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Kobayashi D, Akagi T, Togano T, Iikawa R, Fukuchi T. Ab interno removal of malpositioned ex-press glaucoma device combined with bleb needling. Jpn J Ophthalmol 2025:10.1007/s10384-025-01203-5. [PMID: 40332644 DOI: 10.1007/s10384-025-01203-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 02/15/2025] [Indexed: 05/08/2025]
Abstract
PURPOSE We present an ab interno removal technique combined with a needling procedure for a malpositioned Ex-PRESS glaucoma shunt. STUDY DESIGN Retrospective case series. METHODS This study examined four cases of malpositioned Ex-PRESS shunts. Needle bleb revision was performed to expand the space under the scleral flap and bleb area. Clinical data, including corneal endothelial cell density (ECD), intraocular pressure (IOP), and anterior segment optical coherence tomography images (AS-OCT), were retrieved from clinical records. RESULTS All four cases underwent ab interno shunt removal combined with needle bleb revision without any serious complications. In three cases of anterior shunt malposition, a reduction in ECD was apparent before surgery but remained relatively stable after surgery. In one patient with posterior shunt malposition, shunt occlusion was suspected before surgery, but bleb formation and IOP improved after surgery. IOP was 8 mmHg to 21 mmHg (median, 10.5 mmHg) before surgery and 5 mmHg to 17 mmHg (median, 10 mmHg) 12 months after surgery. No additional glaucoma surgery was required within the first 12 months; however, after 12 months, two patients required additional glaucoma surgery. CONCLUSION Ab interno Ex-PRESS device removal combined with bleb needling is an important procedure in patients with malpositioned Ex-PRESS devices.
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Affiliation(s)
- Daigo Kobayashi
- Division of Ophthalmology and Visual Science, Niigata University Graduate School of Medical and Dental Sciences, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Tadamichi Akagi
- Division of Ophthalmology and Visual Science, Niigata University Graduate School of Medical and Dental Sciences, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.
| | - Tetsuya Togano
- Division of Ophthalmology and Visual Science, Niigata University Graduate School of Medical and Dental Sciences, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Ryu Iikawa
- Division of Ophthalmology and Visual Science, Niigata University Graduate School of Medical and Dental Sciences, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Takeo Fukuchi
- Division of Ophthalmology and Visual Science, Niigata University Graduate School of Medical and Dental Sciences, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
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Matsumae H, Kataoka K, Yagi-Yaguchi Y, Higa K, Suzuki T, Kasamatsu H, Shimazaki J, Yamaguchi T. Correlation between preoperative aqueous cytokine levels and mid-term corneal endothelial cell loss following penetrating keratoplasty. Eye (Lond) 2025; 39:1286-1291. [PMID: 39833574 PMCID: PMC12043822 DOI: 10.1038/s41433-025-03610-x] [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: 12/05/2023] [Revised: 11/29/2024] [Accepted: 01/09/2025] [Indexed: 01/22/2025] Open
Abstract
OBJECTIVE To investigate the association between preoperative aqueous humour (AqH) cytokines and mid-term endothelial cell density (ECD) following penetrating keratoplasty (PKP). METHODS This study analysed a total of 87 eyes of which 54 underwent PKP and 33 eyes underwent cataract surgery. AqH samples were collected at the beginning of surgery. The levels of cytokines (interleukins [ILs]-1α, -1β, -4, -6, -8, -10, -17A, monocyte chemotactic protein [MCP]-1, interferon [IFN]-α, IFN-γ, E-selectin, P-selectin, and soluble intercellular adhesion molecule-1 [sICAM-1]) in the AqH were measured using a multiplex beads immunoassay. The subjects who underwent PKP were classified into two groups: Group 1: ECD < 1200 cells/mm2 at 36 months and graft failure during follow-up (38 eyes); Group 2 ECD ≥ 1200 cells/mm2 at 36 months (16 eyes). RESULTS The ECD reduction per year was significantly correlated with the preoperative levels of protein (r = 0.48; P < 0.001), IL-6 (r = 0.29; P = 0.048), IL-8 (r = 0.42; P = 0.003), IL-12p70 (r = 0.46; P = .007), MCP-1 (r = 0.28; P = 0.049), IFN -γ (r = 0.43; P = 0.008), and s-ICAM-1 (r = 0.30; P = 0.03). The preoperative levels of IL-8, and IFN-γ in AqH were significantly higher in eyes with ECD < 1200 cells/mm2 compared to those with ECD ≥ 1200 cells/mm2 at 3 years (P ≤ 0.02). CONCLUSION Preoperative AqH cytokine levels are associated with mid-term ECD reduction after PKP. Pathological alterations of the AqH microenvironment may affect mid-term corneal endothelial cell survival.
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Affiliation(s)
- Hiroshi Matsumae
- Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kaon Kataoka
- Department of Ophthalmology, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan
| | - Yukari Yagi-Yaguchi
- Department of Ophthalmology, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan
| | - Kazunari Higa
- Department of Ophthalmology, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan
| | - Takanori Suzuki
- Department of Ophthalmology, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan
| | - Hirotsugu Kasamatsu
- Department of Ophthalmology, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan
| | - Jun Shimazaki
- Department of Ophthalmology, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan
| | - Takefumi Yamaguchi
- Department of Ophthalmology, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan.
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Lee S, Dohlman TH, Dana R. Immunology in corneal transplantation-From homeostasis to graft rejection. Transplant Rev (Orlando) 2025; 39:100909. [PMID: 39798206 PMCID: PMC11975484 DOI: 10.1016/j.trre.2025.100909] [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: 09/21/2024] [Revised: 12/19/2024] [Accepted: 01/08/2025] [Indexed: 01/15/2025]
Abstract
Immunology depends on maintaining a delicate balance within the human body, and disruptions can result in conditions such as autoimmune diseases, immunodeficiencies, and hypersensitivity reactions. This balance is especially crucial in transplantation immunology, where one of the primary challenges is preventing graft rejection. Such rejection can lead to organ failure, increased patient mortality, and higher healthcare costs due to the limited availability of donor tissues relative to patient needs. Xenotransplantation, like using porcine corneas for human transplants, offers a potential solution to the donor tissue shortage but faces substantial immunological rejection issues. To prevent rejection in both allo- and xenotransplantation, a deep understanding of how the body maintains immunological balance is essential, particularly since achieving tolerance to non-self tissues is considered the "holy grail" of the field. The cornea, the most frequently transplanted solid organ, has a high acceptance rate due to its immune-privileged status and serves as an ideal model for studying graft rejection mechanisms that disrupt tolerance. However, multiple immune pathways complicate our understanding of these mechanisms. This review examines the rejection mechanisms in corneal transplantation, identifying key cells involved and potential therapeutic strategies to induce and maintain immunological tolerance in both allo- and xenografts across various transplants.
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Affiliation(s)
- Seokjoo Lee
- Laboratory of Ocular Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Thomas H Dohlman
- Laboratory of Ocular Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Reza Dana
- Laboratory of Ocular Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
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Jammes M, Tabasi A, Bach T, Ritter T. Healing the cornea: Exploring the therapeutic solutions offered by MSCs and MSC-derived EVs. Prog Retin Eye Res 2025; 105:101325. [PMID: 39709150 DOI: 10.1016/j.preteyeres.2024.101325] [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: 09/18/2024] [Revised: 12/16/2024] [Accepted: 12/17/2024] [Indexed: 12/23/2024]
Abstract
Affecting a large proportion of the population worldwide, corneal disorders constitute a concerning health hazard associated to compromised eyesight or blindness for most severe cases. In the last decades, mesenchymal stem/stromal cells (MSCs) demonstrated promising abilities in improving symptoms associated to corneal diseases or alleviating these affections, especially through their anti-inflammatory, immunomodulatory and pro-regenerative properties. More recently, MSC therapeutic potential was shown to be mediated by the molecules they release, and particularly by their extracellular vesicles (EVs; MSC-EVs). Consequently, using MSC-EVs emerged as a pioneering strategy to mitigate the risks related to cell therapy while providing MSC therapeutic benefits. Despite the promises given by MSC- and MSC-EV-based approaches, many improvements are considered to optimize the therapeutic significance of these therapies. This review aspires to provide a comprehensive and detailed overview of current knowledge on corneal therapies involving MSCs and MSC-EVs, the strategies currently under evaluation, and the gaps remaining to be addressed for clinical implementation. From encapsulating MSCs or their EVs into biomaterials to enhance the ocular retention time to loading MSC-EVs with therapeutic drugs, a wide range of ground-breaking strategies are currently contemplated to lead to the safest and most effective treatments. Promising research initiatives also include diverse gene therapies and the targeting of specific cell types through the modification of the EV surface, paving the way for future therapeutic innovations. As one of the most important challenges, MSC-EV large-scale production strategies are extensively investigated and offer a wide array of possibilities to meet the needs of clinical applications.
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Affiliation(s)
- Manon Jammes
- Regenerative Medicine Institute, School of Medicine, University of Galway, Galway, Ireland
| | - Abbas Tabasi
- Regenerative Medicine Institute, School of Medicine, University of Galway, Galway, Ireland
| | - Trung Bach
- Regenerative Medicine Institute, School of Medicine, University of Galway, Galway, Ireland
| | - Thomas Ritter
- Regenerative Medicine Institute, School of Medicine, University of Galway, Galway, Ireland; CURAM Centre for Research in Medical Devices, University of Galway, Galway, Ireland.
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Liu Y, Kong X, Teng J, Wang Z, Cao W. Expression of Matrix Metalloproteinase-3 in the Aqueous Humor of Patients with Posner-Schlossman Syndrome. Curr Eye Res 2024; 49:1180-1183. [PMID: 39143748 DOI: 10.1080/02713683.2024.2374840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 01/31/2024] [Accepted: 06/24/2024] [Indexed: 08/16/2024]
Abstract
PURPOSE To explore the expression of matrix metalloproteinase-3 (MMP-3) in the aqueous humor of patients with Posner-Schlossman syndrome (PSS), and the association between MMP-3 and PSS. METHODS Peripheral blood and aqueous humor were routinely collected from 29 patients with PSS (PSS group) and 30 patients with age-related-cataract (ARC) (control group). The content of MMP-3 in serum and aqueous humor was measured by immunoturbidimetry. The correlation between MMP-3 and ophthalmic examination results were verified by Spearman's correlation analysis. RESULTS The MMP-3 level in the aqueous humor of the PSS group was (25.86 ± 13.4)ng/ml, significantly higher than that in the control group (3.9 ± 2.7)ng/ml(p < 0.001), while there was no significant difference in serum MMP-3 level between the two groups (p = 0.125). The endothelial cell density (ECD) in the aqueous humor of the PSS group was (2078 ± 440) cell/mm2, intraocular pressure (IOP) in the aqueous humor of the PSS group was (33 ± 12) mmHg. The correlation analysis of aqueous humor MMP-3 and various ophthalmic examination results showed that aqueous humor MMP-3 had a moderate correlation with IOP and the difference in ECD between the affected eye and the fellow eye. CONCLUSIONS MMP-3 level is elevated in the aqueous humor of PSS patients, and it may play an important role in the pathogenesis of PSS.
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Affiliation(s)
- Yu Liu
- Department of Clinical Laboratory, Eye and ENT Hospital of Fudan University, Shanghai, China
| | - Xiangmei Kong
- Department of Ophthalmology, Eye and ENT Hospital of Fudan University, Shanghai, China
| | - Jisen Teng
- Department of Clinical Laboratory, Eye and ENT Hospital of Fudan University, Shanghai, China
| | - Zhujian Wang
- Department of Clinical Laboratory, Eye and ENT Hospital of Fudan University, Shanghai, China
| | - Wenjun Cao
- Department of Clinical Laboratory, Eye and ENT Hospital of Fudan University, Shanghai, China
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Lee Y, Park J, Bang S, Kwon Y. A Standardized Extract of Green-Cotyledon Small Black Soybean (EYESOY®) Ameliorates Dry Eye Syndrome in an Animal Model. Curr Eye Res 2024; 49:1021-1029. [PMID: 38856074 DOI: 10.1080/02713683.2024.2357599] [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: 11/29/2023] [Revised: 04/22/2024] [Accepted: 05/14/2024] [Indexed: 06/11/2024]
Abstract
PURPOSE Dry eye syndrome is a common ocular disease that causes morbidity, high healthcare burden, and decreased quality of life. In this study, we evaluated the beneficial effects of a standardized extract of small black soybean (EYESOY®) in a benzalkonium chloride (BAC)-induced murine model of dry eye. METHODS Experimental dry eye was induced by instillation of 0.02% BAC on the right eye of the Sprague-Dawley rats. Saline solution or EYESOY were administered orally every day for 8 weeks. RESULTS EYESOY significantly improved tear volume in the cornea compared with that in the BAC group. Moreover, EYESOY inhibited damage to the corneal epithelial cells and lacrimal glands by suppressing the oxidative and inflammatory responses in a mouse dry eye model. It also increased the goblet cell density and mucin integrity in the conjunctiva. CONCLUSIONS Our results suggest that EYESOY has the potential to alleviate dry eye syndrome.
