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Article ; Online: Calcium-Signalling in Human Glaucoma Lamina Cribrosa Myofibroblasts.

Irnaten, Mustapha / O'Brien, Colm J

International journal of molecular sciences

2023 Volume 24, Issue 2

Abstract: Glaucoma is one of the most common causes of treatable visual impairment in the developed world, affecting approximately 64 million people worldwide, some of whom will be bilaterally blind from irreversible optic nerve damage. The optic nerve head is a ... ...

Abstract	Glaucoma is one of the most common causes of treatable visual impairment in the developed world, affecting approximately 64 million people worldwide, some of whom will be bilaterally blind from irreversible optic nerve damage. The optic nerve head is a key site of damage in glaucoma where there is fibrosis of the connective tissue in the lamina cribrosa (LC) extracellular matrix. As a ubiquitous second messenger, calcium (Ca
MeSH term(s)	Humans ; Calcium/metabolism ; Myofibroblasts/metabolism ; Glaucoma/metabolism ; Optic Disk/metabolism ; Fibrosis ; Intraocular Pressure
Chemical Substances	Calcium (SY7Q814VUP)
Language	English
Publishing date	2023-01-09
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24021287
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: p53 and Myofibroblast Apoptosis in Organ Fibrosis.

McElhinney, Kealan / Irnaten, Mustapha / O'Brien, Colm

International journal of molecular sciences

2023 Volume 24, Issue 7

Abstract: Organ fibrosis represents a dysregulated, maladaptive wound repair response that results in progressive disruption of normal tissue architecture leading to detrimental deterioration in physiological function, and significant morbidity/mortality. Fibrosis ...

Abstract	Organ fibrosis represents a dysregulated, maladaptive wound repair response that results in progressive disruption of normal tissue architecture leading to detrimental deterioration in physiological function, and significant morbidity/mortality. Fibrosis is thought to contribute to nearly 50% of all deaths in the Western world with current treatment modalities effective in slowing disease progression but not effective in restoring organ function or reversing fibrotic changes. When physiological wound repair is complete, myofibroblasts are programmed to undergo cell death and self-clearance, however, in fibrosis there is a characteristic absence of myofibroblast apoptosis. It has been shown that in fibrosis, myofibroblasts adopt an apoptotic-resistant, highly proliferative phenotype leading to persistent myofibroblast activation and perpetuation of the fibrotic disease process. Recently, this pathological adaptation has been linked to dysregulated expression of tumour suppressor gene p53. In this review, we discuss p53 dysregulation and apoptotic failure in myofibroblasts and demonstrate its consistent link to fibrotic disease development in all types of organ fibrosis. An enhanced understanding of the role of p53 dysregulation and myofibroblast apoptosis may aid in future novel therapeutic and/or diagnostic strategies in organ fibrosis.
MeSH term(s)	Humans ; Myofibroblasts/metabolism ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Fibrosis ; Apoptosis ; Wound Healing ; Cell Differentiation
Chemical Substances	Tumor Suppressor Protein p53
Language	English
Publishing date	2023-04-04
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24076737
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Article ; Online: p53 and Myofibroblast Apoptosis in Organ Fibrosis

Kealan McElhinney / Mustapha Irnaten / Colm O’Brien

International Journal of Molecular Sciences, Vol 24, Iss 6737, p

2023 Volume 6737

Abstract	Organ fibrosis represents a dysregulated, maladaptive wound repair response that results in progressive disruption of normal tissue architecture leading to detrimental deterioration in physiological function, and significant morbidity/mortality. Fibrosis is thought to contribute to nearly 50% of all deaths in the Western world with current treatment modalities effective in slowing disease progression but not effective in restoring organ function or reversing fibrotic changes. When physiological wound repair is complete, myofibroblasts are programmed to undergo cell death and self-clearance, however, in fibrosis there is a characteristic absence of myofibroblast apoptosis. It has been shown that in fibrosis, myofibroblasts adopt an apoptotic-resistant, highly proliferative phenotype leading to persistent myofibroblast activation and perpetuation of the fibrotic disease process. Recently, this pathological adaptation has been linked to dysregulated expression of tumour suppressor gene p53. In this review, we discuss p53 dysregulation and apoptotic failure in myofibroblasts and demonstrate its consistent link to fibrotic disease development in all types of organ fibrosis. An enhanced understanding of the role of p53 dysregulation and myofibroblast apoptosis may aid in future novel therapeutic and/or diagnostic strategies in organ fibrosis.
Keywords	fibrosis ; p53 ; apoptosis ; myofibroblast ; extracellular matrix ; glaucoma ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2023-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Glaucoma - 'A Stiff Eye in a Stiff Body'.

