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Cao J, Hu W, Chen Y, Ailikaiti A, Zhang Z, Rong L, Yu H, Wang H. Adrenal High-Expressional CYP27A1 Mediates Bile Acid Increase and Functional Impairment in Adult Male Offspring by Prenatal Dexamethasone Exposure. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2413299. [PMID: 39950753 PMCID: PMC11984885 DOI: 10.1002/advs.202413299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 01/16/2025] [Indexed: 04/12/2025]
Abstract
Prenatal dexamethasone exposure (PDE) can impact adrenal corticosteroid synthesis in adult offspring. Furthermore, the adrenal gland can autonomously synthesize bile acids, but local bile acids accumulation has cytotoxic effects. This study found that PDE increased histone 3 lysine 27 acetylation (H3K27ac) levels in the promoter region of cholesterol 27 hydroxylase (CYP27A1) and its expression, as well as total bile acids (TBA) concentrations and enhanced endoplasmic reticulum stress (ERS) and inhibit steroid synthesis in adult male offspring rat adrenal glands. However, it is reversed in females. Tracing back to the prenatal stage and in combination with cellular experiments, it is further revealed that dexamethasone can regulate glucocorticoid receptor (GR)/SET binding protein 1 (SETBP1)/CYP27A1 signal pathway, consequently cause intracellular increase of bile acids. Finally, administration of nilvadipine (CYP27A1 inhibitor) to male offspring for 4 weeks after birth resulted in the reversal of PDE-induced adrenal morphological and functional damage. In conclusion, PDE induces fetal adrenal corticosteroid dysfunction in adult male offspring by upregulating CYP27A1 promoter region H3K27ac levels and expression in the adrenal gland through the GR/SETBP1 signaling pathway. This effect persists beyond birth, leading to bile acids local increase and subsequent enhancement of ERS, ultimately inducing cellular dysfunction in adult adrenal glands.
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Affiliation(s)
- Jiangang Cao
- Department of Pharmacology, School of Basic Medical SciencesWuhan UniversityWuhan430071China
- Institute of Clinical Pharmacy ResearchThe Affiliated Nanhua HospitalHengyang Medical SchoolUniversity of South ChinaHengyangHunan421001China
| | - Wen Hu
- Department of PharmacyZhongnan Hospital of Wuhan UniversityWuhan430071China
- Hubei Provincial Key Laboratory of Developmentally Originated DiseaseWuhan430071China
| | - Yawen Chen
- Department of Pharmacology, School of Basic Medical SciencesWuhan UniversityWuhan430071China
| | | | - Ziyi Zhang
- Department of Pharmacology, School of Basic Medical SciencesWuhan UniversityWuhan430071China
| | - Lingbo Rong
- Department of Pharmacology, School of Basic Medical SciencesWuhan UniversityWuhan430071China
| | - Hong Yu
- Department of Pharmacology, School of Basic Medical SciencesWuhan UniversityWuhan430071China
- Hubei Provincial Key Laboratory of Developmentally Originated DiseaseWuhan430071China
| | - Hui Wang
- Department of Pharmacology, School of Basic Medical SciencesWuhan UniversityWuhan430071China
- Hubei Provincial Key Laboratory of Developmentally Originated DiseaseWuhan430071China
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Xiong F, Wang C, Lu J, Bai G, Zhou D, Ling J. 4-PBA exerts brain-protective effects against sepsis-associated encephalopathy in a mouse model of sepsis. Exp Neurol 2024; 375:114738. [PMID: 38395217 DOI: 10.1016/j.expneurol.2024.114738] [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: 12/18/2023] [Revised: 02/09/2024] [Accepted: 02/20/2024] [Indexed: 02/25/2024]
Abstract
BACKGROUND Neuroinflammation assumes a pivotal role in both the etiological underpinnings and the dynamic progression of sepsis-associated encephalopathy (SAE). The occurrence of cognitive deficits with SAE is associated with neuroinflammation. 4-phenyl butyrate (4-PBA) may control inflammation by inhibiting endoplasmic reticulum stress (ERS). The primary objective of this investigation is to scrutinize the effectiveness of 4-PBA in mitigating neuroinflammation induced by lipopolysaccharides (LPS) and its consequent impact on cognitive function decline. METHODS LPS-injected mice with SAE and LPS-treated BV2 cell were established to serve as experimental paradigms, both contributing to the investigative framework of the study. Cognitive functions were assessed by behavioral tests. Hippocampal neuronal damage was assessed using Golgi staining and Nissl staining. Quantitative PCR assay and immunofluorescence were used to analyze neuroinflammation. Mitochondrial function was examined using transmission electron microscopy. Protein expression analysis was conducted through the application of western blotting methodology, serving as the investigative approach to elucidate molecular signatures in the experimental framework. Endoplasmic reticulum and mitochondrial calcium flow were detected using flow cytometry. To delve deeper into the mechanistic intricacies, the administration of 4μ8c was employed to selectively impede the IRE1α/Xbp1s pathway, constituting a strategic intervention aimed at elucidating underlying regulatory processes. RESULT Expression levels of ERS-related proteins exhibited a significant upregulation in hippocampal tissues of LPS-treated mice when compared to wild-type (WT) counterparts. The administration of 4-PBA notably ameliorated memory deficits in LPS-treated mice. Furthermore, 4-PBA treatment was found to alleviate oxidative stress and neuroinflammation. Mechanistically, the IRE1α/Xbp1s-Ca2+ signaling pathway played a crucial role in mediating the beneficial effects of mitigating oxidative stress and maintaining mitochondrial calcium homeostasis, with inhibition of the IRE-related pathway displaying opposing effects. CONCLUSION Our results suggest that administration of 4-PBA treatment significantly attenuates ERS, alleviates cognitive decline, reduces inflammatory damage, and restores mitochondrial dynamics via the IRE1α/Xbp1s-Ca2+-associated pathway, which provides a new potential therapeutic approach to SAE.
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Affiliation(s)
- Feng Xiong
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong university of science and technology, Wuhan 430000, China; Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong university of science and technology, Wuhan 430000, China
| | - Cailin Wang
- Department of Neurology, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
| | - Jun Lu
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong university of science and technology, Wuhan 430000, China; Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong university of science and technology, Wuhan 430000, China
| | - Guangyang Bai
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong university of science and technology, Wuhan 430000, China; Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong university of science and technology, Wuhan 430000, China
| | - Daixing Zhou
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong university of science and technology, Wuhan 430000, China; Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong university of science and technology, Wuhan 430000, China.
| | - Jianmin Ling
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong university of science and technology, Wuhan 430000, China; Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong university of science and technology, Wuhan 430000, China.
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Jinyi L, Keyu Y, Shanshan D, Shuyang H, Ruirui L, Qingyu G, Fei L. ERS Mediated by GRP-78/PERK/CHOP Signaling Is Involved in Fluoride-Induced Ameloblast Apoptosis. Biol Trace Elem Res 2024; 202:1103-1114. [PMID: 37410266 DOI: 10.1007/s12011-023-03746-5] [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: 02/24/2023] [Accepted: 06/24/2023] [Indexed: 07/07/2023]
Abstract
Fluoride can be widely ingested from the environment, and its excessive intake could result in adverse effects. Dental fluorosis is an early sign of fluoride toxicity which can cause esthetic and functional problems. Though apoptosis in ameloblasts is one of the potential mechanisms, the specific signal cascade is in-conclusive. High-throughput sequencing and molecular biological techniques were used in this study to explore the underlying pathogenesis of dental fluorosis, for its prevention and treatment. A fluorosis cell model was established. Viability and apoptosis rate of mouse ameloblast-derived cell line (LS8 cells) was measured using cell counting kit-8 (CCK-8) assay and flow cytometry analysis. Cells were harvested with or without 2-mM sodium fluoride (NaF) stimulation for high-throughput sequencing. Based on the sequencing data, subcellular structures, endoplasmic reticulum stress (ERS), and apoptosis related biomarkers were verified using transmission electron microscopy, quantitative real-time polymerase chain reaction, and Western blotting techniques. Expression of ERS markers, apoptosis related proteins, and enamel formation enzymes were detected using Western blotting after addition of 4-phenylbutyrate (4-PBA). NaF-inhibited LS8 cells displayed time- and dose- dependent viability. Additionally, apoptosis and morphological changes were observed. RNA-sequencing data showed that protein processing in endoplasmic reticulum was obviously affected. ERS and apoptosis were induced by excessive NaF. Downregulation of kallikrein-related peptidase 4 (KLK4) was also observed. Inhibition of ERS by 4-PBA rescued the apoptotic and functional protein changes in cells. Excessive fluoride induces apoptosis by activating ERS, which is mediated by GRP-78/PERK/CHOP signaling. Key proteinase is present in maturation-stage enamel; KLK4 was also affected by fluoride, but rescued by 4-PBA. This study presents a possibility for therapeutic strategies for dental fluorosis, while further exploration is required.