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Affiliation(s)
- Yoonhee Lee
- Bio Technology R&D Center, WiLab Co., Ltd, Seoul, Republic of Korea
- Department of Food and Nutrition, Sookmyung Women's University, Seoul, Republic of Korea
| | - Juyeon Park
- Bio Technology R&D Center, WiLab Co., Ltd, Seoul, Republic of Korea
| | - Sunah Bang
- Bio Technology R&D Center, WiLab Co., Ltd, Seoul, Republic of Korea
| | - Yongbum Kwon
- Bio Technology R&D Center, WiLab Co., Ltd, Seoul, Republic of Korea
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Guo R, Yu Y, Xu C, Ma M, Hou C, Dong X, Wu J, Ouyang C, Ling J, Huang T. Protective effects of curcumin on corneal endothelial cell PANoptosis and monocyte adhesion induced by tumor necrosis factor-alpha and interferon-gamma in rats. Exp Eye Res 2024; 245:109952. [PMID: 38838973 DOI: 10.1016/j.exer.2024.109952] [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: 02/18/2024] [Revised: 04/18/2024] [Accepted: 06/02/2024] [Indexed: 06/07/2024]
Abstract
Decrease of human corneal endothelial cell (CEC) density leads to corneal edema, progressive corneal opacity, and reduced visual acuity. A reduction in CEC density may be related to elevated levels of inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interferon (INF)-γ. PANoptosis, characterized by the activation of apoptosis, necroptosis, and pyroptosis, could be a factor in the loss of CECs driven by TNF-α and INF-γ. Cytokines also stimulate monocytes adhesion to endothelium. It has been shown in previous research that curcumin plays protective roles against numerous corneal inflammatory diseases. However, it is not determined whether curcumin acts as an anti-PANoptotic agent or if it mitigates monocyte adhesion to CECs. Therefore, this research aimed to explor the potential therapeutic effects of curcumin and its underlying mechanisms in the loss of CECs. CEC injury models were established, and curcumin was injected subconjunctivally. Clinical evaluation of the corneas was conducted using a scoring system and anterior segment photography. Corneal observation was performed with hematoxylin and eosin staining and immunostaining of zona occludens-1(ZO-1). Apoptotic cells within the corneal endothelium were observed using TUNEL staining. The detection of primary proteins expression was accomplished through Western blot analysis. Interleukin (IL)-1β and macrophage chemotactic protein 1 (MCP-1) levels were determined via ELISA, while the expression of cleaved caspase-3, gasdermin-D (GSDMD), phosphor-mixed lineage kinase domain-like protein (p-MLKL) and intercellular cell adhesion molecule-1 were confirmed by immunofluorescence. Myeloperoxidase (MPO) activity was measured in aqueous humors. Curcumin treatment attenuated the loss of CECs and corneal edema caused by TNF-α and IFN-γ. Besides, it decreased the count of TUNEL-positive cells, and inhibited the upregulation of cleaved caspase-3, cleaved caspase-6, cleaved caspase-7, and cleaved poly (ADP-ribose) polymerase. Moreover, both the expression and phosphorylation of MLKL and receptor-interacting protein 3 were decreased in curcumin-treated rats. Furthermore, curcumin also lowered the expression of cleaved caspase-1, diminished the levels of IL1β and MCP-1, and inhibited the activity of MPO. Besides, the expression of intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, as well as the number of CD11b-positive cells adhered to the CECs decreased for the administration of curcumin.
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Affiliation(s)
- Ruilin Guo
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Yi Yu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Chenjia Xu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Minglu Ma
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Chao Hou
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Xiaojuan Dong
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Jing Wu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Chen Ouyang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Jie Ling
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Ting Huang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China.
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Ramm L, Spoerl E, Terai N, Herber R, Pillunat LE. Association Between Corneal Changes and Retinal Oximetry in Diabetes Mellitus. Clin Ophthalmol 2024; 18:1235-1243. [PMID: 38737594 PMCID: PMC11088381 DOI: 10.2147/opth.s456020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 04/21/2024] [Indexed: 05/14/2024] Open
Abstract
Purpose Diabetes mellitus (DM) causes different corneal changes that are associated with the severity of diabetic retinopathy. To identify the pathophysiological reasons for this, corneal tomography and optical densitometry (COD) were combined with retinal oximetry. Methods Patients with DM and healthy subjects were included in this pilot study. Spatially resolved corneal thickness and COD were assessed using the Pentacam HR (Oculus). The pachymetry difference (PACDiff) was calculated as an indicator of an increase in the peripheral corneal thickness. Oxygen saturation (SO2) of the retinal vessels was measured using the Retinal Vessel Analyzer (Imedos Systems UG). Subsequently, the associations between corneal and retinal parameters were analyzed. Results Data from 30 patients with DM were compared with those from 30 age-matched healthy subjects. In DM, arterial (P = 0.048) and venous (P < 0.001) SO2 levels were increased, and arteriovenous SO2 difference was decreased (P < 0.001). In patients, PACDiff was higher than that in healthy subjects (P < 0.05), indicating a stronger increase in peripheral corneal thickness. The COD was reduced in DM (P = 0.004). The PACDiff of concentric rings with a diameter of 4 mm (r = -0.404; P = 0.033) to 8 mm (r = -0.522; P = 0.004) was inversely correlated with the arteriovenous SO2 difference. Furthermore, PACDiff 4 mm was negatively associated with arterial SO2 (r = -0.389; P = 0.041), and the COD of the peripheral corneal areas correlated positive with arterial SO2 (COD total 10-12 mm: r = 0.408; P = 0.025). Conclusion These associations might indicate a common pathogenesis of corneal and retinal changes in DM, which could be caused by reduced oxygen supply, mitochondrial dysfunction, oxidative stress, and cytokine effects.
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Affiliation(s)
- Lisa Ramm
- Department of Ophthalmology, University Hospital Carl Gustav Carus, TU Dresden, Dresden, 01307, Germany
| | - Eberhard Spoerl
- Department of Ophthalmology, University Hospital Carl Gustav Carus, TU Dresden, Dresden, 01307, Germany
| | - Naim Terai
- Department of Ophthalmology, University Hospital Carl Gustav Carus, TU Dresden, Dresden, 01307, Germany
| | - Robert Herber
- Department of Ophthalmology, University Hospital Carl Gustav Carus, TU Dresden, Dresden, 01307, Germany
| | - Lutz E Pillunat
- Department of Ophthalmology, University Hospital Carl Gustav Carus, TU Dresden, Dresden, 01307, Germany
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Zidan AA, Zhu S, Elbasiony E, Najafi S, Lin Z, Singh RB, Naderi A, Yin J. Topical application of calcitonin gene-related peptide as a regenerative, antifibrotic, and immunomodulatory therapy for corneal injury. Commun Biol 2024; 7:264. [PMID: 38438549 PMCID: PMC10912681 DOI: 10.1038/s42003-024-05934-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 02/19/2024] [Indexed: 03/06/2024] Open
Abstract
Calcitonin gene-related peptide (CGRP) is a multifunctional neuropeptide abundantly expressed by corneal nerves. Using a murine model of corneal mechanical injury, we found CGRP levels in the cornea significantly reduced after injury. Topical application of CGRP as an eye drop accelerates corneal epithelial wound closure, reduces corneal opacification, and prevents corneal edema after injury in vivo. CGRP promotes corneal epithelial cell migration, proliferation, and the secretion of laminin. It reduces TGF-β1 signaling and prevents TGF-β1-mediated stromal fibroblast activation and tissue fibrosis. CGRP preserves corneal endothelial cell density, morphology, and pump function, thus reducing corneal edema. Lastly, CGRP reduces neutrophil infiltration, macrophage maturation, and the production of inflammatory cytokines in the cornea. Taken together, our results show that corneal nerve-derived CGRP plays a cytoprotective, pro-regenerative, anti-fibrotic, and anti-inflammatory role in corneal wound healing. In addition, our results highlight the critical role of sensory nerves in ocular surface homeostasis and injury repair.
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Affiliation(s)
- Asmaa A Zidan
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Shuyan Zhu
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Elsayed Elbasiony
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Sheyda Najafi
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Zhirong Lin
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Rohan Bir Singh
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Amirreza Naderi
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Jia Yin
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
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10
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Wang C, He J, Chen C, Luo W, Dang X, Mao L. A potential role of human esophageal cancer-related gene-4 in cardiovascular homeostasis. Gene 2024; 894:147977. [PMID: 37956966 DOI: 10.1016/j.gene.2023.147977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 10/10/2023] [Accepted: 11/08/2023] [Indexed: 11/19/2023]
Abstract
Human esophageal cancer related gene-4 (ECRG-4) encodes a 148-aminoacid pre-pro-peptide that can be processed tissue-dependently into multiple small peptides possessing multiple functions distinct from, similar to, or opposite to the tumor suppressor function of the full-length Ecrg4. Ecrg-4 is covalently bound to the cell surface through its signal peptide, colocalized with the innate immunity complex (TLR4-CD14-MD2), and functions as a 'sentinel' molecule in the maintenance of epithelium and leukocyte homeostasis, meaning that the presence of Ecrg-4 on the cell surface signals the maintained homeostasis, whereas the loss of Ecrg-4 due to tissue injury activates pro-inflammatory and tissue proliferative responses, and the level of Ecrg-4 gradually returns to its pre-injury level upon wound healing. Interestingly, Ecrg-4 is also highly expressed in the heart and its conduction system, endothelial cells, and vascular smooth muscle cells. Accumulating evidence has shown that Ecrg-4 is involved in cardiac rate/rhythm control, the development of atrial fibrillation, doxorubicin-induced cardiotoxicity, the ischemic response of the heart and hypoxic response in the carotid body, the pathogenesis of atherosclerosis, and likely the endemic incidence of idiopathic dilated cardiomyopathy. These preliminary discoveries suggest that Ecrg-4 may function as a 'sentinel' molecule in cardiovascular system as well. Here, we briefly review the basic characteristics of ECRG-4 as a tumor suppressor gene and its regulatory functions on inflammation and apoptosis; summarize the discoveries about its distribution in cardiovascular system and involvement in the development of CVDs, and discuss its potential as a novel therapeutic target for the maintenance of cardiovascular system homeostasis.
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Affiliation(s)
- Chaoying Wang
- The Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, China
| | - Jianghui He
- The Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, China
| | - Chunyue Chen
- The Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, China
| | - Wenjun Luo
- The Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, China
| | - Xitong Dang
- The Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, China.
| | - Liang Mao
- The Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, China; Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China.
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Jha A, Verma A, Priya C. Effects of chewing tobacco on corneal endothelium in patients with diabetes mellitus. Eye (Lond) 2023; 37:3392-3397. [PMID: 37072470 PMCID: PMC10630435 DOI: 10.1038/s41433-023-02515-x] [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: 11/15/2022] [Revised: 03/06/2023] [Accepted: 03/27/2023] [Indexed: 04/20/2023] Open
Abstract
OBJECTIVE To determine the impact of tobacco chewing on corneal endothelial structure in patients with diabetes mellitus (DM). METHODS Corneal endothelial parameters (endothelial cell count, ECD; coefficient of variation, CV; hexagonality, Hex, and central corneal thickness, CCT) were analysed in 1234 eyes of 1234 patients using non-contact specular microscopy (EM 4000 Tomey Nishi-Ku, Nagoya, Aichi, Japan). The study group (with a present history of tobacco chewing) comprising of 948 subjects, with 473 having DM was compared with age and gender-matched control group comprising of 286 subjects (139 having DM) with no history of tobacco use in any form. RESULTS Tobacco chewers had a significantly reduced ECD (P = 0.024) and Hex (P = 0.009) as compared with non-chewers. Similar results were noted in ECD (P = 0.004) and Hex (P = 0.005) in patients with DM. Tobacco chewers had a significantly decreased ECD values among males, HbA1C ≤ 7.5% and duration of DM ≤ 20 years, and significantly decreased Hex among those with >50 years of age, females, and duration of DM > 20 years. The CV and CCT values were comparable between the study and the control groups. Tobacco chewers showed a significant association of ECD with age, HbA1C, and duration of DM; CV with HbA1C; Hex with age and duration of DM; and CCT with gender, age, HbA1C and duration of DM. CONCLUSIONS Tobacco chewing may negatively impact corneal health, especially confounded by additional factors like age and DM. These factors must be accounted for in the pre-operative evaluation of such patients prior to any intra-ocular surgery.
