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Article: Oxidative Stress and Cellular Protein Accumulation Are Present in Keratoconus, Macular Corneal Dystrophy, and Fuchs Endothelial Corneal Dystrophy.

Vottonen, Linda / Koskela, Ali / Felszeghy, Szabolcs / Wylegala, Adam / Kryszan, Katarzyna / Gurubaran, Iswariyaraja Sridevi / Kaarniranta, Kai / Wylegala, Edward

Journal of clinical medicine

2023 Volume 12, Issue 13

Abstract: The aim of the study was to investigate oxidative stress as well as cellular protein accumulation in corneal diseases including keratoconus (KC), macular corneal dystrophy (MCD), and Fuchs endothelial corneal dystrophy (FECD) at their primary affecting ... ...

Abstract	The aim of the study was to investigate oxidative stress as well as cellular protein accumulation in corneal diseases including keratoconus (KC), macular corneal dystrophy (MCD), and Fuchs endothelial corneal dystrophy (FECD) at their primary affecting sites. Corneal buttons from KC, MCD, and FECD patients, as well as healthy controls, were analyzed immunohistochemically to evaluate the presence of oxidative stress and the function of the proteostasis network. 4-Fydroxynonenal (4-HNE) was used as a marker of oxidative stress, whereas the levels of catalase and heat-shock protein 70 (HSP70) were analyzed to evaluate the response of the antioxidant defense system and molecular chaperones, respectively. Sequestosome 1 (SQSTM1) levels were determined to assess protein aggregation and the functionality of autophagic degradation. Basal epithelial cells of the KC samples showed increased levels of oxidative stress marker 4-HNE and antioxidant enzyme catalase together with elevated levels of HSP70 and accumulation of SQSTM1. Corneal stromal cells and endothelial cells from MCD and FECD samples, respectively, showed similarly increased levels of these markers. All corneal diseases showed the presence of oxidative stress and activation of the molecular chaperone response to sustain protein homeostasis. However, the accumulation of protein aggregates suggests insufficient function of the protective mechanisms to limit the oxidative damage and removal of protein aggregates via autophagy. These results suggest that oxidative stress has a role in KC, MCD, and FECD at the cellular level as a secondary outcome. Thus, antioxidant- and autophagy-targeted therapies could be included as supporting care when treating KC or corneal dystrophies.
Language	English
Publishing date	2023-06-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm12134332
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Article ; Online: Dietary Polyphenols in Age-Related Macular Degeneration: Protection against Oxidative Stress and Beyond.

Pawlowska, Elzbieta / Szczepanska, Joanna / Koskela, Ali / Kaarniranta, Kai / Blasiak, Janusz

Oxidative medicine and cellular longevity

2019 Volume 2019, Page(s) 9682318

Abstract: Age-related macular degeneration (AMD) is a multifactorial disease of the retina featured by degeneration and loss of photoreceptors and retinal pigment epithelium (RPE) cells with oxidative stress playing a role in its pathology. Although systematic ... ...