Powell, Sarah / Irnaten, Mustapha / O'Brien, Colm

Current eye research

2022 Volume 48, Issue 2, Page(s) 152–160

Abstract: Glaucoma is a progressive, age-related optic neuropathy, whereby the prevalence increases sharply over the age of 60 and is associated with increased systemic tissue stiffness. On a molecular basis, this is associated with increased deposition of ... ...

Abstract	Glaucoma is a progressive, age-related optic neuropathy, whereby the prevalence increases sharply over the age of 60 and is associated with increased systemic tissue stiffness. On a molecular basis, this is associated with increased deposition of collagen and loss of elastin structure, resulting in aberrant biomechanical compliance and reduced tissue elasticity. Increased tissue stiffness is a known driver of myofibroblast activation and persistence, especially in chronic cellular injuries via mechanotransduction pathways mediated by integrins and focal adhesion kinases. Evidence from histological and imaging studies plus force measurements of glaucomatous eyes show that several ocular tissues are stiffer than normal, healthy age-matched controls including the trabecular meshwork, Schlemm's canal, cornea, sclera and the lamina cribrosa. This is associated with increased extracellular matrix deposition and fibrosis. This review reports on the evidence to support the concept that glaucoma represents 'a stiff eye in a stiff body' and addresses potential mechanisms to attenuate this.
MeSH term(s)	Humans ; Mechanotransduction, Cellular ; Glaucoma ; Cornea ; Extracellular Matrix ; Integrins ; Trabecular Meshwork
Chemical Substances	Integrins
Language	English
Publishing date	2022-03-07
Publishing country	England
Document type	Review ; Journal Article
ZDB-ID	82079-9
ISSN	1460-2202 ; 0271-3683
ISSN (online)	1460-2202
ISSN	0271-3683
DOI	10.1080/02713683.2022.2039204
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Article: The Intertwined Roles of Oxidative Stress and Endoplasmic Reticulum Stress in Glaucoma.

Hurley, Daire John / Normile, Caoimhe / Irnaten, Mustapha / O'Brien, Colm

Antioxidants (Basel, Switzerland)

2022 Volume 11, Issue 5

Abstract: Glaucoma is the leading cause of irreversible blindness worldwide, and the burden of the disease continues to grow as the global population ages. Currently, the only treatment option is to lower intraocular pressure. A better understanding of glaucoma ... ...

Abstract	Glaucoma is the leading cause of irreversible blindness worldwide, and the burden of the disease continues to grow as the global population ages. Currently, the only treatment option is to lower intraocular pressure. A better understanding of glaucoma pathogenesis will help us to develop novel therapeutic options. Oxidative stress has been implicated in the pathogenesis of many diseases. Oxidative stress occurs when there is an imbalance in redox homeostasis, with reactive oxygen species producing processes overcoming anti-oxidant defensive processes. Oxidative stress works in a synergistic fashion with endoplasmic reticulum stress, to drive glaucomatous damage to trabecular meshwork, retinal ganglion cells and the optic nerve head. We discuss the oxidative stress and endoplasmic reticulum stress pathways and their connections including their key intermediary, calcium. We highlight therapeutic options aimed at disrupting these pathways and discuss their potential role in glaucoma treatment.
Language	English
Publishing date	2022-04-29
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox11050886
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Article: Role of Epithelial-to-Mesenchymal Transition of Retinal Pigment Epithelial Cells in Glaucoma Cupping.

O'Driscoll, Eabha / Hughes, Emily / Irnaten, Mustapha / Kuehn, Markus / Wallace, Deborah / O'Brien, Colm

Journal of clinical medicine

2023 Volume 12, Issue 7

Abstract: Optic nerve head (ONH) cupping is a clinical feature of glaucoma associated with extracellular matrix (ECM) remodelling and lamina cribrosa (LC) fibrosis. Peripapillary atrophy (PPA) occurs commonly in glaucoma, and is characterised by the loss of ... ...