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Affiliation(s)
- Li Jinyi
- Key laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710004, People's Republic of China
- Department of Pediatric Dentistry, College of Stomatology, Xi'an Jiaotong University, Xi Wu Road No.98, Xi'an 710004, 710041, People's Republic of China
| | - Yang Keyu
- National Regional Children's Medical Center (Northwest), Xi'an Children's Hospital, Affiliated Children's Hospital of Xi'an Jiaotong University, Xi'an, 710003, People's Republic of China
| | - Dai Shanshan
- Key laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710004, People's Republic of China
- Department of Pediatric Dentistry, College of Stomatology, Xi'an Jiaotong University, Xi Wu Road No.98, Xi'an 710004, 710041, People's Republic of China
| | - He Shuyang
- Faculty of dentistry, The university of Hong Kong, Hong Kong, SAR, People's Republic of China
| | - Liu Ruirui
- Key laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710004, People's Republic of China
- Department of Prosthodontics, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710004, People's Republic of China
| | - Guo Qingyu
- Key laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710004, People's Republic of China.
- Department of Pediatric Dentistry, College of Stomatology, Xi'an Jiaotong University, Xi Wu Road No.98, Xi'an 710004, 710041, People's Republic of China.
| | - Liu Fei
- Key laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710004, People's Republic of China.
- Department of Pediatric Dentistry, College of Stomatology, Xi'an Jiaotong University, Xi Wu Road No.98, Xi'an 710004, 710041, People's Republic of China.
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Rico-Llanos G, Porras-Perales Ó, Escalante S, Vázquez-Calero DB, Valiente L, Castillo MI, Pérez-Tejeiro JM, Baglietto-Vargas D, Becerra J, Reguera JM, Duran I, Csukasi F. Cellular stress modulates severity of the inflammatory response in lungs via cell surface BiP. Front Immunol 2022; 13:1054962. [DOI: 10.3389/fimmu.2022.1054962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 10/27/2022] [Indexed: 11/21/2022] Open
Abstract
Inflammation is a central pathogenic feature of the acute respiratory distress syndrome (ARDS) in COVID-19. Previous pathologies such as diabetes, autoimmune or cardiovascular diseases become risk factors for the severe hyperinflammatory syndrome. A common feature among these risk factors is the subclinical presence of cellular stress, a finding that has gained attention after the discovery that BiP (GRP78), a master regulator of stress, participates in the SARS-CoV-2 recognition. Here, we show that BiP serum levels are higher in COVID-19 patients who present certain risk factors. Moreover, early during the infection, BiP levels predict severe pneumonia, supporting the use of BiP as a prognosis biomarker. Using a mouse model of pulmonary inflammation, we observed increased levels of cell surface BiP (cs-BiP) in leukocytes during inflammation. This corresponds with a higher number of neutrophiles, which show naturally high levels of cs-BiP, whereas alveolar macrophages show a higher than usual exposure of BiP in their cell surface. The modulation of cellular stress with the use of a clinically approved drug, 4-PBA, resulted in the amelioration of the lung hyperinflammatory response, supporting the anti-stress therapy as a valid therapeutic strategy for patients developing ARDS. Finally, we identified stress-modulated proteins that shed light into the mechanism underlying the cellular stress-inflammation network in lungs.
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Choi Y, Lee EG, Jeong JH, Yoo WH. 4-Phenylbutyric acid, a potent endoplasmic reticulum stress inhibitor, attenuates the severity of collagen-induced arthritis in mice via inhibition of proliferation and inflammatory responses of synovial fibroblasts. Kaohsiung J Med Sci 2021; 37:604-615. [PMID: 33759334 DOI: 10.1002/kjm2.12376] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 02/02/2021] [Accepted: 02/07/2021] [Indexed: 11/11/2022] Open
Abstract
4-Phenylbutyric acid (4-PBA) exerts potent pharmacological effects, including anti-inflammatory properties, via inhibition of endoplasmic reticulum (ER) stress. However, it is not known whether 4-PBA attenuates the severity of rheumatoid arthritis. The present study aimed to determine whether the inhibition of ER stress by 4-PBA ameliorated experimentally induced arthritis. The proliferation of synovial fibroblasts (SFs) and expression of matrix metalloproteinases (MMPs) were evaluated in the presence of interleukin (IL)-1β with or without 4-PBA. The effect of 4-PBA on the phosphorylation of Mitogen-activated protein kinase (MAPK) and the activation of Nuclear factor-κB (NF-κB) in IL-1β-stimulated SFs was assessed. In an in vivo study, the effects of 4-PBA were investigated using DBA/1 mice with collagen-induced arthritis (CIA). Clinical, histological, and serological assessments of CIA treated with 4-PBA were performed to determine the therapeutic effect of 4-PBA. In vitro, 4-PBA inhibited the proliferation and expression of IL-1β-stimulated SFs and MMP-1 and MMP-3 through the suppression of both the phosphorylation of MAPKs and NF-κB in IL-1β-stimulated SFs. The 4-PBA treatment markedly attenuated the severity of arthritis in CIA mice. The 4-PBA treatment ameliorated joint swelling and the degree of bone erosion and destruction and decreased the level of inflammatory cytokines and MMP-3 and Cox-2. Furthermore, remarkable improvements in histopathological findings occurred in 4-PBA-treated mice. These findings suggested that 4-PBA could attenuate the severity of arthritis in CIA mice by partially blocking the phosphorylation of MAPKs and the activation of NF-κB in SFs. Thus, through the inhibition of ER stress, 4-PBA may be a potent agent for the treatment of RA.
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Affiliation(s)
- Yunjung Choi
- Division of Rheumatology, Department of Internal Medicine, Jeonbuk National University Hospital, Jeonju, Republic of Korea.,Research Institute of Clinical Medicine, Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Republic of Korea.,Department of Internal Medicine, Jeonbuk National University Medical School, Jeonju, Republic of Korea
| | - Eun-Gyeong Lee
- Research Institute of Clinical Medicine, Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Republic of Korea.,Department of Internal Medicine, Jeonbuk National University Medical School, Jeonju, Republic of Korea
| | - Ji-Hyeon Jeong
- Research Institute of Clinical Medicine, Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Republic of Korea.,Department of Internal Medicine, Jeonbuk National University Medical School, Jeonju, Republic of Korea
| | - Wan-Hee Yoo
- Division of Rheumatology, Department of Internal Medicine, Jeonbuk National University Hospital, Jeonju, Republic of Korea.,Research Institute of Clinical Medicine, Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Republic of Korea.,Department of Internal Medicine, Jeonbuk National University Medical School, Jeonju, Republic of Korea
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Jerotic D, Suvakov S, Matic M, Alqudah A, Grieve DJ, Pljesa-Ercegovac M, Savic-Radojevic A, Damjanovic T, Dimkovic N, McClements L, Simic T. GSTM1 Modulates Expression of Endothelial Adhesion Molecules in Uremic Milieu. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6678924. [PMID: 33574979 PMCID: PMC7860968 DOI: 10.1155/2021/6678924] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/22/2020] [Accepted: 12/26/2020] [Indexed: 01/08/2023]
Abstract
Deletion polymorphism of glutathione S-transferase M1 (GSTM1), a phase II detoxification and antioxidant enzyme, increases susceptibility to end-stage renal disease (ESRD) as well as the development of cardiovascular diseases (CVD) among ESRD patients and leads to their shorter cardiovascular survival. The mechanisms by which GSTM1 downregulation contributes to oxidative stress and inflammation in endothelial cells in uremic conditions have not been investigated so far. Therefore, the aim of the present study was to elucidate the effects of GSTM1 knockdown on oxidative stress and expression of a panel of inflammatory markers in human umbilical vein endothelial cells (HUVECs) exposed to uremic serum. Additionally, we aimed to discern whether GSTM1-null genotype is associated with serum levels of adhesion molecules in ESRD patients. HUVECs treated with uremic serum exhibited impaired redox balance characterized by enhanced lipid peroxidation and decreased antioxidant enzyme activities, independently of the GSTM1 knockdown. In response to uremic injury, HUVECs exhibited alteration in the expression of a series of inflammatory cytokines including retinol-binding protein 4 (RBP4), regulated on activation, normal T cell expressed and secreted (RANTES), C-reactive protein (CRP), angiogenin, dickkopf-1 (Dkk-1), and platelet factor 4 (PF4). GSTM1 knockdown in HUVECs showed upregulation of monocyte chemoattractant protein-1 (MCP-1), a cytokine involved in the regulation of monocyte migration and adhesion. These cells also have shown upregulated intracellular and vascular cell adhesion molecules (ICAM-1 and VCAM-1). In accordance with these findings, the levels of serum ICAM-1 and VCAM-1 (sICAM-1 and sVCAM-1) were increased in ESRD patients lacking GSTM1, in comparison with patients with the GSTM1-active genotype. Based on these results, it may be concluded that incubation of endothelial cells in uremic serum induces redox imbalance accompanied with altered expression of a series of cytokines involved in arteriosclerosis and atherosclerosis. The association of GSTM1 downregulation with the altered expression of adhesion molecules might be at least partly responsible for the increased susceptibility of ESRD patients to CVD.