Abstract	Age-related macular degeneration (AMD) is a multifactorial disease of the retina featured by degeneration and loss of photoreceptors and retinal pigment epithelium (RPE) cells with oxidative stress playing a role in its pathology. Although systematic reviews do not support the protective role of diet rich in antioxidants against AMD, dietary polyphenols (DPs) have been reported to have beneficial effects on vision. Some of them, such as quercetin and cyanidin-3-glucoside, can directly scavenge reactive oxygen species (ROS) due to the presence of two hydroxyl groups in their B ring structure. Apart from direct ROS scavenging, DPs can lower oxidative stress in several other pathways. Many DPs induce NRF2 (nuclear factor, erythroid 2-like 2) activation and expression of phase II enzymes that are under transcriptional control of this factor. DPs can inhibit A2E photooxidation in RPE cells, which is a source of oxidative stress. Anti-inflammatory action of DPs in RPE cells is associated with regulation of various interleukins and signaling pathways, including IL-6/JAK2 (Janus kinase 2)/STAT3. Some DPs can improve impaired cellular waste clearance, including AMD-specific deficient phagocytosis of the A
MeSH term(s)	Diet ; Humans ; Macular Degeneration/drug therapy ; Macular Degeneration/pathology ; Models, Biological ; Oxidative Stress/drug effects ; Polyphenols/chemistry ; Polyphenols/pharmacology ; Polyphenols/therapeutic use ; Protective Agents/pharmacology ; Protective Agents/therapeutic use
Chemical Substances	Polyphenols ; Protective Agents
Language	English
Publishing date	2019-03-24
Publishing country	United States
Document type	Journal Article ; Review
ISSN	1942-0994
ISSN (online)	1942-0994
DOI	10.1155/2019/9682318
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Article: Nature-Inspired Hybrids (NIH) Improve Proteostasis by Activating Nrf2-Mediated Protective Pathways in Retinal Pigment Epithelial Cells

Koskela, Ali / Manai, Federico / Basagni, Filippo / Liukkonen, Mikko / Rosini, Michela / Govoni, Stefano / Monte, Massimo Dal / Smedowski, Adrian / Kaarniranta, Kai / Amadio, Marialaura

Antioxidants. 2022 July 18, v. 11, no. 7

2022

Abstract: Antioxidant systems play key roles in many elderly diseases, including age-related macular degeneration (AMD). Oxidative stress, autophagy impairment and inflammation are well-described in AMD, especially in retinal pigment epithelial (RPE) cells. The ... ...

Abstract	Antioxidant systems play key roles in many elderly diseases, including age-related macular degeneration (AMD). Oxidative stress, autophagy impairment and inflammation are well-described in AMD, especially in retinal pigment epithelial (RPE) cells. The master regulator of antioxidant defense Nrf2 has been linked to AMD, autophagy and inflammation. In this study, in human ARPE-19 cells, some nature-inspired hybrids (NIH1–3) previously shown to induce Nrf2-mediated protection against oxidative stress were further investigated for their potential against cellular stress caused by dysfunction of protein homeostasis. NIH1–3 compounds increased the expression of two Nrf2-target genes coding defense proteins, HO-1 and SQSTM1/p62, in turn exerting beneficial effects on intracellular redox balance without modification of the autophagy flux. NIH1–3 treatments predisposed ARPE-19 cells to a better response to following exposure to proteasome and autophagy inhibitors, as revealed by the increase in cell survival and decreased secretion of the pro-inflammatory IL-8 compared to NIH-untreated cells. Interestingly, NIH4 compound, through an Nrf2-independent pathway, also increased cell viability and decreased IL-8 secretion, although to a lesser extent than NIH1–3, suggesting that all NIHs are worthy of further investigation into their cytoprotective properties. This study confirms Nrf2 as a valuable pharmacological target in contexts characterized by oxidative stress, such as AMD.
Keywords	antioxidant activity ; antioxidants ; autophagy ; cell viability ; elderly ; epithelium ; homeostasis ; humans ; inflammation ; interleukin-8 ; macular degeneration ; oxidative stress ; proteasome endopeptidase complex ; secretion
Language	English
Dates of publication	2022-0718
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox11071385
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Article ; Online: Resvega Alleviates Hydroquinone-Induced Oxidative Stress in ARPE-19 Cells.

Bhattarai, Niina / Korhonen, Eveliina / Toppila, Maija / Koskela, Ali / Kaarniranta, Kai / Mysore, Yashavanthi / Kauppinen, Anu

International journal of molecular sciences

2020 Volume 21, Issue 6

Abstract: Retinal pigment epithelial (RPE) cells maintain homeostasis at the retina and they are under continuous oxidative stress. Cigarette smoke is a prominent environmental risk factor for age-related macular degeneration (AMD), which further increases the ... ...