Abstract	Optic nerve head (ONH) cupping is a clinical feature of glaucoma associated with extracellular matrix (ECM) remodelling and lamina cribrosa (LC) fibrosis. Peripapillary atrophy (PPA) occurs commonly in glaucoma, and is characterised by the loss of retinal pigment epithelium (RPE) adjacent to the ONH. Under pro-fibrotic conditions, epithelial cells throughout the body can differentiate into fibroblast-like cells through epithelial-to-mesenchymal transition (EMT) and contribute to ECM fibrosis. This is investigated here in the context of glaucoma and PPA. Human-donor ONH sections were assessed for the presence of the RPE cell-specific marker RPE65 using immunofluorescence. We examined the EMT response of ARPE-19 cells to the following glaucoma-related stimuli: cyclic mechanical stretch, mechanical stiffness, transforming growth factor beta (TGFβ), and tumour necrosis factor alpha (TNFα). The gene expression was measured using the PCR of the epithelial tight junction marker zona occludens 1 (ZO-1) and the mesenchymal markers alpha smooth muscle actin (αSMA) and vimentin. A scratch assay was used to assess the ARPE-19 migration. Significant RPE-65 staining was demonstrated in the glaucomatous ONH. The cyclic stretching and substrate stiffness of the ARPE-19 cells caused a significant decrease in ZO-1 (
Language	English
Publishing date	2023-04-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm12072737
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Article ; Online: Metformin and Glaucoma-Review of Anti-Fibrotic Processes and Bioenergetics.

Hurley, Daire J / Irnaten, Mustapha / O'Brien, Colm

Cells

2021 Volume 10, Issue 8

Abstract: Glaucoma is the leading cause of irreversible blindness globally. With an aging population, disease incidence will rise with an enormous societal and economic burden. The treatment strategy revolves around targeting intraocular pressure, the principle ... ...

Abstract	Glaucoma is the leading cause of irreversible blindness globally. With an aging population, disease incidence will rise with an enormous societal and economic burden. The treatment strategy revolves around targeting intraocular pressure, the principle modifiable risk factor, to slow progression of disease. However, there is a clear unmet clinical need to find a novel therapeutic approach that targets and halts the retinal ganglion cell (RGC) degeneration that occurs with fibrosis. RGCs are highly sensitive to metabolic fluctuations as a result of multiple stressors and thus their viability depends on healthy mitochondrial functioning. Metformin, known for its use in type 2 diabetes, has come to the forefront of medical research in multiple organ systems. Its use was recently associated with a 25% reduced risk of glaucoma in a large population study. Here, we discuss its application to glaucoma therapy, highlighting its effect on fibrotic signalling pathways, mitochondrial bioenergetics and NAD oxidation.
MeSH term(s)	Animals ; Fibrosis/drug therapy ; Fibrosis/metabolism ; Glaucoma/drug therapy ; Glaucoma/metabolism ; Humans ; Metformin/therapeutic use ; Signal Transduction/drug effects
Chemical Substances	Metformin (9100L32L2N)
Language	English
Publishing date	2021-08-19
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells10082131
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Article ; Online: Role of Epithelial-to-Mesenchymal Transition of Retinal Pigment Epithelial Cells in Glaucoma Cupping

Eabha O’Driscoll / Emily Hughes / Mustapha Irnaten / Markus Kuehn / Deborah Wallace / Colm O’Brien