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Affiliation(s)
- Djurdja Jerotic
- Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Sonja Suvakov
- Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Marija Matic
- Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Abdelrahim Alqudah
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmaceutical Sciences, The Hashemite University, P.O. Box 330127 Zarqa 13133, Jordan
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
| | - David J. Grieve
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
| | - Marija Pljesa-Ercegovac
- Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Ana Savic-Radojevic
- Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Tatjana Damjanovic
- Clinical Department for Renal Diseases, Zvezdara University Medical Center, 11000 Belgrade, Serbia
| | - Nada Dimkovic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
- Clinical Department for Renal Diseases, Zvezdara University Medical Center, 11000 Belgrade, Serbia
| | - Lana McClements
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
- School of Life Sciences, Faculty of Science, University of Technology Sydney, 2007, NSW, Australia
| | - Tatjana Simic
- Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
- Serbian Academy of Sciences and Arts, 11000 Belgrade, Serbia
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4-Phenylbutyric Acid Attenuates Endoplasmic Reticulum Stress-Mediated Intestinal Epithelial Cell Apoptosis in Rats with Severe Acute Pancreatitis. Dig Dis Sci 2019; 64:1535-1547. [PMID: 30607691 DOI: 10.1007/s10620-018-5437-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 12/15/2018] [Indexed: 12/13/2022]
Abstract
OBJECTIVES The present study aimed to determine whether intestinal epithelial cell (IECs) apoptosis could be induced by endoplasmic reticulum stress (ERS) in severe acute pancreatitis (SAP), and the role of chemical chaperone 4-phenylbutyric acid (4-PBA) in SAP-associated intestinal barrier injury. METHODS Twenty-four male Sprague Dawley rats were randomly divided into three groups: the sham operation group, the SAP group, and the SAP model plus 4-PBA treatment group (4-PBA group). A rat model of SAP was induced by retrograde injection of 5% sodium taurocholate (STC) into the biliopancreatic duct; in the 4-PBA group, 4-PBA was injected intraperitoneally at a dose of 50 mg/kg body weight for 3 days before modeling. RESULTS The results indicated that 4-PBA attenuated the following: (1) pancreas and intestinal pathological injuries, (2) serum TNF-α, IL-1β, and IL-6, (3) serum DAO level, serum endotoxin level, (4) the apoptosis of IECs, (5) ER stress markers (caspase-12, CHOP, GRP78, PERK, IRE1α, ATF6) and caspase-3 expression in intestinal. However, the serum AMY, LIPA levels, and the expression of caspase-9, caspase-8 were just slightly decreased. CONCLUSIONS ERS may be considered a predominant pathway, which is involved in the apoptosis of IECs during SAP. Furthermore, 4-PBA protects IECs against apoptosis in STC-induced SAP by attenuating the severity of ERS.
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Lipid-regulating properties of butyric acid and 4-phenylbutyric acid: Molecular mechanisms and therapeutic applications. Pharmacol Res 2019; 144:116-131. [PMID: 30954630 DOI: 10.1016/j.phrs.2019.04.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 02/08/2019] [Accepted: 04/01/2019] [Indexed: 12/30/2022]
Abstract
In the past two decades, significant advances have been made in the etiology of lipid disorders. Concomitantly, the discovery of liporegulatory functions of certain short-chain fatty acids has generated interest in their clinical applications. In particular, butyric acid (BA) and its derivative, 4-phenylbutyric acid (PBA), which afford health benefits against lipid disorders while being generally well tolerated by animals and humans have been assessed clinically. This review examines the evidence from cell, animal and human studies pertaining to the lipid-regulating effects of BA and PBA, their molecular mechanisms and therapeutic potential. Collectively, the evidence supports the view that intakes of BA and PBA benefit lipid homeostasis across biological systems. We reviewed the evidence that BA and PBA downregulate de novo lipogenesis, ameliorate lipotoxicity, slow down atherosclerosis progression, and stimulate fatty acid β-oxidation. Central to their mode of action, BA appears to function as a histone deacetylase (HDAC) inhibitor while PBA acts as a chemical chaperone and/or a HDAC inhibitor. Areas of further inquiry include the effects of BA and PBA on adipogenesis, lipolysis and apolipoprotein metabolism.
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Endoplasmic Reticulum Stress, a Driver or an Innocent Bystander in Endothelial Dysfunction Associated with Hypertension? Curr Hypertens Rep 2018; 19:64. [PMID: 28717886 DOI: 10.1007/s11906-017-0762-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
PURPOSE OF REVIEW Hypertension (htn) is a polygenic disorder that effects up to one third of the US population. The endoplasmic reticulum (ER) stress response is a homeostatic pathway that regulates membrane structure, protein folding, and secretory function. Emerging evidence suggests that ER stress may induce endothelial dysfunction; however, it is unclear whether ER stress-associated endothelial dysfunction modulates htn. RECENT FINDINGS Exogenous and endogenous molecules activate ER stress in the endothelium, and ER stress mediates some forms of neurogenic htn, such as angiotensin II-dependent htn. Human studies suggest that ER stress induces endothelial dysfunction, though direct evidence that ER stress augments blood pressure in humans is lacking. However, animal and cellular models demonstrate direct evidence that ER stress influences htn. ER stress is likely one of many players in a complex interplay among molecular pathways that influence the expression of htn. Targeted activation of specific ER stress pathways may provide novel therapeutic opportunities.
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He L, Wang KN, Zheng Y, Cao JJ, Zhang MF, Tan CP, Ji LN, Mao ZW. Cyclometalated iridium(iii) complexes induce mitochondria-derived paraptotic cell death and inhibit tumor growthin vivo. Dalton Trans 2018; 47:6942-6953. [DOI: 10.1039/c8dt00783g] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
A potent anticancer Ir(iii) complex induces paraptotic cell death by causing mitochondrial dysfunction rapidly and inhibits tumor growth significantlyin vivo.
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Affiliation(s)
- Liang He
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry
- School of Chemistry
- Sun Yat-sen University
- Guangzhou 510275
- P. R. China
| | - Kang-Nan Wang
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry
- School of Chemistry
- Sun Yat-sen University
- Guangzhou 510275
- P. R. China
| | - Yue Zheng
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry
- School of Chemistry
- Sun Yat-sen University
- Guangzhou 510275
- P. R. China
| | - Jian-Jun Cao
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry
- School of Chemistry
- Sun Yat-sen University
- Guangzhou 510275
- P. R. China
| | - Ming-Fang Zhang
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry
- School of Chemistry
- Sun Yat-sen University
- Guangzhou 510275
- P. R. China
| | - Cai-Ping Tan
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry
- School of Chemistry
- Sun Yat-sen University
- Guangzhou 510275
- P. R. China
| | - Liang-Nian Ji
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry
- School of Chemistry
- Sun Yat-sen University
- Guangzhou 510275
- P. R. China
| | - Zong-Wan Mao
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry
- School of Chemistry
- Sun Yat-sen University
- Guangzhou 510275
- P. R. China
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The Role of Endoplasmic Reticulum Stress in Cardiovascular Disease and Exercise. Int J Vasc Med 2017; 2017:2049217. [PMID: 28875043 PMCID: PMC5569752 DOI: 10.1155/2017/2049217] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Accepted: 07/06/2017] [Indexed: 12/18/2022] Open
Abstract
Endoplasmic reticulum (ER) stress, which is highly associated with cardiovascular disease, is triggered by a disturbance in ER function because of protein misfolding or an increase in protein secretion. Prolonged disruption of ER causes ER stress and activation of the unfolded protein response (UPR) and leads to various diseases. Eukaryotic cells respond to ER stress via three major sensors that are bound to the ER membrane: activating transcription factor 6 (ATF6), inositol-requiring protein 1α (IRE1α), and protein kinase RNA-like ER kinase (PERK). Chronic activation of ER stress causes damage in endothelial cells (EC) via apoptosis, inflammation, and oxidative stress signaling pathways. The alleviation of ER stress has recently been accepted as a potential therapeutic target to treat cardiovascular diseases such as heart failure, hypertension, and atherosclerosis. Exercise training is an effective nonpharmacological approach for preventing and alleviating cardiovascular disease. We here review the recent viewing of ER stress-mediated apoptosis and inflammation signaling pathways in cardiovascular disease and the role of exercise in ER stress-associated diseases.
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Kooman JP, Dekker MJ, Usvyat LA, Kotanko P, van der Sande FM, Schalkwijk CG, Shiels PG, Stenvinkel P. Inflammation and premature aging in advanced chronic kidney disease. Am J Physiol Renal Physiol 2017; 313:F938-F950. [PMID: 28701312 DOI: 10.1152/ajprenal.00256.2017] [Citation(s) in RCA: 155] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Revised: 06/29/2017] [Accepted: 07/06/2017] [Indexed: 12/22/2022] Open
Abstract
Systemic inflammation in end-stage renal disease is an established risk factor for mortality and a catalyst for other complications, which are related to a premature aging phenotype, including muscle wasting, vascular calcification, and other forms of premature vascular disease, depression, osteoporosis, and frailty. Uremic inflammation is also mechanistically related to mechanisms involved in the aging process, such as telomere shortening, mitochondrial dysfunction, and altered nutrient sensing, which can have a direct effect on cellular and tissue function. In addition to uremia-specific causes, such as abnormalities in the phosphate-Klotho axis, there are remarkable similarities between the pathophysiology of uremic inflammation and so-called "inflammaging" in the general population. Potentially relevant, but still somewhat unexplored in this respect, are abnormal or misplaced protein structures, as well as abnormalities in tissue homeostasis, which evoke danger signals through damage-associated molecular patterns, as well as the senescence-associated secretory phenotype. Systemic inflammation, in combination with the loss of kidney function, can impair the resilience of the body to external and internal stressors by reduced functional and structural tissue reserves, and by impairing normal organ crosstalk, thus providing an explanation for the greatly increased risk of homeostatic breakdown in this population. In this review, the relationship between uremic inflammation and a premature aging phenotype, as well as potential causes and consequences, are discussed.
