University, Quanzhou, 362021, China
| | - Yong Diao
- School of Medicine, Huaqiao University, Quanzhou, 362021, China.
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10
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Mao Y, Zhan S, Qiao J, Li L, Liu H, Chen R. Kallistatin in follicular fluid of women with endometriosis and its correlation with IVF outcome. Gynecol Endocrinol 2021; 37:1102-1106. [PMID: 34236276 DOI: 10.1080/09513590.2021.1928067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
BACKGROUND Endometriosis (EM) affects 10% women of reproductive age and alters fertility. Its management is still debated notably the timing of surgery and ART in infertility. Kallistatin (KS) is an endogenous protein that regulates differential signaling pathways and biological functions. However, the function and the underlying molecular mechanism in EM and its correlation with in vitro fertilization (IVF) outcome have not been determined. The purpose of this study was to evaluate KS concentrations in follicular fluid (FF) of women with EM and controls women without EM who underwent IVF with embryo transfer (IVF-ET). METHODS FF KS concentrations from 40 patients with EM and 40 non-EM patients were measured by ELISA. RESULTS Compared with the non-EM patients, patients with EM had lower KS levels in FF (281.67 ± 104.60 vs. 490.70 ± 216.33 pg/ml). The rates of fertilization (61.64 ± 22.42 vs. 71.00 ± 24.39%), available embryo (45.96 ± 19.83 vs. 50.61 ± 26.26%), and top-quality embryo (12.71 ± 21.01 vs. 16.04 ± 16.87%) were significantly lower in the EM group than in the control group. The KS concentrations in the FF of women who conceived consequent to the treatment were significantly higher than those from women who did not in the combined EM and control groups. CONCLUSIONS These results indicate that the KS concentration in FF could be used as a predictor for IVF-ET outcomes. This may contribute to the pathologic mechanism responsible for the poor outcome of IVF in patients with EM.
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Affiliation(s)
- Yuling Mao
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China
- Key Laboratory for Reproductive Medicine of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China
| | - Shaoquan Zhan
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China
- Key Laboratory for Reproductive Medicine of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China
| | - JingDa Qiao
- Institute of Neuroscience and Department of Neurology, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China
| | - Lei Li
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China
- Key Laboratory for Reproductive Medicine of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China
| | - Hanyan Liu
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China
- Key Laboratory for Reproductive Medicine of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China
| | - Rui Chen
- Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China
- Key Laboratory for Reproductive Medicine of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China
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11
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Schönborn M, Łączak P, Pasieka P, Borys S, Płotek A, Maga P. Pro- and Anti-Angiogenic Factors: Their Relevance in Diabetic Foot Syndrome-A Review. Angiology 2021; 73:299-311. [PMID: 34541892 DOI: 10.1177/00033197211042684] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Peripheral arterial disease can involve tissue loss in up to 50% of patients with diabetic foot syndrome (DFS). Consequently, revascularization of narrowed or occluded arteries is one of the most common forms of comprehensive treatment. However, technically successful angioplasty does not always result in the healing of ulcers. The pathomechanism of this phenomenon is still not fully understood, but inadequate angiogenesis in tissue repair may play an essential role. Changes in pro- and anti-angiogenic factors among patients with DFS are not always clear and conclusive. In particular, some studies underline the role of decreased concentration of pro-angiogenic factors and higher levels of anti-angiogenic mediators. Nevertheless, there are still controversial issues, including the paradox of impaired wound healing despite high concentrations of some pro-angiogenic factors, dynamics of their expression during the healing process, and their mutual relationships. Exploring this process among diabetic patients may provide new insight into well-known methods of treatment and show their real benefits and chances for improving outcomes.
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Affiliation(s)
- Martyna Schönborn
- Department of Angiology, Faculty of Medicine, 162261Jagiellonian University Medical College, Krakow, Poland.,Doctoral School of Medical and Health Sciences, 162261Jagiellonian University, Krakow, Poland
| | - Patrycja Łączak
- Department of Angiology, Faculty of Medicine, 162261Jagiellonian University Medical College, Krakow, Poland
| | - Paweł Pasieka
- Department of Angiology, Faculty of Medicine, 162261Jagiellonian University Medical College, Krakow, Poland
| | - Sebastian Borys
- Department of Metabolic Diseases, Faculty of Medicine, 162261Jagiellonian University Medical College, Krakow, Poland
| | - Anna Płotek
- Department of Angiology, Faculty of Medicine, 162261Jagiellonian University Medical College, Krakow, Poland
| | - Paweł Maga
- Department of Angiology, Faculty of Medicine, 162261Jagiellonian University Medical College, Krakow, Poland
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12
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Sahar T, Nigam A, Anjum S, Gupta N, Wajid S. Secretome Profiling and Computational Biology of Human Leiomyoma Samples Unravel Molecular Signatures with Potential for Diagnostic and Therapeutic Interventions. Reprod Sci 2021; 28:2672-2684. [PMID: 33905083 DOI: 10.1007/s43032-021-00580-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 04/11/2021] [Indexed: 10/21/2022]
Abstract
In recent years, significant advancements have been made in the way the complex proteome samples are compared but the ultimate goal of routine biomarker discovery has yet to be achieved. Based on reverse genetic strategy, our study involved the spotting of genes showing expressional variability in uterine leiomyoma females. Serum samples were taken from uterine leiomyomas subjects (n=6) and healthy control subjects (n=6) for proteomic studies. Additionally, leiomyoma tissue samples (n=25) and normal myometrium samples (n=25) were taken for validation studies. In this study, we profiled the proteomes of uterine leiomyoma patient's serum and healthy control, along with relative quantification using Nano LC-MS/MS analysis. A total of 146 proteins were reported to be significantly differentially expressed (P value less than 0.05) in case and control sample. Statistical analysis identified a number of molecular signatures distinguishing healthy from diseased serum. Among these, five proteins lumican, ficolin, MASP2, EMSY, and kallistatin were further chosen according to their function for validation. Kallistatin was downregulated while ficolin, MASP2, lumican, and EMSY were found to be upregulated in the diseased sample. The expression modulations in the identified genes were further validated in twenty-five cases. Interactions among the differentially expressed proteins were identified followed with network analysis. Network analysis emphasized important pathways that are highly deregulated in myoma, and functional significance of these pathways in the pathology of the disease was discussed. Comparative expression analysis reveals distinct molecular signatures and their probable role in diagnosis of the disease.
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Affiliation(s)
- Tahreem Sahar
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Aruna Nigam
- Department of Obstetrics and Gynecology, HIMSR and HAH Centenary Hospital, Jamia Hamdard, New Delhi, 110062, India
| | - Shadab Anjum
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Nimisha Gupta
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Saima Wajid
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India.
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13
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Protease nexin-1 deficiency increases mouse hindlimb neovascularisation following ischemia and accelerates femoral artery perfusion. Sci Rep 2021; 11:13412. [PMID: 34183729 PMCID: PMC8238971 DOI: 10.1038/s41598-021-92794-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 06/15/2021] [Indexed: 11/28/2022] Open
Abstract
We previously identified the inhibitory serpin protease nexin-1 (PN-1) as an important player of the angiogenic balance with anti-angiogenic activity in physiological conditions. In the present study, we aimed to determine the role of PN-1 on pathological angiogenesis and particularly in response to ischemia, in the mouse model induced by femoral artery ligation. In wild-type (WT) muscle, we observed an upregulation of PN-1 mRNA and protein after ischemia. Angiography analysis showed that femoral artery perfusion was more rapidly restored in PN-1−/− mice than in WT mice. Moreover, immunohistochemistry showed that capillary density increased following ischemia to a greater extent in PN-1−/− than in WT muscles. Moreover, leukocyte recruitment and IL-6 and MCP-1 levels were also increased in PN-1−/− mice compared to WT after ischemia. This increase was accompanied by a higher overexpression of the growth factor midkine, known to promote leukocyte trafficking and to modulate expression of proinflammatory cytokines. Our results thus suggest that the higher expression of midkine observed in PN-1- deficient mice can increase leukocyte recruitment in response to higher levels of MCP-1, finally driving neoangiogenesis. Thus, PN-1 can limit neovascularisation in pathological conditions, including post-ischemic reperfusion of the lower limbs.
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14
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Qian LL, Ji JJ, Guo JQ, Wu YP, Ma GS, Yao YY. Protective role of serpina3c as a novel thrombin inhibitor against atherosclerosis in mice. Clin Sci (Lond) 2021; 135:447-463. [PMID: 33458764 DOI: 10.1042/cs20201235] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 01/13/2021] [Accepted: 01/18/2021] [Indexed: 12/26/2022]
Abstract
Abnormal vascular smooth muscle cell (VSMC) proliferation is a critical step in the development of atherosclerosis. Serpina3c is a serine protease inhibitor (serpin) that plays a key role in metabolic diseases. The present study aimed to investigate the role of serpina3c in atherosclerosis and regulation of VSMC proliferation and possible mechanisms. Serpina3c is down-regulated during high-fat diet (HFD)-induced atherosclerosis. An Apoe-/-/serpina3c-/--double-knockout mouse model was used to determine the role of serpina3c in atherosclerosis after HFD for 12 weeks. Compared with Apoe-/- mice, the Apoe-/-/serpina3c-/- mice developed more severe atherosclerosis, and the number of VSMCs and macrophages in aortic plaques was significantly increased. The present study revealed serpina3c as a novel thrombin inhibitor that suppressed thrombin activity. In circulating plasma, thrombin activity was high in the Apoe-/-/serpina3c-/- mice, compared with Apoe-/- mice. Immunofluorescence staining showed thrombin and serpina3c colocalization in the liver and aortic cusp. In addition, inhibition of thrombin by dabigatran in serpina3c-/- mice reduced neointima lesion formation due to partial carotid artery ligation. Moreover, an in vitro study confirmed that thrombin activity was also decreased by serpina3c protein, supernatant and cell lysate that overexpressed serpina3c. The results of experiments showed that serpina3c negatively regulated VSMC proliferation in culture. The possible mechanism may involve serpina3c inhibition of ERK1/2 and JNK signaling in thrombin/PAR-1 system-mediated VSMC proliferation. Our results highlight a protective role for serpina3c as a novel thrombin inhibitor in the development of atherosclerosis, with serpina3c conferring protection through the thrombin/PAR-1 system to negatively regulate VSMC proliferation through ERK1/2 and JNK signaling.
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Affiliation(s)
- Ling-Lin Qian
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210009, China
| | - Jing-Jing Ji
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210009, China
| | - Jia-Qi Guo
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210009, China
| | - Yan-Ping Wu
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210009, China
| | - Gen-Shan Ma
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210009, China
| | - Yu-Yu Yao
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210009, China
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15
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Qu W, Zhao J, Wu Y, Xu R, Liu S. Recombinant Adeno-associated Virus 9-mediated Expression of Kallistatin Suppresses Lung Tumor Growth in Mice. Curr Gene Ther 2021; 21:72-80. [PMID: 33183200 DOI: 10.2174/1566523220999201111194257] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 10/22/2020] [Accepted: 10/26/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Lung cancer remains the most common cause of cancer-related deaths in China and worldwide. Traditional surgery and chemotherapy do not offer an effective cure, although gene therapy may be a promising future alternative. Kallistatin (Kal) is an endogenous inhibitor of angiogenesis and tumorigenesis. Recombinant adeno-associated virus (rAAV) is considered the most promising vector for gene therapy of many diseases due to persistent and long-term transgenic expression. OBJECTIVE The aim of this study was to investigate whether rAAV9-Kal inhibited NCI-H446 subcutaneous xenograft tumor growth in mice. METHODS The subcutaneous xenograft mode was induced by subcutaneous injection of 2×107 H446 cells into the dorsal skin of BALB/c nude mice. The mice were administered with ssrAAV9-Kal (single- stranded rAAV9) or dsrAAV9-Kal (double-stranded rAAV9) by intraperitoneal injection (I.P.). Tumor microvessel density (MVD) was examined by anti-CD34 staining to evaluate tumor angiogenesis. RESULTS Compared with the PBS (blank control) group, tumor growth in the high-dose ssrAAV9-Kal group was inhibited by 40% by day 49, and the MVD of tumor tissues was significantly decreased. CONCLUSION The results indicate that this therapeutic strategy is a promising approach for clinical cancer therapy and implicate rAAV9-Kal as a candidate for gene therapy of lung cancer.
