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Ochoa Mendoza V, de Oliveira AA, Nunes KP. Blockade of HSP70 Improves Vascular Function in a Mouse Model of Type 2 Diabetes. Cells 2025; 14:424. [PMID: 40136673 PMCID: PMC11941590 DOI: 10.3390/cells14060424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Revised: 03/08/2025] [Accepted: 03/11/2025] [Indexed: 03/27/2025] Open
Abstract
Type 2 diabetes (T2D) is a chronic disease that damages blood vessels and increases the risk of cardiovascular disease (CVD). Heat-shock protein 70 (HSP70), a family of chaperone proteins, has been recently reported as a key player in vascular reactivity that affects large blood vessels like the aorta. Hyperglycemia, a hallmark of diabetes, correlates with the severity of vascular damage and circulating HSP70 levels. In diabetes, blood vessels often show impaired contractility, contributing to vascular dysfunction. However, HSP70's specific role in T2D-related vascular contraction remains unclear. We hypothesized that blocking HSP70 would improve vascular function in a widely used diabetic mouse model (db/db). To test this, we measured both vascular intracellular and serum circulating HSP70 levels in control and diabetic male mice using immunofluorescence and Western blotting. We also examined the aorta's contractile response using a wire myograph system, which measured the force produced in response to phenylephrine (PE), both with and without VER155008, a pharmacological inhibitor that targets the ATPase domain of HSP70, and after removing extracellular calcium. Our findings show that intracellular HSP70 (iHSP70) levels were similar in control and diabetic groups, while circulating HSP70 (eHSP70) levels were higher in the serum of diabetic mice, altering the iHSP70/eHSP70 ratio. Even though VER155008 attenuated both phases of the contractile curve in the diabetic and control groups, enhanced vasoconstriction to PE was only observed in the tonic phase of the curve in the db/db group, which was prevented by iHSP70 inhibition. This effect involved calcium mobilization, as both the maximal and total contraction forces to PE were restored in groups treated with VER155008. Additionally, internal calcium levels in aortic rings treated with VER155008 decreased, as observed in force generation upon calcium reintroduction, which was further corroborated using a biochemical calcium assay. In conclusion, our study demonstrates that blocking HSP70 improves vascular reactivity in the hyperglycemic state of T2D by restoring proper vascular contraction.
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Affiliation(s)
| | | | - Kenia Pedrosa Nunes
- Laboratory of Vascular Biology, Department of Biomedical Engineering and Sciences, Florida Institute of Technology, Melbourne, FL 32901, USA; (V.O.M.)
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Cao WL, Yu CP, Zhang LL. Serum proteins differentially expressed in gestational diabetes mellitus assessed using isobaric tag for relative and absolute quantitation proteomics. World J Clin Cases 2024; 12:1395-1405. [PMID: 38576811 PMCID: PMC10989458 DOI: 10.12998/wjcc.v12.i8.1395] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 01/08/2024] [Accepted: 02/18/2024] [Indexed: 03/12/2024] Open
Abstract
BACKGROUND As a well-known fact to the public, gestational diabetes mellitus (GDM) could bring serious risks for both pregnant women and infants. During this important investigation into the linkage between GDM patients and their altered expression in the serum, proteomics techniques were deployed to detect the differentially expressed proteins (DEPs) of in the serum of GDM patients to further explore its pathogenesis, and find out possible biomarkers to forecast GDM occurrence. AIM To investigation serum proteins differentially expressed in GDM were assessed using isobaric tag for relative and absolute quantitation (iTRAQ) proteomics and bioinformatics analyses. METHODS Subjects were divided into GDM and normal control groups according to the IADPSG diagnostic criteria. Serum samples were randomly selected from four cases in each group at 24-28 wk of gestation, and the blood samples were identified by applying iTRAQ technology combined with liquid chromatography-tandem mass spectrometry. Key proteins and signaling pathways associated with GDM were identified by bioinformatics analysis, and the expression of key proteins in serum from 12 wk to 16 wk of gestation was further verified using enzyme-linked immunosorbent assay (ELISA). RESULTS Forty-seven proteins were significantly differentially expressed by analyzing the serum samples between the GDM gravidas as well as the healthy ones. Among them, 31 proteins were found to be upregulated notably and the rest 16 proteins were downregulated remarkably. Bioinformatic data report revealed abnormal expression of proteins associated with lipid metabolism, coagulation cascade activation, complement system and inflammatory response in the GDM group. ELISA results showed that the contents of RBP4, as well as ANGPTL8, increased in the serum of GDM gravidas compared with the healthy ones, and this change was found to initiate from 12 wk to 16 wk of gestation. CONCLUSION GDM symptoms may involve abnormalities in lipid metabolism, coagulation cascade activation, complement system and inflammatory response. RBP4 and ANGPTL8 are expected to be early predictors of GDM.
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Affiliation(s)
- Wei-Li Cao
- Department of Women’s Health Care, Maternal and Child Health Hospital of Hubei Province, Wuhan 430070, Hubei Province, China
| | - Cui-Ping Yu
- Obstetrical Department, The First People’s Hospital of Jiangxia District Wuhan City (Union Jiangnan Hospital Huazhong University of Science and Technology), Wuhan 430200, Hubei Province, China
| | - Ling-Li Zhang
- Department of Gynecology, Maternal and Child Health Hospital of Hubei Province, Wuhan 430070, Hubei Province, China
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Simon D, Erdő-Bonyár S, Böröcz K, Balázs N, Badawy A, Bajnok A, Nörenberg J, Serény-Litvai T, Várnagy Á, Kovács K, Hantosi E, Mezősi E, Németh P, Berki T. Altered Levels of Natural Autoantibodies against Heat Shock Proteins in Pregnant Women with Hashimoto's Thyroiditis. Int J Mol Sci 2024; 25:1423. [PMID: 38338701 PMCID: PMC10855109 DOI: 10.3390/ijms25031423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 01/19/2024] [Accepted: 01/21/2024] [Indexed: 02/12/2024] Open
Abstract
The function of natural autoantibodies (nAAbs) in maintaining immunological tolerance has been comprehensively explained; however, their function in pregnant patients dealing with autoimmune diseases has not been thoroughly investigated. As Hashimoto's thyroiditis (HT) is the predominant organ-specific autoimmune condition of women of childbearing age, this study's objective was to evaluate IgM and IgG nAAbs targeting mitochondrial citrate synthase (CS) and heat shock proteins (Hsp60 and Hsp70) in women diagnosed with HT who were pregnant (HTP). Serum samples collected from HTP and healthy pregnant (HP) women in the first and third trimesters were tested using in-house-developed enzyme-linked immunosorbent assays (ELISAs). Our findings indicate the stability of nAAbs against CS and Hsps throughout the pregnancies of both healthy women and those with HT. However, during both trimesters, HTP patients displayed elevated levels of IgM isotype nAAbs against Hsp60 and Hsp70 compared to HP women, suggesting a regulatory role of IgM nAAbs during the pregnancies of patients with HT. Nonetheless, levels of IgG isotype nAAbs against Hsps were lower solely in the third trimester among HTP patients, resulting in a higher IgM/IgG ratio, which indicates their importance in alterations of the nAAb network during pregnancy in patients with HT.