Abstract	Retinal pigment epithelial (RPE) cells maintain homeostasis at the retina and they are under continuous oxidative stress. Cigarette smoke is a prominent environmental risk factor for age-related macular degeneration (AMD), which further increases the oxidant load in retinal tissues. In this study, we measured oxidative stress and inflammatory markers upon cigarette smoke-derived hydroquinone exposure on human ARPE-19 cells. In addition, we studied the effects of commercial Resvega product on hydroquinone-induced oxidative stress. Previously, it was observed that Resvega induces autophagy during impaired protein clearance in ARPE-19 cells, for which it has the potential to alleviate pro-inflammatory pathways. Cell viability was determined while using the lactate dehydrogenase (LDH) and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, and the cytokine levels were measured using the enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) production were measured using the 2',7'-dichlorofluorescin diacetate (H
MeSH term(s)	Antioxidants/pharmacology ; Biomarkers ; Cell Survival/drug effects ; Cytokines/metabolism ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Humans ; Hydroquinones/pharmacology ; Inflammation Mediators/metabolism ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Retinal Pigment Epithelium/cytology ; Retinal Pigment Epithelium/metabolism
Chemical Substances	Antioxidants ; Biomarkers ; Cytokines ; Hydroquinones ; Inflammation Mediators ; Reactive Oxygen Species ; hydroquinone (XV74C1N1AE)
Language	English
Publishing date	2020-03-17
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms21062066
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Article ; Online: Crosstalk of protein clearance, inflammasome, and Ca

Karema-Jokinen, Viivi / Koskela, Ali / Hytti, Maria / Hongisto, Heidi / Viheriälä, Taina / Liukkonen, Mikko / Torsti, Tommi / Skottman, Heli / Kauppinen, Anu / Nymark, Soile / Kaarniranta, Kai

The Journal of biological chemistry

2023 Volume 299, Issue 6, Page(s) 104770

Abstract: Degeneration and/or dysfunction of retinal pigment epithelium (RPE) is generally detected as the formation of intracellular and extracellular protein aggregates, called lipofuscin and drusen, respectively, in patients with age-related macular ... ...

Abstract	Degeneration and/or dysfunction of retinal pigment epithelium (RPE) is generally detected as the formation of intracellular and extracellular protein aggregates, called lipofuscin and drusen, respectively, in patients with age-related macular degeneration (AMD), the leading cause of blindness in the elderly population. These clinical hallmarks are linked to dysfunctional protein homeostasis and inflammation and furthermore, are both regulated by changes in intracellular Ca
MeSH term(s)	Aged ; Humans ; Autophagy ; Inflammasomes/metabolism ; Inflammation/metabolism ; Macular Degeneration/metabolism ; Macular Degeneration/pathology ; Retinal Pigment Epithelium/metabolism ; Retinal Pigment Epithelium/pathology
Chemical Substances	Inflammasomes
Language	English
Publishing date	2023-05-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2023.104770
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Article: [Pathogenesis of age-related macular degeneration - dialogue between autophagy and inflammasomes] .

Kivinen, Niko / Koskela, Ali / Kauppinen, Anu / Kaarniranta, Kai

Duodecim; laaketieteellinen aikakauskirja

2017 Volume 133, Issue 7, Page(s) 641–646

Abstract: Age-related macular degeneration is a condition affecting central vision, and is the leading cause of blindness and visual impairment in the western countries. For a long time, inflammation has been associated with the pathogenesis of the condition, and ... ...