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Affiliation(s)
- Jeroen P Kooman
- Maastricht University Medical Center, Maastricht, Netherlands;
| | | | - Len A Usvyat
- Fresenius Medical Care North America, Waltham, Massachusetts
| | - Peter Kotanko
- Renal Research Institute, New York, New York.,Icahn School of Medicine at Mount Sinai, New York, New York
| | | | | | - Paul G Shiels
- Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom; and
| | - Peter Stenvinkel
- Divsion of Renal Medicine, Department of Clinical Science Technology and Intervention, Karolinska Institutet, Stockholm, Sweden
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4-Phenylbutyric Acid Reveals Good Beneficial Effects on Vital Organ Function via Anti-Endoplasmic Reticulum Stress in Septic Rats. Crit Care Med 2017; 44:e689-701. [PMID: 26958745 DOI: 10.1097/ccm.0000000000001662] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Sepsis and septic shock are the common complications in ICUs. Vital organ function disorder contributes a critical role in high mortality after severe sepsis or septic shock, in which endoplasmic reticulum stress plays an important role. Whether anti-endoplasmic reticulum stress with 4-phenylbutyric acid is beneficial to sepsis and the underlying mechanisms are not known. DESIGN Laboratory investigation. SETTING State Key Laboratory of Trauma, Burns and Combined Injury. SUBJECTS Sprague-Dawley rats. INTERVENTIONS Using cecal ligation and puncture-induced septic shock rats, lipopolysaccharide-treated vascular smooth muscle cells, and cardiomyocytes, effects of 4-phenylbutyric acid on vital organ function and the relationship with endoplasmic reticulum stress and endoplasmic reticulum stress-mediated inflammation, apoptosis, and oxidative stress were observed. MEASUREMENTS AND MAIN RESULTS Conventional treatment, including fluid resuscitation, vasopressin, and antibiotic, only slightly improved the hemodynamic variable, such as mean arterial blood pressure and cardiac output, and slightly improved the vital organ function and the animal survival of septic shock rats. Supplementation of 4-phenylbutyric acid (5 mg/kg; anti-endoplasmic reticulum stress), especially administered at early stage, significantly improved the hemodynamic variables, vital organ function, such as liver, renal, and intestinal barrier function, and animal survival in septic shock rats. 4-Phenylbutyric acid application inhibited the endoplasmic reticulum stress and endoplasmic reticulum stress-related proteins, such as CCAAT/enhancer-binding protein homologous protein in vital organs, such as heart and superior mesenteric artery after severe sepsis. Further studies showed that 4-phenylbutyric acid inhibited endoplasmic reticulum stress-mediated cytokine release, apoptosis, and oxidative stress via inhibition of nuclear factor-κB, caspase-3 and caspase-9, and increasing glutathione peroxidase and superoxide dismutase expression, respectively. CONCLUSIONS Anti-endoplasmic reticulum stress with 4-phenylbutyric acid is beneficial to septic shock. This beneficial effect of 4-phenylbutyric acid is closely related to the inhibition of endoplasmic reticulum stress-mediated oxidative stress, apoptosis, and cytokine release. This finding provides a potential therapeutic measure for clinical critical conditions, such as severe sepsis.
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Khan S, Komarya SK, Jena G. Phenylbutyrate and β-cell function: contribution of histone deacetylases and ER stress inhibition. Epigenomics 2017; 9:711-720. [PMID: 28470097 DOI: 10.2217/epi-2016-0160] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Incidences of diabetes are increasing globally due to involvement of genetic and epigenetic factors. Phenylbutyrate (PBA) is a US FDA approved drug for treatment of urea cycle disorder in children. PBA reduces endoplasmic reticulum (ER) stress and is proven as a potent histone deacetylases (HDACs) inhibitor. Chronic ER stress results in unfolding protein response, which triggers apoptosis. Abnormal ER homoeostasis is responsible for defective processing of several genes/proteins and contributes to β-cell death/failure. Accumulated evidences indicated that HDACs modulate key biochemical pathways and HDAC inhibitors improve β-cell function and insulin resistance by modulating multiple targets. This review highlights the role of PBA on β-cell functions, insulin resistance for possible treatment of diabetes through inhibition of ER stress and HDACs.
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Affiliation(s)
- Sabbir Khan
- Facility for Risk Assessment & Intervention Studies, Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education & Research, Sector-67, SAS Nagar, Punjab-160062, India
| | - Sandeep K Komarya
- Facility for Risk Assessment & Intervention Studies, Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education & Research, Sector-67, SAS Nagar, Punjab-160062, India
| | - Gopabandhu Jena
- Facility for Risk Assessment & Intervention Studies, Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education & Research, Sector-67, SAS Nagar, Punjab-160062, India
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Species Differences in the Binding of Sodium 4-Phenylbutyrate to Serum Albumin. J Pharm Sci 2017; 106:2860-2867. [PMID: 28456727 DOI: 10.1016/j.xphs.2017.04.025] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Revised: 04/13/2017] [Accepted: 04/13/2017] [Indexed: 01/30/2023]
Abstract
Sodium 4-phenylbutyrate (PB) is clinically used as a drug for treating urea cycle disorders. Recent research has shown that PB also has other pharmacologic activities, suggesting that it has the potential for use as a drug for treating other disorders. In the process of drug development, preclinical testing using experimental animals is necessary to verify the efficacy and safety of PB. Although the binding of PB to human albumin has been studied, our knowledge of its binding to albumin from the other animal species is extremely limited. To address this issue, we characterized the binding of PB to albumin from several species (human, bovine, rabbit, and rat). The results indicated that PB interacts with 1 high-affinity site of albumin from these species, which corresponds to site II of human albumin. The affinities of PB to human and bovine albumins were higher than those to rabbit and rat albumin, and that to rabbit albumin was the lowest. Binding and molecular docking studies using structurally related compounds of PB suggested that species differences in the affinity are attributed to differences in the structural feature of the PB-binding sites on albumins (e.g., charge distribution, hydrophobicity, shape, or size).
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Di Pietro N, Marcovecchio ML, Di Silvestre S, de Giorgis T, Cordone VGP, Lanuti P, Chiarelli F, Bologna G, Mohn A, Pandolfi A. Plasma from pre-pubertal obese children impairs insulin stimulated Nitric Oxide (NO) bioavailability in endothelial cells: Role of ER stress. Mol Cell Endocrinol 2017; 443:52-62. [PMID: 28062198 PMCID: PMC5320395 DOI: 10.1016/j.mce.2017.01.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 11/16/2016] [Accepted: 01/02/2017] [Indexed: 12/12/2022]
Abstract
Childhood obesity is commonly associated with early signs of endothelial dysfunction, characterized by impairment of insulin signaling and vascular Nitric Oxide (NO) availability. However, the underlying mechanisms remain to be established. Hence, we tested the hypothesis that endothelial insulin-stimulated NO production and availability was impaired and related to Endoplasmic Reticulum (ER) in human umbilical vein endothelial cells (HUVECs) cultured with plasma obtained from pre-pubertal obese (OB) children. OB children (N = 28, age: 8.8 ± 2.2; BMI z-score: 2.15 ± 0.39) showed impaired fasting glucose, insulin and HOMA-IR than normal weight children (CTRL; N = 28, age: 8.8 ± 1.7; BMI z-score: 0.17 ± 0.96). The in vitro experiments showed that OB-plasma significantly impaired endothelial insulin-stimulated NO production and bioavailability compared to CTRL-plasma. In parallel, in HUVECs OB-plasma increased GRP78 and activated PERK, eIF2α, IkBα and ATF6 (all ER stress markers). Moreover, OB-plasma increased NF-κB activation and its nuclear translocation. Notably, all these effects proved to be significantly restored by using PBA and TUDCA, known ER stress inhibitors. Our study demonstrate for the first time that plasma from obese children is able to induce in vitro endothelial insulin resistance, which is characterized by reduced insulin-stimulated NO production and bioavailability, endothelial ER stress and increased NF-κB activation.