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Affiliation(s)
- Diána Simon
- Department of Immunology and Biotechnology, Clinical Center, Medical School, University of Pécs, 7624 Pécs, Hungary
- National Laboratory on Human Reproduction, University of Pécs, 7624 Pécs, Hungary
| | - Szabina Erdő-Bonyár
- Department of Immunology and Biotechnology, Clinical Center, Medical School, University of Pécs, 7624 Pécs, Hungary
- National Laboratory on Human Reproduction, University of Pécs, 7624 Pécs, Hungary
| | - Katalin Böröcz
- Department of Immunology and Biotechnology, Clinical Center, Medical School, University of Pécs, 7624 Pécs, Hungary
| | - Noémi Balázs
- Department of Immunology and Biotechnology, Clinical Center, Medical School, University of Pécs, 7624 Pécs, Hungary
- National Laboratory on Human Reproduction, University of Pécs, 7624 Pécs, Hungary
| | - Ahmed Badawy
- Department of Immunology and Biotechnology, Clinical Center, Medical School, University of Pécs, 7624 Pécs, Hungary
- National Laboratory on Human Reproduction, University of Pécs, 7624 Pécs, Hungary
| | - Anna Bajnok
- National Laboratory on Human Reproduction, University of Pécs, 7624 Pécs, Hungary
- Szentágothai Research Centre, University of Pécs, 7624 Pécs, Hungary
- Department of Obstetrics and Gynecology, Clinical Center, Medical School, University of Pécs, 7624 Pécs, Hungary
| | - Jasper Nörenberg
- National Laboratory on Human Reproduction, University of Pécs, 7624 Pécs, Hungary
- Department of Obstetrics and Gynecology, Clinical Center, Medical School, University of Pécs, 7624 Pécs, Hungary
| | - Tímea Serény-Litvai
- Department of Immunology and Biotechnology, Clinical Center, Medical School, University of Pécs, 7624 Pécs, Hungary
- National Laboratory on Human Reproduction, University of Pécs, 7624 Pécs, Hungary
- Szentágothai Research Centre, University of Pécs, 7624 Pécs, Hungary
| | - Ákos Várnagy
- National Laboratory on Human Reproduction, University of Pécs, 7624 Pécs, Hungary
- Department of Obstetrics and Gynecology, Clinical Center, Medical School, University of Pécs, 7624 Pécs, Hungary
| | - Kálmán Kovács
- National Laboratory on Human Reproduction, University of Pécs, 7624 Pécs, Hungary
- Department of Obstetrics and Gynecology, Clinical Center, Medical School, University of Pécs, 7624 Pécs, Hungary
| | - Eszter Hantosi
- Department of Obstetrics and Gynecology, Clinical Center, Medical School, University of Pécs, 7624 Pécs, Hungary
| | - Emese Mezősi
- National Laboratory on Human Reproduction, University of Pécs, 7624 Pécs, Hungary
- First Department of Internal Medicine, Clinical Center, Medical School, University of Pécs, 7624 Pécs, Hungary
| | - Péter Németh
- Department of Immunology and Biotechnology, Clinical Center, Medical School, University of Pécs, 7624 Pécs, Hungary
- National Laboratory on Human Reproduction, University of Pécs, 7624 Pécs, Hungary
| | - Tímea Berki
- Department of Immunology and Biotechnology, Clinical Center, Medical School, University of Pécs, 7624 Pécs, Hungary
- National Laboratory on Human Reproduction, University of Pécs, 7624 Pécs, Hungary
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Increased eHSP70-to-iHSP70 ratio disrupts vascular responses to calcium and activates the TLR4-MD2 complex in type 1 diabetes. Life Sci 2022; 310:121079. [DOI: 10.1016/j.lfs.2022.121079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 09/24/2022] [Accepted: 10/11/2022] [Indexed: 11/09/2022]
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Zafaranieh S, Dieberger AM, Leopold-Posch B, Huppertz B, Granitzer S, Hengstschläger M, Gundacker C, Desoye G, van Poppel MNM. Physical Activity and Sedentary Time in Pregnancy: An Exploratory Study on Oxidative Stress Markers in the Placenta of Women with Obesity. Biomedicines 2022; 10:biomedicines10051069. [PMID: 35625806 PMCID: PMC9138298 DOI: 10.3390/biomedicines10051069] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 04/28/2022] [Accepted: 04/29/2022] [Indexed: 02/05/2023] Open
Abstract
Regular moderate-to-vigorous physical activity (MVPA) and reduced sedentary time (ST) improve maternal glucose metabolism in pregnancy. More MVPA and less ST outside pregnancy increase antioxidant capacity, hence, are beneficial in preventing oxidative stress. The placenta is the first line of defense for the fetus from an adverse maternal environment, including oxidative stress. However, effects of MVPA and ST on oxidative stress markers in the placenta are unknown. The purpose of this study was to assess the association of MVPA and ST in pregnancy with oxidative stress markers in placentas of overweight/obese women (BMI ≥ 29 kg/m2). MVPA and ST were objectively measured with accelerometers at <20 weeks, 24−27 and 35−37 weeks of gestation. Using linear Bayesian multilevel models, the associations of MVPA and ST (mean and changes) with mRNA expression of a panel of 11 oxidative stress related markers were assessed in 96 women. MVPA was negatively correlated with HSP70 mRNA expression in a sex-independent manner and with GCLM expression only in placentas of female fetuses. ST was positively associated with HO-1 mRNA expression in placentas of male neonates. None of the other markers were associated with MVPA or ST. We speculate that increasing MVPA and reducing ST attenuates the oxidative stress state in placentas of obese pregnant women.
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Affiliation(s)
- Saghi Zafaranieh
- Institute of Human Movement Science, Sport and Health, University of Graz, 8010 Graz, Austria;
| | - Anna M. Dieberger
- Department of Obstetrics and Gynecology, Medical University of Graz, 8036 Graz, Austria; (A.M.D.); (B.L.-P.); (G.D.)
| | - Barbara Leopold-Posch
- Department of Obstetrics and Gynecology, Medical University of Graz, 8036 Graz, Austria; (A.M.D.); (B.L.-P.); (G.D.)
| | - Berthold Huppertz
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, 8010 Graz, Austria;
| | - Sebastian Granitzer
- Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, 1090 Vienna, Austria; (S.G.); (M.H.); (C.G.)
- Karl-Landsteiner Private University for Health Sciences, 3500 Krems, Austria
| | - Markus Hengstschläger
- Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, 1090 Vienna, Austria; (S.G.); (M.H.); (C.G.)
| | - Claudia Gundacker
- Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, 1090 Vienna, Austria; (S.G.); (M.H.); (C.G.)
| | - Gernot Desoye
- Department of Obstetrics and Gynecology, Medical University of Graz, 8036 Graz, Austria; (A.M.D.); (B.L.-P.); (G.D.)
| | - Mireille N. M. van Poppel
- Institute of Human Movement Science, Sport and Health, University of Graz, 8010 Graz, Austria;
- Correspondence: ; Tel.: +43-(0)-316-380-2335
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de Oliveira AA, Mendoza VO, Rastogi S, Nunes KP. New insights into the role and therapeutic potential of HSP70 in diabetes. Pharmacol Res 2022; 178:106173. [PMID: 35278625 DOI: 10.1016/j.phrs.2022.106173] [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: 01/07/2022] [Revised: 03/06/2022] [Accepted: 03/07/2022] [Indexed: 10/18/2022]
Abstract
Emerging evidence indicates that HSP70 represents a key mechanism in the pathophysiology of β-cell dysfunction, insulin resistance, and various diabetic complications, including micro- and macro-vascular alterations, as well as impaired hemostasis. Hyperglycemia, a hallmark of both types of diabetes, increases the circulating levels of HSP70 (eHSP70), but there is still divergence about whether diabetes up- or down-regulates the intracellular fraction of this protein (iHSP70). Here, we consider that iHSP70 levels reduce in diabetic arterial structures and that the vascular system is in direct contact with all other systems in the body suggesting that a systemic response might also be happening for iHSP70, which is characterized by decreased levels of HSP70 in the vasculature. Furthermore, although many pathways have been proposed to explain HSP70's functions in diabetes, and organs/tissues/cells-specific variations occur, the membrane-bound receptor of the innate immune system, Toll-like receptor 4, and its downstream signal transduction pathways appear to be a constant, not only when we explore the actions of eHSP70, but also when we assess the contributions of iHSP70. In this review, we focus on discussing the multiple roles of HSP70 across organs/tissues/cells affected by hyperglycemia to further explore the possibility of targeting this protein with pharmacological and non-pharmacological approaches in the context of diabetes.
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Affiliation(s)
- Amanda Almeida de Oliveira
- Laboratory of Vascular Biology, Department of Biomedical and Chemical Engineering and Sciences, Florida Institute of Technology, Melbourne, United States
| | - Valentina Ochoa Mendoza
- Laboratory of Vascular Biology, Department of Biomedical and Chemical Engineering and Sciences, Florida Institute of Technology, Melbourne, United States
| | - Swasti Rastogi
- Laboratory of Vascular Biology, Department of Biomedical and Chemical Engineering and Sciences, Florida Institute of Technology, Melbourne, United States
| | - Kenia Pedrosa Nunes
- Laboratory of Vascular Biology, Department of Biomedical and Chemical Engineering and Sciences, Florida Institute of Technology, Melbourne, United States.