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Affiliation(s)
- Ashok Jha
- Department of Ophthalmology, Military Hospital Gaya, Gaya, 823005, India.
| | - Aditya Verma
- Department of Ophthalmology and Visual Sciences, University of Louisville, 310 E Muhammad Ali Blvd, Louisville, 40202, Kentucky, USA
| | - Charima Priya
- Shree Vishveshwara Netraalaya, Gaya, Gaya, 823001, Bihar, India
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Otsuka M, Tojo N, Hayashi A. Corneal endothelial cell loss after EX-PRESS surgery depends on site of insertion, cornea or trabecular meshwork. Int Ophthalmol 2023; 43:3471-3477. [PMID: 37273152 DOI: 10.1007/s10792-023-02752-9] [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: 10/20/2022] [Accepted: 05/21/2023] [Indexed: 06/06/2023]
Abstract
PURPOSE Previously, we reported that the Ex-press® shunt (EXP) was associated with more rapid reduction in corneal endothelial cells when inserted into the cornea rather than the trabecular meshwork (TM). We compared the reduction rate of corneal endothelial cells between the corneal insertion group and TM insertion group. METHODS This was a retrospective study. We included patients who had undergone EXP surgery and were followed for > 5 years. We analyzed the corneal endothelial cell density (ECD) before and after EXP implantation. RESULTS We included 25 patients in the corneal insertion group and 53 patients in the TM insertion group. One patient in the corneal insertion group developed bullous keratopathy. The ECD decreased significantly more rapidly in the corneal insertion group (p < 0.0001), in whom the mean ECD decreased from 2227 ± 443 to 1415 ± 573 cells/mm2 at 5 years with a mean 5-year survival rate of 64.9 ± 21.9%. By contrast, in the TM insertion group, the mean ECD decreased from 2356 ± 364 to 2124 ± 579 cells/mm2 at 5 years, and the mean 5-year survival rate was 89.3 ± 18.0%. The decrease rate of ECD was calculated as 8.3%/year in the corneal insertion group and 2.2%/year in the TM insertion group. CONCLUSIONS Insertion into cornea is a risk factor for rapid ECD loss. The EXP should be inserted into the TM to preserve the corneal endothelial cells.
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Affiliation(s)
- Mitusya Otsuka
- Department of Ophthalmology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Naoki Tojo
- Department of Ophthalmology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
| | - Atsushi Hayashi
- Department of Ophthalmology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
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Chihara E, Tanito M, Kono M, Matsuda A, Honda R, Ishida K, Funaki T, Hamanaka T. Different patterns in the corneal endothelial cell loss after pars plana and pars limbal insertion of the Baerveldt glaucoma implant. Am J Ophthalmol 2023; 253:12-21. [PMID: 37119996 DOI: 10.1016/j.ajo.2023.03.038] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 03/20/2023] [Accepted: 03/24/2023] [Indexed: 05/01/2023]
Abstract
PURPOSE To assess corneal endothelial cell (CE) loss after pars plana (PP) and pars limbal (PL) insertion of a Baerveldt glaucoma implant (BGI). DESIGN Retrospective multicenter interventional comparative study. METHODS We studied central CE loss for 5 years after BGI surgery in 192 eyes. RESULTS The prevalence of bullous keratopathy (BK) was greater in the PL cohort than in the PP cohort (P = .003). The CE loss after simultaneous PP vitrectomy and tube insertion into the vitreous cavity was 11.9% in the first year, which was greater than that of 2.9% in eyes where the tube was inserted simply into the vitreous cavity after a prior vitrectomy (P = .046). The annual percentage CE loss after the first year decreased unidirectionally in both of those groups and was 1.3% and 1.0% in the fifth year, respectively (P < .001). For limbal insertion, the CE loss in the simple PL cohort was biphasic, decreasing from 10.5% in the first year to 7.0% in the fifth year. Simultaneous cataract and BGI surgery enhanced the CE loss slightly in the first year in the PP and PL cohorts to 13.0% and 14.0%, respectively. However, these increases were not significant (P = .816 and .358, respectively). Low preoperative CE density (P < .001) and insertion site (P = .020) were significant risk factors for the development of BK. CONCLUSIONS CE loss in the PL and PP cohorts was biphasic and unidirectional, respectively. The difference in annual CE loss became evident over time. PP tube implantation may be advantageous when the preoperative CE density is low.
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Affiliation(s)
- Etsuo Chihara
- From the Sensho-kai Eye Institute (E.C.), Kyoto; Department of Ophthalmology, Shimane University Faculty of Medicine (E.C., M.T., M.K.), Shimane.
| | - Masaki Tanito
- Department of Ophthalmology, Shimane University Faculty of Medicine (E.C., M.T., M.K.), Shimane
| | - Michihiro Kono
- Department of Ophthalmology, Shimane University Faculty of Medicine (E.C., M.T., M.K.), Shimane
| | - Akira Matsuda
- Department of Ophthalmology, Juntendo University (A.M., R.H.), Tokyo
| | - Rio Honda
- Department of Ophthalmology, Juntendo University (A.M., R.H.), Tokyo
| | - Kyoko Ishida
- Department of Ophthalmology, Toho University Ohashi Medical Center (K.I.), Tokyo
| | - Toshinari Funaki
- Department of Ophthalmology, Japanese Red Cross Medical Center (T.F., T.H.), Tokyo, Japan
| | - Teruhiko Hamanaka
- Department of Ophthalmology, Japanese Red Cross Medical Center (T.F., T.H.), Tokyo, Japan
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Bortoletto E, Pieretti F, Brun P, Venier P, Leonardi A, Rosani U. Meta-Analysis of Keratoconus Transcriptomic Data Revealed Altered RNA Editing Levels Impacting Keratin Genomic Clusters. Invest Ophthalmol Vis Sci 2023; 64:12. [PMID: 37279397 DOI: 10.1167/iovs.64.7.12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023] Open
Abstract
Introduction Keratoconus (KC) is an ocular disorder with a multifactorial origin. Transcriptomic analyses (RNA-seq) revealed deregulations of coding (mRNA) and non-coding RNAs (ncRNAs) in KC, suggesting that mRNA-ncRNA co-regulations can promote the onset of KC. The present study investigates the modulation of RNA editing mediated by the adenosine deaminase acting on dsRNA (ADAR) enzyme in KC. Materials The level of ADAR-mediated RNA editing in KC and healthy corneas were determined by two indexes in two different sequencing datasets. REDIportal was used to localize known editing sites, whereas new putative sites were de novo identified in the most extended dataset only and their possible impact was evaluated. Western Blot analysis was used to measure the level of ADAR1 in the cornea from independent samples. Results KC was characterized by a statistically significant lower RNA-editing level compared to controls, resulting in a lower editing frequency, and less edited bases. The distribution of the editing sites along the human genome showed considerable differences between groups, particularly relevant in the chromosome 12 regions encoding for Keratin type II cluster. A total of 32 recoding sites were characterized, 17 representing novel sites. JUP, KRT17, KRT76, and KRT79 were edited with higher frequencies in KC than in controls, whereas BLCAP, COG3, KRT1, KRT75, and RRNAD1 were less edited. Both gene expression and protein levels of ADAR1 appeared not regulated between diseased and controls. Conclusions Our findings demonstrated an altered RNA-editing in KC possibly linked to the peculiar cellular conditions. The functional implications should be further investigated.
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Affiliation(s)
| | - Fabio Pieretti
- Department of Molecular Medicine, Histology Unit, University of Padova, Padova, Italy
| | - Paola Brun
- Department of Molecular Medicine, Histology Unit, University of Padova, Padova, Italy
| | - Paola Venier
- Department of Biology, University of Padova, Padova, Italy
| | - Andrea Leonardi
- Department of Neuroscience, Ophthalmology Unit, University of Padova, Padova, Italy
| | - Umberto Rosani
- Department of Biology, University of Padova, Padova, Italy
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Park J, Hong T, An G, Park H, Song G, Lim W. Triadimenol promotes the production of reactive oxygen species and apoptosis with cardiotoxicity and developmental abnormalities in zebrafish. THE SCIENCE OF THE TOTAL ENVIRONMENT 2023; 862:160761. [PMID: 36502969 DOI: 10.1016/j.scitotenv.2022.160761] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 11/30/2022] [Accepted: 12/04/2022] [Indexed: 06/17/2023]
Abstract
Various types of fungicides, especially triazole fungicides, are used to prevent fungal diseases on farmlands. However, the developmental toxicity of one of the triazole fungicides, triadimenol, remains unclear. Therefore, we used the zebrafish animal model, a representative toxicological model, to investigate it. Triadimenol induced morphological alterations in the eyes and body length along with yolk sac and heart edema. It also stimulated the production of reactive oxygen species and expression of inflammation-related genes and caused apoptosis in the anterior regions of zebrafish, especially in the heart. The phosphorylation levels of Akt, ERK, JNK, and p38 proteins involved in the PI3K and MAPK pathways, which are important for the development process, were also reduced by triadimenol. These changes led to malformation of the heart and vascular structures, as observed in the flk1:eGFP transgenic zebrafish models and a reduction in the heart rate. In addition, the expression of genes associated with cardiac and vascular development was also reduced. Therefore, we elucidated the mechanisms associated with triadimenol toxicity that leads to various abnormalities and developmental toxicity in zebrafish.
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Affiliation(s)
- Junho Park
- Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea
| | - Taeyeon Hong
- Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Garam An
- Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea
| | - Hahyun Park
- Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea
| | - Gwonhwa Song
- Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
| | - Whasun Lim
- Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Republic of Korea.
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16
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Yang Y, Ma Y, Yu S, Lin Z, Yan C, Wang Y, Yuan Q, Meng Z, Yan G, Wu Z, Tang H, Peng Z, Huang J, Zhuang G. TIPE2 knockout reduces myocardial cell damage by inhibiting IFN-γ-mediated ferroptosis. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166566. [PMID: 36216021 DOI: 10.1016/j.bbadis.2022.166566] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 09/18/2022] [Accepted: 10/04/2022] [Indexed: 11/19/2022]
Abstract
Acute rejection of the transplanted heart is mediated by oxidative programmed cell death through the synergistic effects of the innate and adaptive immune systems. However, the role of ferroptosis, a newly discovered form of oxidative cell death, has not been widely evaluated. Tumor necrosis factor-α-induced protein-8 like 2 (TNFAIP8L2), also known as TIPE2, is required for maintaining immune homeostasis. To characterize the role of TIPE2 in mediating heart allografts, BALB/c hearts were transplanted into C57BL/6 wild-type (WT) and TIPE2-/- recipient mice. In TIPE2-/- recipient mice, allograft injury in BALB/c allograft hearts was significantly reduced through the inhibition of allograft ferroptosis. On day 3 and day 6 post-transplantation, the numbers of CD3+, CD4+, and CD8+ cells among splenocytes and draining lymph node cells were significantly decreased, and the activation of CD4+ and CD8+ cells in grafts was decreased in TIPE2-/- recipient mice compared with WT mice. Moreover, CD4+ and CD8+ T cells in TIPE2-/- recipient mice were characterized by deficient capacities for interferon-γ (IFN-γ) production through the TBK1 signaling axis and increased glutathione peroxidase 4 (GPX4). In cell experiments, treatment with IFN-γ enhanced ferroptosis-specific lipid peroxidation in myocardial cells and correlated inversely with GPX4 expression. Mechanistically, IFN-γ administration decreased the expression of GPX4 by inhibiting MEK/ERK phosphorylation. In summary, our findings demonstrated that TIPE2 deficiency inhibits T-cell production of IFN-γ to reduce ferroptosis in allografts by restraining lipid peroxidation.