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Affiliation(s)
- Natalia Di Pietro
- Department of Medicine and Aging Sciences, University "G. d'Annunzio", Chieti-Pescara, Italy; Centro Scienze dell'Invecchiamento e Medicina Traslazionale (CeSI-MeT), University "G. d'Annunzio", Chieti-Pescara, Italy; "G. d'Annunzio" University Foundation, Chieti, Italy.
| | - M Loredana Marcovecchio
- Department of Medicine and Aging Sciences, University "G. d'Annunzio", Chieti-Pescara, Italy; Centro Scienze dell'Invecchiamento e Medicina Traslazionale (CeSI-MeT), University "G. d'Annunzio", Chieti-Pescara, Italy; "G. d'Annunzio" University Foundation, Chieti, Italy
| | - Sara Di Silvestre
- Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio", Chieti-Pescara, Italy; Centro Scienze dell'Invecchiamento e Medicina Traslazionale (CeSI-MeT), University "G. d'Annunzio", Chieti-Pescara, Italy; "G. d'Annunzio" University Foundation, Chieti, Italy
| | - Tommaso de Giorgis
- Department of Medicine and Aging Sciences, University "G. d'Annunzio", Chieti-Pescara, Italy; Centro Scienze dell'Invecchiamento e Medicina Traslazionale (CeSI-MeT), University "G. d'Annunzio", Chieti-Pescara, Italy; "G. d'Annunzio" University Foundation, Chieti, Italy
| | - Vincenzo Giuseppe Pio Cordone
- Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio", Chieti-Pescara, Italy; Centro Scienze dell'Invecchiamento e Medicina Traslazionale (CeSI-MeT), University "G. d'Annunzio", Chieti-Pescara, Italy; "G. d'Annunzio" University Foundation, Chieti, Italy
| | - Paola Lanuti
- Department of Medicine and Aging Sciences, University "G. d'Annunzio", Chieti-Pescara, Italy; Centro Scienze dell'Invecchiamento e Medicina Traslazionale (CeSI-MeT), University "G. d'Annunzio", Chieti-Pescara, Italy; "G. d'Annunzio" University Foundation, Chieti, Italy
| | - Francesco Chiarelli
- Department of Medicine and Aging Sciences, University "G. d'Annunzio", Chieti-Pescara, Italy; Centro Scienze dell'Invecchiamento e Medicina Traslazionale (CeSI-MeT), University "G. d'Annunzio", Chieti-Pescara, Italy; "G. d'Annunzio" University Foundation, Chieti, Italy
| | - Giuseppina Bologna
- Department of Medicine and Aging Sciences, University "G. d'Annunzio", Chieti-Pescara, Italy; Centro Scienze dell'Invecchiamento e Medicina Traslazionale (CeSI-MeT), University "G. d'Annunzio", Chieti-Pescara, Italy; "G. d'Annunzio" University Foundation, Chieti, Italy
| | - Angelika Mohn
- Department of Medicine and Aging Sciences, University "G. d'Annunzio", Chieti-Pescara, Italy; Centro Scienze dell'Invecchiamento e Medicina Traslazionale (CeSI-MeT), University "G. d'Annunzio", Chieti-Pescara, Italy; "G. d'Annunzio" University Foundation, Chieti, Italy
| | - Assunta Pandolfi
- Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio", Chieti-Pescara, Italy; Centro Scienze dell'Invecchiamento e Medicina Traslazionale (CeSI-MeT), University "G. d'Annunzio", Chieti-Pescara, Italy; "G. d'Annunzio" University Foundation, Chieti, Italy
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Della Bella E, Pagani S, Giavaresi G, Capelli I, Comai G, Donadei C, Cappuccilli M, La Manna G, Fini M. Uremic Serum Impairs Osteogenic Differentiation of Human Bone Marrow Mesenchymal Stromal Cells. J Cell Physiol 2017; 232:2201-2209. [DOI: 10.1002/jcp.25732] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 12/13/2016] [Indexed: 12/21/2022]
Affiliation(s)
- Elena Della Bella
- Laboratory of Preclinical and Surgical Studies; Rizzoli Orthopedic Institute; Bologna Italy
- Department of Experimental, Diagnostic and Specialty Medicine; University of Bologna; Bologna Italy
| | - Stefania Pagani
- Laboratory of Preclinical and Surgical Studies; Rizzoli Orthopedic Institute; Bologna Italy
- Laboratory of Biocompatibility, Innovative Technologies and Advanced Therapies; Department Rizzoli RIT; Bologna Italy
| | - Gianluca Giavaresi
- Laboratory of Preclinical and Surgical Studies; Rizzoli Orthopedic Institute; Bologna Italy
- Laboratory of Biocompatibility, Innovative Technologies and Advanced Therapies; Department Rizzoli RIT; Bologna Italy
| | - Irene Capelli
- Nephrology Dialysis and Transplantation Unit, Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola Hospital; University of Bologna; Bologna Italy
| | - Giorgia Comai
- Nephrology Dialysis and Transplantation Unit, Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola Hospital; University of Bologna; Bologna Italy
| | - Chiara Donadei
- Nephrology Dialysis and Transplantation Unit, Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola Hospital; University of Bologna; Bologna Italy
| | - Maria Cappuccilli
- Nephrology Dialysis and Transplantation Unit, Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola Hospital; University of Bologna; Bologna Italy
| | - Gaetano La Manna
- Nephrology Dialysis and Transplantation Unit, Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola Hospital; University of Bologna; Bologna Italy
| | - Milena Fini
- Laboratory of Preclinical and Surgical Studies; Rizzoli Orthopedic Institute; Bologna Italy
- Laboratory of Biocompatibility, Innovative Technologies and Advanced Therapies; Department Rizzoli RIT; Bologna Italy
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Novel Treatment of Chronic Graft-Versus-Host Disease in Mice Using the ER Stress Reducer 4-Phenylbutyric Acid. Sci Rep 2017; 7:41939. [PMID: 28165054 PMCID: PMC5292729 DOI: 10.1038/srep41939] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 01/04/2017] [Indexed: 12/20/2022] Open
Abstract
Chronic graft-versus-host disease (cGVHD) is a notorious complication of allogeneic hematopoietic stem cell transplantation and causes disabling systemic inflammation and fibrosis. In this novel study, we focused on a relationship between endoplasmic reticulum (ER) stress and cGVHD, and aimed to create effective treatment of cGVHD. A series of experiments were conducted using a mouse model of cGVHD. Our data suggested (1) that ER stress was elevated in organs affected by cGVHD and (2) that 4-phenylbutyric acid (PBA) could reduce cGVHD-induced ER stress and thereby alleviate systemic inflammation and fibrosis. Because fibroblasts are thought to be implicated in cGVHD-elicited fibrosis and because macrophages are reported to play a role in the development of cGVHD, we investigated cGVHD-triggered ER stress in fibroblasts and macrophages. Our investigation demonstrated (1) that indicators for ER stress and activation markers for fibroblasts were elevated in cGVHD-affected lacrimal gland fibroblasts and (2) that they could be reduced by PBA. Our work also indicated that splenic macrophages from PBA-dosed mice exhibited the lower levels of ER stress and M2 macrophage markers than those from cGVHD-affected mice. Collectively, this study suggests that the reduction of ER stress utilizing PBA can be a clinically translatable method to treat systemic cGVHD.
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Abstract
OBJECTIVE To screen for mRNAs associated with blood stasis syndrome and to explore the genetic mechanisms of blood stasis syndrome in hypertension. METHODS This study involved groups of patients with hypertension and blood stasis, including those with Qi deficiency, Qi stagnation, cold retention and heat retention; as well as hypertensive patients without blood stasis and healthy individuals. Human umbilical vein endothelial cells were co-cultured with the sera of these healthy individuals and patients with blood stasis syndrome. Total RNA was extracted from these cells and assessed by a high-throughput sequencing method (Solexa) and digital gene expression. Differentially expressed genes among these six groups were compared using whole genome sequences, and mRNAs associated with blood stasis syndrome identified. Differences in gene use and gene ontology function were analyzed. Genes enriched significantly and their pathways were determined, as were network interactions, and encoded proteins. Gene identities were confirmed by real-time polymerase chain reactions. RESULTS Compared with cells cultured in sera of the blood stasis groups, those culture in sera of healthy individuals and of the non-blood stasis group showed 11 and 301 differences, respectively in stasis-related genes. Genes identified as differing between the blood stasis and healthy groups included activating transcription factor 4, activating transcription factor 3, DNA-damage inducible transcription factor 3, Tribbles homolog 3, CCAAT/enhancer binding protein-β, and Jun proto-oncogene (JUN). Pathway and protein interaction network analyses showed that these genes were associated with endoplasmic reticulum stress. Cells cultured in sera of patients with blood stasis and Qi deficiency, Qi stagnation, heat retention, and cold retention were compared with cells cultured in sera of patients with the other types blood stasis syndrome. The comparison showed differences in expression of 28, 28, 34, and 32 specific genes, respectively. CONCLUSION The pathogenesis of blood stasis syndrome in hypertension is related to endoplasmic reticulum stress and involves the differential expression of the activating transcription factor 4, activating transcription factor 3, DNA-damage inducible transcription factor 3, Tribbles homolog 3, CCAAT/enhancer binding protein-β, and JUN genes.
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He L, Yuan J, Xu Q, Chen R, Chen L, Fang M. miRNA-1283 Regulates the PERK/ATF4 Pathway in Vascular Injury by Targeting ATF4. PLoS One 2016; 11:e0159171. [PMID: 27537404 PMCID: PMC4990291 DOI: 10.1371/journal.pone.0159171] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 06/28/2016] [Indexed: 12/31/2022] Open
Abstract
Background In our previous study, we found significant differences in the mRNA and microRNA (miRNA) levels among hypertensive patients with different degrees of vascular endothelial cells damage. These differences were closely associated with endoplasmic reticulum stress (ERS)-related proteins. Moreover, compared to the control group, the expression of transcription factor activating factor 4 (ATF4) was also found to be significantly different in the hypertensive patients with different degrees of vascular endothelial cells damage groups. These results were confirmed using gene prediction software, which showed synergistic effects between ATF4 and miR-1283. ATF4 is a key molecule in ERS. Three ERS pathways exist:protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6) and inositol-requiring enzyme-1 (IRE-1)-induced apoptosis. The PERK pathway is the most important and also includes the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) and ATF4. In this report, we studied the regulatory effects of miR-1283 and ATF4 on the PERK-eIF2α-ATF4 signaling pathway using human umbilical vein endothelial cells (HUVECs) and mice. Methodology/Principal Findings We verified the relationship between miR-1283 and ATF4 using a luciferase activity assay and observed the regulatory effects of miR-1283 and ATF4 on the PERK-eIF2α-ATF4 signaling pathway in vivo and in vitro. Conclusions/Significance ATF4 is a target gene of miR-1283, which regulates the PERK-eIF2α-ATF4 signaling pathway by inhibiting ATF4, and it plays a critical role in inducing injury in HUVECs and mouse heart tissue.