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Yang Y, Xia J, Yang Z, Wu G, Yang J. The abnormal level of HSP70 is related to Treg/Th17 imbalance in PCOS patients. J Ovarian Res 2021; 14:155. [PMID: 34781996 PMCID: PMC8591891 DOI: 10.1186/s13048-021-00867-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 08/19/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Polycystic ovary syndrome (PCOS) is a disease with chronic nonspecific low-grade inflammation. The imbalance of immune cells exists in PCOS. Several studies have found that heat shock protein 70 (HSP70) may be involved in the immunological pathogenesis of PCOS, but the relationship between HSP70 and Regulatory T cell (Treg)/T helper cell 17(Th17) ratio remains unclear. This study aims to explore the correlation between HSP70 and Treg/Th17 ratio and to provide evidence for the role of HSP70 in the immunological etiology of PCOS. RESULTS There was no significant difference in age and body mass index (BMI) between the two groups. The concentrations of basal estradiol (E2), basal follicle-stimulating hormone (FSH) did not show a significant difference between the two groups. The concentrations of basal luteinizing hormone (LH) (P < 0.01), testosterone (T) (P < 0.01), glucose (P < 0.001) and insulin (P < 0.001) in PCOS patients were significantly higher than those in the control group. The protein levels of HSP70 were significantly higher in serum in the PCOS group (P < 0.001). The percentage of Treg cells was significantly lower (P < 0.01), while the percentage of the Th17 cells of the PCOS group was significantly higher than that of the control group (P < 0.05). The ratio of Treg/Th17 in the PCOS group was significantly lower (P < 0.001). The concentrations of Interleukin (IL)-6, IL-17, and IL-23 were significantly higher, while the levels of IL-10 and Transforming growth factor-β (TGF-β) were significantly lower in the PCOS group (P < 0.001). Spearman rank correlation analysis showed a strong negative correlation of serum HSP70 levels with Treg/Th17 ratio, IL-10, and TGF-β levels. In contrast, HSP70 levels were significantly positively correlated with IL-6, IL-17, IL-23, LH, insulin, and glucose levels. CONCLUSION The abnormal level of HSP70 is correlated with Treg/Th17 imbalance and corresponding cytokines, which indicates that HSP70 may play an important role in PCOS immunologic pathogenesis.
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Affiliation(s)
- Yiqing Yang
- Reproductive Medical Centre, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China.,Hubei Clinical Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, 430060, People's Republic of China
| | - Jing Xia
- Reproductive Medical Centre, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China.,Hubei Clinical Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, 430060, People's Republic of China
| | - Zhe Yang
- Reproductive Medical Centre, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China.,Hubei Clinical Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, 430060, People's Republic of China
| | - Gengxiang Wu
- Reproductive Medical Centre, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China. .,Hubei Clinical Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, 430060, People's Republic of China.
| | - Jing Yang
- Reproductive Medical Centre, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China. .,Hubei Clinical Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, 430060, People's Republic of China.
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Iqbal Z, Fachim HA, Gibson JM, Baricevic-Jones I, Campbell AE, Geary B, Donn RP, Hamarashid D, Syed A, Whetton AD, Soran H, Heald AH. Changes in the Proteome Profile of People Achieving Remission of Type 2 Diabetes after Bariatric Surgery. J Clin Med 2021; 10:3659. [PMID: 34441954 PMCID: PMC8396849 DOI: 10.3390/jcm10163659] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/17/2021] [Accepted: 08/17/2021] [Indexed: 02/07/2023] Open
Abstract
Bariatric surgery (BS) results in metabolic pathway recalibration. We have identified potential biomarkers in plasma of people achieving type 2 diabetes mellitus (T2DM) remission after BS. Longitudinal analysis was performed on plasma from 10 individuals following Roux-en-Y gastric bypass (n = 7) or sleeve gastrectomy (n = 3). Sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) was done on samples taken at 4 months before (baseline) and 6 and 12 months after BS. Four hundred sixty-seven proteins were quantified by SWATH-MS. Principal component analysis resolved samples from distinct time points after selection of key discriminatory proteins: 25 proteins were differentially expressed between baseline and 6 months post-surgery; 39 proteins between baseline and 12 months. Eight proteins (SHBG, TF, PRG4, APOA4, LRG1, HSPA4, EPHX2 and PGLYRP) were significantly different to baseline at both 6 and 12 months post-surgery. The panel of proteins identified as consistently different included peptides related to insulin sensitivity (SHBG increase), systemic inflammation (TF and HSPA4-both decreased) and lipid metabolism (APOA4 decreased). We found significant changes in the proteome for eight proteins at 6- and 12-months post-BS, and several of these are key components in metabolic and inflammatory pathways. These may represent potential biomarkers of remission of T2DM.
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Affiliation(s)
- Zohaib Iqbal
- The School of Medicine and Manchester Academic Health Sciences Centre, Manchester University, Manchester M13 9PL, UK; (Z.I.); (J.M.G.); (R.P.D.); (H.S.)
- Department of Endocrinology, Diabetes and Metabolism, Salford Royal Foundation Trust, Salford M6 8HD, UK; (D.H.); (A.S.)
| | - Helene A. Fachim
- The School of Medicine and Manchester Academic Health Sciences Centre, Manchester University, Manchester M13 9PL, UK; (Z.I.); (J.M.G.); (R.P.D.); (H.S.)
- Department of Endocrinology, Diabetes and Metabolism, Salford Royal Foundation Trust, Salford M6 8HD, UK; (D.H.); (A.S.)
| | - J. Martin Gibson
- The School of Medicine and Manchester Academic Health Sciences Centre, Manchester University, Manchester M13 9PL, UK; (Z.I.); (J.M.G.); (R.P.D.); (H.S.)
- Department of Endocrinology, Diabetes and Metabolism, Salford Royal Foundation Trust, Salford M6 8HD, UK; (D.H.); (A.S.)
| | - Ivona Baricevic-Jones
- Stoller Biomarker Discovery Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK; (I.B.-J.); (A.E.C.); (B.G.); (A.D.W.)
| | - Amy E. Campbell
- Stoller Biomarker Discovery Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK; (I.B.-J.); (A.E.C.); (B.G.); (A.D.W.)
| | - Bethany Geary
- Stoller Biomarker Discovery Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK; (I.B.-J.); (A.E.C.); (B.G.); (A.D.W.)
| | - Rachelle P. Donn
- The School of Medicine and Manchester Academic Health Sciences Centre, Manchester University, Manchester M13 9PL, UK; (Z.I.); (J.M.G.); (R.P.D.); (H.S.)
| | - Dashne Hamarashid
- Department of Endocrinology, Diabetes and Metabolism, Salford Royal Foundation Trust, Salford M6 8HD, UK; (D.H.); (A.S.)
| | - Akheel Syed
- Department of Endocrinology, Diabetes and Metabolism, Salford Royal Foundation Trust, Salford M6 8HD, UK; (D.H.); (A.S.)
| | - Anthony D. Whetton
- Stoller Biomarker Discovery Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK; (I.B.-J.); (A.E.C.); (B.G.); (A.D.W.)
- Manchester National Institute for Health Research Biomedical Research Centre, Manchester M13 9WL, UK
| | - Handrean Soran
- The School of Medicine and Manchester Academic Health Sciences Centre, Manchester University, Manchester M13 9PL, UK; (Z.I.); (J.M.G.); (R.P.D.); (H.S.)
| | - Adrian H. Heald
- The School of Medicine and Manchester Academic Health Sciences Centre, Manchester University, Manchester M13 9PL, UK; (Z.I.); (J.M.G.); (R.P.D.); (H.S.)
- Department of Endocrinology, Diabetes and Metabolism, Salford Royal Foundation Trust, Salford M6 8HD, UK; (D.H.); (A.S.)