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Affiliation(s)
- Yan Yang
- Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, Organ Transplantation Institute, School of Medicine, Xiamen University, Xiamen, China
| | - Yunhan Ma
- Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, Organ Transplantation Institute, School of Medicine, Xiamen University, Xiamen, China
| | - Shengnan Yu
- Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, Organ Transplantation Institute, School of Medicine, Xiamen University, Xiamen, China
| | - Zeyang Lin
- Department of Pathology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Changxiu Yan
- Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, Organ Transplantation Institute, School of Medicine, Xiamen University, Xiamen, China
| | - Yinan Wang
- Department of Basic Medicine, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Qian Yuan
- Department of Basic Medicine, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Zhe Meng
- Department of Basic Medicine, School of Medicine, Xiamen University, Xiamen, Fujian, China; Department of Obstetrics and Gynecology, Dongfang Affiliated Hospital of Xiamen University, Fuzhou, China
| | - Guoliang Yan
- Department of Basic Medicine, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Zhengxin Wu
- Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Huamei Tang
- Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, Organ Transplantation Institute, School of Medicine, Xiamen University, Xiamen, China; Department of General Surgery, Xiang An Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Zhihai Peng
- Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, Organ Transplantation Institute, School of Medicine, Xiamen University, Xiamen, China; Department of General Surgery, Xiang An Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
| | - Jiyi Huang
- The Fifth Hospital of Xiamen, Xiamen, Fujian, China; The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China.
| | - Guohong Zhuang
- Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, Organ Transplantation Institute, School of Medicine, Xiamen University, Xiamen, China.
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Sekhon AS, He B, Iovieno A, Yeung SN. Pathophysiology of Corneal Endothelial Cell Loss in Dry Eye Disease and Other Inflammatory Ocular Disorders. Ocul Immunol Inflamm 2023; 31:21-31. [PMID: 34678119 DOI: 10.1080/09273948.2021.1980808] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
PURPOSE Dry eye disease (DED) and other inflammatory ocular disorders have been reported to be associated with decreased corneal endothelial cell density (CECD), however the mechanism of underlying endothelial cell loss remains unknown. METHODS We conducted a comprehensive literature search of English-written publications on dry eye disease, corneal endothelial cell loss, Sjögren's syndrome, and Graft Vs Host Disease (GVHD), to review the effects of DED and other inflammatory ocular surface conditions on CECD. RESULTS A total of 78 studies were included in our study. Loss of corneal neurotrophic support, cytotoxic stress, and a heightened immune response, all of which may occur secondarily to a common causative agent such as inflammation, are major contributors to reduced CECD. CONCLUSION More studies are needed to determine how the interrelated pathways of altered corneal nerve function and upregulated expression of inflammatory activity influence corneal endothelial cell loss.
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Affiliation(s)
- Amardeep S Sekhon
- Department of Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada
| | - Bonnie He
- Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Alfonso Iovieno
- Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, Canada
| | - Sonia N Yeung
- Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, Canada
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18
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Sonmez K, Hekimsoy HK. Outcomes and predictors of vitrectomy and silicone oil tamponade in retinal detachments complicated by proliferative vitreoretinopathy. Int J Ophthalmol 2022; 15:1279-1289. [PMID: 36017034 DOI: 10.18240/ijo.2022.08.09] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 06/13/2022] [Indexed: 11/23/2022] Open
Abstract
AIM To evaluate outcomes and determine factors influencing the outcomes of vitrectomy with silicone oil (SO) endotamponade for the management of rhegmatogenous retinal detachment (RRD) complicated by advanced proliferative vitreoretinopathy (PVR). METHODS This is a retrospective, interventional case series of eyes with PVR grade C associated RRD with or without prior surgery that underwent vitreoretinal surgery and SO tamponade. Eyes with a minimum follow-up of 6mo after SO extraction were included. Eyes were classified into three PVR subgroups according to severity and extension of proliferation. The influence of several preoperative, intraoperative and postoperative factors upon the functional and anatomical outcomes was assessed using multivariate logistic regression analysis. RESULTS A hundred and one eyes of 101 patients that met the inclusion criteria were studied. Seventy-five of 101 eyes (74.3%) had successful retinal reattachment after one operation. Increased aqueous cell and flare at the first week exam had a statistically significant association with redetachment, recurrent membrane proliferation and keratopathy. Visual acuity improvement was significantly associated with faint postoperative aqueous inflammation values, primary vitrectomy and PVR outside of the posterior pole. CONCLUSION Although encouraging anatomical and functional outcomes are achieved after vitrectomy and SO tamponade in eyes with RRD complicated by PVR, an increase in aqueous flare or cells at the first week follow-up is most likely to result in postoperative late complications. Primary vitrectomy, PVR associated with minimal posterior pole extension and absent to mild postoperative aqueous inflammation are associated with improved post-operative final visual acuity.
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Affiliation(s)
- Kenan Sonmez
- University of Health Sciences, Ulucanlar Eye Education and Research Hospital, Ankara 06240, Turkey
| | - Hilal Kilinc Hekimsoy
- University of Health Sciences, Ulucanlar Eye Education and Research Hospital, Ankara 06240, Turkey
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19
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Kholodenko IV, Gisina AM, Manukyan GV, Majouga AG, Svirshchevskaya EV, Kholodenko RV, Yarygin KN. Resistance of Human Liver Mesenchymal Stem Cells to FAS-Induced Cell Death. Curr Issues Mol Biol 2022; 44:3428-3443. [PMID: 36005132 PMCID: PMC9406952 DOI: 10.3390/cimb44080236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/26/2022] [Accepted: 07/28/2022] [Indexed: 11/05/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have a pronounced therapeutic potential in various pathological conditions. Though therapeutic effects of MSC transplantation have been studied for a long time, the underlying mechanisms are still not clear. It has been shown that transplanted MSCs are rapidly eliminated, presumably by apoptosis. As the mechanisms of MSC apoptosis are not fully understood, in the present work we analyzed MSC sensitivity to Fas-induced apoptosis using MSCs isolated from the biopsies of liver fibrosis patients (L-MSCs). The level of cell death was analyzed by flow cytometry in the propidium iodide test. The luminescent ATP assay was used to measure cellular ATP levels; and the mitochondrial membrane potential was assessed using the potential-dependent dye JC-1. We found that human L-MSCs were resistant to Fas-induced cell death over a wide range of FasL and anti-Fas mAb concentrations. At the same time, intrinsic death signal inducers CoCl2 and staurosporine caused apoptosis of L-MSCs in a dose-dependent manner. Despite the absence of Fas-induced cell death treatment of L-MSCs with low concentrations of FasL or anti-Fas mAb resulted in a cellular ATP level decrease, while high concentrations of the inducers caused a decline of the mitochondrial membrane potential. Pre-incubation of L-MSCs with the pro-inflammatory cytokine TNF-α did not promote L-MSC cell death. Our data indicate that human L-MSCs have increased resistance to receptor-mediated cell death even under inflammatory conditions.
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Affiliation(s)
- Irina V. Kholodenko
- Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia; (A.M.G.); (K.N.Y.)
- Correspondence: ; Tel.: +7-(905)7765062; Fax: +7-(499)2450857
| | - Alisa M. Gisina
- Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia; (A.M.G.); (K.N.Y.)
| | - Garik V. Manukyan
- Petrovsky Russian Research Center of Surgery, 119991 Moscow, Russia;
| | - Alexander G. Majouga
- Faculty of Chemical and Pharmaceutical Technologies and Biomedical Products, Mendeleev University of Chemical Technology of Russia, 125047 Moscow, Russia;
| | - Elena V. Svirshchevskaya
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (E.V.S.); (R.V.K.)
| | - Roman V. Kholodenko
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (E.V.S.); (R.V.K.)
| | - Konstantin N. Yarygin
- Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia; (A.M.G.); (K.N.Y.)
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20
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Bonelli F, Lasagni Vitar RM, Merlo Pich FG, Fonteyne P, Rama P, Mondino A, Ferrari G. Corneal endothelial cell reduction and increased Neurokinin-1 receptor expression in a graft-versus-host disease preclinical model. Exp Eye Res 2022; 220:109128. [DOI: 10.1016/j.exer.2022.109128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 05/19/2022] [Accepted: 05/23/2022] [Indexed: 11/04/2022]
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21
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Sun P, Shen L, Li YB, Du LQ, Wu XY. Long-term observation after transplantation of cultured human corneal endothelial cells for corneal endothelial dysfunction. Stem Cell Res Ther 2022; 13:228. [PMID: 35659288 PMCID: PMC9166479 DOI: 10.1186/s13287-022-02889-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 02/01/2022] [Indexed: 11/10/2022] Open
Abstract
Background Corneal transplantation is the only way to treat serious corneal diseases caused by corneal endothelial dysfunction. However, the shortage of donor corneal tissues and human corneal endothelial cells (HCECs) remains a worldwide challenge. We cultivated HCECs by the use of a conditioned medium from orbital adipose-derived stem cells (OASC-CM) in vitro. Then the HCECs were used to treat animal corneal endothelial dysfunction models via cell transplantation. The purpose of this study was to conduct a long-term observation and evaluation after cell transplantation. Methods Orbital adipose-derived stem cells (OASCs) were isolated to prepare the conditioned medium (CM). HCECs were cultivated and expanded by the usage of the CM (CM-HCECs). Then, related corneal endothelial cell (CEC) markers were analyzed by immunofluorescence. The cell proliferation ability was also tested. CM-HCECs were then transplanted into monkey corneal endothelial dysfunction models by injection. We carried out a 24-month postoperative preclinical observation and verified the long-term effect by histological examination and transcriptome sequencing. Results CM-HCECs strongly expressed CEC-related markers and maintained polygonal cell morphology even after 10 passages. At 24 months after cell transplantation, there was a CEC density of more than 2400 cells per square millimeter (range, 2408–2685) in the experimental group. A corneal thickness (CT) of less than 550 μm (range, 490–510) was attained. Gene sequencing showed that the gene expression pattern of CM-HCECs was similar to that of transplanted cells and HCECs. Conclusions Transplantation of CM-HCECs into monkey corneal endothelial dysfunction models resulted in a transparent cornea after 24 months. This research provided a promising prospect of cell-based therapy for corneal endothelial diseases. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02889-x.
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Affiliation(s)
- Peng Sun
- Department of Ophthalmology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Lin Shen
- Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, China
| | - Yuan-Bin Li
- Department of Ophthalmology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Li-Qun Du
- Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, China
| | - Xin-Yi Wu
- Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, China.
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Obuchowska I, Konopińska J. Corneal Endothelial Cell Loss in Patients After Minimally Invasive Glaucoma Surgery: Current Perspectives. Clin Ophthalmol 2022; 16:1589-1600. [PMID: 35642179 PMCID: PMC9148582 DOI: 10.2147/opth.s359305] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 05/17/2022] [Indexed: 12/14/2022] Open
Abstract
Minimally invasive glaucoma surgery (MIGS) is a rapidly expanding category of surgical glaucoma treatment options that offer a superior safety profile compared with traditional approaches for reducing intraocular pressure. However, MIGS may cause corneal endothelial cell loss; therefore, it has been receiving increasing attention. This systematic review aimed to evaluate and compare the rate and degree of corneal endothelial loss after MIGS. First, this paper presents an overview of the theoretical effectiveness of MIGS, the fundamental aspects regarding the roles of endothelial cells, and the effect of cataract surgery on the quality and count of endothelial cells. Further, we detail the various surgical techniques involved in MIGS, the development of these techniques over the time, and clinical aspects to consider with respect to the endothelial cell count. We discuss in detail the COMPASS-XT study, which was based on data collected over 5 years, reported that withdrawal of the CyPass Micro-Stent (Alcon Laboratories) yielded increased corneal endothelial cell loss. Generally, MIGS procedures are considered safe, with the incidence of complications ranging from 1% to 20% depending on the surgery type; however, there is still need for studies with longer follow-up. Thus, an adequate count of endothelial cells in the central cornea portion is recommended as necessary for candidate patients for MIGS.