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Affiliation(s)
- Ling He
- Department of Chinese Medicine, Medical College of Jinan University, Guangzhou, 510632, Guangdong Province, PR China
| | - Jing Yuan
- Department of Chinese Medicine, Medical College of Jinan University, Guangzhou, 510632, Guangdong Province, PR China
| | - Qingyun Xu
- Department of Chinese Medicine, Medical College of Jinan University, Guangzhou, 510632, Guangdong Province, PR China
| | - Ruixue Chen
- Department of Chinese Medicine, Medical College of Jinan University, Guangzhou, 510632, Guangdong Province, PR China
| | - Liguo Chen
- Department of Chinese Medicine, Medical College of Jinan University, Guangzhou, 510632, Guangdong Province, PR China
- * E-mail: (LC); (MF)
| | - Meixia Fang
- Institute of Laboratory Animals, Jinan University, Guangzhou, 510632, Guangdong Province, PR China
- * E-mail: (LC); (MF)
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Hong YP, Guo WY, Wang WX, Zhao L, Xiang MW, Mei FC, Abliz A, Hu P, Deng WH, Yu J. 4-Phenylbutyric Acid Attenuates Pancreatic Beta-Cell Injury in Rats with Experimental Severe Acute Pancreatitis. Int J Endocrinol 2016; 2016:4592346. [PMID: 27656209 PMCID: PMC5021485 DOI: 10.1155/2016/4592346] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Accepted: 08/10/2016] [Indexed: 02/06/2023] Open
Abstract
Endoplasmic reticulum (ER) stress is a particular process with an imbalance of homeostasis, which plays an important role in pancreatitis, but little is known about how ER stress is implicated in severe acute pancreatitis (SAP) induced pancreatic beta-cell injury. To investigate the effect of 4-phenylbutyric acid (4-PBA) on the beta-cell injury following SAP and the underlying mechanism, twenty-four Sprague-Dawley rats were randomly divided into sham-operation (SO) group, SAP model group, and 4-PBA treatment group. SAP model was induced by infusion of 5% sodium taurocholate into the biliopancreatic duct. 4-PBA or normal saline was injected intraperitoneally for 3 days in respective group before successful modeling. Results showed that 4-PBA attenuated the following: (1) pancreas and islet pathological injuries, (2) serum TNF-α and IL-1β, (3) serum insulin and glucose, (4) beta-cell ultrastructural changes, (5) ER stress markers (BiP, ORP150, and CHOP), Caspase-3, and insulin expression in islet. These results suggested that 4-PBA mitigates pancreatic beta-cell injury and endocrine disorder in SAP, presumably because of its role in inhibiting excessive endoplasmic reticulum stress. This may serve as a new therapeutic target for reducing pancreatic beta-cell injury and endocrine disorder in SAP upon 4-PBA treatment.
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Affiliation(s)
- Yu-pu Hong
- Department of General Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei Province 430060, China
- Key Laboratory of Hubei Province for Digestive System Disease, 9 Zhangzhidong Road, Wuhan, Hubei Province 430060, China
| | - Wen-yi Guo
- Department of General Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei Province 430060, China
| | - Wei-xing Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei Province 430060, China
- *Wei-xing Wang:
| | - Liang Zhao
- Department of General Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei Province 430060, China
- Central Laboratory, Renmin Hospital of Wuhan University, 9 Zhangzhidong Road, Wuhan, Hubei Province 430060, China
| | - Ming-wei Xiang
- Department of General Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei Province 430060, China
- Central Laboratory, Renmin Hospital of Wuhan University, 9 Zhangzhidong Road, Wuhan, Hubei Province 430060, China
| | - Fang-chao Mei
- Department of General Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei Province 430060, China
- Key Laboratory of Hubei Province for Digestive System Disease, 9 Zhangzhidong Road, Wuhan, Hubei Province 430060, China
| | - Ablikim Abliz
- Department of General Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei Province 430060, China
| | - Peng Hu
- Department of General Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei Province 430060, China
| | - Wen-hong Deng
- Department of General Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei Province 430060, China
| | - Jia Yu
- Department of General Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei Province 430060, China
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Cystatin C attenuates insulin signaling transduction by promoting endoplasmic reticulum stress in hepatocytes. FEBS Lett 2015; 589:3938-44. [DOI: 10.1016/j.febslet.2015.11.029] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 11/11/2015] [Indexed: 12/16/2022]
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Hamada J, Onuma H, Ochi F, Hirai H, Takemoto K, Miyoshi A, Matsushita M, Kadota Y, Ohashi J, Kawamura R, Takata Y, Nishida W, Hashida S, Ishii E, Osawa H. Endoplasmic reticulum stress induced by tunicamycin increases resistin messenger ribonucleic acid through the pancreatic endoplasmic reticulum eukaryotic initiation factor 2α kinase-activating transcription factor 4-CAAT/enhancer binding protein-α homologous protein pathway in THP-1 human monocytes. J Diabetes Investig 2015; 7:312-23. [PMID: 27330716 PMCID: PMC4847884 DOI: 10.1111/jdi.12434] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Revised: 09/09/2015] [Accepted: 09/23/2015] [Indexed: 01/06/2023] Open
Abstract
AIMS/INTRODUCTION Resistin, secreted from adipocytes, causes insulin resistance in mice. In humans, the resistin gene is mainly expressed in monocytes and macrophages. Tunicamycin is known to induce endoplasmic reticulum (ER) stress, and reduce resistin gene expression in 3T3-L1 mouse adipocytes. The aim of the present study was to examine whether ER stress affects resistin gene expression in human monocytes. MATERIALS AND METHODS The relationship between resistin messenger ribonucleic acid (mRNA) and ER stress markers mRNA was analyzed by reverse transcription polymerase chain reaction in isolated monocytes of 30 healthy volunteers. The effect of endotoxin/lipopolysaccharides or tunicamycin on resistin gene expression was analyzed in THP-1 human monocytes. Signaling pathways leading to resistin mRNA were assessed by the knockdown using small interfering RNA or overexpression of key molecules involved in unfolded protein response. RESULTS Resistin mRNA was positively associated with immunoglobulin heavy chain-binding protein (BiP) or CAAT/enhancer binding protein-α homologous protein (CHOP) mRNA in human isolated monocytes. In THP-1 cells, lipopolysaccharides increased mRNA of BiP, pancreatic endoplasmic reticulum eukaryotic initiation factor 2α kinase (PERK) and CHOP, as well as resistin. Tunicamycin also increased resistin mRNA. This induction appeared to be dose- and time-dependent. Tunicamycin-induced resistin mRNA was inhibited by chemical chaperone, 4-phenylbutyric acid. The knockdown of either PERK, activating transcription factor 4 (ATF4) or CHOP reduced tunicamycin-induced resistin mRNA. Conversely, overexpression of ATF4 or CHOP increased resistin mRNA. CONCLUSIONS Endoplasmic reticulum stress induced by tunicamycin increased resistin mRNA through the PERK-ATF4-CHOP pathway in THP-1 human monocytes. ER stress could lead to insulin resistance through enhanced resistin gene expression in human monocytes.