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Borçari NR, dos Santos JF, Reigado GR, Freitas BL, Araújo MDS, Nunes VA. Vitamins Modulate the Expression of Antioxidant Genes in Progesterone-Treated Pancreatic β Cells: Perspectives for Gestational Diabetes Management. Int J Endocrinol 2020; 2020:8745120. [PMID: 33014046 PMCID: PMC7512066 DOI: 10.1155/2020/8745120] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 08/28/2020] [Accepted: 09/03/2020] [Indexed: 11/18/2022] Open
Abstract
Gestational diabetes (GD) is a condition defined as carbohydrate intolerance and hyperglycemia beginning in the second trimester of pregnancy, which overlaps with the progesterone exponential increase. Progesterone has been shown to cause pancreatic β-cell death by a mechanism dependent on the generation of reactive oxygen species and oxidative stress. Herein, we studied the effect of this hormone on the expression of 84 genes related to oxidative stress and oxidant defense in pancreatic RINm5F cell lineage. Cells were incubated with 0.1, 1.0, or 100 μM progesterone for 6 or 24 h, in the presence or absence of the vitamins E and C. Among the investigated genes, five of them had their expression increased, at least 2-fold, in two different concentrations independently of the time of incubation, or at the same concentration at the different time points, including those that encode for stearoyl-CoA desaturase 1 (Scd1), dual oxidase 1 (Duox1), glutathione peroxidase 6 (GPx6), heme oxygenase 1 (Hmox1), and heat shock protein a1a (Hspa1a). Vitamins E and C were able to increase, in progesterone-treated cells, the expression of genes with antioxidant function such as Hmox1, but decreased Scd1 expression, a gene with prooxidant function. At cytoplasmic level, progesterone positively modulated Hmox1 and Hspa1a content. These results suggest that the protein encoded by these genes might protect cells against progesterone induced-oxidative damage, opening perspectives to elucidate the molecular mechanism involved in progesterone action in GD, as well as for the development of antioxidant strategies for the prevention and treatment of this disease.
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Affiliation(s)
| | | | | | | | | | - Viviane Abreu Nunes
- Department of Biotechnology, University of Sao Paulo (USP), Sao Paulo, Brazil
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Munteanu C, EMEKSIZ MA, ULUSOY Y, KİLİC B. Investigation of the Therapeutic Effects of Hot Springs Waters Sourced from Afyonkarahisar Region on Experimentally-induced Myocardial infarctus in Rats. BALNEO RESEARCH JOURNAL 2020. [DOI: 10.12680/balneo.2020.348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Myocardial infarction is an important public health problem in human and animals. In this study, myocardial infarction was induced by intraperitoneally injected isoproterenol hydrochloride in saline solution at a dose of 85 mg/kg body weight for 2 days. After myocardial infarction formation, three animals were exed to collect blood and histopathological specimens. The remaining 32 rats were divided into control and study groups for treatment. In the treatment stage; the control group animals were treated with tap water, while the study group animals were received Süreyya I hot spring mineral water. Clinical, hematological, blood biochemical and histopathological examinations was performed in all the animals before study, after myocardial infarction, and on 1st, 7th, 14th and 21st days after treatment. In terms of T, P and R, there were significant differences (p <0.05) with respect to time periods between control and study groups (p <0.05). WBC, NOTR, MON MCH, HCT ve MCV levels decreased, while RBC, HG, HCT, LENF, MCH and MCHC levels increased following treatmen in both groups. These changes were significant in study group comaper to control. It was also seen that ALT, AST, CK and CRP levels of blood biochemical parameters were significantly increased (p <0.05) after myocardial infarction formation. By begining treatment, TP, ALB and GLU levels increased, whereas ALT, AST, CK and CRP levels decreased, especially on the 21st day of the study in the SG. It was concluded that in the correct temperature and time to use Süreyya I hot spring water as drinking and bathing was very successful in the treatment of myocardial infarction, either itself or along with other medical treatments.
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Affiliation(s)
| | | | - Yavuz ULUSOY
- 3. Ministry of Agriculture and Forestry, Veterinary Control Central Research Institute, Pathology Laboratory, Ankara/ Turkey
| | - Bahadir KİLİC
- 3. Ministry of Agriculture and Forestry, Veterinary Control Central Research Institute, Pathology Laboratory, Ankara/ Turkey
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11
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Sharps MC, Baker BC, Guevara T, Bischof H, Jones RL, Greenwood SL, Heazell AEP. Increased placental macrophages and a pro-inflammatory profile in placentas and maternal serum in infants with a decreased growth rate in the third trimester of pregnancy. Am J Reprod Immunol 2020; 84:e13267. [PMID: 32421915 DOI: 10.1111/aji.13267] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 04/23/2020] [Accepted: 05/13/2020] [Indexed: 12/16/2022] Open
Abstract
PROBLEM There is growing evidence for the role of placental inflammation in the pathophysiology of pregnancy complications including fetal growth restriction (FGR). This study aimed to characterize the inflammatory profile in the maternal circulation and the placenta of infants who were growth restricted and those that were small for gestational age (SGA). METHOD OF STUDY Placental villous tissue and maternal serum were obtained from pregnancies where infants were SGA at birth or who had a decreasing growth rate (≥25 centiles) across the third trimester. Immunohistochemical and histological analyses of placental samples were conducted for macrophage number, alongside vascular and cell turnover analysis. Inflammatory profile was analyzed in maternal and placental compartments via ELISAs and multiplex assays. RESULTS There were significantly more CD163+ macrophages in placentas of infants with a decreased growth rate compared to controls, but not in SGA infants (median 8.6/ nuclei vs 3.8 and 2.9, P = .008 and P = .003, respectively). Uric acid (P = .0007) and IL-8 (P = .0008) were increased in placentas, and S100A8 (P < .0002) was increased in maternal serum of infants with decreased growth rate. No changes in the maternal serum or placental lysates of SGA infants were observed. CONCLUSION The evidence of an altered inflammatory profile in infants with a decreasing growth rate, but not in those that were born SGA, provides further evidence that inflammation plays a role in true FGR. It remains unclear whether the increased placental macrophages occur as a direct result, or as a consequence of the pro-inflammatory environment observed in fetal growth restriction.
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Affiliation(s)
- Megan C Sharps
- Division of Developmental Biology & Medicine, Faculty of Biology, Medicine & Health, Tommy's Maternal and Fetal Health Research Centre, 5th Floor St. Mary's Hospital, University of Manchester, Manchester, UK
| | - Bernadette C Baker
- Division of Developmental Biology & Medicine, Faculty of Biology, Medicine & Health, Tommy's Maternal and Fetal Health Research Centre, 5th Floor St. Mary's Hospital, University of Manchester, Manchester, UK
| | - Tatiana Guevara
- Division of Developmental Biology & Medicine, Faculty of Biology, Medicine & Health, Tommy's Maternal and Fetal Health Research Centre, 5th Floor St. Mary's Hospital, University of Manchester, Manchester, UK
| | - Helen Bischof
- Division of Developmental Biology & Medicine, Faculty of Biology, Medicine & Health, Tommy's Maternal and Fetal Health Research Centre, 5th Floor St. Mary's Hospital, University of Manchester, Manchester, UK
| | - Rebecca L Jones
- Division of Developmental Biology & Medicine, Faculty of Biology, Medicine & Health, Tommy's Maternal and Fetal Health Research Centre, 5th Floor St. Mary's Hospital, University of Manchester, Manchester, UK
| | - Susan L Greenwood
- Division of Developmental Biology & Medicine, Faculty of Biology, Medicine & Health, Tommy's Maternal and Fetal Health Research Centre, 5th Floor St. Mary's Hospital, University of Manchester, Manchester, UK
| | - Alexander E P Heazell
- Division of Developmental Biology & Medicine, Faculty of Biology, Medicine & Health, Tommy's Maternal and Fetal Health Research Centre, 5th Floor St. Mary's Hospital, University of Manchester, Manchester, UK.,Manchester Academic Health Science Centre, St. Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK
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12
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de Oliveira AA, Webb RC, Nunes KP. Toll-Like Receptor 4 and Heat-Shock Protein 70: Is it a New Target Pathway for Diabetic Vasculopathies? Curr Drug Targets 2020; 20:51-59. [PMID: 30129410 DOI: 10.2174/1389450119666180821105544] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 04/09/2018] [Accepted: 08/17/2018] [Indexed: 12/17/2022]
Abstract
Diabetes is one of the most concerning diseases in modern times. Despite considerable advances in therapeutic management, the prevalence of diabetes and its contribution to death and disability continue to be a major health problem. Diabetic vasculopathies are the leading cause of mortality and morbidity in diabetic patients. Its pathophysiology includes oxidative stress, advanced glycation end products, and a low-grade inflammatory state. Lately, actions of the innate immune system via Toll-like receptors (TLRs) have been suggested as a new insight in this field. TLRs are pattern recognition receptors activated by highly conserved structural motifs of exogenous or endogenous ligands. Heat-shock proteins (HSPs), normally known for their ability to protect cells during stressful conditions, when released from injured cells bind to TLR4 and trigger the release of pro-inflammatory cytokines in a MyD88-dependent pathway. This pathway had been investigated in pancreatic beta cells and skeletal muscle, but it has not yet been explored in the vascular system and deserves investigation. In this work, the interplay between TLR4 and HSP70 in the vasculature during diabetes is reviewed and discussed. The current literature and preliminary results from our laboratory led us to hypothesize that hyperglycemia-associated HSP70 plays an important role in the pathophysiology of diabetic vasculopathies via the TLR4 pathway and might be a new target for therapeutic intervention.