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Affiliation(s)
- Weihong Qu
- Department of School of Pharmacy & Life Science, Jiujiang University, Jiujiang, Jiangxi 332000, China
| | - Jianguo Zhao
- Department of School of Pharmacy & Life Science, Jiujiang University, Jiujiang, Jiangxi 332000, China
| | - Yaqing Wu
- Department of School of Pharmacy & Life Science, Jiujiang University, Jiujiang, Jiangxi 332000, China
| | - Ruian Xu
- School of Medicine and Institute of Molecular Medicine, Huaqiao University, Quanzhou, Fujian 361021, China
| | - Shaowu Liu
- Department of School of Pharmacy & Life Science, Jiujiang University, Jiujiang, Jiangxi 332000, China
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16
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Tao QR, Chu YM, Wei L, Tu C, Han YY. Antiangiogenic therapy in diabetic nephropathy: A double‑edged sword (Review). Mol Med Rep 2021; 23:260. [PMID: 33655322 PMCID: PMC7893700 DOI: 10.3892/mmr.2021.11899] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 01/21/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes and the associated complications are becoming a serious global threat and an increasing burden to human health and the healthcare systems. Diabetic nephropathy (DN) is the primary cause of end-stage kidney disease. Abnormal angiogenesis is well established to be implicated in the morphology and pathophysiology of DN. Factors that promote or inhibit angiogenesis serve an important role in DN. In the present review, the current issues associated with the vascular disease in DN are highlighted, and the challenges in the development of treatments are discussed.
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Affiliation(s)
- Qian-Ru Tao
- Department of Nephrology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, P.R. China
| | - Ying-Ming Chu
- Department of Integrated Traditional Chinese Medicine, Peking University First Hospital, Beijing 100034, P.R. China
| | - Lan Wei
- Department of Internal Medicine, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, P.R. China
| | - Chao Tu
- Department of Internal Medicine, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, P.R. China
| | - Yuan-Yuan Han
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, Yunnan 650118, P.R. China
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Al-Asmakh M, Bawadi H, Hamdan M, Gupta I, Kheraldine H, Jabeen A, Rizeq B, Al Moustafa AE. Dasatinib and PD-L1 inhibitors provoke toxicity and inhibit angiogenesis in the embryo. Biomed Pharmacother 2020; 134:111134. [PMID: 33341672 DOI: 10.1016/j.biopha.2020.111134] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Revised: 12/07/2020] [Accepted: 12/10/2020] [Indexed: 12/20/2022] Open
Abstract
Dasatinib is a targeted cancer therapy, while programmed death ligand 1 (PD-L1) inhibitors are a form of immune checkpoint therapy used to treat various types of cancers. Several studies showed the potential efficacy of these drugs in the management of triple-negative breast cancer- an aggressive subtype of breast cancer, which can develop during pregnancy. Nevertheless, side effects of Dasatinib (DA) and PD-L1 drugs during pregnancy, especially in the early stages of embryogenesis are not explored yet. The aim of this study is to assess the individual and combined toxicity of DA and PD-L1 inhibitors during the early stages of embryogenesis and to evaluate their effect(s) on angiogenesis using the chorioallantoic membrane (CAM) model of the embryo. Our results show that embryos die at greater rates after exposure to DA and PD-L1 inhibitors as compared to their matched controls. Moreover, treatment with these drugs significantly inhibits angiogenesis of the CAM. To further elucidate key regulator genes of embryotoxicity induced by the actions of PD-L1 and DA, an RT-PCR analysis was performed for seven target genes that regulate cell proliferation, angiogenesis, and survival (ATF3, FOXA2, MAPRE2, RIPK1, INHBA, SERPINA4, and VEGFC). Our data revealed that these genes are significantly deregulated in the brain, heart, and liver tissues of exposed embryos, compared to matched control tissues. Nevertheless, further studies are necessary to evaluate the effects of these anti breast cancer drugs and elucidate their role during pregnancy.
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Affiliation(s)
- Maha Al-Asmakh
- Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar; Biomedical Research Centre, Qatar University, Doha, P.O. Box 2713, Qatar; Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar.
| | - Hiba Bawadi
- Department of Nutrition, College of Health Sciences, QU Health, Qatar University, P. O. Box 2713, Doha, Qatar.
| | - Munia Hamdan
- Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar; Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar.
| | - Ishita Gupta
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar; College of Medicine, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar.
| | - Hadeel Kheraldine
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar; College of Medicine, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar.
| | - Ayesha Jabeen
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar; College of Medicine, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar.
| | - Balsam Rizeq
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar; College of Medicine, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar.
| | - Ala-Eddin Al Moustafa
- Biomedical Research Centre, Qatar University, Doha, P.O. Box 2713, Qatar; Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar; College of Medicine, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar; Oncology Department, Faculty of Medicine, McGill University, Montreal, QC, Canada.
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18
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Güralp O, Tüten N, Gök K, Hamzaoglu K, Bulut H, Schild-Suhren M, Malik E, Tüten A. Serum kallistatin level is decreased in women with preeclampsia. J Perinat Med 2020; 49:60-66. [PMID: 32866127 DOI: 10.1515/jpm-2020-0142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 07/30/2020] [Indexed: 11/15/2022]
Abstract
OBJECTIVES To evaluate the serum levels of the serine proteinase inhibitor kallistatin in women with preeclampsia (PE). METHODS The clinical and laboratory parameters of 55 consecutive women with early-onset PE (EOPE) and 55 consecutive women with late-onset PE (LOPE) were compared with 110 consecutive gestational age (GA)-matched (±1 week) pregnant women with an uncomplicated pregnancy and an appropriate for gestational age fetus. RESULTS Mean serum kallistatin was significantly lower in women with PE compared to the GA-matched-controls (27.74±8.29 ng/mL vs. 37.86±20.64 ng/mL, p<0.001); in women with EOPE compared to that of women in the control group GA-matched for EOPE (24.85±6.65 ng/mL vs. 33.37±17.46 ng/mL, p=0.002); and in women with LOPE compared to that of women in the control group GA-matched for LOPE (30.87±8.81 ng/mL vs. 42.25±22.67 ng/mL, p=0.002). Mean serum kallistatin was significantly lower in women with EOPE compared to LOPE (24.85±6.65 ng/mL vs. 30.87±8.81 ng/mL, p<0.001). Serum kallistatin had negative correlations with systolic and diastolic blood pressure, creatinine, and positive correlation with GA at sampling and GA at birth. CONCLUSIONS Serum kallistatin levels are decreased in preeclamptic pregnancies compared to the GA-matched-controls. This decrease was also significant in women with EOPE compared to LOPE. Serum kallistatin had negative correlation with systolic and diastolic blood pressure, creatinine and positive correlation with GA at sampling and GA at birth.
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Affiliation(s)
- Onur Güralp
- Carl von Ossietzky Oldenburg University, University Hospital for Gynecology and Obstetrics, Klinikum Oldenburg AöR, Oldenburg, Germany
| | - Nevin Tüten
- Obstetrics and Gynecology, Kanuni Sultan Suleyman Education and Research Hospital, Istanbul, Turkey
| | - Koray Gök
- Obstetrics and Gynecology, Sakarya University, Education and Research Hospital, Sakarya, Turkey
| | - Kübra Hamzaoglu
- Department of Obstetrics and Gynecology, Istanbul Cerrahpasa University, Istanbul, Turkey
| | - Huri Bulut
- Medical Biochemistry Department, Istinye University, Faculty of Medicine, Istanbul, Turkey
| | - Meike Schild-Suhren
- Carl von Ossietzky Oldenburg University, University Hospital for Gynecology and Obstetrics, Klinikum Oldenburg AöR, Oldenburg, Germany
| | - Eduard Malik
- Carl von Ossietzky Oldenburg University, University Hospital for Gynecology and Obstetrics, Klinikum Oldenburg AöR, Oldenburg, Germany
| | - Abdullah Tüten
- Department of Obstetrics and Gynecology, Istanbul Cerrahpasa University, Istanbul, Turkey
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Nijhawan P, Behl T, Khullar G, Pal G, Kandhwal M, Goyal A. HDAC in obesity: A critical insight. ACTA ACUST UNITED AC 2020. [DOI: 10.1016/j.obmed.2020.100212] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Ma L, Wu J, Zheng Y, Shu Z, Wei Z, Sun Y, Carrell RW, Zhou A. Heparin Blocks the Inhibition of Tissue Kallikrein 1 by Kallistatin through Electrostatic Repulsion. Biomolecules 2020; 10:E828. [PMID: 32481593 PMCID: PMC7356578 DOI: 10.3390/biom10060828] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 05/26/2020] [Accepted: 05/26/2020] [Indexed: 11/16/2022] Open
Abstract
Kallistatin, also known as SERPINA4, has been implicated in the regulation of blood pressure and angiogenesis, due to its specific inhibition of tissue kallikrein 1 (KLK1) and/or by its heparin binding ability. The binding of heparin on kallistatin has been shown to block the inhibition of KLK1 by kallistatin but the detailed molecular mechanism underlying this blockade is unclear. Here we solved the crystal structures of human kallistatin and its complex with heparin at 1.9 and 1.8 Å resolution, respectively. The structures show that kallistatin has a conserved serpin fold and undergoes typical stressed-to-relaxed conformational changes upon reactive loop cleavage. Structural analysis and mutagenesis studies show that the heparin binding site of kallistatin is located on a surface with positive electrostatic potential near a unique protruded 310 helix between helix H and strand 2 of β-sheet C. Heparin binding on this site would prevent KLK1 from docking onto kallistatin due to the electrostatic repulsion between heparin and the negatively charged surface of KLK1, thus blocking the inhibition of KLK1 by kallistatin. Replacement of the acidic exosite 1 residues of KLK1 with basic amino acids as in thrombin resulted in accelerated inhibition. Taken together, these data indicate that heparin controls the specificity of kallistatin, such that kinin generation by KLK1 within the microcirculation will be locally protected by the binding of kallistatin to the heparin-like glycosaminoglycans of the endothelium.
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Affiliation(s)
- Lina Ma
- Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (L.M.); (J.W.); (Z.S.); (Z.W.)
| | - Jiawei Wu
- Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (L.M.); (J.W.); (Z.S.); (Z.W.)
| | - Ying Zheng
- Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (L.M.); (J.W.); (Z.S.); (Z.W.)
| | - Zimei Shu
- Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (L.M.); (J.W.); (Z.S.); (Z.W.)
| | - Zhenquan Wei
- Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (L.M.); (J.W.); (Z.S.); (Z.W.)
| | - Yinbiao Sun
- Randall Division of Cell & Molecular Biophysics, Faculty of Life Sciences & Medicine, King’s College London, New Hunt’s House, Guy’s Campus, London SE1 1UL, UK;
| | - Robin W. Carrell
- Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK;
| | - Aiwu Zhou
- Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (L.M.); (J.W.); (Z.S.); (Z.W.)