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Affiliation(s)
- Junpei Hamada
- Department of Pediatrics Ehime University Graduate School of Medicine Ehime Japan
| | - Hiroshi Onuma
- Department of Diabetes and Molecular Genetics Ehime University Graduate School of Medicine Ehime Japan
| | - Fumihiro Ochi
- Department of Pediatrics Ehime University Graduate School of Medicine Ehime Japan
| | - Hiroki Hirai
- Department of Pediatrics Ehime University Graduate School of Medicine Ehime Japan
| | - Koji Takemoto
- Department of Pediatrics Ehime University Graduate School of Medicine Ehime Japan
| | - Akiko Miyoshi
- Department of Diabetes and Molecular Genetics Ehime University Graduate School of Medicine Ehime Japan
| | - Manami Matsushita
- Department of Diabetes and Molecular Genetics Ehime University Graduate School of Medicine Ehime Japan
| | - Yuko Kadota
- Department of Diabetes and Molecular Genetics Ehime University Graduate School of Medicine Ehime Japan
| | - Jun Ohashi
- Department of Biological Sciences Tokyo University Graduate School of Science Tokyo Japan
| | - Ryoichi Kawamura
- Department of Diabetes and Molecular Genetics Ehime University Graduate School of Medicine Ehime Japan
| | - Yasunori Takata
- Department of Diabetes and Molecular Genetics Ehime University Graduate School of Medicine Ehime Japan
| | - Wataru Nishida
- Department of Diabetes and Molecular Genetics Ehime University Graduate School of Medicine Ehime Japan
| | - Seiichi Hashida
- Institute for Health Sciences Tokushima Bunri University Tokushima Japan
| | - Eiichi Ishii
- Department of Pediatrics Ehime University Graduate School of Medicine Ehime Japan
| | - Haruhiko Osawa
- Department of Diabetes and Molecular Genetics Ehime University Graduate School of Medicine Ehime Japan
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Pterostilbene exerts an anti-inflammatory effect via regulating endoplasmic reticulum stress in endothelial cells. Cytokine 2015; 77:88-97. [PMID: 26551859 DOI: 10.1016/j.cyto.2015.11.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Revised: 11/01/2015] [Accepted: 11/02/2015] [Indexed: 11/23/2022]
Abstract
Pterostilbene (PT), an analog of resveratrol, exerts a potent anti-inflammatory effect. However, the protective effects of PT against inflammation in endothelial cells have not been elucidated. Previous studies have confirmed that endoplasmic reticulum stress (ERS) plays an important role in regulating the pathological process of endothelial cell inflammation. In this study, we explored the effect of PT on the tumor necrosis factor-α (TNF-α)-induced inflammatory response in human umbilical vein endothelial cells (HUVECs) and elaborated the role of ERS in this process. TNF-α treatment significantly upregulated the levels of inflammation-related molecules in cell culture media, increased the adhesion of monocytes to HUVECs, and enhanced the expression of the MMP9 and ICAM proteins in HUVECs. Additionally, TNF-α potently increased ERS-related protein levels, such as GRP78 and p-eIF2α. However, PT treatment reversed the increased production of inflammatory cytokines and the adhesion of monocytes to HUVECs, as well as reduced the TNF-α-induced effects exerted by ERS-related molecules. Furthermore, thapsigargin (THA), an ERS inducer, attenuated the protective effect of PT against TNF-α-induced inflammation and ERS in HUVECs. Additionally, the downregulation of ERS signaling using siRNA targeting eIF2α and IRE1 not only inhibited ERS-related molecules but also simulated the therapeutic effects of PT on TNF-α-induced inflammation. In summary, PT treatment potently attenuates inflammation in vascular endothelial cells, which at least partly depends on the reduction of ERS.
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25
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Lin P, Weng X, Liu F, Ma Y, Chen H, Shao X, Zheng W, Liu X, Ye H, Li X. Bushen Zhuangjin decoction inhibits TM-induced chondrocyte apoptosis mediated by endoplasmic reticulum stress. Int J Mol Med 2015; 36:1519-28. [PMID: 26497741 PMCID: PMC4678159 DOI: 10.3892/ijmm.2015.2387] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2015] [Accepted: 10/08/2015] [Indexed: 12/15/2022] Open
Abstract
Chondrocyte apoptosis triggered by endoplasmic reticulum (ER) stress plays a vital role in the pathogenesis of osteoarthritis (OA). Bushen Zhuangjin decoction (BZD) has been widely used in the treatment of OA. However, the cellular and molecular mechanisms responsible for the inhibitory effects of BZD on chondrocyte apoptosis remain to be elucidated. In the present study, we investigated the effects of BZD on ER stress-induced chondrocyte apoptosis using a chondrocyte in vitro model of OA. Chondrocytes obtained from the articular cartilage of the knee joints of Sprague Dawley (SD) rats were detected by immunohistochemical staining for type II collagen. The ER stress-mediated apoptosis of tunicamycin (TM)-stimulated chondrocytes was detected using 4-phenylbutyric acid (4-PBA). We found that 4-PBA inhibited TM-induced chondrocyte apoptosis, which confirmed the successful induction of chondrocyte apoptosis. BZD enhanced the viability of the TM-stimulated chondrocytes in a dose- and time-dependent manner, as shown by MTT assay. The apoptotic rate and the loss of mitochondrial membrane potential (ΔΨm) of the TM-stimulated chondrocytes treated with BZD was markedly decreased compared with those of chondrocytes not treated with BZD, as shown by 4′,6-diamidino-2-phenylindole (DAPI) staining, Annexin V-FITC binding assay and JC-1 assay. To further elucidate the mechanisms responsible for the inhibitory effects of BZD on TM-induced chondrocyte apoptosis mediated by ER stress, the mRNA and protein expression levels of binding immunoglobulin protein (Bip), X-box binding protein 1 (Xbp1), activating transcription factor 4 (Atf4), C/EBP-homologous protein (Chop), caspase-9, caspase-3, B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) were measured by reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis. In the TM-stimulated chondrocytes treated with BZD, the mRNA and protein expression levels of Bip, Atf4, Chop, caspase-9, caspase-3 and Bax were significantly decreased, whereas the mRNA and protein expression levels of Xbp1 and Bcl-2 were significantly increased compared with the TM-stimulated chondrocytes not treated with BZD. Additionally, all our findings demonstrated that there was no significant difference between the TM-stimulated chondrocytes treated with BZD and those treated with 4-PBA. Taken together, our results indicate that BZD inhibits TM-induced chondrocyte apoptosis mediated by ER stress. Thus, BZD may be a potential therapeutic agent for use in the treatment of OA.
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Affiliation(s)
- Pingdong Lin
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Xiaping Weng
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Fayuan Liu
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Yuhuan Ma
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Houhuang Chen
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Xiang Shao
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Wenwei Zheng
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Xianxiang Liu
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Hongzhi Ye
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Xihai Li
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
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Chriett S, Pirola L. Essential roles of four-carbon backbone chemicals in the control of metabolism. World J Biol Chem 2015; 6:223-230. [PMID: 26322177 PMCID: PMC4549763 DOI: 10.4331/wjbc.v6.i3.223] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 04/27/2015] [Accepted: 05/18/2015] [Indexed: 02/05/2023] Open
Abstract
The increasing incidence of obesity worldwide and its related cardiometabolic complications is an urgent public health problem. While weight gain results from a negative balance between the energy expenditure and calorie intake, recent research has demonstrated that several small organic molecules containing a four-carbon backbone can modulate this balance by favoring energy expenditure, and alleviating endoplasmic reticulum stress and oxidative stress. Such small molecules include the bacterially produced short chain fatty acid butyric acid, its chemically produced derivative 4-phenylbutyric acid, the main ketone body D-β-hydroxybutyrate - synthesized by the liver - and the recently discovered myokine β-aminoisobutyric acid. Conversely, another butyrate-related molecule, α-hydroxybutyrate, has been found to be an early predictor of insulin resistance and glucose intolerance. In this minireview, we summarize recent advances in the understanding of the mechanism of action of these molecules, and discuss their use as therapeutics to improve metabolic homeostasis or their detection as early biomarkers of incipient insulin resistance.
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27
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Wu S, Gao X, Yang S, Meng M, Yang X, Ge B. The role of endoplasmic reticulum stress in endothelial dysfunction induced by homocysteine thiolactone. Fundam Clin Pharmacol 2015; 29:252-9. [PMID: 25623775 DOI: 10.1111/fcp.12101] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2014] [Revised: 08/21/2014] [Accepted: 01/20/2015] [Indexed: 12/21/2022]
Abstract
Our and other studies have reported that homocysteine thiolactone (HTL) could induce endothelial dysfunction. However, the precise mechanism was largely unknown. In this study, we tested the most possible factor-endoplasmic reticulum (ER) stress, which was demonstrated to be involved in endothelial dysfunction in cardiovascular disease. Acetylcholine (Ach)-induced endothelium-dependent relaxation (EDR) and biochemical parameters were measured in rat isolated aorta. The level of reactive oxygen species (ROS) and NO was designed by specific fluorescent probe DCFH-DA and DAF-FM DA separately. The nuclear translocation of the NF-κB was studied by immune-fluorescence. The mRNA expression and protein expression of GRP78--a key indicator for the induction of ER stress--were assessed by real-time PCR and Western blot. Two ER stress inhibitors-4-PBA (5 mm) and Tudca (500 μg/mL)--significantly prevented HTL-impaired EDR and increased NO release, endothelial nitric oxide synthase (eNOS) and SOD activity, decreased ROS production, NADPH activity, NOX-4 mRNA and MDA level. We also found that 4-PBA and Tudca blocked HTL--induced NF-κB activation thus inhibiting the downstream target gene production including TNF-α and ICAM-1. Simultaneously, HTL increased the mRNA and protein level of GRP78. HTL could induce ER stress leading to a downstream enhancement of oxidative stress and inflammation, which finally caused vascular endothelial dysfunction.