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Affiliation(s)
- Amanda Almeida de Oliveira
- Department of Biological Sciences, College of Sciences, Florida Institute of Technology, Melbourne, FL, United States
| | - R Clinton Webb
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - Kenia Pedrosa Nunes
- Department of Biological Sciences, College of Sciences, Florida Institute of Technology, Melbourne, FL, United States
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13
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Genome-wide association study identifies novel risk variants from RPS6KA1, CADPS, VARS, and DHX58 for fasting plasma glucose in Arab population. Sci Rep 2020; 10:152. [PMID: 31932636 PMCID: PMC6957513 DOI: 10.1038/s41598-019-57072-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 12/20/2019] [Indexed: 12/14/2022] Open
Abstract
Consanguineous populations of the Arabian Peninsula, which has seen an uncontrolled rise in type 2 diabetes incidence, are underrepresented in global studies on diabetes genetics. We performed a genome-wide association study on the quantitative trait of fasting plasma glucose (FPG) in unrelated Arab individuals from Kuwait (discovery-cohort:n = 1,353; replication-cohort:n = 1,196). Genome-wide genotyping in discovery phase was performed for 632,375 markers from Illumina HumanOmniExpress Beadchip; and top-associating markers were replicated using candidate genotyping. Genetic models based on additive and recessive transmission modes were used in statistical tests for associations in discovery phase, replication phase, and meta-analysis that combines data from both the phases. A genome-wide significant association with high FPG was found at rs1002487 (RPS6KA1) (p-discovery = 1.64E-08, p-replication = 3.71E-04, p-combined = 5.72E-11; β-discovery = 8.315; β-replication = 3.442; β-combined = 6.551). Further, three suggestive associations (p-values < 8.2E-06) with high FPG were observed at rs487321 (CADPS), rs707927 (VARS and 2Kb upstream of VWA7), and rs12600570 (DHX58); the first two markers reached genome-wide significance in the combined analysis (p-combined = 1.83E-12 and 3.07E-09, respectively). Significant interactions of diabetes traits (serum triglycerides, FPG, and glycated hemoglobin) with homeostatic model assessment of insulin resistance were identified for genotypes heterozygous or homozygous for the risk allele. Literature reports support the involvement of these gene loci in type 2 diabetes etiology.
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14
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Burlina S, Banfi C, Brioschi M, Visentin S, Dalfrà MG, Traldi P, Lapolla A. Is the placental proteome impaired in well-controlled gestational diabetes? JOURNAL OF MASS SPECTROMETRY : JMS 2019; 54:359-365. [PMID: 30675960 DOI: 10.1002/jms.4336] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 01/18/2019] [Accepted: 01/19/2019] [Indexed: 06/09/2023]
Abstract
In pregnancy complicated by gestational diabetes mellitus (GDM), the human placenta shows several pathological functional and structural changes, but the extent to which maternal glycemic control contributes to placental abnormalities remains unclear. The aim of this study was to profile and compare the proteome of placentas from healthy pregnant women and those with GDM, to investigate the placenta-specific protein composition and possible changes of its function in presence of GDM. Quantitative proteomic analysis, based on LC-MSE approach, revealed that higher (approximately 15% increase) levels of galectin 1 and collagen alpha-1 XIV chain (although the difference regarding the latter was at the limit of significance) were present in GDM samples, while heat shock 70 kDa protein 1A/1B was less abundant in GDM placental tissue. These data seem to indicate that GDM, when well controlled, did not markedly affect the placental proteome.
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Affiliation(s)
- Silvia Burlina
- Department of Medicine - DIMED, University of Padova, Padova, Italy
| | | | | | - Silvia Visentin
- Department of Woman's and Child's Health, University of Padova, Padova, Italy
| | | | - Pietro Traldi
- Istituto di Ricerche Pediatriche Città della Speranza, Padova, Italy
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15
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Stygar D, Skrzep-Poloczek B, Romuk E, Chełmecka E, Poloczek J, Sawczyn T, Maciarz J, Kukla M, Karcz KW, Jochem J. The influence of high-fat, high-sugar diet and bariatric surgery on HSP70 and HSP90 plasma and liver concentrations in diet-induced obese rats. Cell Stress Chaperones 2019; 24:427-439. [PMID: 30840227 PMCID: PMC6439084 DOI: 10.1007/s12192-019-00976-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 01/22/2019] [Accepted: 01/30/2019] [Indexed: 12/31/2022] Open
Abstract
Metabolic surgery ameliorates insulin resistance and is associated with long-term, effective weight loss, but the mechanisms involved remain unknown. Here, the duodenal-jejunal omega switch (DJOS) surgery in combination with high-fat, high-carbohydrate diet was performed on diet obese rats and joint effects of bariatric surgery and different dietary patterns on heat shock protein 70 (HSP70) and HSP90 plasma and liver concentrations were measured. We found that plasma and liver levels of HSP70 were lower after DJOS surgery in comparison to the control in the groups of animals kept on control diet (CD) and high-fat, high-sugar diet (HFS) but the postoperative change of the diet led to the increase in HSP70 in plasma and liver concentration in DJOS-operated animals. A high-calorie meal, rich in carbohydrates and fats, significantly increased circulating levels of HSP90, reducing the normalising effect of DJOS. The HFS diet applied during all stages of the experiment led to the higher levels of liver HSP90 concentration. The combination of CD and DJOS surgery was the most efficient in the lowering of the HSP90 liver concentration. The normalisation of circulating levels and liver concentrations of HSP70 and HSP90 may be achieved in a combination of DJOS procedure with a proper dietary plan.
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Affiliation(s)
- Dominika Stygar
- Department of Physiology, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland.
| | - Bronisława Skrzep-Poloczek
- Department of Physiology, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Ewa Romuk
- Department of Biochemistry, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Elżbieta Chełmecka
- Department of Statistics, Department of Instrumental Analysis, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Katowice, Poland
| | - Jakub Poloczek
- Department of Rehabilitation, 3rd Specialist Hospital in Rybnik, Rybnik, Poland
| | - Tomasz Sawczyn
- Department of Physiology, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Justyna Maciarz
- Department of Physiology, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Michał Kukla
- Department of Gastroenterology and Hepatology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Konrad W Karcz
- Clinic of General, Visceral, Transplantation and Vascular Surgery, Hospital of the Ludwig Maximilian University, Munich, Germany
| | - Jerzy Jochem
- Department of Physiology, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland
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16
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Brien ME, Baker B, Duval C, Gaudreault V, Jones RL, Girard S. Alarmins at the maternal-fetal interface: involvement of inflammation in placental dysfunction and pregnancy complications 1. Can J Physiol Pharmacol 2018; 97:206-212. [PMID: 30485131 DOI: 10.1139/cjpp-2018-0363] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Inflammation is known to be associated with placental dysfunction and pregnancy complications. Infections are well known to be a cause of inflammation but they are frequently undetectable in pregnancy complications. More recently, the focus has been extended to inflammation of noninfectious origin, namely caused by endogenous mediators known as "damage-associated molecular patterns (DAMPs)" or alarmins. In this manuscript, we review the mechanism by which inflammation, sterile or infectious, can alter the placenta and its function. We discuss some classical DAMPs, such as uric acid, high mobility group box 1 (HMGB1), cell-free fetal deoxyribonucleic acid (DNA) (cffDNA), S100 proteins, heat shock protein 70 (HSP70), and adenosine triphosphate (ATP) and their impact on the placenta. We focus on the main placental cells (i.e., trophoblast and Hofbauer cells) and describe the placental response to, and release of, DAMPs. We also covered the current state of knowledge about the role of DAMPs in pregnancy complications including preeclampsia, fetal growth restriction, preterm birth, and stillbirth and possible therapeutic strategies to preserve placental function.