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21
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Yang Y, He X, Cheng R, Chen Q, Shan C, Chen L, Ma JX. Diabetes-induced upregulation of kallistatin levels exacerbates diabetic nephropathy via RAS activation. FASEB J 2020; 34:8428-8441. [PMID: 32352602 PMCID: PMC7302980 DOI: 10.1096/fj.201903149r] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 03/28/2020] [Accepted: 04/14/2020] [Indexed: 12/14/2022]
Abstract
Kallistatin is an inhibitor of tissue kallikrein and also inhibits the Wnt pathway. Its role in diabetic nephropathy (DN) is uncertain. Here we reported that serum kallistatin levels were significantly increased in diabetic patients with DN compared to those in diabetic patients without DN and healthy controls, and positively correlated with urinary albumin excretion. In addition, renal kallistatin levels were significantly upregulated in mouse models of type 1 (Akita, OVE26) and type 2 diabetes (db/db). To unveil the effects of kallistatin on DN and its underlying mechanism, we crossed transgenic mice overexpressing kallistatin with OVE26 mice (KS‐tg/OVE). Kallistatin overexpression exacerbated albuminuria, renal fibrosis, inflammation, and oxidative stress in diabetes. Kallikrein activity was inhibited while the renin‐angiotensin system (RAS) upregulated in the kidney of KS‐tg/OVE mice compared to WT/OVE mice, suggesting a disturbed balance between the RAS and kallikrein‐kinin systems. As shown by immunostaining of endothelial makers, renal vascular densities were decreased accompanied by increased HIF‐1α and erythropoietin levels in the kidneys of KS‐tg/OVE mice. Taken together, high levels of kallistatin exacerbate DN at least partly by inducing RAS overactivation and hypoxia. The present study demonstrated a positive correlation between kallistatin levels and DN, suggesting a potential biomarker for prognosis of DN.
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Affiliation(s)
- Yanhui Yang
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin, China.,Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Xuemin He
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.,Department of Endocrinology and Metabolism Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Rui Cheng
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Qian Chen
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Chunyan Shan
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin, China
| | - Liming Chen
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin, China
| | - Jian-Xing Ma
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
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22
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Nijhawans P, Behl T, Bhardwaj S. Angiogenesis in obesity. Biomed Pharmacother 2020; 126:110103. [PMID: 32200253 DOI: 10.1016/j.biopha.2020.110103] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 03/03/2020] [Accepted: 03/11/2020] [Indexed: 12/17/2022] Open
Abstract
PURPOSE Angiogenesis is considered as a major progenitor in the progression of obesity. The current manuscript enumerates the extrinsic role of angiogenesis in obesity. RESULT High caloric diet and lack of physical exercise are the most common causes of obesity and related metabolic conditions. A grossly elevated levels of fat in adipose tissue escalate certain complications which further worsen the state of obesity. Enlargement of white adipose tissue (WAT), deposition of fat mass, proliferation of endothelial cells, production of inflammatory cytokines induces the formation of denovo capillaries from parent microvasculature. Also, several intracellular signaling pathways precipitate obesity. Though, angiostatic molecules (endostatin, angiostatin and TNP-470) have been designed to combat obesity and associated complications. CONCLUSION Adipose tissue trigger growth of blood capillaries, and in turn adipose tissue endothelial cells promote pre-adipocyte proliferation. Modulation of angiogenesis and treatment with angiostatic substances may have the potential to impair the progression of obesity.
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Affiliation(s)
- Priya Nijhawans
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
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23
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Liu X, Huang H, Gao Y, Zhou L, Yang J, Li X, Li Y, Zhao H, Su S, Ke C, Pei Z. Visualization of gene therapy with a liver cancer-targeted adeno-associated virus 3 vector. J Cancer 2020; 11:2192-2200. [PMID: 32127946 PMCID: PMC7052912 DOI: 10.7150/jca.39579] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Accepted: 01/03/2020] [Indexed: 12/13/2022] Open
Abstract
Background: To evaluate the feasibility of a self-complementing recombinant adeno-associated virus 3 (scrAAV3) vector targeting liver cancer and non-invasively monitor gene therapy of liver cancer. Materials and methods: An scrAAV3-HSV1-TK-kallistatin (ATK) gene drug was constructed, which contained the herpes virus thymidine kinase (HSV1-TK) reporter gene and human endogenous angiogenesis inhibitor (kallistatin) gene for non-invasive imaging of gene expression. Subcutaneous xenografted tumors of hepatoma in nude mice were generated for positron emission tomography/computed tomography (PET/CT) imaging. The ATK group was injected with the ATK gene through the tail vein, and an imaging agent was injected 2 weeks later. PET/CT imaging was performed at 1 hour after injection of the imaging agent. The control group was injected with phosphate-buffered saline at the same volume as the ATK gene drug. HE staining is used for pathological observation of tumor sections. HSV1-TK and kallistatin expression was identified by immunofluorescence, real-time quantitative PCR, and western blotting. Results: Radioactivity on PET/CT images was significantly higher in the ATK group compared with the control group. 18F-FHBG uptake values of left forelegs in ATK and control groups were 0.591±0.151% and 0.017 ± 0.011% ID/g (n=5), respectively (P<0.05). After injection of the ATK gene drug, mRNA and protein expression of HSV1-TK and kallistatin in subcutaneous xenograft tumors was detected successfully. In vitro analysis demonstrated significant differences in the expression of HSV1-TK and kallistatin between ATK and control groups (P<0.05). Conclusions: The scrAAV3 vector has a strong liver cancer-targeting ability, and the ATK gene drug can be used for targeted and non-invasive monitoring of liver cancer gene therapy.
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Affiliation(s)
- Xusheng Liu
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Hanling Huang
- Health management center, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Yan Gao
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Lumeng Zhou
- Postgraduate Training Base of Taihe Hospital, Jinzhou Medical University, Jinzhou, 121000, China
| | - Jianwei Yang
- Postgraduate Training Base of Taihe Hospital, Jinzhou Medical University, Jinzhou, 121000, China
| | - Xiaohui Li
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Yang Li
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Haiwen Zhao
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Shanchun Su
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Changbin Ke
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Zhijun Pei
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
- Hubei Key Laboratory of WudangLocal Chinese Medicine Research, Shiyan, 442000, China
- Hubei Key Laboratory of Embryonic Stem Cell Research, Shiyan, 442000, China
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24
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Sobhey OM, Jouda AA, Metwally A, Shawky NM, Elkhashab MN. Evaluation of serum kallistatin level as a predictor of esophageal varices in cirrhotic patients. ALEXANDRIA JOURNAL OF MEDICINE 2020. [DOI: 10.1080/20905068.2020.1714191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Affiliation(s)
- Osama M. Sobhey
- Tropical Medicine Department, Faculty of Medicine, Zagazig University and Zagazig University Hospitals, Zagazig, Sharqueya, Egypt
| | - Amal A. Jouda
- Tropical Medicine Department, Faculty of Medicine, Zagazig University and Zagazig University Hospitals, Zagazig, Sharqueya, Egypt
| | - Ashraf Metwally
- Tropical Medicine Department, Faculty of Medicine, Zagazig University and Zagazig University Hospitals, Zagazig, Sharqueya, Egypt
| | - Nagwa M. Shawky
- Clinical Pathology Department, Faculty of Medicine, Zagazig University and Zagazig University Hospitals, Zagazig, Sharqueya, Egypt
| | - Mohammad N. Elkhashab
- Tropical Medicine Department, Faculty of Medicine, Zagazig University and Zagazig University Hospitals, Zagazig, Sharqueya, Egypt
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25
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Wu H, Li R, Zhang Z, Jiang H, Ma H, Yuan C, Sun C, Li Y, Kong B. Kallistatin inhibits tumour progression and platinum resistance in high-grade serous ovarian cancer. J Ovarian Res 2019; 12:125. [PMID: 31884974 PMCID: PMC6935502 DOI: 10.1186/s13048-019-0601-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 12/10/2019] [Indexed: 11/10/2022] Open
Abstract
Ovarian cancer is the most lethal gynaecologic malignancy. Although there are various subtypes of ovarian cancer, high-grade serous ovarian cancer (HGSOC) accounts for 70% of ovarian cancer deaths. Chemoresistance is the primary reason for the unfavourable prognosis of HGSOC. Kallistatin (KAL), also known as SERPINA4, is part of the serpin family. Kallistatin has been discovered to exert multiple effects on angiogenesis, inflammation and tumour progression. However, the roles and clinical significance of kallistatin in HGSOC remain unclear. Here, we showed that kallistatin was significantly downregulated in HGSOC compared to normal fallopian tube (FT) tissues. Low expression of kallistatin was associated with unfavourable prognosis and platinum resistance in HGSOC. Overexpression of kallistatin significantly inhibited proliferation and metastasis, and enhanced platinum sensitivity and apoptosis in ovarian cancer cells. Collectively, these findings demonstrate that kallistatin serves as a prognostic predictor and provide a potential therapeutic target for HGSOC.
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Affiliation(s)
- Huan Wu
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Ji'nan, Shandong, 250012, People's Republic of China.,Shandong Key Laboratory of Gynecologic Oncology, Qilu Hospital of Shandong University, Ji'nan, Shandong, People's Republic of China
| | - Rongrong Li
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Ji'nan, Shandong, 250012, People's Republic of China.,Shandong Key Laboratory of Gynecologic Oncology, Qilu Hospital of Shandong University, Ji'nan, Shandong, People's Republic of China
| | - Zhiwei Zhang
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Ji'nan, Shandong, 250012, People's Republic of China.,Shandong Key Laboratory of Gynecologic Oncology, Qilu Hospital of Shandong University, Ji'nan, Shandong, People's Republic of China
| | - Huiyang Jiang
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Ji'nan, Shandong, 250012, People's Republic of China.,Shandong Key Laboratory of Gynecologic Oncology, Qilu Hospital of Shandong University, Ji'nan, Shandong, People's Republic of China
| | - Hanlin Ma
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Ji'nan, Shandong, 250012, People's Republic of China.,Shandong Key Laboratory of Gynecologic Oncology, Qilu Hospital of Shandong University, Ji'nan, Shandong, People's Republic of China
| | - Cunzhong Yuan
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Ji'nan, Shandong, 250012, People's Republic of China.,Shandong Key Laboratory of Gynecologic Oncology, Qilu Hospital of Shandong University, Ji'nan, Shandong, People's Republic of China
| | - Chenggong Sun
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Ji'nan, Shandong, 250012, People's Republic of China.,Shandong Key Laboratory of Gynecologic Oncology, Qilu Hospital of Shandong University, Ji'nan, Shandong, People's Republic of China
| | - Yingwei Li
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Ji'nan, Shandong, 250012, People's Republic of China.,Shandong Key Laboratory of Gynecologic Oncology, Qilu Hospital of Shandong University, Ji'nan, Shandong, People's Republic of China
| | - Beihua Kong
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Ji'nan, Shandong, 250012, People's Republic of China. .,Shandong Key Laboratory of Gynecologic Oncology, Qilu Hospital of Shandong University, Ji'nan, Shandong, People's Republic of China.