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Affiliation(s)
- Shujin Wu
- Department of Pharmacy, Gan Su Provincial Hospital, Lan Zhou, 73000, China
| | - Xiang Gao
- Department of Pharmacy, Gan Su Provincial Hospital, Lan Zhou, 73000, China
| | - Shehua Yang
- Department of Pharmacy, Gan Su Provincial Hospital, Lan Zhou, 73000, China
| | - Min Meng
- Department of Pharmacy, Gan Su Provincial Hospital, Lan Zhou, 73000, China
| | - Xiaolai Yang
- Department of Pharmacy, Gan Su Provincial Hospital, Lan Zhou, 73000, China
| | - Bin Ge
- Department of Pharmacy, Gan Su Provincial Hospital, Lan Zhou, 73000, China
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28
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Wang G, Liu K, Li Y, Yi W, Yang Y, Zhao D, Fan C, Yang H, Geng T, Xing J, Zhang Y, Tan S, Yi D. Endoplasmic reticulum stress mediates the anti-inflammatory effect of ethyl pyruvate in endothelial cells. PLoS One 2014; 9:e113983. [PMID: 25470819 PMCID: PMC4254754 DOI: 10.1371/journal.pone.0113983] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Accepted: 11/02/2014] [Indexed: 12/16/2022] Open
Abstract
Ethyl pyruvate (EP) is a simple aliphatic ester of the metabolic intermediate pyruvate that has been demonstrated to be a potent anti-inflammatory agent in a variety of in vivo and in vitro model systems. However, the protective effects and mechanisms underlying the actions of EP against endothelial cell (EC) inflammatory injury are not fully understood. Previous studies have confirmed that endoplasmic reticulum stress (ERS) plays an important role in regulating the pathological process of EC inflammation. In this study, our aim was to explore the effects of EP on tumor necrosis factor-α (TNF-α)-induced inflammatory injury in human umbilical vein endothelial cells (HUVECs) and to explore the role of ERS in this process. TNF-α treatment not only significantly increased the adhesion of monocytes to HUVECs and inflammatory cytokine (sICAM1, sE-selectin, MCP-1 and IL-8) production in cell culture supernatants but it also increased ICAM and MMP9 protein expression in HUVECs. TNF-α also effectively increased the ERS-related molecules in HUVECs (GRP78, ATF4, caspase12 and p-PERK). EP treatment effectively reversed the effects of the TNF-α-induced adhesion of monocytes on HUVECs, inflammatory cytokines and ERS-related molecules. Furthermore, thapsigargin (THA, an ERS inducer) attenuated the protective effects of EP against TNF-α-induced inflammatory injury and ERS. The PERK siRNA treatment not only inhibited ERS-related molecules but also mimicked the protective effects of EP to decrease TNF-α-induced inflammatory injury. In summary, we have demonstrated for the first time that EP can effectively reduce vascular endothelial inflammation and that this effect at least in part depends on the attenuation of ERS.
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Affiliation(s)
- Ge Wang
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi′an 710032, China
- Department of Cardiovascular Surgery, Guangdong Provincial Corps Hospital of Chinese People's Armed Police Forces, Guangzhou Medical University, 268 Yanling Road, Guangzhou 510507, China
| | - Kan Liu
- School of Basic Medical Sciences, The Fourth Military Medical University, 169 Changle West Road, Xi′an 710032, China
| | - Yue Li
- Department of Air Logistics, The 463rd Hospital of PLA, 46 Xiaoheyan Road, Shenyang 110042, China
| | - Wei Yi
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi′an 710032, China
| | - Yang Yang
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi′an 710032, China
| | - Dajun Zhao
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi′an 710032, China
| | - Chongxi Fan
- Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi′an 710038, China
| | - Honggang Yang
- Department of Cardiovascular Surgery, Guangdong Provincial Corps Hospital of Chinese People's Armed Police Forces, Guangzhou Medical University, 268 Yanling Road, Guangzhou 510507, China
| | - Ting Geng
- Department of Cardiovascular Surgery, Guangdong Provincial Corps Hospital of Chinese People's Armed Police Forces, Guangzhou Medical University, 268 Yanling Road, Guangzhou 510507, China
| | - Jianzhou Xing
- Department of Cardiovascular Surgery, Guangdong Provincial Corps Hospital of Chinese People's Armed Police Forces, Guangzhou Medical University, 268 Yanling Road, Guangzhou 510507, China
| | - Yu Zhang
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi′an 710032, China
| | - Songtao Tan
- Department of Cardiovascular Surgery, Guangdong Provincial Corps Hospital of Chinese People's Armed Police Forces, Guangzhou Medical University, 268 Yanling Road, Guangzhou 510507, China
- * E-mail: (DY); (ST)
| | - Dinghua Yi
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi′an 710032, China
- * E-mail: (DY); (ST)
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29
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Luo T, Kim JK, Chen B, Abdel-Latif A, Kitakaze M, Yan L. Attenuation of ER stress prevents post-infarction-induced cardiac rupture and remodeling by modulating both cardiac apoptosis and fibrosis. Chem Biol Interact 2014; 225:90-8. [PMID: 25450231 DOI: 10.1016/j.cbi.2014.10.032] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Revised: 10/15/2014] [Accepted: 10/30/2014] [Indexed: 12/20/2022]
Abstract
Endoplasmic reticulum (ER) stress is implicated in the pathophysiology of various cardiovascular diseases, but the role of ER stress in cardiac rupture and/or remodeling after myocardial infarction (MI) is still unclear. Here we investigated whether ER stress plays a major role for these processes in mice. We ligated the left coronary artery (LCA) without reperfusion in mice and administered either NaCl or 4-phenylbutyric acid (4-PBA, 20 mg/kg/d) intraperitoneally for 4 weeks. Cardiac rupture rates during the first week of MI were 37.5% and 18.2% in the control and 4-PBA groups, respectively. The extent of ventricular aneurysm and fibrosis was less, and the cardiac function better, in the 4-PBA group compared with the control group. The protein levels of ER stress markers in the heart tissues of the control group remained elevated during the entire 4-week period after MI, while pro-apoptotic proteins mainly increased in the early phase, and the pro-fibrotic proteins markedly increased in the late phase post MI; 4-PBA decreased all of these protein levels. In the primary cultured neonatal rat cardiomyocytes or fibroblasts, hypoxia (3% O2) increased the number of apoptotic cardiomyocytes and promoted the proliferation and migration of fibroblasts, all of which were attenuated by 4-PBA (0.5 mM). These findings indicate that MI induces ER stress and provokes cardiac apoptosis and fibrosis, culminating in cardiac rupture and remodeling, and that the attenuation of ER stress could be an effective therapeutic target to prevent post-MI complications.
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Affiliation(s)
- Tao Luo
- Division of Cardiology, Department of Medicine, University of California Irvine Medical Center, Orange, CA 92868, USA; Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Medicine, Jinan University, Guangzhou 510632, China.
| | - Jin Kyung Kim
- Division of Cardiology, Department of Medicine, University of California Irvine Medical Center, Orange, CA 92868, USA
| | - Baihe Chen
- Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Ahmed Abdel-Latif
- Saha Cardiovascular Research Center, University of Kentucky, Lexington 40536-0509, USA
| | - Masafumi Kitakaze
- Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, 5-7-1 Fujishirodai, Suita 5675-8565, Japan
| | - Liang Yan
- Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Medicine, Jinan University, Guangzhou 510632, China
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30
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Buendía P, Carracedo J, Soriano S, Madueño JA, Ortiz A, Martín-Malo A, Aljama P, Ramírez R. Klotho Prevents NFκB Translocation and Protects Endothelial Cell From Senescence Induced by Uremia. J Gerontol A Biol Sci Med Sci 2014; 70:1198-209. [PMID: 25246106 DOI: 10.1093/gerona/glu170] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Accepted: 08/14/2014] [Indexed: 12/25/2022] Open
Abstract
In patients with renal disease, uremia raises oxidative stress and senescence in endothelial cells, which can lead to endothelial dysfunction and cardiovascular disease. Klotho protein is a β-glucuronidase capable of hydrolyzing steroid β-glucuronides. This protein is recognized as an antiaging gene, that modulate both stress-induced senescence and functional response. The aim of the study was to investigate how senescence and oxidative stress induced by uremia in endothelial cells affects Klotho expression and whether intra or extracellular Klotho has effects on the response of these cells. Senescence and oxidative stress was obtained by exposure to uremic serum. Telomere length, the enzyme β-galactosidase, and oxidative stress were studied by flow cytometry. Nuclear factor kappa B activity was determined by electrophoretic mobility shift assay. The expression of Klotho decreased with the uremia and preceded the manifestations of cell aging. Levels of intracellular Klotho decreases associated to endothelial senescence, and exogenous Klotho prevents cellular senescence by inhibiting the increase in oxidative stress induced by uremia and diminished the nuclear factor kappa B-DNA binding ability.
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Affiliation(s)
- Paula Buendía
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Hospital Universitaro Reina Sofía, Córdoba, Spain
| | - Julia Carracedo
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Hospital Universitaro Reina Sofía, Córdoba, Spain.
| | - Sagrario Soriano
- Nephrology Unit, Hospital Universitaro Reina Sofía, Córdoba, Spain
| | - Juan Antonio Madueño
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Hospital Universitaro Reina Sofía, Córdoba, Spain
| | - Alberto Ortiz
- REDinREN, Servicio de Nefrología, Fundación para la Investigación Biomédica del Hospital Universitario La Paz, Instituto de Salud Carlos III, Fondos FEDER, Madrid, Spain. Unidad de Diálisis, Fundación Jiménez Díaz, Madrid, Spain
| | | | | | - Rafael Ramírez
- REDinREN, Servicio de Nefrología, Fundación para la Investigación Biomédica del Hospital Universitario La Paz, Instituto de Salud Carlos III, Fondos FEDER, Madrid, Spain. Physiology Department, Alcala de Henares University, Madrid, Spain
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