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Affiliation(s)
- Marie-Eve Brien
- a Ste-Justine Hospital Research Center, Department of Obstetrics and Gynecology, Université de Montréal, Montreal, QC H3T 1J4, Canada.,b Department of Microbiology, Infectiology and Immunology, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada
| | - Bernadette Baker
- c Maternal and Fetal Health Research Centre, University of Manchester, Manchester, M13 9WL, United Kingdom.,d St. Mary's Hospital, Central Manchester University Hospital National Health Service Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, United Kingdom
| | - Cyntia Duval
- a Ste-Justine Hospital Research Center, Department of Obstetrics and Gynecology, Université de Montréal, Montreal, QC H3T 1J4, Canada.,e Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada
| | - Virginie Gaudreault
- a Ste-Justine Hospital Research Center, Department of Obstetrics and Gynecology, Université de Montréal, Montreal, QC H3T 1J4, Canada.,e Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada
| | - Rebecca L Jones
- c Maternal and Fetal Health Research Centre, University of Manchester, Manchester, M13 9WL, United Kingdom.,d St. Mary's Hospital, Central Manchester University Hospital National Health Service Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, United Kingdom
| | - Sylvie Girard
- a Ste-Justine Hospital Research Center, Department of Obstetrics and Gynecology, Université de Montréal, Montreal, QC H3T 1J4, Canada.,b Department of Microbiology, Infectiology and Immunology, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada.,e Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada
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17
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Miraee-Nedjad S, Sims PFG, Schwartz JM, Doig AJ. Effect of IAPP on the proteome of cultured Rin-5F cells. BMC BIOCHEMISTRY 2018; 19:9. [PMID: 30419808 PMCID: PMC6233276 DOI: 10.1186/s12858-018-0099-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 10/22/2018] [Indexed: 11/12/2022]
Abstract
Background Islet amyloid polypeptide (IAPP) or amylin deposits can be found in the islets of type 2 diabetes patients. The peptide is suggested to be involved in the etiology of the disease through formation of amyloid deposits and destruction of β islet cells, though the underlying molecular events leading from IAPP deposition to β cell death are still largely unknown. Results We used OFFGEL™ proteomics to study how IAPP exposure affects the proteome of rat pancreatic insulinoma Rin-5F cells. The OFFGEL™ methodology is highly effective at generating quantitative data on hundreds of proteins affected by IAPP, with its accuracy confirmed by In Cell Western and Quantitative Real Time PCR results. Combining data on individual proteins identifies pathways and protein complexes affected by IAPP. IAPP disrupts protein synthesis and degradation, and induces oxidative stress. It causes decreases in protein transport and localization. IAPP disrupts the regulation of ubiquitin-dependent protein degradation and increases catabolic processes. IAPP causes decreases in protein transport and localization, and affects the cytoskeleton, DNA repair and oxidative stress. Conclusions Results are consistent with a model where IAPP aggregates overwhelm the ability of a cell to degrade proteins via the ubiquitin system. Ultimately this leads to apoptosis. IAPP aggregates may be also toxic to the cell by causing oxidative stress, leading to DNA damage or by decreasing protein transport. The reversal of any of these effects, perhaps by targeting proteins which alter in response to IAPP, may be beneficial for type II diabetes. Electronic supplementary material The online version of this article (10.1186/s12858-018-0099-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Samaneh Miraee-Nedjad
- Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK
| | - Paul F G Sims
- Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK
| | - Jean-Marc Schwartz
- Division of Evolution & Genomic Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK
| | - Andrew J Doig
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK.
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18
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Skórzyńska-Dziduszko KE, Kimber-Trojnar Ż, Patro-Małysza J, Stenzel-Bembenek A, Oleszczuk J, Leszczyńska-Gorzelak B. Heat Shock Proteins as a Potential Therapeutic Target in the Treatment of Gestational Diabetes Mellitus: What We Know so Far. Int J Mol Sci 2018; 19:ijms19103205. [PMID: 30336561 PMCID: PMC6213996 DOI: 10.3390/ijms19103205] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 10/14/2018] [Accepted: 10/15/2018] [Indexed: 12/16/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is a complex condition that involves a variety of pathological mechanisms, including pancreatic β-cell failure, insulin resistance, and inflammation. There is an increasing body of literature suggesting that these interrelated phenomena may arise from the common mechanism of endoplasmic reticulum (ER) stress. Both obesity-associated nutrient excess and hyperglycemia disturb ER function in protein folding and transport. This results in the accumulation of polypeptides in the ER lumen and impairs insulin secretion and signaling. Exercise elicits metabolic adaptive responses, which may help to restore normal chaperone expression in insulin-resistant tissues. Pharmacological induction of chaperones, mimicking the metabolic effect of exercise, is a promising therapeutic tool for preventing GDM by maintaining the body's natural stress response. Metformin, a commonly used diabetes medication, has recently been identified as a modulator of ER-stress-associated inflammation. The results of recent studies suggest the potential use of chemical ER chaperones and antioxidant vitamins as therapeutic interventions that can prevent glucose-induced ER stress in GDM placentas. In this review, we discuss whether chaperones may significantly contribute to the pathogenesis of GDM, as well as whether they can be a potential therapeutic target in GDM treatment.
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Affiliation(s)
| | - Żaneta Kimber-Trojnar
- Department of Obstetrics and Perinatology, Medical University of Lublin, K. Jaczewskiego 8 Street, 20-954 Lublin, Poland.
| | - Jolanta Patro-Małysza
- Department of Obstetrics and Perinatology, Medical University of Lublin, K. Jaczewskiego 8 Street, 20-954 Lublin, Poland.
| | - Agnieszka Stenzel-Bembenek
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, W. Chodźki 1 Street, 20-093 Lublin, Poland.
| | - Jan Oleszczuk
- Department of Obstetrics and Perinatology, Medical University of Lublin, K. Jaczewskiego 8 Street, 20-954 Lublin, Poland.
| | - Bożena Leszczyńska-Gorzelak
- Department of Obstetrics and Perinatology, Medical University of Lublin, K. Jaczewskiego 8 Street, 20-954 Lublin, Poland.
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19
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Pockley AG, Henderson B. Extracellular cell stress (heat shock) proteins-immune responses and disease: an overview. Philos Trans R Soc Lond B Biol Sci 2018; 373:rstb.2016.0522. [PMID: 29203707 DOI: 10.1098/rstb.2016.0522] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/07/2017] [Indexed: 12/11/2022] Open
Abstract
Extracellular cell stress proteins are highly conserved phylogenetically and have been shown to act as powerful signalling agonists and receptors for selected ligands in several different settings. They also act as immunostimulatory 'danger signals' for the innate and adaptive immune systems. Other studies have shown that cell stress proteins and the induction of immune reactivity to self-cell stress proteins can attenuate disease processes. Some proteins (e.g. Hsp60, Hsp70, gp96) exhibit both inflammatory and anti-inflammatory properties, depending on the context in which they encounter responding immune cells. The burgeoning literature reporting the presence of stress proteins in a range of biological fluids in healthy individuals/non-diseased settings, the association of extracellular stress protein levels with a plethora of clinical and pathological conditions and the selective expression of a membrane form of Hsp70 on cancer cells now supports the concept that extracellular cell stress proteins are involved in maintaining/regulating organismal homeostasis and in disease processes and phenotype. Cell stress proteins, therefore, form a biologically complex extracellular cell stress protein network having diverse biological, homeostatic and immunomodulatory properties, the understanding of which offers exciting opportunities for delivering novel approaches to predict, identify, diagnose, manage and treat disease.This article is part of the theme issue 'Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective'.