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Affiliation(s)
- Iwona Obuchowska
- Department of Ophthalmology, Medical University of Bialystok, Bialystok, 15-276, Poland
| | - Joanna Konopińska
- Department of Ophthalmology, Medical University of Bialystok, Bialystok, 15-276, Poland
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23
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Gu S, Peng R, Xiao G, Hong J. Severe Corneal Edema Increases ECL From Grafts After DSAEK-Corneal Edema and ECL After DSAEK. Eye Contact Lens 2022; 48:250-255. [PMID: 34739409 PMCID: PMC9119398 DOI: 10.1097/icl.0000000000000857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/22/2021] [Indexed: 11/25/2022]
Abstract
OBJECTIVES To determine the relationship between the preoperative degree of corneal edema in the recipient and the endothelial cell density in grafts after Descemet stripping automated endothelial keratoplasty (DSAEK). METHODS This retrospective case series enrolled 111 eyes of 107 patients who underwent DSAEK. The preoperative and postoperative central corneal thickness (CCT) was measured by anterior-segment optical coherence tomography. Eyes were divided into three groups according to the preoperative recipient CCT: group A (mild edema): 550 μm RESULTS The recipient CCT (all groups combined) was 805.99±132.70 μm preoperatively and decreased to 656.31±105.02 μm at 1 month, decreased to 626.08±81.40 μm at 6 months, and remained stable between 12 (P=0.144) and 24 months (P=0.485) postoperatively. The mean ECL was 27.34±15.43%, 33.56±17.13%, 39.18±16.71%, and 45.87±14.27% at 1, 6, 12, and 24 months, respectively. The percentage of ECL in group C was higher than that in the other 2 groups through the 24-month follow-up. The difference in ECL between groups A and C was significant at 24 months (group A: 42.45±14.47%; group C: 52.49±10.65%; P=0.019). CONCLUSIONS The degree of corneal edema in the recipient was associated with implant ECL. Compared with mild and moderate corneal edema, the severe corneal edema may cause greater ECL after DSAEK.
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Affiliation(s)
- Shaofeng Gu
- Department of Ophthalmology (S.G., R.P., G.X., J.H.), Peking University Third Hospital, Beijing, China; and Beijing Key Laboratory of Restoration of Damaged Ocular Nerve (S.G., R.P., G.X., J.H.), Peking University Third Hospital, Beijing, China.
| | - Rongmei Peng
- Department of Ophthalmology (S.G., R.P., G.X., J.H.), Peking University Third Hospital, Beijing, China; and Beijing Key Laboratory of Restoration of Damaged Ocular Nerve (S.G., R.P., G.X., J.H.), Peking University Third Hospital, Beijing, China.
| | - Gege Xiao
- Department of Ophthalmology (S.G., R.P., G.X., J.H.), Peking University Third Hospital, Beijing, China; and Beijing Key Laboratory of Restoration of Damaged Ocular Nerve (S.G., R.P., G.X., J.H.), Peking University Third Hospital, Beijing, China.
| | - Jing Hong
- Department of Ophthalmology (S.G., R.P., G.X., J.H.), Peking University Third Hospital, Beijing, China; and Beijing Key Laboratory of Restoration of Damaged Ocular Nerve (S.G., R.P., G.X., J.H.), Peking University Third Hospital, Beijing, China.
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24
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Zhang Z, Xia DJ, Xu AD. Therapeutic effect of fastigial nucleus stimulation is mediated by the microRNA-182 & microRNA-382/BDNF signaling pathways in the treatment of post-stroke depression. Biochem Biophys Res Commun 2022; 627:137-145. [DOI: 10.1016/j.bbrc.2022.05.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 05/11/2022] [Indexed: 11/29/2022]
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Kim YN, Sim KS, Park S, Sohn HY, Kim T, Kim JH. In Vitro and In Vivo Anti-Inflammatory Effects of Cannabis sativa Stem Extract. J Med Food 2022; 25:408-417. [PMID: 35438555 DOI: 10.1089/jmf.2021.k.0200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
With growing scientific interest in cannabinoids, a number of studies have focused on biological activities of cannabidiol and its major source, inflorescence and leaf of Cannabis sativa plant. However, recent analytical chemistry studies have reported the pharmacological significance of non-cannabinoid phytochemicals that are rich in other parts of the plant. Thus, the objective of this study was to investigate the anti-inflammatory effects of Cannabis extracts from plant parts of shelled seeds, roots, and stems containing no or trace amounts of cannabinoids. Among water and ethanol extracts from three plant parts, Cannabis stem ethanol extract (CSE) had the most potent free radical scavenging activities and suppressive effects on the production of nitric oxide from macrophages. In further studies using macrophages, CSE effectively inhibited lipopolysaccharide (LPS)-induced inflammatory responses by suppressing proinflammatory cytokines, nuclear factor-κB and mitogen-activated protein kinase phosphorylations, and cellular accumulation of reactive oxygen species. Moreover, in mice exposed to LPS, CSE reduced tumor necrosis factor-α production and normalized activations of proapoptotic proteins in the liver, kidney, and spleen. Gas chromatography/mass spectrometry analyses of CSE showed several active compounds that might be associated with its antioxidant and anti-inflammatory effects. Collectively, these findings indicate that CSE counteracts LPS-induced acute inflammation and apoptosis, suggesting pharmaceutical applications for the stem part of C. sativa.
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Affiliation(s)
- Ye Na Kim
- Department of Vaccine Development, Gyeongbuk Institute for Bio-industry, Andong, Republic of Korea
| | - Kyu Sang Sim
- Biomaterials Research Institute, Kyochon F&B, Andong, Republic of Korea
| | - Song Park
- Department of Food Science and Biotechnology, Andong National University, Andong, Republic of Korea
| | - Ho-Yong Sohn
- Department of Food and Nutrition, Andong National University, Andong, Republic of Korea
| | - Taewan Kim
- Department of Food Science and Biotechnology, Andong National University, Andong, Republic of Korea
| | - Jun Ho Kim
- Department of Food Science and Biotechnology, Andong National University, Andong, Republic of Korea
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26
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Frifelt LEW, Subhi Y, Holm LM, Singh A. Impact of tobacco use on corneal thickness and endothelial health: a systematic review with meta-analyses. Acta Ophthalmol 2022; 100:26-34. [PMID: 34021700 DOI: 10.1111/aos.14897] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 03/12/2021] [Accepted: 04/18/2021] [Indexed: 12/20/2022]
Abstract
PURPOSE To investigate the impact of tobacco use on corneal thickness and corneal endothelial health. METHODS We searched the PubMed/MEDLINE, EMBASE, the Cochrane Central and all affiliated databases of the Web of Science on 20 July 2020. Two authors reviewed the studies and extracted the data in an independent fashion. Studies were reviewed qualitatively in the text, and central corneal thickness (CCT) and corneal endothelial characteristics (endothelial cell density, endothelial cell variability, average of endothelial cell size and endothelial cell hexagonality) were introduced for quantitative analyses. RESULTS Eighteen studies (2077 were smokers and 6429 non-smokers) were identified, of which 17 studies provided data eligible for one or more of the quantitative analyses. When compared to non-smokers, smokers had a higher CCT (+3.3 μm, 95% CI: +0.9 to +5.7 μm, p = 0.007) and a lower endothelial cell density (-140 cells/mm2 , 95% CI: -30 to -250 cells/mm2 , p = 0.01). Other corneal endothelial measures did not differ significantly. CONCLUSION Tobacco use is associated with a higher CCT and lower corneal endothelium cell density, but the clinical impact of these findings is small. Further studies are warranted on patients with a priori poor corneal health, where smoking may constitute an important risk of further progression, for example upon anterior segment surgery.
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Affiliation(s)
| | - Yousif Subhi
- Department of Ophthalmology Rigshospitalet‐Glostrup Copenhagen Denmark
| | - Lars Morten Holm
- Department of Ophthalmology Rigshospitalet‐Glostrup Copenhagen Denmark
- Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark
| | - Amardeep Singh
- Department of Ophthalmology Rigshospitalet‐Glostrup Copenhagen Denmark
- Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark
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27
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Lužnik Marzidovšek Z, Blanco T, Sun Z, Alemi H, Ortiz G, Nakagawa H, Chauhan SK, Taylor AW, Jurkunas UV, Yin J, Dana R. The Neuropeptide Alpha-Melanocyte-Stimulating Hormone Is Critical for Corneal Endothelial Cell Protection and Graft Survival after Transplantation. THE AMERICAN JOURNAL OF PATHOLOGY 2022; 192:270-280. [PMID: 34774519 PMCID: PMC8908049 DOI: 10.1016/j.ajpath.2021.10.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 10/15/2021] [Accepted: 10/25/2021] [Indexed: 02/03/2023]
Abstract
Corneal transplantation is the most common form of tissue transplantation. The success of corneal transplantation mainly relies on the integrity of corneal endothelial cells (CEnCs), which maintain tissue transparency by pumping out excess water from the cornea. After transplantation, the rate of CEnC loss far exceeds that seen with normal aging, which can threaten sight. The underlying mechanisms are poorly understood. Alpha-melanocyte-stimulating hormone (α-MSH) is a neuropeptide that is constitutively found in the aqueous humor with both cytoprotective and immunomodulatory effects. The curent study found high expression of melanocortin 1 receptor (MC1R), the receptor for α-MSH, on CEnCs. The effect of α-MSH/MC1R signaling on endothelial function and allograft survival in vitro and in vivo was investigated using MC1R signaling-deficient mice (Mc1re/e mice with a nonfunctional MC1R). Herein, the results indicate that in addition to its well-known immunomodulatory effect, α-MSH has cytoprotective effects on CEnCs after corneal transplantation, and the loss of MC1R signaling significantly decreases long-term graft survival in vivo. In conclusion, α-MSH/MC1R signaling is critical for CEnC function and graft survival after corneal transplantation.
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Affiliation(s)
- Zala Lužnik Marzidovšek
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts,Eye Hospital, University Medical Centre, Ljubljana, Slovenia
| | - Tomas Blanco
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Zhongmou Sun
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Hamid Alemi
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Gustavo Ortiz
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Hayate Nakagawa
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Sunil K. Chauhan
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Andrew W. Taylor
- Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts
| | - Ula V. Jurkunas
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Jia Yin
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts,Address correspondence to Reza Dana, M.D., M.P.H., M.Sc., or Jia Yin, M.D., Ph.D., M.P.H., Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, 20 Staniford St., Boston, MA 02114.
| | - Reza Dana
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts,Address correspondence to Reza Dana, M.D., M.P.H., M.Sc., or Jia Yin, M.D., Ph.D., M.P.H., Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, 20 Staniford St., Boston, MA 02114.
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Corneal Endothelial Cell Loss in Glaucoma and Glaucoma Surgery and the Utility of Management with Descemet Membrane Endothelial Keratoplasty (DMEK). J Ophthalmol 2022; 2022:1315299. [PMID: 35637682 PMCID: PMC9148223 DOI: 10.1155/2022/1315299] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 01/10/2022] [Indexed: 01/15/2023] Open
Abstract
The corneal endothelium has a crucial role in maintaining a clear and healthy cornea. Corneal endothelial cell loss occurs naturally with age; however, a diagnosis of glaucoma and surgical intervention for glaucoma can exacerbate a decline in cell number and impairment in morphology. In glaucoma, the mechanisms for this are not well understood and this accelerated cell loss can result in corneal decompensation. Given the high prevalence of glaucoma worldwide, this review aims to explore the abnormalities observed in the corneal endothelium in differing glaucoma phenotypes and glaucoma therapies (medical or surgical including with new generation microinvasive glaucoma surgeries). Descemet membrane endothelial keratoplasty (DMEK) is increasingly being used to manage corneal endothelial failure for glaucoma patients and we aim to review the recent literature evaluating the use of this technique in this clinical scenario.
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29
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Elmonem MA, Veys KRP, Prencipe G. Nephropathic Cystinosis: Pathogenic Roles of Inflammation and Potential for New Therapies. Cells 2022; 11:cells11020190. [PMID: 35053306 PMCID: PMC8773784 DOI: 10.3390/cells11020190] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 01/03/2022] [Accepted: 01/05/2022] [Indexed: 01/18/2023] Open
Abstract
The activation of several inflammatory pathways has recently been documented in patients and different cellular and animal models of nephropathic cystinosis. Upregulated inflammatory signals interact with many pathogenic aspects of the disease, such as enhanced oxidative stress, abnormal autophagy, inflammatory cell recruitment, enhanced cell death, and tissue fibrosis. Cysteamine, the only approved specific therapy for cystinosis, ameliorates many but not all pathogenic aspects of the disease. In the current review, we summarize the inflammatory mechanisms involved in cystinosis and their potential impact on the disease pathogenesis and progression. We further elaborate on the crosstalk between inflammation, autophagy, and apoptosis, and discuss the potential of experimental drugs for suppressing the inflammatory signals in cystinosis.