Abstract	Age-related macular degeneration is a condition affecting central vision, and is the leading cause of blindness and visual impairment in the western countries. For a long time, inflammation has been associated with the pathogenesis of the condition, and according to current knowledge, inflammation in the retinal pigment epithelial cells (RPE) results from an impairment of intracellular cleansing systems. In combination with the degeneration of RPE cells, this eventually leads to the destruction of light-sensing cells. By influencing the accumulation or elimination of waste material or the inflammatory reaction following its accumulation we may in the future possibly slow the progression of the disease or, in the best case, even cure it.
MeSH term(s)	Age Factors ; Autophagy ; Disease Progression ; Humans ; Inflammasomes ; Inflammation/immunology ; Inflammation/pathology ; Macular Degeneration/immunology ; Macular Degeneration/pathology
Chemical Substances	Inflammasomes
Language	Finnish
Publishing date	2017
Publishing country	Finland
Document type	Journal Article ; Review ; English Abstract
ZDB-ID	127604-9
ISSN	0012-7183
ISSN	0012-7183
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Article ; Online: Epithelial-mesenchymal transition-related serum markers ET-1, IL-8 and TGF-β2 are elevated in a Finnish wet age-related macular degeneration cohort.

Liukkonen, Mikko P K / Paterno, Jussi J / Kivinen, Niko / Siintamo, Leea / Koskela, Ali K J / Kaarniranta, Kai

Acta ophthalmologica

2021 Volume 100, Issue 5, Page(s) e1153–e1162

Abstract: Purpose: It has been hypothesized that epithelial-mesenchymal transition (EMT) may occur in the retinal pigment epithelium of advanced stage age-related macular degeneration (AMD). Various serum and plasma growth factors and inflammatory mediators have ... ...

Abstract	Purpose: It has been hypothesized that epithelial-mesenchymal transition (EMT) may occur in the retinal pigment epithelium of advanced stage age-related macular degeneration (AMD). Various serum and plasma growth factors and inflammatory mediators have been linked to AMD. We were interested in finding out whether systemic levels of EMT-associated markers were altered in the serum of wet AMD patients. Serum biomarkers associated with the various pathological processes of AMD may present an avenue towards identifying and characterizing the birth mechanisms of wet AMD, its progression and severity, paving the way towards the application of precision medicine. Methods: We chose to measure the serum levels of known biomarkers of EMT - EGF (epidermal growth factor), ET-1 (endothelin 1), IL-8 (interleukin 8), TGF-β1 and TGF-β2 (transforming growth factor-beta 1 and 2) and VEGF-A (vascular endothelial growth factor A) - using enzyme-linked immunosorbent assays. We measured them from 71 Finnish wet AMD patients who were receiving intravitreal anti-VEGF-A injection treatments, as well as 64 age-adjusted controls. Results: We found significantly elevated levels of ET-1, IL-8 and TGF-β2 in the serums of wet AMD patients. Conclusions: ET-1, IL-8 and TGF-β2 appear to be useful serum biomarkers in understanding active wet AMD. However, we cannot conclude that local retinal EMT-processes could be observed from the corresponding systemic serum biomarkers in patients undergoing anti-VEGF-A treatments.
MeSH term(s)	Biomarkers ; Epithelial-Mesenchymal Transition ; Finland ; Humans ; Interleukin-8 ; Transforming Growth Factor beta2/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; Wet Macular Degeneration/diagnosis
Chemical Substances	Biomarkers ; Interleukin-8 ; Transforming Growth Factor beta2 ; Vascular Endothelial Growth Factor A
Language	English
Publishing date	2021-10-26
Publishing country	England
Document type	Journal Article
ZDB-ID	2408333-1
ISSN	1755-3768 ; 1755-375X
ISSN (online)	1755-3768
ISSN	1755-375X
DOI	10.1111/aos.15051
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Article ; Online: Autophagy regulates death of retinal pigment epithelium cells in age-related macular degeneration.

Kaarniranta, Kai / Tokarz, Paulina / Koskela, Ali / Paterno, Jussi / Blasiak, Janusz

Cell biology and toxicology

2017 Volume 33, Issue 2, Page(s) 113–128

Abstract: Age-related macular degeneration (AMD) is an eye disease underlined by the degradation of retinal pigment epithelium (RPE) cells, photoreceptors, and choriocapillares, but the exact mechanism of cell death in AMD is not completely clear. This mechanism ... ...