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Affiliation(s)
- A Graham Pockley
- John van Geest Cancer Research Centre, Nottingham Trent University, Nottingham NG11 8NS, UK
| | - Brian Henderson
- Division of Microbial Diseases, UCL Eastman Dental Institute, London WC1X 8LD, UK
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20
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Angelini G, Salinari S, Bertuzzi A, Iaconelli A, Mingrone G. Metabolic surgery improves insulin resistance through the reduction of gut-secreted heat shock proteins. Commun Biol 2018; 1:69. [PMID: 30271951 PMCID: PMC6123703 DOI: 10.1038/s42003-018-0069-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 05/07/2018] [Indexed: 12/29/2022] Open
Abstract
Metabolic surgery improves insulin resistance and is associated with the remission of type 2 diabetes, but the mechanisms involved remain unknown. We find that human jejunal mucosa secretes heat shock proteins (HSPs) in vitro, in particular HSP70 and GRP78. Circulating levels of HSP70 are higher in people resistant to insulin, compared to the healthy and normalize after duodenal-jejunal bypass. Insulin sensitivity negatively correlates with the plasma level of HSP70, while body mass index does not. A high-energy diet increases the circulating levels of HSP70 and insulin resistance. HSP70 stimulates the accumulation of lipid droplets and inhibits Ser473 phosphorylation of Akt and glucose uptake in immortalized liver cells and peripheral blood cells. Serum depleted of HSPs, as well as the serum from the insulin-resistant people subjected to a duodenal-jejunal bypass, reverse these features, identifying gut-secreted HSPs as possible causes of insulin resistance. Duodenal-jejunal bypass might reduce the secretion of HSPs either by shortening the food transit or by decreasing the fat stimulation of endocrine cells.
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Affiliation(s)
- Giulia Angelini
- Department of Internal Medicine, Catholic University, Largo A. Gemelli 8, 00168, Rome, Italy
| | - Serenella Salinari
- Department of Computer, Control, and Management Engineering "Antonio Ruberti", University of Rome "Sapienza", Via Ariosto 25, 00185, Rome, Italy
| | - Alessandro Bertuzzi
- CNR-Institute of Systems Analysis and Computer Science (IASI), Via dei Taurini 19, 00185, Rome, Italy
| | - Amerigo Iaconelli
- Department of Internal Medicine, Catholic University, Largo A. Gemelli 8, 00168, Rome, Italy
| | - Geltrude Mingrone
- Department of Internal Medicine, Catholic University, Largo A. Gemelli 8, 00168, Rome, Italy. .,Diabetes and Nutritional Sciences, Hodgkin Building, Guy's Campus, King's College London, London, UK.
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21
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Preventive and promotive effects of habitual hot spa-bathing on the elderly in Japan. Sci Rep 2018; 8:133. [PMID: 29317745 PMCID: PMC5760572 DOI: 10.1038/s41598-017-18488-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 12/12/2017] [Indexed: 12/19/2022] Open
Abstract
Although body-warming with hot spa-bathing has been proposed to exert medical therapeutic effects on certain diseases, whether body-warming has preventive and promotive effects remains unknown. To clarify this issue, an epidemiological questionnaire study regarding personal hot spa-bathing habits and disease history was carried out in Japan, where individuals engage in daily warm water bathing. Questionnaires regarding hot spa-bathing habits and disease history were randomly sent to 20,000 residents aged ≥65 years living in Beppu, a city in Japan that has the highest concentration of hot spa sources in the world. The results showed that habitual hot spa-bathing exerts preventive or promotive effects on the occurrence of certain diseases, such as hypertension (preventive) and collagen disease (promotive) in women, and cardiovascular diseases (preventive) and colon cancer survival (promotive) in men. These findings suggest that habitual body warming is an effective and economical method with beneficial preventive and promotive effects on various diseases.
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Upadhyaya B, Larsen T, Barwari S, Louwagie EJ, Baack ML, Dey M. Prenatal Exposure to a Maternal High-Fat Diet Affects Histone Modification of Cardiometabolic Genes in Newborn Rats. Nutrients 2017; 9:E407. [PMID: 28425976 PMCID: PMC5409746 DOI: 10.3390/nu9040407] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2017] [Revised: 04/12/2017] [Accepted: 04/14/2017] [Indexed: 12/15/2022] Open
Abstract
Infants born to women with diabetes or obesity are exposed to excess circulating fuels during fetal heart development and are at higher risk of cardiac diseases. We have previously shown that late-gestation diabetes, especially in conjunction with a maternal high-fat (HF) diet, impairs cardiac functions in rat-offspring. This study investigated changes in genome-wide histone modifications in newborn hearts from rat-pups exposed to maternal diabetes and HF-diet. Chromatin-immunoprecipitation-sequencing revealed a differential peak distribution on gene promoters in exposed pups with respect to acetylation of lysines 9 and 14 and to trimethylation of lysines 4 and 27 in histone H3 (all, false discovery rate, FDR < 0.1). In the HF-diet exposed offspring, 54% of the annotated genes showed the gene-activating mark trimethylated lysine 4. Many of these genes (1) are associated with the "metabolic process" in general and particularly with "positive regulation of cholesterol biosynthesis" (FDR = 0.03); (2) overlap with 455 quantitative trait loci for blood pressure, body weight, serum cholesterol (all, FDR < 0.1); and (3) are linked to cardiac disease susceptibility/progression, based on disease ontology analyses and scientific literature. These results indicate that maternal HF-diet changes the cardiac histone signature in offspring suggesting a fuel-mediated epigenetic reprogramming of cardiac tissue in utero.
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Affiliation(s)
- Bijaya Upadhyaya
- Department of Health and Nutritional Sciences, Box 2203, South Dakota State University, Brookings, SD 57007, USA.
| | - Tricia Larsen
- Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104, USA.
| | - Shivon Barwari
- Department of Health and Nutritional Sciences, Box 2203, South Dakota State University, Brookings, SD 57007, USA.
| | - Eli J Louwagie
- Sanford School of Medicine-University of South Dakota, Sioux Falls, SD 57105, USA.
| | - Michelle L Baack
- Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104, USA.
- Sanford School of Medicine-University of South Dakota, Sioux Falls, SD 57105, USA.
- Children's Health Specialty Clinic, Sanford Children's Hospital, Sioux Falls, SD 57117, USA.
| | - Moul Dey
- Department of Health and Nutritional Sciences, Box 2203, South Dakota State University, Brookings, SD 57007, USA.
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Higher β-HCG concentrations and higher birthweights ensue from single vitrified embryo transfers. Reprod Biomed Online 2016; 33:149-60. [DOI: 10.1016/j.rbmo.2016.04.014] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Revised: 04/20/2016] [Accepted: 04/20/2016] [Indexed: 11/18/2022]
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Serum Malondialdehyde Concentration and Glutathione Peroxidase Activity in a Longitudinal Study of Gestational Diabetes. PLoS One 2016; 11:e0155353. [PMID: 27228087 PMCID: PMC4882015 DOI: 10.1371/journal.pone.0155353] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 04/27/2016] [Indexed: 01/02/2023] Open
Abstract
Aims The main goal of this study was to evaluate the presence of oxidative damage and to quantify its level in gestational diabetes. Methods Thirty-six healthy women and thirty-six women with gestational diabetes were studied in the three trimesters of pregnancy regarding their levels of oxidative stress markers. These women were diagnosed with diabetes in the second trimester of pregnancy. Blood glucose levels after 100g glucose tolerance test were higher than 190, 165 or 145 mg/dl, 1, 2 or 3 hours after glucose intake. Results The group of women with gestational diabetes had higher serum malondialdehyde levels, with significant differences between groups in the first and second trimester. The mean values of serum glutathione peroxidase activity in the diabetic women were significantly lower in the first trimester. In the group of women with gestational diabetes there was a negative linear correlation between serum malondialdehyde concentration and glutathione peroxidase activity in the second and third trimester. Conclusions In this observational and longitudinal study in pregnant women, the alterations attributable to oxidative stress were present before the biochemical detection of the HbA1c increase. Usual recommendations once GD is detected (adequate metabolic control, as well as any other normally proposed to these patients) lowered the concentration of malondialdehyde at the end of pregnancy to the same levels of the healthy controls. Serum glutathione peroxidase activity in women with gestational diabetes increased during the gestational period.