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Affiliation(s)
- Mohamed A. Elmonem
- Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo 11628, Egypt
- Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo 11517, Egypt
- Correspondence:
| | - Koenraad R. P. Veys
- Laboratory of Pediatric Nephrology, Department of Development & Regeneration, KU Leuven, 3000 Leuven, Belgium;
- Department of Pediatrics, AZ Delta Campus, 8820 Torhout, Belgium
| | - Giusi Prencipe
- Laboratory of Immuno-Rheumatology, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy;
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30
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Association between aqueous humor cytokines and postoperative corneal endothelial cell loss after Descemet stripping automated endothelial keratoplasty. PLoS One 2021; 16:e0260963. [PMID: 34914797 PMCID: PMC8675763 DOI: 10.1371/journal.pone.0260963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 11/21/2021] [Indexed: 11/23/2022] Open
Abstract
This study measured the intraoperative anterior aqueous humor concentrations of various cytokines during corneal endothelial transplantation and searched for relationships between these concentrations and postoperative corneal endothelial cell (CEC) depletion. We recruited 30 consecutive patients who underwent corneal endothelial transplantation with Descemet’s stripping automated endothelial keratoplasty (DSAEK) at Tohoku University Hospital between February 2014 and July 2017. During surgery, we obtained aqueous humor samples and later measured the concentrations of 27 cytokines with a Multiplex Bead Assay (Bio-Plex Pro). We counted CECs 1, 6 and 12 months after surgery, and used Spearman’s rank correlation coefficient to identify relationships between CEC depletion and the concentrations of detected cytokines. The loss of CECs 1–6 months after surgery was significantly correlated with IL-7, IP-10, MIP-1a and MIP-1b concentrations (-0.67, -0.48, -0.39, and -0.45, respectively, all P <0.01). CEC loss 1–12 months after surgery was significantly correlated with IL-1b, IL-7, IP-10 and RANTES concentrations (-0.46, -0.52, -0.48, and -0.43, respectively). Multiple regression analysis showed that IL-7 concentration was significantly associated with CEC loss 1–6 months after surgery (b = -0.65, P < 0.01) and IP-10 concentration was associated with CEC loss 1–12 months after surgery (β = -0.38, P < 0.05). These results suggest that not only inflammatory cytokines but also IL-7, a cytokine related to lymphocytes, may be involved in the depletion of CECs after DSAEK, particularly depletion that occurs relatively early.
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31
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Fisenko NV, Trufanov SV, Avetisov KS, Vtorushina VV, Subbot AM. [Evaluation of aqueous cytokine levels in eyes with Fuchs endothelial corneal dystrophy and bullous keratopathy]. Vestn Oftalmol 2021; 137:13-18. [PMID: 34156773 DOI: 10.17116/oftalma202113703113] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
PURPOSE To evaluate cytokine levels in the aqueous humor (AH) of patients with Fuchs endothelial corneal dystrophy (FECD) and bullous keratopathy (BK). MATERIAL AND METHODS The study included 74 patients (74 eyes). The first group consisted of 31 patients (72.7±9.2 years) with FECD; the second group included 35 patients (72.4±9.1 years) with BK. The control group comprised 8 patients (74.3±4.1 years) with immature cataract. Before surgery, patients underwent pachymetry of the central cornea (RTvue-100 OCT, Optovue, USA). Patients of groups 1 and 2 underwent endothelial keratoplasty (DSAEK or DMEK), or penetrating corneal transplantation. Patients of the control group underwent phacoemulsification with implantation of intraocular lens. The initial stage of the surgery involved AH sample collection for evaluation of cytokine levels (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12(p70), IL-13, IL-17, G-CSF, GM-CSF, IFNγ, MCP-1, MIP-1β and TNF-α) by fluorescent flow cytometry using the Bio-Plex Pro Human Cytokine Panel, 17-plex (Bio-Rad, USA). RESULTS Multiplex analysis of the AH content did not show any statistically significant differences in cytokine levels between decompensated FECD and BK eyes. The levels of IL-6, IL-8, GM-CSF, IFNγ, MCP-1, MIP-1β were significantly elevated in FECD and BK eyes compared with healthy control. An insignificant deviation of IL-4 and IL-13 levels was detected in FECD and BK eyes compared with healthy controls. There were no significant differences in IL-1β and TNF-α (indicators of acute inflammation) between the study groups. CONCLUSION The obtained data confirm that FECD and BK are associated with disruption of ocular immune privilege that leads to chronic local inflammation, which in turn causes remodeling of the corneal tissues resulting in fibrosis.
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Affiliation(s)
- N V Fisenko
- Research Institute of Eye Diseases, Moscow, Russia
| | - S V Trufanov
- Research Institute of Eye Diseases, Moscow, Russia
| | - K S Avetisov
- Research Institute of Eye Diseases, Moscow, Russia
| | - V V Vtorushina
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Moscow, Russia
| | - A M Subbot
- Research Institute of Eye Diseases, Moscow, Russia
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32
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Tummanapalli SS, Kuppusamy R, Yeo JH, Kumar N, New EJ, Willcox MDP. The role of nitric oxide in ocular surface physiology and pathophysiology. Ocul Surf 2021; 21:37-51. [PMID: 33940170 DOI: 10.1016/j.jtos.2021.04.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 04/19/2021] [Accepted: 04/19/2021] [Indexed: 12/31/2022]
Abstract
Nitric oxide (NO) has a wide array of biological functions including the regulation of vascular tone, neurotransmission, immunomodulation, stimulation of proinflammatory cytokine expression and antimicrobial action. These functions may depend on the type of isoform that is responsible for the synthesis of NO. NO is found in various ocular tissues playing a pivotal role in physiological mechanisms, namely regulating vascular tone in the uvea, retinal blood circulation, aqueous humor dynamics, neurotransmission and phototransduction in retinal layers. Unregulated production of NO in ocular tissues may result in production of toxic superoxide free radicals that participate in ocular diseases such as endotoxin-induced uveitis, ischemic proliferative retinopathy and neurotoxicity of optic nerve head in glaucoma. However, the role of NO on the ocular surface in mediating physiology and pathophysiological processes is not fully understood. Moreover, methods used to measure levels of NO in the biological samples of the ocular surface are not well established due to its rapid oxidation. The purpose of this review is to highlight the role of NO in the physiology and pathophysiology of ocular surface and propose suitable techniques to measure NO levels in ocular surface tissues and tears. This will improve the understanding of NO's role in ocular surface biology and the development of new NO-based therapies to treat various ocular surface diseases. Further, this review summarizes the biochemistry underpinning NO's antimicrobial action.
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Affiliation(s)
| | - Rajesh Kuppusamy
- School of Optometry & Vision Science, University of New South Wales, Australia; School of Chemistry, University of New South Wales, Australia
| | - Jia Hao Yeo
- The University of Sydney, School of Chemistry, NSW, 2006, Australia
| | - Naresh Kumar
- School of Chemistry, University of New South Wales, Australia
| | - Elizabeth J New
- The University of Sydney, School of Chemistry, NSW, 2006, Australia; The University of Sydney Nano Institute (Sydney Nano), The University of Sydney, NSW, 2006, Australia
| | - Mark D P Willcox
- School of Optometry & Vision Science, University of New South Wales, Australia
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33
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Psychobiological mechanisms underlying the mood benefits of meditation: A narrative review. COMPREHENSIVE PSYCHONEUROENDOCRINOLOGY 2021; 6:100037. [PMID: 35757358 PMCID: PMC9216450 DOI: 10.1016/j.cpnec.2021.100037] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 02/22/2021] [Indexed: 01/19/2023] Open
Abstract
Psychological stressors can lead to distress and result in autonomic arousal and activation of a stress response. Ongoing or persistent stress can disrupt the stress response feedback mechanisms and result in elevated cortisol and pro-inflammatory cytokines which can cause damage to brain regions involved in the regulation of mood and emotion. We propose that the magnitude of the stress response experienced in response to psychological stressors depends on a number of modifiable psychological processes including an individual’s level of self-compassion, dispositional mindfulness, tendency to ruminate and attentional bias. We further propose that the stress response elected by psychological stressors can be meditated by influencing these modifiable psychological processes, and that meditation practices can decrease stress and improve mood by decreasing stress reactivity on a psychological, physiological and neurobiological level. We explore this in a narrative review.
Meditation decreases blood pressure, heart rate, cortisol and cytokine levels. Meditation increases self-compassion, dispositional mindfulness and meta-cognition. Meditation improves attention and memory. Meditation results in brain changes in regions related to emotion regulation.
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34
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Gomez A, Serrano A, Salero E, Tovar A, Amescua G, Galor A, Keane RW, de Rivero Vaccari JP, Sabater AL. Tumor necrosis factor-alpha and interferon-gamma induce inflammasome-mediated corneal endothelial cell death. Exp Eye Res 2021; 207:108574. [PMID: 33848524 DOI: 10.1016/j.exer.2021.108574] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 03/19/2021] [Accepted: 04/06/2021] [Indexed: 12/27/2022]
Abstract
PURPOSE Chronic corneal endothelial cell (CEC) loss results in corneal edema and vision loss in conditions such as pseudophakic bullous keratopathy (PBK), Fuchs' dystrophy, and corneal graft failure. Low CEC density has been associated with an elevation of intraocular pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α and interferon (INF)-γ. These cytokines are capable of triggering pyroptosis, a programmed cell death mechanism mediated by the inflammasome, prompting the activation of the pro-inflammatory cytokine interleukin (IL)-1β, the perpetuation of inflammation, and subsequent damage of corneal endothelial tissue. Therefore, the purpose of this study was to determine the deleterious contribution of the inflammasome and pyroptosis to CEC loss. METHODS CECs from human donor corneas were treated ex vivo with TNF-α and IFN-γ for 48 h. Levels of caspase-1 and IL-1β were then assayed by ELISA, and the expression of caspase-1 and gasdermin-D (GSDM-D) were confirmed by immunofluorescence. Endothelial cell damage was analyzed by a lactate dehydrogenase (LDH) release assay, and oxidative stress was determined by measuring the levels of reactive oxygen species (ROS) in the culture media. RESULTS Inflammasome activation and oxidative stress were elevated in CECs following exposure to TNF-α and IFN-γ, which resulted in cell death by pyroptosis as determined by LDH release which was inhibited by the caspase-1 inhibitor Ac-YVAD-cmk. CONCLUSION CEC death is induced by the pro-inflammatory cytokines TNF-α and IFN-γ, which contribute to inflammasome activation. Moreover, the inflammasome is a promising therapeutic target for the treatment of chronic CEC loss.
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Affiliation(s)
- Angela Gomez
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Andres Serrano
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Enrique Salero
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Arianna Tovar
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Guillermo Amescua
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Anat Galor
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Robert W Keane
- Department of Physiology and Biophysics, University of Miami Miller School of Medicine, FL, USA
| | - Juan Pablo de Rivero Vaccari
- Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, FL, USA
| | - Alfonso L Sabater
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
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Kossl J, Bohacova P, Hermankova B, Javorkova E, Zajicova A, Holan V. Antiapoptotic Properties of Mesenchymal Stem Cells in a Mouse Model of Corneal Inflammation. Stem Cells Dev 2021; 30:418-427. [PMID: 33607933 DOI: 10.1089/scd.2020.0195] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) represent a population of adult stem cells that have potent immunoregulatory, anti-inflammatory, and antiapoptotic properties. In addition, they have ability to migrate to the site of inflammation or injury, where they contribute to the regeneration and healing process. For these properties, MSCs have been used as therapeutic cells in several models, including treatment of damages or disorders of the ocular surface. If the damage of the ocular surface is extensive and involves a limbal region where limbal stem cell reside, MSC therapy has been proved as the effective treatment approach. Although the anti-inflammatory properties of MSCs have been well characterized, mechanisms of antiapoptotic action of MSCs are not well recognized. Using a chemically damaged cornea in a mouse model, we showed that the injury decreases expression of the gene for antiapoptotic molecule Bcl-2 and increases the expression of proapoptotic genes Bax and p53. These changes were attenuated by local transplantation of MSCs after corneal damage. The antiapoptotic effect of MSCs was tested in an in vitro model of co-cultivation of corneal explants with MSCs. The apoptosis of corneal cells in the explants was induced by proinflammatory cytokines and was significantly inhibited in the presence of MSCs. The antiapoptotic effect of MSCs was mediated by paracrine action, as confirmed by separation of the explants in inserts or by supernatants from MSCs. In addition, MSCs decreased the expression of genes for the molecules associated with endoplasmic reticulum stress Atf4, Bip, and p21, which are associated with apoptosis. The results show that MSCs inhibit the expression of proapoptotic genes and decrease the number of apoptotic cells in the damaged corneas, and this action might be one of the mechanisms of the therapeutic action of MSCs.