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26
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Feng J, Dong C, Long Y, Mai L, Ren M, Li L, Zhou T, Yang Z, Ma J, Yan L, Yang X, Gao G, Qi W. Elevated Kallikrein-binding protein in diabetes impairs wound healing through inducing macrophage M1 polarization. Cell Commun Signal 2019; 17:60. [PMID: 31182110 PMCID: PMC6558923 DOI: 10.1186/s12964-019-0376-9] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Accepted: 05/22/2019] [Indexed: 12/12/2022] Open
Abstract
Background The accumulation of M1-polarized macrophages and excessive inflammation are important in the pathogenesis of diabetic foot ulcer (DFU). However, the underlying mechanism of DFU pathogenesis and the crucial regulators of DFU are less well known. Our previous study reported that kallikrein-binding protein (KBP), an angiogenesis inhibitor, was significantly upregulated in diabetic patients compared to its levels in controls. The effects of KBP on monocyte chemotaxis and macrophage M1 polarization were elucidated in this study. Methods Plasma KBP levels and monocyte counts were assessed by ELISA and flow cytometry. Wound closure rates in different groups were monitored daily. The phenotype and recruitment of macrophages were measured by real-time PCR, western blot and immunofluorescence assays. The expression of Notch and NF-κB signalling pathway members was determined by the methods mentioned above. ChIP and dual-luciferase reporter gene assays were employed to explore the binding and transcriptional regulation of Hes1 and iNOS. Results We found that plasma KBP levels and circulating monocytes were elevated in diabetic patients compared to those in nondiabetic controls, and both were higher in diabetic patients with DFU than in diabetic patients without DFU. KBP delayed wound healing in normal mice; correspondingly, KBP-neutralizing antibody ameliorated delayed wound healing in diabetic mice. Circulating monocytes and macrophage infiltration in the wound were upregulated in KBP-TG mice compared to those in control mice. KBP promoted the recruitment and M1 polarization of macrophages. Mechanistically, KBP upregulated iNOS by activating the Notch1/RBP-Jκ/Hes1 signalling pathway. Hes1 downregulated CYLD, a negative regulator of NF-κB signalling, and then activated the IKK/IκBα/NF-κB signalling pathway. Conclusions Our findings demonstrate that KBP is the key regulator of excessive inflammation in DFUs and provide a novel target for DFU therapy. Electronic supplementary material The online version of this article (10.1186/s12964-019-0376-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Juan Feng
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China.,School of stomatology and medicine, Foshan University, Foshan, 528000, China
| | - Chang Dong
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China
| | - Yanlan Long
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China
| | - Lifang Mai
- Department of Endocrinology, the Second Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510030, China
| | - Meng Ren
- Department of Endocrinology, the Second Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510030, China
| | - Lingyi Li
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China
| | - Ti Zhou
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China
| | - Zhonghan Yang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China
| | - Jianxing Ma
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Li Yan
- Department of Endocrinology, the Second Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510030, China.
| | - Xia Yang
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. .,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China. .,Guangdong Engineering & Technology Research Center for Gene Manipulation and Biomacromolecular Products, Sun Yat-sen University, Guangzhou, China.
| | - Guoquan Gao
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. .,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China. .,Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
| | - Weiwei Qi
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. .,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China.
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27
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Yao Y, Li B, Liu C, Fu C, Li P, Guo Y, Ma G, Liu N, Chao L, Chao J. Reduced Plasma Kallistatin Is Associated With the Severity of Coronary Artery Disease, and Kallistatin Treatment Attenuates Atherosclerotic Plaque Formation in Mice. J Am Heart Assoc 2018; 7:e009562. [PMID: 30554563 PMCID: PMC6404169 DOI: 10.1161/jaha.118.009562] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Background Kallistatin exerts beneficial effects on organ injury by inhibiting oxidative stress and inflammation. However, the role of kallistatin in atherosclerosis is largely unknown. Here, we investigated the role and mechanisms of kallistatin in patients with coronary artery disease ( CAD ), atherosclerotic plaques of apoE-/- mice, and endothelial activation. Methods and Results Plasma kallistatin levels were analyzed in 453 patients at different stages of CAD . Kallistatin levels were significantly lower in patients with CAD and negatively associated with CAD severity and oxidative stress. Human kallistatin cDNA in an adenoviral vector was injected intravenously into apoE-/- mice after partial carotid ligation, with or without nitric oxide synthase inhibitor (Nω-nitro-L-arginine methyl ester) or sirtuin 1 inhibitor (nicotinamide). Kallistatin gene delivery significantly reduced macrophage deposition, oxidative stress, and plaque volume in the carotid artery, compared with control adenoviral injection. Kallistatin administration increased endothelial nitrous oxide synthase, sirtuin 1, interleukin-10, superoxide dismutase 2, and catalase expression in carotid plaques. The beneficial effects of kallistatin in mice were mitigated by Nω-nitro-L-arginine methyl ester or nicotinamide. Furthermore, human kallistatin protein suppressed tumor necrosis factor-α-induced NADPH oxidase activity and increased endothelial nitrous oxide synthase and sirtuin 1 expression in cultured human endothelial cells. These effects were also abolished by Nω-nitro-L-arginine methyl ester or nicotinamide. Conclusions This was the first study to demonstrate that reduced plasma kallistatin levels in patients are associated with CAD severity and oxidative stress. Kallistatin treatment prevents carotid atherosclerotic plaque formation in mice by stimulating the sirtuin 1/endothelial nitrous oxide synthase pathway. These findings indicate the potential protective effects of kallistatin on atherosclerosis in human subjects and mouse models.
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Affiliation(s)
- Yuyu Yao
- 1 Department of Cardiology Zhongda Hospital Medical School of Southeast University Nanjing China
| | - Bing Li
- 1 Department of Cardiology Zhongda Hospital Medical School of Southeast University Nanjing China
| | - Chang Liu
- 1 Department of Cardiology Zhongda Hospital Medical School of Southeast University Nanjing China
| | - Cong Fu
- 1 Department of Cardiology Zhongda Hospital Medical School of Southeast University Nanjing China
| | - Pengfei Li
- 2 Department of Biochemistry and Molecular Biology Medical University of South Carolina Charleston SC
| | - Youming Guo
- 2 Department of Biochemistry and Molecular Biology Medical University of South Carolina Charleston SC
| | - Genshan Ma
- 1 Department of Cardiology Zhongda Hospital Medical School of Southeast University Nanjing China
| | - Naifeng Liu
- 1 Department of Cardiology Zhongda Hospital Medical School of Southeast University Nanjing China
| | - Lee Chao
- 2 Department of Biochemistry and Molecular Biology Medical University of South Carolina Charleston SC
| | - Julie Chao
- 2 Department of Biochemistry and Molecular Biology Medical University of South Carolina Charleston SC
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Frühbeck G, Gómez-Ambrosi J, Rodríguez A, Ramírez B, Valentí V, Moncada R, Becerril S, Unamuno X, Silva C, Salvador J, Catalán V. Novel protective role of kallistatin in obesity by limiting adipose tissue low grade inflammation and oxidative stress. Metabolism 2018; 87:123-135. [PMID: 29679615 DOI: 10.1016/j.metabol.2018.04.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 03/19/2018] [Accepted: 04/09/2018] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Kallistatin plays an important role in the inhibition of inflammation, oxidative stress, fibrosis and angiogenesis. We aimed to determine the impact of kallistatin on obesity and its associated metabolic alterations as well as its role in adipocyte inflammation and oxidative stress. METHODS Samples obtained from 95 subjects were used in a case-control study. Circulating concentrations and expression levels of kallistatin as well as key inflammation, oxidative stress and extracellular matrix remodelling-related genes were analyzed. Circulating kallistatin concentrations were measured before and after weight loss achieved by Roux-en-Y gastric bypass (RYGB). The impact of kallistatin on lipopolysaccharide (LPS)- and tumour necrosis factor (TNF)-α-mediated inflammatory as well as oxidative stress signalling pathways was evaluated. RESULTS We show that the reduced (P < 0.00001) circulating levels of kallistatin in obese patients increased (P < 0.00001) after RYGB. Moreover, gene expression levels of SERPINA4, the gene coding for kallistatin, were downregulated (P < 0.01) in the liver from obese subjects with non-alcoholic fatty liver disease. Additionally, we revealed that kallistatin reduced (P < 0.05) the expression of inflammation-related genes (CCL2, IL1B, IL6, IL8, TNFA, TGFB) and, conversely, upregulated (P < 0.05) mRNA levels of ADIPOQ and KLF4 in human adipocytes in culture. Kallistatin inhibited (P < 0.05) LPS- and TNF-α-induced inflammation in human adipocytes via downregulating the expression and secretion of key inflammatory markers. Furthermore, kallistatin also blocked (P < 0.05) TNF-α-mediated lipid peroxidation as well as NOX2 and HIF1A expression while stimulating (P < 0.05) the expression of SIRT1 and FOXO1. CONCLUSIONS These findings provide, for the first time, evidence of a novel role of kallistatin in obesity and its associated comorbidities by limiting adipose tissue inflammation and oxidative stress.
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Affiliation(s)
- Gema Frühbeck
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain.
| | - Javier Gómez-Ambrosi
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Amaia Rodríguez
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Beatriz Ramírez
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Víctor Valentí
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Department of Surgery, Clínica Universidad de Navarra, Pamplona, Spain
| | - Rafael Moncada
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Department of Anesthesia, Clínica Universidad de Navarra, Pamplona, Spain
| | - Sara Becerril
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain
| | - Xabier Unamuno
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
| | - Camilo Silva
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain; Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain
| | - Javier Salvador
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain; Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain
| | - Victoria Catalán
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
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Hangul M, Ozturk D, Keti DB, Demirkan FG, Kose M. Plasma Kallistatin Levels in Children with Community-Acquired Pneumonia. PEDIATRIC ALLERGY, IMMUNOLOGY, AND PULMONOLOGY 2018; 31:146-150. [PMID: 36348576 DOI: 10.1089/ped.2017.0854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Purpose: Community-acquired pneumonia (CAP) is a potentially lethal lower respiratory tract infection affecting children all over the world. In this study, we aimed to evaluate plasma kallistatin levels in children at the time of admission and on the fourth day of treatment to determine if this is effective in deciding whether to hospitalize patients and to assess the response to treatment in patients with CAP. Methods: This prospective case/control study was conducted between November 2015 and May 2016 at Erciyes University School of Medicine, in the Department of Paediatric Pulmonology. Fifty-three patients, who were diagnosed with CAP with clinical and radiological findings, were included in the study. The patients were divided into various subgroups such as inpatients, outpatients, those with complications, those without complications, and dead patients. The levels of kallistatin were compared between the control group and the patient group. Results: A total of 53 children with a diagnosis of CAP and 55 healthy children were enrolled in the study. The plasma kallistatin level of CAP patients at admission was significantly higher than that of the control group [1.6 (1.2-2.9) ng/mL], [0.9 (0.7-1.1) ng/mL] (P < 0.001). The patient group was divided into 3 subgroups: those with complications, those with no complications, and those who died. In patients who were hospitalized, who died, and who were in need of mechanical ventilation (MV), kallistatin levels were significantly higher than in the other patients (P = 0.027 for hospitalization; P = 0.022 for exitus; and P = 0.008 for MV) at the time of diagnosis and on the fourth day of treatment. Conclusion: A higher plasma kallistatin level was found to be significant in CAP. Patients with high kallistatin levels should be carefully monitored for hospitalization and for unwanted side effects such as MV need and death.