Journal of Clinical Medicine, Vol 12, Iss 2737, p

2023 Volume 2737

Abstract	Optic nerve head (ONH) cupping is a clinical feature of glaucoma associated with extracellular matrix (ECM) remodelling and lamina cribrosa (LC) fibrosis. Peripapillary atrophy (PPA) occurs commonly in glaucoma, and is characterised by the loss of retinal pigment epithelium (RPE) adjacent to the ONH. Under pro-fibrotic conditions, epithelial cells throughout the body can differentiate into fibroblast-like cells through epithelial-to-mesenchymal transition (EMT) and contribute to ECM fibrosis. This is investigated here in the context of glaucoma and PPA. Human-donor ONH sections were assessed for the presence of the RPE cell-specific marker RPE65 using immunofluorescence. We examined the EMT response of ARPE-19 cells to the following glaucoma-related stimuli: cyclic mechanical stretch, mechanical stiffness, transforming growth factor beta (TGFβ), and tumour necrosis factor alpha (TNFα). The gene expression was measured using the PCR of the epithelial tight junction marker zona occludens 1 (ZO-1) and the mesenchymal markers alpha smooth muscle actin (αSMA) and vimentin. A scratch assay was used to assess the ARPE-19 migration. Significant RPE-65 staining was demonstrated in the glaucomatous ONH. The cyclic stretching and substrate stiffness of the ARPE-19 cells caused a significant decrease in ZO-1 ( p = 0.04), and an increase in αSMA ( p = 0.04). The scratch assays demonstrated increased migration of ARPE19 in the presence of TNFα ( p = 0.02). Furthermore, ARPE-19 cells undergo an EMT-like transition (gain of αSMA, loss of ZO-1 and increased migration) in response to glaucomatous stimuli. This suggests that during PPA, RPE cells have the potential to migrate into the ONH and differentiate into fibroblast-like cells, contributing to glaucomatous ONH cupping.
Keywords	glaucoma ; peripapillary atrophy ; epithelial mesenchymal transition ; retinal pigment epithelium cell ; Medicine ; R
Subject code	610
Language	English
Publishing date	2023-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Intra-Cellular Calcium Signaling Pathways (PKC, RAS/RAF/MAPK, PI3K) in Lamina Cribrosa Cells in Glaucoma.

Irnaten, Mustapha / Duff, Aisling / Clark, Abbot / O'Brien, Colm

Journal of clinical medicine

2020 Volume 10, Issue 1

Abstract: The lamina cribrosa (LC) is a key site of fibrotic damage in glaucomatous optic neuropathy and the precise mechanisms of LC change remain unclear. Elevated ... ...

Abstract	The lamina cribrosa (LC) is a key site of fibrotic damage in glaucomatous optic neuropathy and the precise mechanisms of LC change remain unclear. Elevated Ca
Language	English
Publishing date	2020-12-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm10010062
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Article ; Online: Intra-Cellular Calcium Signaling Pathways (PKC, RAS/RAF/MAPK, PI3K) in Lamina Cribrosa Cells in Glaucoma

Mustapha Irnaten / Aisling Duff / Abbot Clark / Colm O’Brien

Journal of Clinical Medicine, Vol 10, Iss 62, p

2021 Volume 62

Abstract: The lamina cribrosa (LC) is a key site of fibrotic damage in glaucomatous optic neuropathy and the precise mechanisms of LC change remain unclear. Elevated Ca 2+ is a major driver of fibrosis, and therefore intracellular Ca 2+ signaling pathways are ... ...

Abstract	The lamina cribrosa (LC) is a key site of fibrotic damage in glaucomatous optic neuropathy and the precise mechanisms of LC change remain unclear. Elevated Ca 2+ is a major driver of fibrosis, and therefore intracellular Ca 2+ signaling pathways are relevant glaucoma-related mechanisms that need to be studied. Protein kinase C (PKC), mitogen-activated MAPK kinases ( p 38 and p 42/44-MAPK), and the PI3K/mTOR axis are key Ca 2+ signal transducers in fibrosis and we therefore investigated their expression and activity in normal and glaucoma cultured LC cells. We show, using Western immune-blotting, that hyposmotic-induced cellular swelling activates PKCα, p 42/ p 44, and p 38 MAPKs, the activity is transient and biphasic as it peaks between 2 min and 10 min. The expression and activity of PKCα, p 38 and p 42/ p 44-MAPKs are significantly ( p < 0.05) increased in glaucoma LC cells at basal level, and at different time-points after hyposmotic stretch. We also found elevated mRNA expression of mRNA expression of PI3K, IP3R, mTOR, and CaMKII in glaucoma LC cells. This study has identified abnormalities in multiple calcium signaling pathways (PKCα, MAPK, PI3K) in glaucoma LC cells, which might have significant functional and therapeutic implications in optic nerve head (ONH) fibrosis and cupping in glaucoma.
Keywords	glaucoma ; lamina cribrosa ; fibrosis ; calcium ; PKCα ; p 38-MAPK ; Medicine ; R
Subject code	333
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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