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Radons J. The human HSP70 family of chaperones: where do we stand? Cell Stress Chaperones 2016; 21:379-404. [PMID: 26865365 PMCID: PMC4837186 DOI: 10.1007/s12192-016-0676-6] [Citation(s) in RCA: 389] [Impact Index Per Article: 43.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Revised: 01/29/2016] [Accepted: 01/29/2016] [Indexed: 01/23/2023] Open
Abstract
The 70-kDa heat shock protein (HSP70) family of molecular chaperones represents one of the most ubiquitous classes of chaperones and is highly conserved in all organisms. Members of the HSP70 family control all aspects of cellular proteostasis such as nascent protein chain folding, protein import into organelles, recovering of proteins from aggregation, and assembly of multi-protein complexes. These chaperones augment organismal survival and longevity in the face of proteotoxic stress by enhancing cell viability and facilitating protein damage repair. Extracellular HSP70s have a number of cytoprotective and immunomodulatory functions, the latter either in the context of facilitating the cross-presentation of immunogenic peptides via major histocompatibility complex (MHC) antigens or in the context of acting as "chaperokines" or stimulators of innate immune responses. Studies have linked the expression of HSP70s to several types of carcinoma, with Hsp70 expression being associated with therapeutic resistance, metastasis, and poor clinical outcome. In malignantly transformed cells, HSP70s protect cells from the proteotoxic stress associated with abnormally rapid proliferation, suppress cellular senescence, and confer resistance to stress-induced apoptosis including protection against cytostatic drugs and radiation therapy. All of the cellular activities of HSP70s depend on their adenosine-5'-triphosphate (ATP)-regulated ability to interact with exposed hydrophobic surfaces of proteins. ATP hydrolysis and adenosine diphosphate (ADP)/ATP exchange are key events for substrate binding and Hsp70 release during folding of nascent polypeptides. Several proteins that bind to distinct subdomains of Hsp70 and consequently modulate the activity of the chaperone have been identified as HSP70 co-chaperones. This review focuses on the regulation, function, and relevance of the molecular Hsp70 chaperone machinery to disease and its potential as a therapeutic target.
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Affiliation(s)
- Jürgen Radons
- Scientific Consulting International, Mühldorfer Str. 64, 84503, Altötting, Germany.
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Qu B, Jia Y, Liu Y, Wang H, Ren G, Wang H. The detection and role of heat shock protein 70 in various nondisease conditions and disease conditions: a literature review. Cell Stress Chaperones 2015; 20:885-92. [PMID: 26139132 PMCID: PMC4595429 DOI: 10.1007/s12192-015-0618-8] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Revised: 06/08/2015] [Accepted: 06/23/2015] [Indexed: 12/26/2022] Open
Abstract
As an intracellular polypeptide, heat shock protein 70 (HSP70) can be exposed on the plasma membrane and/or released into the circulation. However, the role of HSP70 in various nondisease and disease conditions remains unknown. Quantitative methods for the detection of HSP70 have been used in clinical studies, revealing that an increase in circulating HSP70 is associated with various types of exercise, elderly patients presenting with inflammation, mobile phones, inflammation, sepsis, chronic obstructive pulmonary disease, asthma, carotid intima-media thickness, glutamine-treated ill patients, mortality, diabetes mellitus, active chronic glomerulonephritis, and cancers. Circulating HSP70 decreases with age in humans and in obstructive sleep apnea, arteriosclerosis, atrial fibrillation (AF) following coronary artery bypass surgery, nonalcoholic fatty liver disease, moderate-to-severe alcoholic fatty liver disease, hepatic steatosis, and Helicobacter pylori infection. In conclusion, quantitative methods can be used to detect HSP70, particularly in determining circulating HSP70 levels, using more convenient and rapid screening methods. Studies have shown that changes in HSP70 are associated with various nondisease and disease conditions; thus, HSP70 might be a novel potential biomarker reflecting various nondisease conditions and also the severity of disease conditions. However, the reliability and accuracy, as well as the underlying mechanism, of this relationship remain poorly understood, and large-sample clinical research must be performed to verify the role.
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Affiliation(s)
- Baoge Qu
- Internal Medicine, Taishan Hospital, No. 3 Tianwaicun Street, Taian City, Shandong, 271000, People's Republic of China.
| | - Yiguo Jia
- Internal Medicine, Taishan Hospital, No. 3 Tianwaicun Street, Taian City, Shandong, 271000, People's Republic of China
| | - Yuanxun Liu
- Internal Medicine, Taishan Hospital, No. 3 Tianwaicun Street, Taian City, Shandong, 271000, People's Republic of China
| | - Hui Wang
- Internal Medicine, Taishan Hospital, No. 3 Tianwaicun Street, Taian City, Shandong, 271000, People's Republic of China
| | - Guangying Ren
- Internal Medicine, Taishan Hospital, No. 3 Tianwaicun Street, Taian City, Shandong, 271000, People's Republic of China
| | - Hong Wang
- Internal Medicine, Taishan Hospital, No. 3 Tianwaicun Street, Taian City, Shandong, 271000, People's Republic of China
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Xing B, Wang L, Li Q, Cao Y, Dong X, Liang J, Wu X. Hsp70 plays an important role in high-fat diet induced gestational hyperglycemia in mice. J Physiol Biochem 2015; 71:649-58. [PMID: 26318018 DOI: 10.1007/s13105-015-0430-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Accepted: 08/14/2015] [Indexed: 02/07/2023]
Abstract
Gestational diabetes mellitus (GDM) has emerged as an epidemic disease during the last decade, affecting about 2 to 5% pregnant women. Even among women who have gestational hyperglycemia may also be positively related to adverse outcomes as GDM. Since heat shock protein (Hsp) 70 has been reported to be associated with diabetes and insulin resistance and its expression was reported to be negatively regulated by the membrane-permeable Hsp70 inhibitor MAL3-101 while positively regulated by the Hsp70 activator BGP-15, we investigated whether Hsp70 played a role in a gestational hyperglycemia mouse model. Mice were divided into non-pregnant and pregnant groups, and each comprised three subgroups: control, high-fat diet (HFD) + MAL3-101, and HFD + BGP-15. We examined the serum levels of triglycerides, total cholesterol, glucose, and insulin, as well as conducted thermal detection of brown adipose tissue (BAT). The role of Hsp70 in BAT apoptosis was also investigated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and caspase-3 staining. Higher serum level of Hsp70 was associated with increased bodyweight gain after pregnancy in mice fed HFD. Circulating Hsp70 was elevated in control pregnant mice compared to control non-pregnant mice. BGP-induced serum Hsp70 expression reduced triglycerides, total cholesterol, glucose, and insulin levels in the serum. Additionally, thermal detection of BAT, TUNEL, and caspase-3 staining revealed relationship correlation between Hsp70 and BAT functions. Hsp70 level is associated with hyperglycemia during pregnancy. Our results support the role of Hsp70 in facilitating BAT activities and protecting BAT cells from apoptosis via caspase-3 pathway.
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Affiliation(s)
- Baoheng Xing
- Department of Obstetrics, Cangzhou City Central Hospital, Cangzhou, 061001, China.
| | - Lili Wang
- Department of Neurology, Cangzhou City People's Hospital, Cangzhou, 061000, China
| | - Qin Li
- Department of Obstetrics, Cangzhou City Central Hospital, Cangzhou, 061001, China
| | - Yalei Cao
- Department of Obstetrics, Cangzhou City Central Hospital, Cangzhou, 061001, China
| | - Xiujuan Dong
- Department of Obstetrics, Cangzhou City Central Hospital, Cangzhou, 061001, China
| | - Jun Liang
- Department of Gynecology and Obstetrics, Bethune International Peace Hospital, Zhongshan West Road, Shijiazhuang, 050051, People's Republic of China
| | - Xiaohua Wu
- Department of Gynecology and Obstetrics, Bethune International Peace Hospital, Zhongshan West Road, Shijiazhuang, 050051, People's Republic of China.
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