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Affiliation(s)
- Melih Hangul
- Division of Paediatric Pulmonology, Department of Paediatrics, School of Medicine, Erciyes University, Kayseri, Turkey
| | - Didem Ozturk
- Division of Paediatric Pulmonology, Department of Paediatrics, School of Medicine, Erciyes University, Kayseri, Turkey
| | - Didem Barlak Keti
- Department of Biochemistry Erciyes University School of Medicine, Kayseri, Turkey
| | - Fatma Gül Demirkan
- Division of Paediatric Pulmonology, Department of Paediatrics, School of Medicine, Erciyes University, Kayseri, Turkey
| | - Mehmet Kose
- Division of Paediatric Pulmonology, Department of Paediatrics, School of Medicine, Erciyes University, Kayseri, Turkey
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Ma C, Luo C, Yin H, Zhang Y, Xiong W, Zhang T, Gao T, Wang X, Che D, Fang Z, Li L, Xie J, Huang M, Zhu L, Jiang P, Qi W, Zhou T, Yang Z, Wang W, Ma J, Gao G, Yang X. Kallistatin inhibits lymphangiogenesis and lymphatic metastasis of gastric cancer by downregulating VEGF-C expression and secretion. Gastric Cancer 2018; 21:617-631. [PMID: 29243194 DOI: 10.1007/s10120-017-0787-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 12/04/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Tumor-induced lymphangiogenesis and lymphatic metastasis are predominant during the metastasis of many types of cancers. However, the endogenous inhibitors that counterbalance the lymphangiogenesis and lymphatic metastasis of tumors have not been well evaluated. Kallistatin has been recognized as an endogenous angiogenesis inhibitor. METHODS AND RESULTS Our recent study showed for the first time that the lymphatic vessel density (LVD) was reduced in lung and stomach sections from kallistatin-overexpressing transgenic mice. Kallistatin expresses anti-lymphangiogenic activity by inhibiting the proliferation, migration, and tube formation of human lymphatic endothelial cells (hLECs). Therefore, the present study focuses on the relationships of changes in kallistatin expression with the lymphangiogenesis and lymphatic metastasis of gastric cancer and its underlying mechanisms. Our results revealed that the expression of kallistatin in cancer tissues, metastatic lymph nodes, and plasma of gastric cancer patients was significantly downregulated and that the plasma level of kallistatin was negatively associated with the phase of lymph node metastasis. Furthermore, treatment with kallistatin recombinant protein decreased LVD and lymph node metastases in the implanted gastric xenograft tumors of nude mice. Mechanically, kallistatin suppressed the lymphangiogenesis and lymphatic metastasis by downregulating VEGF-C expression and secretion through the LRP6/IKK/IҡB/NF-ҡB signaling pathway in gastric cancer cells. CONCLUSIONS These findings demonstrated that kallistatin functions as an endogenous lymphangiogenesis inhibitor and has an important part in the lymphatic metastasis of gastric cancer.
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Affiliation(s)
- Caiqi Ma
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Chuanghua Luo
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Haofan Yin
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Yang Zhang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Wenjun Xiong
- Department of Gastrointestinal Surgery, Traditional Chinese Medicine Hospital of Guangdong Province, Guangzhou, China
| | - Ting Zhang
- Department of Clinical Laboratory, Guangzhou First People's Hospital, Guangzhou, China
| | - Tianxiao Gao
- Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510080, China
| | - Xi Wang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Di Che
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Zhenzhen Fang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Lei Li
- Reproductive Medicine Center, the Third Hospital Affiliated to Guangzhou Medical University, Guangzhou, China
| | - Jinye Xie
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Mao Huang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Liuqing Zhu
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Ping Jiang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Weiwei Qi
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Ti Zhou
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Zhonghan Yang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Wei Wang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Jianxing Ma
- Department of Physiology, University of Oklahoma, Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Guoquan Gao
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China. .,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China. .,China Key Laboratory of Tropical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou, 510080, China. .,Department of Biochemistry, Zhongshan Medical School, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China.
| | - Xia Yang
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China. .,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China. .,Guangdong Engineering & Technology Research Center for Gene Manipulation and Biomacromolecular Products, Sun Yat-sen University, Guangzhou, 510080, China. .,Department of Biochemistry, Zhongshan Medical School, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China.
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Cell surface expression of nucleolin mediates the antiangiogenic and antitumor activities of kallistatin. Oncotarget 2017; 9:2220-2235. [PMID: 29416766 PMCID: PMC5788634 DOI: 10.18632/oncotarget.23346] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Accepted: 11/20/2017] [Indexed: 12/26/2022] Open
Abstract
Kallistatin is a unique serine proteinase inhibitor and heparin-binding protein. A previous study conducted by our group indicated that kallistatin has antiangiogenic and antitumoral activities. In the present study, we report that kallistatin specifically binds to membrane surface-expressed nucleolin with high affinity. Antibody-mediated neutralization or siRNA-induced nucleolin knockdown results in loss of kallistatin suppression of endothelial cell proliferation and migration in vitro and tumor angiogenesis and growth in vivo. In addition, we show that kallistatin is internalized and transported into cell nuclei of endothelial cells via nucleolin. Within the nucleus, kallistatin inhibits the phosphorylation of nucleolin, which is a critical step required for cell proliferation. Thus, we demonstrate that nucleolin is a novel functional receptor of kallistatin that mediates its antiangiogenic and antitumor activities. These findings provide mechanistic insights into the inhibitory effects of kallistatin on endothelial cell growth, tumor cell proliferation, and tumor-related angiogenesis.
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Opposing Effects of Oxygen Regulation on Kallistatin Expression: Kallistatin as a Novel Mediator of Oxygen-Induced HIF-1-eNOS-NO Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:5262958. [PMID: 29387292 PMCID: PMC5745740 DOI: 10.1155/2017/5262958] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Accepted: 10/25/2017] [Indexed: 12/03/2022]
Abstract
Oxidative stress has both detrimental and beneficial effects. Kallistatin, a key component of circulation, protects against vascular and organ injury. Serum kallistatin levels are reduced in patients and animal models with hypertension, diabetes, obesity, and cancer. Reduction of kallistatin levels is inversely associated with elevated thiobarbituric acid-reactive substance. Kallistatin therapy attenuates oxidative stress and increases endothelial nitric oxide synthase (eNOS) and NO levels in animal models. However, kallistatin administration increases reactive oxygen species formation in immune cells and bacterial killing activity in septic mice. High oxygen inhibits kallistatin expression via activating the JNK-FOXO1 pathway in endothelial cells. Conversely, mild oxygen/hyperoxia stimulates kallistatin, eNOS, and hypoxia-inducible factor-1 (HIF-1) expression in endothelial cells and in the kidney of normal mice. Likewise, kallistatin stimulates eNOS and HIF-1, and kallistatin antisense RNA abolishes oxygen-induced eNOS and HIF-1 expression, indicating a role of kallistatin in mediating mild oxygen's stimulation on antioxidant genes. Protein kinase C (PKC) activation mediates HIF-1-induced eNOS synthesis in response to hyperoxia/exercise; thus, mild oxygen through PKC activation stimulates kallistatin-mediated HIF-1 and eNOS synthesis. In summary, oxidative stress induces down- or upregulation of kallistatin expression, depending on oxygen concentration, and kallistatin plays a novel role in mediating oxygen/exercise-induced HIF-1-eNOS-NO pathway.
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Chao J, Li P, Chao L. Kallistatin: double-edged role in angiogenesis, apoptosis and oxidative stress. Biol Chem 2017; 398:1309-1317. [DOI: 10.1515/hsz-2017-0180] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Accepted: 07/18/2017] [Indexed: 01/25/2023]
Abstract
AbstractKallistatin, via its two structural elements – an active site and a heparin-binding domain – displays a double-edged function in angiogenesis, apoptosis and oxidative stress. First, kallistatin has both anti-angiogenic and pro-angiogenic effects. Kallistatin treatment attenuates angiogenesis and tumor growth in cancer-bearing mice. Kallistatin via its heparin-binding site inhibits angiogenesis by blocking vascular endothelial growth factor (VEGF)-induced growth, migration and adhesion of endothelial cells. Conversely, kallistatin via the active site promotes neovascularization by stimulating VEGF levels in endothelial progenitor cells. Second, kallistatin inhibits or induces apoptosis depending on cell types. Kallistatin attenuates organ injury and apoptosis in animal models, and its heparin-binding site is essential for blocking tumor necrosis factor (TNF)-α-induced apoptosis in endothelial cells. However, kallistatin via its active site induces apoptosis in breast cancer cells by up-regulating miR-34a and down-regulating miR-21 and miR-203 synthesis. Third, kallistatin can act as an antioxidant or pro-oxidant. Kallistatin treatment inhibits oxidative stress and tissue damage in animal models and cultured cells. Kallistatin via the heparin-binding domain antagonizes TNF-α-induced oxidative stress, whereas its active site is crucial for stimulating antioxidant enzyme expression. In contrast, kallistatin provokes oxidant formation, leading to blood pressure reduction and bacterial killing. Kallistatin-mediated vasodilation is partly mediated by H2O2, as the effect is abolished by the antioxidant enzyme catalase. Moreover, kallistatin exerts a bactericidal effect by stimulating superoxide production in neutrophils of mice with microbial infection as well as in cultured immune cells. Thus, kallistatin’s dual roles in angiogenesis, apoptosis and oxidative stress contribute to its beneficial effects in various diseases.
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34
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Bateman NW, Dubil EA, Wang G, Hood BL, Oliver JM, Litzi TA, Gist GD, Mitchell DA, Blanton B, Phippen NT, Tian C, Zahn CM, Cohn DE, Havrilesky LJ, Berchuck A, Shriver CD, Darcy KM, Hamilton CA, Conrads TP, Maxwell GL. Race-specific molecular alterations correlate with differential outcomes for black and white endometrioid endometrial cancer patients. Cancer 2017; 123:4004-4012. [PMID: 28654152 DOI: 10.1002/cncr.30813] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 04/28/2017] [Accepted: 05/03/2017] [Indexed: 12/16/2022]
Abstract
BACKGROUND The objective of this study was to identify molecular alterations associated with disease outcomes for white and black patients with endometrioid endometrial cancer (EEC). METHODS EEC samples from black (n = 17) and white patients (n = 13) were analyzed by proteomics (liquid chromatography-tandem mass spectrometry) and transcriptomics (RNA-seq). Coordinate alterations were validated with RNA-seq data from black (n = 49) and white patients (n = 216). Concordantly altered candidates were further tested for associations with race-specific progression-free survival (PFS) in black (n = 64) or white patients (n = 267) via univariate and multivariate Cox regression modeling and log-rank testing. RESULTS Discovery analyses revealed significantly altered candidate proteins and transcripts between black and white patients, suggesting modulation of tumor cell viability in black patients and cell death signaling in black and white patients. Eighty-nine candidates were validated as altered between these patient cohorts, and a subset significantly correlated with differential PFS. White-specific PFS candidates included serpin family A member 4 (SERPINA4; hazard ratio [HR], 0.89; Wald P value = .02), integrin subunit α3 (ITGA3; HR, 0.76; P = .03), and Bet1 Golgi vesicular membrane trafficking protein like (BET1L; HR, 0.48; P = .04). Black-specific PFS candidates included family with sequence similarity 228 member B (FAM228B; HR, 0.13; P = .001) and HEAT repeat containing 6 (HEATR6; HR, 4.94; P = .047). Several candidates were also associated with overall survival (SERPINA4 and ITGA3) as well as PFS independent of disease stage, grade and myometrial invasion (SERPINA4, BET1L and FAM228B). CONCLUSIONS This study has identified and validated molecular alterations in tumors from black and white EEC patients, including candidates significantly associated with altered disease outcomes within these patient cohorts. Cancer 2017;123:4004-12. © 2017 American Cancer Society.