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Affiliation(s)
- Jan Kossl
- Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
| | - Pavla Bohacova
- Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
| | - Barbora Hermankova
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
| | - Eliska Javorkova
- Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
| | - Alena Zajicova
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
| | - Vladimir Holan
- Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
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Kang C, Lu Z, Zhu G, Chen Y, Wu Y. Knockdown of TRIM22 Relieves Oxygen-Glucose Deprivation/Reoxygenation-Induced Apoptosis and Inflammation Through Inhibition of NF-κB/NLRP3 Axis. Cell Mol Neurobiol 2021; 41:341-351. [PMID: 32335773 PMCID: PMC11448583 DOI: 10.1007/s10571-020-00855-w] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 04/16/2020] [Indexed: 02/06/2023]
Abstract
Tripartite motif-containing 22 (TRIM22) has been documented to participate in numerous cellular activities during human diseases. However, whether TRIM22 is involved in the regulation of neuronal survival during the progression of cerebral ischemia/reperfusion (I/R) injury remains unknown. In the present study, treatment of HCN-2 cells with oxygen-glucose deprivation/reoxygenation (OGD/R) markedly upregulated TRIM22 expression. A significant increase in TRIM22 expression was observed in the ischemic cortex tissues from middle cerebral artery occlusion/reperfusion mice. OGD/R inhibited the viability and induced the apoptosis of HCN-2 cells, which was accompanied by an increase in caspase-3 activity and an increase in LDH release. Furthermore, OGD/R increased the levels of tumor necrosis factor-alpha, interleukin (IL)-1 beta, IL-6, and monocyte chemoattractant protein-1 and induced NLRP3 inflammasome activation, as evidenced by increases in NACHT, LRR and PYD domains-containing protein 3, apoptosis-associated speck-like protein containing a caspase recruitment domain and cleaved caspase-1 expression and caspase-1 activity. However, these changes induced by OGD/R were blocked by silencing of TRIM22. In addition, TRIM22 regulated NF-κB activity in HCN-2 cells undergoing OGD/R stimulation. Furthermore, inhibition of NF-κB by pyrrolidine dithiocarbamate inhibited OGD/R-induced NLRP3 inflammasome activation in HCN-2 cells. Taken together, silencing of TRIM22 protects neurons against OGD/R-induced apoptosis and inflammation. The anti-inflammatory effect of TRIM22 knockdown was the consequence of inhibition of NF-κB/NLRP3 axis. TRIM22 may be a potential target for treating cerebral I/R injury.
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Affiliation(s)
- Chongyang Kang
- Department of Emergency, First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
| | - Zhaofeng Lu
- Department of Emergency, First Affiliated Hospital of Henan University of Science and Technology, Luoyang, 471003, China.
- Department of Emergency, First Affiliated Hospital of Henan University of Science and Technology, No.24, Jinghua road, Luoyang, 471000, China.
| | - Gangyi Zhu
- Department of Emergency, First Affiliated Hospital of Henan University of Science and Technology, Luoyang, 471003, China
| | - Yuehua Chen
- Department of Emergency, First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
| | - Yafang Wu
- Department of Emergency, First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
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Boraldi F, Lofaro FD, Quaglino D. Apoptosis in the Extraosseous Calcification Process. Cells 2021; 10:cells10010131. [PMID: 33445441 PMCID: PMC7827519 DOI: 10.3390/cells10010131] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/07/2021] [Accepted: 01/10/2021] [Indexed: 12/13/2022] Open
Abstract
Extraosseous calcification is a pathologic mineralization process occurring in soft connective tissues (e.g., skin, vessels, tendons, and cartilage). It can take place on a genetic basis or as a consequence of acquired chronic diseases. In this last case, the etiology is multifactorial, including both extra- and intracellular mechanisms, such as the formation of membrane vesicles (e.g., matrix vesicles and apoptotic bodies), mitochondrial alterations, and oxidative stress. This review is an overview of extraosseous calcification mechanisms focusing on the relationships between apoptosis and mineralization in cartilage and vascular tissues, as these are the two tissues mostly affected by a number of age-related diseases having a progressively increased impact in Western Countries.
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Affiliation(s)
- Federica Boraldi
- Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; (F.D.L.); (D.Q.)
- Correspondence:
| | - Francesco Demetrio Lofaro
- Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; (F.D.L.); (D.Q.)
| | - Daniela Quaglino
- Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; (F.D.L.); (D.Q.)
- Interuniversity Consortium for Biotechnologies (CIB), Italy
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Li X, Li L, Ouyang D, Zhu Y, Yuan T. The abnormal expression of kisspeptin regulates pro-inflammatory cytokines, cell viability and apoptosis of macrophages in hyperandrogenism induced by testosterone. Gynecol Endocrinol 2021; 37:72-77. [PMID: 32988245 DOI: 10.1080/09513590.2020.1811964] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 07/08/2020] [Accepted: 08/15/2020] [Indexed: 10/23/2022] Open
Abstract
BACKGROUND Increasing evidences have proposed that kisspeptins may be involved in polycystic ovary syndrome (PCOS) including hyperandrogenism. This work aimed to investigate the effect of kisspeptin in hyperandrogenism induced by testosterone. METHODS The most suitable concentration of testosterone to induce hyperandrogenism was determined by detecting the mRNA changes of kisspeptin and macrophages pro-inflammatory cytokines. The role of kisspeptin in hyperandrogenism was investigated by RT-PCR of kisspeptin and pro-inflammatory cytokines, by CCK-8 of cell viability, by Annexin V-FITC/PI staining followed by flow cytometry of apoptosis, by ELISA of pro-inflammatory cytokines and by Western blot of kisspeptin and antiapoptotic Bcl-2 and proapoptotic Bax. RESULTS We found that testosterone elevated kisspeptin, pro-inflammatory cytokines expressions and nitrite release in excessive androgen stimulated macrophages and further inhibited the macrophages cell viability and increased apoptosis. Kisspeptin knockdown reversed the tendency caused by testosterone and decreased apoptosis in macrophages treated with testosterone. Moreover, mRNA and protein expression levels of Bcl-2 and Bax were assessed. We showed a reduction in Bcl-2 mRNA and protein expression levels and an overexpression of Bax mRNA and protein expression levels. Kiss1 silencing reversed Bcl-2 and Bax expressions. CONCLUSION Kisspeptin inactivation confers resistance in hyperandrogenism by inhibiting pro-inflammatory cytokines expressions and apoptosis. Our results may help to comprehend the role of kisspeptin in the mechanisms of hyperandrogenism.
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Affiliation(s)
- Xiao Li
- Gynecology Department, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Lingchuan Li
- Gynecology Department, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Dimei Ouyang
- Gynecology Department, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Yuyao Zhu
- Gynecology Department, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Tao Yuan
- Gynecology Department, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
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Voluntary Wheel Running Improves Spatial Learning Memory by Suppressing Inflammation and Apoptosis via Inactivation of Nuclear Factor Kappa B in Brain Inflammation Rats. Int Neurourol J 2020; 24:96-103. [PMID: 33271006 PMCID: PMC7731883 DOI: 10.5213/inj.2040432.216] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Accepted: 11/05/2020] [Indexed: 12/18/2022] Open
Abstract
Purpose Exercise has been shown to protect against diverse brain diseases. Voluntary exercise improves cognition and has a neuroprotective effect. The aim of this investigation is to study the effect of voluntary wheel running on brain inflammation in rats with regard to inflammation and apoptosis. Methods Brain inflammation was caused by intracranial injection of lipopolysaccharide using a stereotaxic instrument. Voluntary wheel running group were conducted during 21 consecutive days, staring 2 days after brain inflammation. Results Brain inflammation increased proinflammatory cytokine production and apoptosis cell death in the hippocampus. There changes in the hippocampus deteriorated spatial learning memory. However, voluntary wheel running suppressed the secretion of inflammatory cytokines and apoptotic neuronal cell death via inactivation of nuclear factor kappa B (NF-κB)/NF-κB inhibitor-α pathway. Voluntary wheel running also promoted the recovery of the spatial learning memory impairment. Conclusions Voluntary wheel running after brain inflammation enhanced spatial learning memory by suppressing proinflammatory cytokine secretion and apoptosis cell death. Voluntary wheel running is also expected to be effective in inflammatory diseases of the urogenital system.
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Coco G, Foulsham W, Nakao T, Yin J, Amouzegar A, Taketani Y, Chauhan SK, Dana R. Regulatory T cells promote corneal endothelial cell survival following transplantation via interleukin-10. Am J Transplant 2020; 20:389-398. [PMID: 31587452 PMCID: PMC6984989 DOI: 10.1111/ajt.15631] [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: 04/17/2019] [Revised: 09/19/2019] [Accepted: 09/20/2019] [Indexed: 01/25/2023]
Abstract
The functional competence of corneal endothelial cells (CEnCs) is critical for survival of corneal allografts, but these cells are often targets of the immune response mediated by graft-attacking effector T cells. Although regulatory T cells (Tregs) have been studied for their role in regulating the host's alloimmune response towards the graft, the cytoprotective function of these cells on CEnCs has not been investigated. The aim of this study was to determine whether Tregs suppress effector T cell-mediated and inflammatory cytokine-induced CEnC death, and to elucidate the mechanism by which this cytoprotection occurs. Using 2 well-established models of corneal transplantation (low-risk and high-risk models), we show that Tregs derived from low-risk graft recipients have a superior capacity in protecting CEnCs against effector T cell-mediated and interferon-γ and tumor necrosis factor-α-induced cell death compared to Tregs derived from high-risk hosts. We further demonstrate that the cytoprotective function of Tregs derived from low-risk hosts occurs independently of direct cell-cell contact and is mediated by the immunoregulatory cytokine IL-10. Our study is the first to report that Tregs provide cytoprotection for CEnCs through secretion of IL-10, indicating potentially novel therapeutic targets for enhancing CEnC survival following corneal transplantation.
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Affiliation(s)
- Giulia Coco
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts,Department of Clinical Science and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - William Foulsham
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts,Institute of Ophthalmology, University College London, London, UK
| | - Takeshi Nakao
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Jia Yin
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Afsaneh Amouzegar
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Yukako Taketani
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Sunil K Chauhan
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Reza Dana
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
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Tojo N, Numata A, Hayashi A. Factors influencing the reduction in corneal endothelial cells after Ex-Press ® surgery. Int Ophthalmol 2020; 40:1201-1208. [PMID: 31930436 DOI: 10.1007/s10792-020-01286-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 01/05/2020] [Indexed: 01/06/2023]
Abstract
PURPOSE We investigated the factors that influence the reduction in corneal endothelial cells after Ex-Press® surgery. METHODS This was a retrospective study. We included patients who had undergone Ex-Press surgery and were followed up for > 2. We analyzed the corneal endothelial cell density (ECD) before and after Ex-Press surgery. We investigated the insertion position (Ex-Press device was inserted into cornea or trabecular meshwork (TM)), Ex-Press-iris touch, cornea-iris touch, peripheral anterior synechiae, history of trabeculotomy, history of selective laser trabeculoplasty, type of glaucoma, and simultaneous cataract surgery as influencing factors. We used multivariate analysis to determine the factors influencing the reduction rate of ECD. RESULTS We included 129 eyes. The mean of ECD had decreased 7.0% at 2 years. Ex-Press surgeries significantly decreased the ECD after 2 years (p = 0.0118). As a result of the multivariate analysis, the factor that led to a significantly faster reduction in ECD was the insertion position of the Ex-Press (p < 0.0001). The reduction rate of ECD after 2 years in cases of insertion into the cornea (27 eyes) was 15.1 ± 3.6%, and in cases of insertion into a TM (102 eyes), it was 5.2 ± 1.4%. CONCLUSIONS Insertion into the cornea was a risk factor for rapid ECD loss. The Ex-Press should be inserted into a TM for long-term protection of the corneal endothelial cells.