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Affiliation(s)
- Nicholas W Bateman
- Gynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, Maryland.,John P. Murtha Cancer Center, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, Maryland
| | - Elizabeth A Dubil
- Gynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, Maryland
| | - Guisong Wang
- Gynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, Maryland
| | - Brian L Hood
- Gynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, Maryland
| | - Julie M Oliver
- Gynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, Maryland
| | - Tracy A Litzi
- Gynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, Maryland
| | - Glenn D Gist
- Gynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, Maryland
| | - David A Mitchell
- Gynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, Maryland
| | - Brian Blanton
- Gynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, Maryland
| | - Neil T Phippen
- Gynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, Maryland
| | - Chunqiao Tian
- Gynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, Maryland
| | | | - David E Cohn
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, College of Medicine, Ohio State University, Columbus, Ohio
| | - Laura J Havrilesky
- Division of Gynecologic Oncology, Duke University Medical Center, Durham, North Carolina
| | - Andrew Berchuck
- Division of Gynecologic Oncology, Duke University Medical Center, Durham, North Carolina
| | - Craig D Shriver
- John P. Murtha Cancer Center, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, Maryland
| | - Kathleen M Darcy
- Gynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, Maryland.,John P. Murtha Cancer Center, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, Maryland
| | - Chad A Hamilton
- Gynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, Maryland.,John P. Murtha Cancer Center, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, Maryland
| | - Thomas P Conrads
- Gynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, Maryland.,John P. Murtha Cancer Center, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, Maryland.,Inova Schar Cancer Institute, Inova Center for Personalized Health, Falls Church, Virginia
| | - G Larry Maxwell
- Gynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, Maryland.,John P. Murtha Cancer Center, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, Maryland.,Inova Schar Cancer Institute, Inova Center for Personalized Health, Falls Church, Virginia.,Department of Obstetrics and Gynecology, Inova Fairfax Medical Campus, Falls Church, Virginia
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Role of Kallistatin Treatment in Aging and Cancer by Modulating miR-34a and miR-21 Expression. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:5025610. [PMID: 28744338 PMCID: PMC5506461 DOI: 10.1155/2017/5025610] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 05/17/2017] [Indexed: 12/19/2022]
Abstract
Kallistatin is an endogenous protein that regulates differential signaling pathways and a wide spectrum of biological activities via its two structural elements: an active site and a heparin-binding domain. Kallistatin via its heparin-binding site inhibits vascular inflammation and oxidative stress by antagonizing TNF-α-induced NADPH oxidase activity, NF-κB activation, and inflammatory gene expression in endothelial cells. Moreover, kallistatin via its active site inhibits microRNA-34a (miR-34a) synthesis and stimulates eNOS and SIRT1 expression in endothelial progenitor cells, whereas its heparin-binding site is crucial for blocking TNF-α-induced miR-21 expression and oxidative stress, thus reducing cellular senescence. By downregulating miR-34a and miR-21 expression, kallistatin treatment attenuates oxidative damage and aortic senescence in streptozotocin-induced diabetic mice and extends Caenorhabditis elegans lifespan under stress conditions. Likewise, kallistatin through the heparin-binding site inhibits TGF-β-induced miR-21 synthesis and oxidative stress in endothelial cells, resulting in inhibition of endothelial-mesenchymal transition, a process contributing to fibrosis and cancer. Furthermore, kallistatin's active site is essential for stimulating miR-34a and p53 expression and inhibiting the miR-21-Akt-Bcl-2 signaling pathway, thus inducing apoptosis in breast cancer cells. These findings reveal novel mechanisms of kallistatin in protection against senescence, aging, and cancer development by modulating miR-34a and miR-21 levels and inhibiting oxidative stress.
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Lin WC, Chen CW, Chao L, Chao J, Lin YS. Plasma kallistatin in critically ill patients with severe sepsis and septic shock. PLoS One 2017; 12:e0178387. [PMID: 28542440 PMCID: PMC5443576 DOI: 10.1371/journal.pone.0178387] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Accepted: 05/14/2017] [Indexed: 02/03/2023] Open
Abstract
Kallistatin, an endogenous serine proteinase inhibitor, is protective against sepsis in animal models. The aim of this study was to determine the plasma concentration of kallistatin in intensive care unit (ICU) patients with severe sepsis and septic shock and to determine their potential correlation with disease severity and outcomes. We enrolled 86 ICU patients with severe sepsis and septic shock. Their plasma concentrations of kallistatin, kallikrein, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 were measured by enzyme-linked immunosorbent assay. The association of kallistatin levels with disease severity and patient outcomes was evaluated. The relationship between kallistatin and other biomarkers was also analyzed. Plasma kallistatin levels on day 1 of ICU admission were lower in patients with septic shock compared with patients with severe sepsis (p = 0.004). Twenty-nine patients who died in the hospital had significantly lower day 1 kallistatin levels than patients who survived (p = 0.031). Using the optimal cutoff value (4 μg/ml) of day 1 plasma kallistatin determined by receiver operating characteristic curves for 60-day mortality, we found that high kallistatin levels were associated with a preferable 60-day survival (p = 0.012) by Kaplan-Meier analysis and lower Sequential Organ Failure Assessment (SOFA) scores over the first 5 days in the ICU (p = 0.001). High kallistatin levels were also independently associated with a decreased risk of septic shock, the development of acute respiratory distress syndrome, and positive blood cultures. In addition, there were inverse correlations between day 1 kallistatin levels and the levels of TNF-α, IL-1β, IL-6, and C-reactive protein, and SOFA scores on day 1. Our results indicate that during severe sepsis and septic shock, a decrease in plasma concentrations of kallistatin reflects increased severity and poorer outcome of disease.
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Affiliation(s)
- Wei-Chieh Lin
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chang-Wen Chen
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Lee Chao
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, United States of America
| | - Julie Chao
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, United States of America
| | - Yee-Shin Lin
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan
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Gateva A, Assyov Y, Velikova T, Kamenov Z. Increased kallistatin levels in patients with obesity and prediabetes compared to normal glucose tolerance. Endocr Res 2017; 42:163-168. [PMID: 28406338 DOI: 10.1080/07435800.2017.1286671] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Accepted: 01/21/2017] [Indexed: 02/08/2023]
Abstract
PURPOSE Kallistatin is a member of serine protease inhibitors (SERPIN) family, which has various functions such as regulation of cardiovascular function and blood vessels development. Its levels are elevated in patients with type 1 and type 2 diabetes with chronic diabetic complications. The aim of the present study was to compare serum kallistatin levels between obese subjects with prediabetes and with normal glucose tolerance. METHODS In this study we included 80 subjects at mean age of 50.4 ± 10.6 years, divided into two age and BMI-matched groups - group 1 with obesity without glycemic disturbances (n = 41) and group 2 with obesity and prediabetes (n = 39). Oral glucose tolerance test with measurement of immunoreactive insulin was performed in all participants and levels of kallistatin were measured using ELISA method. RESULTS We found significantly higher levels of kallistatin in patients with prediabetes compared to controls (data are presented as median (min; max) because data were not normally distributed) (6.3 (4.4; 9.0) vs. 5.6 (3.1; 8.7) ng/ml; p = 0.022) and in patients with metabolic syndrome compared to those without (6.0 (4.9; 9.0) vs. 5.5 (3.1; 7.7); p = 0.006), but the levels were similar in patients with and without insulin resistance. CONCLUSIONS The levels of kallistatin are higher in individuals with prediabetes, but are similar in subjects with and without insulin resistance, which indicates that the main factor for its increased levels may be hyperglycemia and not insulin sensitivity state.
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Affiliation(s)
- Antoaneta Gateva
- a Clinic of Endocrinology, University Hospital "Alexandrovska" , Department of Internal Diseases, Medical University - Sofia , Sofia , Bulgaria
| | - Yavor Assyov
- a Clinic of Endocrinology, University Hospital "Alexandrovska" , Department of Internal Diseases, Medical University - Sofia , Sofia , Bulgaria
| | - Tsvetelina Velikova
- b Laboratory of Clinical Immunology, University Hospital "St. Ivan Rilski" , Department of Clinical Laboratory and Clinical Immunology, Medical University - Sofia , Sofia , Bulgaria
| | - Zdravko Kamenov
- a Clinic of Endocrinology, University Hospital "Alexandrovska" , Department of Internal Diseases, Medical University - Sofia , Sofia , Bulgaria
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Chao J, Li P, Chao L. Kallistatin suppresses cancer development by multi-factorial actions. Crit Rev Oncol Hematol 2017; 113:71-78. [PMID: 28427524 PMCID: PMC5441310 DOI: 10.1016/j.critrevonc.2017.03.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 02/17/2017] [Accepted: 03/11/2017] [Indexed: 01/07/2023] Open
Abstract
Kallistatin was first identified in human plasma as a tissue kallikrein-binding protein and a serine proteinase inhibitor. Kallistatin via its two structural elements regulates differential signaling cascades, and thus a wide spectrum of biological functions. Kallistatin's active site is essential for: inhibiting tissue kallikrein's activity; stimulating endothelial nitric oxide synthase and sirtuin 1 expression and activation; and modulating the synthesis of the microRNAs, miR-34a, miR-21 and miR-203. Kallistatin's heparin-binding site is crucial for antagonizing the signaling pathways of vascular endothelial growth factor, tumor necrosis factor-α, Wnt, transforming growth factor-β and epidermal growth factor. Circulating kallistatin levels are markedly reduced in patients with prostate and colon cancer. Kallistatin administration attenuates angiogenesis, inflammation, tumor growth and invasion in animal models and cultured cells. Therefore, tumor progression may be substantially suppressed by kallistatin's pleiotropic activities. In this review, we will discuss the role and mechanisms of kallistatin in the regulation of cancer development.
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Affiliation(s)
- Julie Chao
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.
| | - Pengfei Li
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
| | - Lee Chao
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
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Ma C, Yin H, Zhong J, Zhang Y, Luo C, Che D, Fang Z, Li L, Qin S, Liang J, Qi W, Yang Z, Zhou T, Ma J, Yang X, Gao G. Kallistatin exerts anti-lymphangiogenic effects by inhibiting lymphatic endothelial cell proliferation, migration and tube formation. Int J Oncol 2017; 50:2000-2010. [PMID: 28440474 PMCID: PMC5435323 DOI: 10.3892/ijo.2017.3972] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2017] [Accepted: 04/10/2017] [Indexed: 12/24/2022] Open
Abstract
Kallistatin has been recognized as an endogenous angiogenic inhibitor. However, its effects on lymphatic endothelial cells and lymphangiogenesis remain poorly understood. Lymphangiogenesis is involved in tumor metastasis via the lymphatic vasculature in various types of tumors. The aim of this study was to investigate the effects of kallistatin on lymphangiogenesis and the mechanism of action involved. Treatment with kallistatin recombinant protein or overexpression of kallistatin inhibited the proliferation, migration and tube formation of human lymphatic endothelial cells (hLECs), and induced apoptosis of hLECs. Furthermore, our results showed that the lymphatic vessel density (LVD) was reduced in lung and stomach sections from kallistatin-overexpressing transgenic mice. Treatment with kallistatin recombinant protein decreased the LVD in the implanted gastric xenograft tumors of nude mice. To the best of our knowledge, the present study is the first to demonstrate that kallistatin possesses anti-lymphangiogenic activity in vitro and in vivo. Moreover, kallistatin inhibited proliferation and migration of hLECs by reducing the phosphorylation of ERK and Akt, respectively. These findings suggested that kallistatin may be a promising agent that could be used to suppress cancer metastasis by inhibiting both angiogenesis and lymphangiogenesis.
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Affiliation(s)
- Caiqi Ma
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Haofan Yin
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Jun Zhong
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Yang Zhang
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Chuanghua Luo
- Department of Biochemistry, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Di Che
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Zhenzhen Fang
- Department of Biochemistry, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Lei Li
- Reproductive Center, The Third Hospital Affiliated to Guangzhou Medical University, Guangzhou, Guangdong 510150, P.R. China
| | - Shuxing Qin
- Department of Biochemistry, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Jieying Liang
- Department of Biochemistry, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Weiwei Qi
- Department of Biochemistry, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Zhonghan Yang
- Department of Biochemistry, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Ti Zhou
- Department of Biochemistry, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Jianxing Ma
- Department of Physiology, University of Oklahoma, Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Xia Yang
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Guoquan Gao
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
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Yiu WH, Wong DWL, Wu HJ, Li RX, Yam I, Chan LYY, Leung JCK, Lan HY, Lai KN, Tang SCW. Kallistatin protects against diabetic nephropathy in db/db mice by suppressing AGE-RAGE-induced oxidative stress. Kidney Int 2017; 89:386-98. [PMID: 26536000 DOI: 10.1038/ki.2015.331] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Revised: 09/05/2015] [Accepted: 09/10/2015] [Indexed: 01/03/2023]
Abstract
Kallistatin is a serine protease inhibitor with anti-inflammatory, anti-angiogenic, and anti-oxidative properties. Since oxidative stress plays a critical role in the pathogenesis of diabetic nephropathy, we studied the effect and mechanisms of action of kallistatin superinduction. Using ultrasound-microbubble-mediated gene transfer, kallistatin overexpression was induced in kidney tubules. In db/db mice, kallistatin overexpression reduced serum creatinine and BUN levels, ameliorated glomerulosclerosis and tubulointerstitial injury, and attenuated renal fibrosis by inhibiting TGF-β signaling. Additionally, downstream PAI-1 and collagens I and IV expression were reduced and kallistatin partially suppressed renal inflammation by inhibiting NF-κB signaling and decreasing tissue kallikrein activity. Kallistatin lowered blood pressure and attenuated oxidative stress as evidenced by suppressed levels of NADPH oxidase 4, and oxidative markers (nitrotyrosine, 8-hydroxydeoxyguanosine, and malondialdehyde) in diabetic renal tissue. Kallistatin also inhibited RAGE expression in the diabetic kidney and AGE-stimulated cultured proximal tubular cells. Reduced AGE-induced reactive oxygen species generation reflected an anti-oxidative mechanism via the AGE-RAGE-reactive oxygen species axis. These results indicate a renoprotective role of kallistatin against diabetic nephropathy by multiple mechanisms including suppression of oxidative stress, anti-fibrotic and anti-inflammatory actions, and blood pressure lowering.
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Wang G, Wang X, Huang X, Yang H, Pang S, Xie X, Zeng S, Lin J, Diao Y. Inhibition of integrin β3, a binding partner of kallistatin, leads to reduced viability, invasion and proliferation in NCI-H446 cells. Cancer Cell Int 2016; 16:90. [PMID: 27980455 PMCID: PMC5134261 DOI: 10.1186/s12935-016-0365-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Accepted: 11/23/2016] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Kallistatin is a serine proteinase inhibitor and heparin-binding protein. It is considered an endogenous angiogenic inhibitor. In addition, multiple studies demonstrated that kallistatin directly inhibits cancer cell growth. However, the molecular mechanisms underlying these effects remain unclear. METHODS Pull-down, immunoprecipitation, and immunoblotting were used for binding experiments. To elucidate the mechanisms, integrin β3 knockdown (siRNA) or blockage (antibody treatment) on the cell surface of small the cell lung cancer NCI-H446 cell line was used. RESULTS Interestingly, kallistatin was capable of binding integrin β3 on the cell surface of NCI-H446 cells. Meanwhile, integrin β3 knockdown or blockage resulted in loss of antitumor activities induced by kallistatin. Furthermore, kallistatin suppressed tyrosine phosphorylation of integrin β3 and its downstream signaling pathways, including FAK/-Src, AKT and Erk/MAPK. Viability, proliferation and migration of NCI-H446 cells were inhibited by kallistatin, with Bcl-2 and Grb2 downregulation, and Bax, cleaved caspase-9 and caspase 3 upregulation. CONCLUSIONS These findings reveal a novel role for kallistatin in preventing small cell lung cancer growth and mobility, by direct interaction with integrin β3, leading to blockade of the related signaling pathway.
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Affiliation(s)
- Guoquan Wang
- Institute of Molecular Medicine, Huaqiao University, Quanzhou, 362021 China
| | - Xiao Wang
- Institute of Molecular Medicine, Huaqiao University, Quanzhou, 362021 China
| | - Xiaoping Huang
- Institute of Molecular Medicine, Huaqiao University, Quanzhou, 362021 China.,College of Chemical Engineering and Materials Sciences, Quanzhou Normal University, Quanzhou, 326000 China.,School of Chemistry and Chemical Engineering of Guangxi Normal University, Guilin, 541004 China
| | - Huiyong Yang
- Institute of Molecular Medicine, Huaqiao University, Quanzhou, 362021 China
| | - Suqiu Pang
- Institute of Molecular Medicine, Huaqiao University, Quanzhou, 362021 China
| | - Xiaolan Xie
- College of Chemical Engineering and Materials Sciences, Quanzhou Normal University, Quanzhou, 326000 China
| | - Shulan Zeng
- School of Chemistry and Chemical Engineering of Guangxi Normal University, Guilin, 541004 China
| | - Junsheng Lin
- Institute of Molecular Medicine, Huaqiao University, Quanzhou, 362021 China
| | - Yong Diao
- Institute of Molecular Medicine, Huaqiao University, Quanzhou, 362021 China
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Wang T, Shi F, Wang J, Liu Z, Su J. Kallistatin Suppresses Cell Proliferation and Invasion and Promotes Apoptosis in Cervical Cancer Through Blocking NF-κB Signaling. Oncol Res 2016; 25:809-817. [PMID: 27983915 PMCID: PMC7841074 DOI: 10.3727/096504016x14799180778233] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Kallistatin has been recognized as an endogenous angiogenesis inhibitor and exerts pleiotropic effects in inhibiting tumor growth, migration, apoptosis, and inflammation. The purpose of the present study was to investigate the potential role and mechanisms of kallistatin in cervical cancer. We demonstrated that kallistatin effectively inhibited cell proliferation and enhanced apoptosis in a dose-dependent manner. Additionally, kallistatin suppressed migration and invasion activities and markedly reduced the expression of matrix-degrading metalloproteinases, progelatinase (MMP-2), MMP-9, and urokinase-type PA (uPA). Kallistatin reversed the epithelial-mesenchymal transition (EMT) and caused the upregulation of epithelial markers such as E-cadherin and inhibited mesenchymal markers such as N-cadherin and vimentin. Moreover, kallistatin led to a marked decrease in the expression of vascular endothelial growth factor (VEGF) and HIF-1α. In a xenograft mouse model, kallistatin treatment reduced tumor growth. Importantly, kallistatin strikingly impeded NF-κB activation by suppressing IκBα degradation and the level of phosphorylation of p65. Interestingly, similar to kallistatin, treatment with PDTC (an inhibitor of NF-κB) also attenuated cell invasion and migration. Taken together, these findings suggest that kallistatin suppresses cervical cancer cell proliferation, migration, and EMT and promotes cell apoptosis by blocking the NF-κB signaling pathway, suggesting that kallistatin may be a novel therapeutic target for cervical cancer treatment.
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Li J, Krishna SM, Golledge J. The Potential Role of Kallistatin in the Development of Abdominal Aortic Aneurysm. Int J Mol Sci 2016; 17:ijms17081312. [PMID: 27529213 PMCID: PMC5000709 DOI: 10.3390/ijms17081312] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 07/29/2016] [Accepted: 08/05/2016] [Indexed: 02/06/2023] Open
Abstract
Abdominal aortic aneurysm (AAA) is a vascular condition that causes permanent dilation of the abdominal aorta, which can lead to death due to aortic rupture. The only treatment for AAA is surgical repair, and there is no current drug treatment for AAA. Aortic inflammation, vascular smooth muscle cell apoptosis, angiogenesis, oxidative stress and vascular remodeling are implicated in AAA pathogenesis. Kallistatin is a serine proteinase inhibitor, which has been shown to have a variety of functions, potentially relevant in AAA pathogenesis. Kallistatin has been reported to have inhibitory effects on tumor necrosis factor alpha (TNF-α) signaling induced oxidative stress and apoptosis. Kallistatin also inhibits vascular endothelial growth factor (VEGF) and Wnt canonical signaling, which promote inflammation, angiogenesis, and vascular remodeling in various pre-clinical experimental models. This review explores the potential protective role of kallistatin in AAA pathogenesis.
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Affiliation(s)
- Jiaze Li
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, 4811 Townsville, Australia.
| | - Smriti Murali Krishna
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, 4811 Townsville, Australia.
| | - Jonathan Golledge
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, 4811 Townsville, Australia.
- Department of Vascular and Endovascular Surgery, The Townsville Hospital, 4811 Townsville, Australia.
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Affiliation(s)
- Julie Chao
- From the Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston (J.C., L.C.); and Division of Molecular Biology and Biochemistry, University of Missouri-Kansas City (G.B.).
| | - Grant Bledsoe
- From the Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston (J.C., L.C.); and Division of Molecular Biology and Biochemistry, University of Missouri-Kansas City (G.B.)
| | - Lee Chao
- From the Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston (J.C., L.C.); and Division of Molecular Biology and Biochemistry, University of Missouri-Kansas City (G.B.)
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Role of heparin and non heparin binding serpins in coagulation and angiogenesis: A complex interplay. Arch Biochem Biophys 2016; 604:128-42. [PMID: 27372899 DOI: 10.1016/j.abb.2016.06.018] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 05/23/2016] [Accepted: 06/27/2016] [Indexed: 12/21/2022]
Abstract
Pro-coagulant, anti-coagulant and fibrinolytic pathways are responsible for maintaining hemostatic balance under physiological conditions. Any deviation from these pathways would result in hypercoagulability leading to life threatening diseases like myocardial infarction, stroke, portal vein thrombosis, deep vein thrombosis (DVT) and pulmonary embolism (PE). Angiogenesis is the process of sprouting of new blood vessels from pre-existing ones and plays a critical role in vascular repair, diabetic retinopathy, chronic inflammation and cancer progression. Serpins; a superfamily of protease inhibitors, play a key role in regulating both angiogenesis and coagulation. They are characterized by the presence of highly conserved secondary structure comprising of 3 β-sheets and 7-9 α-helices. Inhibitory role of serpins is modulated by binding to cofactors, specially heparin and heparan sulfate proteoglycans (HSPGs) present on cell surfaces and extracellular matrix. Heparin and HSPGs are the mainstay of anti-coagulant therapy and also have therapeutic potential as anti-angiogenic inhibitors. Many of the heparin binding serpins that regulate coagulation cascade are also potent inhibitors of angiogenesis. Understanding the molecular mechanism of the switch between their specific anti-coagulant and anti-angiogenic role during inflammation, stress and regular hemostasis is important. In this review, we have tried to integrate the role of different serpins, their interaction with cofactors and their interplay in regulating coagulation and angiogenesis.