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Affiliation(s)
- Naoki Tojo
- Department of Ophthalmology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
| | - Ayaka Numata
- Department of Ophthalmology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Atsushi Hayashi
- Department of Ophthalmology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
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Effect of Graft Shift Direction on Graft Detachment and Endothelial Cell Survival After Descemet Membrane Endothelial Keratoplasty. Cornea 2019; 38:970-975. [DOI: 10.1097/ico.0000000000002015] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Hori J, Yamaguchi T, Keino H, Hamrah P, Maruyama K. Immune privilege in corneal transplantation. Prog Retin Eye Res 2019; 72:100758. [PMID: 31014973 DOI: 10.1016/j.preteyeres.2019.04.002] [Citation(s) in RCA: 111] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 04/14/2019] [Accepted: 04/16/2019] [Indexed: 12/13/2022]
Abstract
Corneal transplantation is the most successful solid organ transplantation performed in humans. The extraordinary success of orthotopic corneal allografts, in both humans and experimental animals, is related to the phenomenon of "immune privilege". Inflammation is self-regulated to preserve ocular functions because the eye has immune privilege. At present, three major mechanisms are considered to provide immune privilege in corneal transplantation: 1) anatomical, cellular, and molecular barriers in the cornea; 2) tolerance related to anterior chamber-associated immune deviation and regulatory T cells; and 3) an immunosuppressive intraocular microenvironment. This review describes the mechanisms of immune privilege that have been elucidated from animal models of ocular inflammation, especially those involving corneal transplantation, and its relevance for the clinic. An update on molecular, cellular, and neural interactions in local and systemic immune regulation is provided. Therapeutic strategies for restoring immune privilege are also discussed.
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Affiliation(s)
- Junko Hori
- Department of Ophthalmology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan; Department of Ophthalmology, Nippon Medical School, Tama-Nagayama Hospital, 1-7-1 Nagayama, Tama, Tokyo, 206-8512, Japan.
| | - Takefumi Yamaguchi
- Department of Ophthalmology, Tokyo Dental College Ichikawa General Hospital, 5-11-13 Sugano, Ichikawa-shi, Chiba, 272-8513, Japan; Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Hiroshi Keino
- Department of Ophthalmology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo, 181-8611, Japan
| | - Pedram Hamrah
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Tufts University, 800 Washington St, Boston, MA, 02111, USA; Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Tufts University, 800 Washington St, Boston, MA, 02111, USA
| | - Kazuichi Maruyama
- Department of Innovative Visual Science, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
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Yazu H, Yamaguchi T, Tsubota K, Shimazaki J. Clinical Factors for Rapid Endothelial Cell Loss After Corneal Transplantation: Novel Findings From the Aqueous Humor. CURRENT OPHTHALMOLOGY REPORTS 2019. [DOI: 10.1007/s40135-019-00204-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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STAT3 signaling maintains homeostasis through a barrier function and cell survival in corneal endothelial cells. Exp Eye Res 2019; 179:132-141. [DOI: 10.1016/j.exer.2018.11.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 10/09/2018] [Accepted: 11/08/2018] [Indexed: 12/13/2022]
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Satitpitakul V, Sun Z, Suri K, Amouzegar A, Katikireddy KR, Jurkunas UV, Kheirkhah A, Dana R. Vasoactive Intestinal Peptide Promotes Corneal Allograft Survival. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:2016-2024. [PMID: 30097165 DOI: 10.1016/j.ajpath.2018.05.010] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 05/11/2018] [Accepted: 05/22/2018] [Indexed: 12/17/2022]
Abstract
Corneal transplantation is the most prevalent form of tissue transplantation. The success of corneal transplantation mainly relies on the integrity of corneal endothelial cells (CEnCs), which maintain graft transparency. CEnC density decreases significantly after corneal transplantation even in the absence of graft rejection. To date, different strategies have been used to enhance CEnC survival. The neuropeptide vasoactive intestinal peptide (VIP) improves CEnC integrity during donor cornea tissue storage and protects CEnCs against oxidative stress-induced apoptosis. However, little is known about the effect of exogenous administration of VIP on corneal transplant outcomes. We found that VIP significantly accelerates endothelial wound closure and suppresses interferon-γ- and tumor necrosis factor-α-induced CEnC apoptosis in vitro in a dose-dependent manner. In addition, we found that intracameral administration of VIP to mice undergoing syngeneic corneal transplantation with endothelial injury increases CEnC density and decreases graft opacity scores. Finally, using a mouse model of allogeneic corneal transplantation, we found for the first time that treatment with VIP significantly suppresses posttransplantation CEnC loss and improves corneal allograft survival.
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Affiliation(s)
- Vannarut Satitpitakul
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts; Department of Ophthalmology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Zhongmou Sun
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Kunal Suri
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Afsaneh Amouzegar
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Kishore R Katikireddy
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Ula V Jurkunas
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Ahmad Kheirkhah
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
| | - Reza Dana
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
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Figueroa F, Mendoza G, Cardozo D, Mohamed F, Oliveros L, Forneris M. Sympathetic innervation regulates macrophage activity in rats with polycystic ovary. J Endocrinol 2018; 238:33-45. [PMID: 29720538 DOI: 10.1530/joe-17-0736] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Accepted: 05/02/2018] [Indexed: 01/14/2023]
Abstract
Polycystic ovarian syndrome (PCOS) is a low-grade inflammatory disease characterized by hyperandrogenism and ovarian hyperinnervation. The aim of this work is to investigate whether in vivo bilateral superior ovarian nerve (SON) section in adult rats with estradiol valerate-induced PCOS (PCO rats) affects macrophage spleen cells (MФ) and modifies the steroidogenic ability of their secretions. Culture media of MФ from PCO rats and PCO rats with SON section (PCO-SON rats) were used to stimulate in vitro intact ovaries. Compared with macrophages PCO, macrophages from PCO-SON rats released less tumor necrosis factor-α and nitric oxide, expressed lower Bax and Nfkb mRNA and showed reduced TUNEL staining. Also, in PCO rats, the SON section decreased kisspeptin and nerve growth factor mRNA expressions, without changes in Trka receptor mRNA levels. Macrophage secretions from PCO-SON rats decreased androstenedione and stimulated progesterone release in PCO ovaries, compared to macrophage secretions from PCO rats. No changes were observed in ovarian estradiol response. These findings emphasize the importance of the SON in spleen MΦ, since its manipulation leads to secondary modifications of immunological and neural mediators, which might influence ovarian steroidogenesis. In PCO ovaries, the reduction of androstenedione and the improvement of progesterone release induced by PCO-SON MΦ secretion, might be beneficial considering the hormonal anomalies characteristic of PCOS. We present functional evidence that modulation of the immune-endocrine function by peripheral sympathetic nervous system might have implications for understanding the pathophysiology of PCOS.
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Affiliation(s)
- Florencia Figueroa
- Laboratorio de Biología de la ReproducciónFacultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis, Argentina
| | - Gisela Mendoza
- Laboratorio de Biología de la ReproducciónFacultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis, Argentina
| | - Darío Cardozo
- Laboratorio de Biología de la ReproducciónFacultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis, Argentina
| | - Fabián Mohamed
- Area MorfologíaFacultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis, Argentina
| | - Liliana Oliveros
- Laboratorio de Biología de la ReproducciónFacultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis, Argentina
| | - Myriam Forneris
- Laboratorio de Biología de la ReproducciónFacultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis, Argentina
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Al-Jarrah MD, Erekat NS. Parkinson disease-induced upregulation of apoptotic mediators could be attenuated in the skeletal muscle following chronic exercise training. NeuroRehabilitation 2018; 41:823-830. [PMID: 29254117 DOI: 10.3233/nre-172196] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND We have shown elevated levels of p53 and active caspase-3 in gastrocnemius skeletal muscle with Parkinson's disease (PD). The main aim of this study is to examine the impact of endurance exercise training on the expression of p53 and active caspase-3 in the skeletal muscle of mouse with induced Parkinsonism. METHODS Sedentary control (SC), sedentary Parkinson diseased (SPD), and exercised Parkinson diseased (EPD) groups were formed; each consisting of 10 randomly selected normal albino mice. Chronic Parkinson disease was induced in the SPD and EPD animals using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTP/p). The expression of p53 and active caspase-3 was investigated, using immunohistochemistry, in the gastrocnemius muscle in each animal group. RESULTS Both p53 and active caspase-3 expression was significantly (p value < 0.05) reduced in the PD gastrocnemius skeletal muscle following endurance exercise training. CONCLUSION Our present data suggest that chronic exercise training reduced Parkinson disease-induced upregulation of p53 and active caspase-3 in gastrocnemius skeletal muscle. Thus, our study suggests that inhibiting p53 and/or active caspase-3 may be considered as a therapeutic approach to ameliorate PD skeletal muscle abnormalities.
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Affiliation(s)
- Muhammed D Al-Jarrah
- Department of Rehabilitation Sciences, Faculty of Applied Medical Sciences, JUST, Irbid, Jordan
| | - Nour S Erekat
- Department of Anatomy, Faculty of Medicine, Jordan University of Science and Technology (JUST), Irbid, Jordan
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Wang Q, Wei C, Ma L, Wang X, Li L, Zhou Q, Shi W. Inflammatory cytokine TNF-α promotes corneal endothelium apoptosis via upregulating TIPE2 transcription during corneal graft rejection. Graefes Arch Clin Exp Ophthalmol 2018; 256:709-715. [DOI: 10.1007/s00417-018-3913-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 12/14/2017] [Accepted: 01/16/2018] [Indexed: 11/30/2022] Open
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Yagi-Yaguchi Y, Yamaguchi T, Higa K, Suzuki T, Aketa N, Dogru M, Satake Y, Shimazaki J. Association between corneal endothelial cell densities and elevated cytokine levels in the aqueous humor. Sci Rep 2017; 7:13603. [PMID: 29051590 PMCID: PMC5648880 DOI: 10.1038/s41598-017-14131-3] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Accepted: 10/06/2017] [Indexed: 12/17/2022] Open
Abstract
Annual reduction rate of corneal endothelial cell density (ECD) varies among etiologies, however, the cause of chronic endothelial cell loss is still unknown. We recently reported the elevation of inflammatory cytokines in the aqueous humor (AqH) in eyes with bullous keratopathy and low ECD. To evaluate the association between ECD and aqueous cytokine levels, we collected a total of 157 AqH samples prospectively. The AqH levels of cytokines were measured and multivariate analyses were conducted to find the correlation between ECD, aqueous cytokine levels and clinical factors, such as number of previous intraocular surgeries and protein concentration in AqH. As a result, ECD was negatively correlated with specific cytokine levels, including IL-1α, IL-4, IL-13, MIP-1β, TNF-α and E-selectin (all P < 0.05). The aqueous cytokine levels showed different correlations with these clinical factors; the number of previous intraocular surgeries was associated with all cytokines except MIP-1α. The AqH protein concentration and the status of intraocular lens showed similar patterns of elevation of IL-1α, IL-4, IL-6, IL-8, IL-10, IL-13, IL-17A, MIP-1β, MCP-1, E-selectin, P-selectin and sICAM-1. In conclusion, elevation of AqH cytokine levels was associated with reduced ECDs. AqH cytokine levels showed significant correlations with clinical factors associated with low ECDs.
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Affiliation(s)
- Yukari Yagi-Yaguchi
- Department of Ophthalmology, Ichikawa General Hospital, Tokyo Dental College, Chiba, Japan
| | - Takefumi Yamaguchi
- Department of Ophthalmology, Ichikawa General Hospital, Tokyo Dental College, Chiba, Japan.
| | - Kazunari Higa
- Department of Ophthalmology, Ichikawa General Hospital, Tokyo Dental College, Chiba, Japan
| | - Terumasa Suzuki
- Department of Ophthalmology, Ichikawa General Hospital, Tokyo Dental College, Chiba, Japan
| | - Naohiko Aketa
- Department of Ophthalmology, Ichikawa General Hospital, Tokyo Dental College, Chiba, Japan
| | - Murat Dogru
- Department of Ophthalmology, Ichikawa General Hospital, Tokyo Dental College, Chiba, Japan
| | - Yoshiyuki Satake
- Department of Ophthalmology, Ichikawa General Hospital, Tokyo Dental College, Chiba, Japan
| | - Jun Shimazaki
- Department of Ophthalmology, Ichikawa General Hospital, Tokyo Dental College, Chiba, Japan
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