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Meta-markers for the differential diagnosis of lung cancer and lung disease. J Proteomics 2016; 148:36-43. [PMID: 27168012 DOI: 10.1016/j.jprot.2016.04.052] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Revised: 04/07/2016] [Accepted: 04/28/2016] [Indexed: 11/22/2022]
Abstract
UNLABELLED Misdiagnosis of lung cancer remains a serious problem due to the difficulty of distinguishing lung cancer from other respiratory lung diseases. As a result, the development of serum-based differential diagnostic biomarkers is in high demand. In this study, 198 clinical serum samples from non-cancer lung disease and lung cancer patients were analyzed using nLC-MRM-MS for the levels of seven lung cancer biomarker candidates. When the candidates were assessed individually, only SERPINEA4 showed statistically significant changes in the serum levels. The MRM results and clinical information were analyzed using a logistic regression analysis to select model for the best 'meta-marker', or combination of biomarkers for differential diagnosis. Also, under consideration of statistical interaction, variables having low significance as a single factor but statistically influencing on meta-marker model were selected. Using this probabilistic classification, the best meta-marker was determined to be made up of two proteins SERPINA4 and PON1 with age factor. This meta-marker showed an enhanced differential diagnostic capability (AUC=0.915) for distinguishing the two patient groups. Our results suggest that a statistical model can determine optimal meta-markers, which may have better specificity and sensitivity than a single biomarker and thus improve the differential diagnosis of lung cancer and lung disease patients. BIOLOGICAL SIGNIFICANCE Diagnosing lung cancer commonly involves the use of radiographic methods. However, an imaging-based diagnosis may fail to differentiate lung cancer from non-cancerous lung disease. In this study, we examined several serum proteins in the sera of 198 lung cancer and non-cancerous lung disease patients by multiple-reaction monitoring. We then used a combination of variables to generate a meta-marker model that is useful as a differential diagnostic biomarker.
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Li P, Guo Y, Bledsoe G, Yang Z, Chao L, Chao J. Kallistatin induces breast cancer cell apoptosis and autophagy by modulating Wnt signaling and microRNA synthesis. Exp Cell Res 2016; 340:305-14. [PMID: 26790955 DOI: 10.1016/j.yexcr.2016.01.004] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Revised: 12/02/2015] [Accepted: 01/10/2016] [Indexed: 01/07/2023]
Abstract
Kallistatin is an endogenous protein that regulates differential signaling pathways and biological functions. Our previous studies showed that kallistatin gene therapy inhibited angiogenesis, tumor growth and metastasis in mice, and kallistatin protein suppressed Wnt-mediated growth, migration and invasion by blocking Wnt/β-catenin signaling pathway in breast cancer cells. In this study, we show that kallistatin reduced cell viability, and increased apoptotic cell death and caspase-3 activity in MDA-MB-231 breast cancer cells. Kallistatin also induced cancer cell autophagy, as evidenced by increased LC3B levels and elevated Atg5 and Beclin-1 expression; however, co-administration of Wnt or PPARγ antagonist GW9662 abolished these effects. Moreover, kallistatin via its heparin-binding site antagonized Wnt3a-induced cancer cell proliferation and increased PPARγ expression. Kallistatin inhibited oncogenic miR-21 synthesis associated with reduced Akt phosphorylation and Bcl-2 synthesis, but increased BAX expression. Kallistatin via PKC-ERK activation reduced miR-203 levels, leading to increased expression of suppressor of cytokine signaling 3 (SOCS3), a tumor suppressor. Conversely, kallistatin stimulated expression of the tumorigenic suppressors miR-34a and p53. Kallistatin's active site is essential for suppressing miR-21 and miR-203, and stimulating miR-34a and SOCS3 expression. This is the first study to demonstrate that kallistatin's heparin-binding site is essential for inhibiting Wnt-mediated effects, and its active site plays a key role in regulating miR-21, miR-203, miR-34a and SOCS3 synthesis in breast cancer cells. These findings reveal novel mechanisms of kallistatin in inducing apoptosis and autophagy in breast cancer cells, thus inhibiting tumor progression by regulation of Wnt/PPARγ signaling, as well as miR-21, miR-203 and miR-34a synthesis.
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Affiliation(s)
- Pengfei Li
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, United States
| | - Youming Guo
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, United States
| | - Grant Bledsoe
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, United States
| | - Zhirong Yang
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, United States
| | - Lee Chao
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, United States
| | - Julie Chao
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, United States.
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Lin WC, Chen CW, Huang YW, Chao L, Chao J, Lin YS, Lin CF. Kallistatin protects against sepsis-related acute lung injury via inhibiting inflammation and apoptosis. Sci Rep 2015. [PMID: 26198099 PMCID: PMC4510498 DOI: 10.1038/srep12463] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Kallistatin, an endogenous plasma protein, exhibits pleiotropic properties in inhibiting inflammation, oxidative stress and apoptosis, as evidenced in various animal models and cultured cells. Here, we demonstrate that kallistatin levels were positively correlated with the concentration of total protein in bronchoalveolar lavage fluids (BALF) from patients with sepsis-related acute respiratory distress syndrome (ARDS), indicating a compensatory mechanism. Lower ratio of kallistatin to total protein in BALF showed a significant trend toward elevated neutrophil counts (P = 0.002) in BALF and increased mortality (P = 0.046). In lipopolysaccharide (LPS)-treated mice, expression of human kallistatin in lung by gene transfer with human kallistatin-encoding plasmid ameliorated acute lung injury (ALI) and reduced cytokine/chemokine levels in BALF. These mice exhibited attenuated lung epithelial apoptosis and decreased Fas/FasL expression compared to the control mice. Mouse survival was improved by kallistatin gene transfer or recombinant human kallistatin treatment after LPS challenge. In LPS-stimulated A549 human lung epithelial cells, kallistatin attenuated apoptosis, down-regulated Fas/FasL signaling, suppressed intracellular reactive oxygen species (ROS) and inhibited ROS-mediated NF-κB activation and inflammation. Furthermore, LPS-induced apoptosis was blocked by antioxidant N-acetylcysteine or NF-κB inhibitor via down-regulating Fas expression. These findings suggest the therapeutic potential of kallistatin for sepsis-related ALI/ARDS.
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Affiliation(s)
- Wei-Chieh Lin
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chang-Wen Chen
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yu-Wen Huang
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Lee Chao
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Julie Chao
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Yee-Shin Lin
- 1] Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan [2] Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan
| | - Chiou-Feng Lin
- 1] Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan [2] Department of Microbiology and Immunology, College of Medicine, Taipei Medical University, Taipei, Taiwan
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Kallistatin ameliorates influenza virus pathogenesis by inhibition of kallikrein-related peptidase 1-mediated cleavage of viral hemagglutinin. Antimicrob Agents Chemother 2015; 59:5619-30. [PMID: 26149981 DOI: 10.1128/aac.00065-15] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Accepted: 06/18/2015] [Indexed: 12/30/2022] Open
Abstract
Proteolytic cleavage of the hemagglutinin (HA) of influenza virus by host trypsin-like proteases is required for viral infectivity. Some serine proteases are capable of cleaving influenza virus HA, whereas some serine protease inhibitors (serpins) inhibit the HA cleavage in various cell types. Kallikrein-related peptidase 1 (KLK1, also known as tissue kallikrein) is a widely distributed serine protease. Kallistatin, a serpin synthesized mainly in the liver and rapidly secreted into the circulation, forms complexes with KLK1 and inhibits its activity. Here, we investigated the roles of KLK1 and kallistatin in influenza virus infection. We show that the levels of KLK1 increased, whereas those of kallistatin decreased, in the lungs of mice during influenza virus infection. KLK1 cleaved H1, H2, and H3 HA molecules and consequently enhanced viral production. In contrast, kallistatin inhibited KLK1-mediated HA cleavage and reduced viral production. Cells transduced with the kallistatin gene secreted kallistatin extracellularly, which rendered them more resistant to influenza virus infection. Furthermore, lentivirus-mediated kallistatin gene delivery protected mice against lethal influenza virus challenge by reducing the viral load, inflammation, and injury in the lung. Taking the data together, we determined that KLK1 and kallistatin contribute to the pathogenesis of influenza virus by affecting the cleavage of the HA peptide and inflammatory responses. This study provides a proof of principle for the potential therapeutic application of kallistatin or other KLK1 inhibitors for influenza. Since proteolytic activation also enhances the infectivity of some other viruses, kallistatin and other kallikrein inhibitors may be explored as antiviral agents against these viruses.
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Guo Y, Li P, Bledsoe G, Yang ZR, Chao L, Chao J. Kallistatin inhibits TGF-β-induced endothelial-mesenchymal transition by differential regulation of microRNA-21 and eNOS expression. Exp Cell Res 2015; 337:103-10. [PMID: 26156753 DOI: 10.1016/j.yexcr.2015.06.021] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Revised: 06/25/2015] [Accepted: 06/28/2015] [Indexed: 11/25/2022]
Abstract
Kallistatin, an endogenous protein, consists of two structural elements: active site and heparin-binding domain. Kallistatin exerts beneficial effects on fibrosis by suppressing transforming growth factor (TGF)-β synthesis in animal models. TGF-β is the most potent inducer of endothelial-mesenchymal transition (EndMT), which contributes to fibrosis and cancer. MicroRNA (miR)-21 is an important player in organ fibrosis and tumor invasion. Here we investigated the potential role of kallistatin in EndMT via modulation of miR-21 in endothelial cells. Human kallistatin treatment blocked TGF-β-induced EndMT, as evidenced by morphological changes as well as increased endothelial and reduced mesenchymal marker expression. Kallistatin also inhibited TGF-β-mediated reactive oxygen species (ROS) formation and NADPH oxidase expression and activity. Moreover, kallistatin antagonized TGF-β-induced miR-21 and Snail1 synthesis, Akt phosphorylation, NF-κB activation, and matrix metalloproteinase 2 (MMP2) synthesis and activation. Kallistatin via its heparin-binding site blocked TGF-β-induced miR-21, Snail1 expression, and ROS formation, as wild-type kallistatin, but not heparin-binding site mutant kallistatin, exerted the effect. Conversely, kallistatin through its active site stimulated the synthesis of endothelial nitric oxide synthase (eNOS), sirtuin 1 (Sirt1) and forkhead box O1 (FoxO1); however, these effects were blocked by genistein, a tyrosine kinase inhibitor. This is the first study to demonstrate that kallistatin's heparin-binding site is crucial for preventing TGF-β-induced miR-21 and oxidative stress, while its active site is key for stimulating the expression of antioxidant genes via interaction with an endothelial surface tyrosine kinase. These findings reveal novel mechanisms of kallistatin in protection against fibrosis and cancer by suppressing EndMT.
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Affiliation(s)
- Youming Guo
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Ave, Charleston, SC 29425-2211, United States
| | - Pengfei Li
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Ave, Charleston, SC 29425-2211, United States
| | - Grant Bledsoe
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Ave, Charleston, SC 29425-2211, United States
| | - Zhi-Rong Yang
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Ave, Charleston, SC 29425-2211, United States
| | - Lee Chao
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Ave, Charleston, SC 29425-2211, United States
| | - Julie Chao
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Ave, Charleston, SC 29425-2211, United States.
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