Abstract	Age-related macular degeneration (AMD) is an eye disease underlined by the degradation of retinal pigment epithelium (RPE) cells, photoreceptors, and choriocapillares, but the exact mechanism of cell death in AMD is not completely clear. This mechanism is important for prevention of and therapeutic intervention in AMD, which is a hardly curable disease. Present reports suggest that both apoptosis and pyroptosis (cell death dependent on caspase-1) as well as necroptosis (regulated necrosis dependent on the proteins RIPK3 and MLKL, caspase-independent) can be involved in the AMD-related death of RPE cells. Autophagy, a cellular clearing system, plays an important role in AMD pathogenesis, and this role is closely associated with the activation of the NLRP3 inflammasome, a central event for advanced AMD. Autophagy can play a role in apoptosis, pyroptosis, and necroptosis, but its contribution to AMD-specific cell death is not completely clear. Autophagy can be involved in the regulation of proteins important for cellular antioxidative defense, including Nrf2, which can interact with p62/SQSTM, a protein essential for autophagy. As oxidative stress is implicated in AMD pathogenesis, autophagy can contribute to this disease by deregulation of cellular defense against the stress. However, these and other interactions do not explain the mechanisms of RPE cell death in AMD. In this review, we present basic mechanisms of autophagy and its involvement in AMD pathogenesis and try to show a regulatory role of autophagy in RPE cell death. This can result in considering the genes and proteins of autophagy as molecular targets in AMD prevention and therapy.
MeSH term(s)	Animals ; Apoptosis ; Autophagy ; Cell Survival ; Humans ; Macular Degeneration/etiology ; Macular Degeneration/pathology ; Models, Biological ; Retinal Pigment Epithelium/pathology
Language	English
Publishing date	2017-04
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	48824-0
ISSN	1573-6822 ; 0742-2091
ISSN (online)	1573-6822
ISSN	0742-2091
DOI	10.1007/s10565-016-9371-8
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Article ; Online: Student-focused virtual histology education: Do new scenarios and digital technology matter?

Felszeghy, Szabolcs / Pasonen-Seppänen, Sanna / Koskela, Ali / Mahonen, Anitta

MedEdPublish (2016)

2017 Volume 6, Page(s) 154

Abstract: This article was migrated. The article was marked as recommended. Innovative changes have become a critical part of teaching when resources are limited. In this study, we examined whether the student-oriented teaching method, when powered by virtual ... ...

Abstract	This article was migrated. The article was marked as recommended. Innovative changes have become a critical part of teaching when resources are limited. In this study, we examined whether the student-oriented teaching method, when powered by virtual microscopy, improves histology learning compared to traditional microscope-based studies. Anonymous and voluntary post-course surveys were administered to students and essays were processed for content analysis. Google Analytics was used to obtain accurate Internet usage monitoring for WEBMICROSCOPE®. Using SPSS statistics, the examination scores for 2016 were compared to those of previous year, when the course was taught with a traditional-microscope-based model. The results demonstrated that the new teaching scenario was an effective tool, based on the mean examination scores in 2016 compared to the identical groups in 2015. The survey analysis showed that the students benefited more from using WEBMICROSCOPE® and that they frequently gained access to the Web server when they were not in class. The new scenario helped clarify the concept of histology for most of the students and was generally appreciated during teamwork-based histology classes. Students perceived that the use of the digital technology significantly influenced their confidence in learning the fundamentals of histology. In addition, changing to the new teaching scenario powered by WEBMICROSCOPE® improved the students' motivation to participate in discussions and better understand the concept of Histology between the 2015 and 2016 academic years. Finally, these changes all had a positive impact on the students' attention and satisfaction.
Language	English
Publishing date	2017-09-07
Publishing country	Scotland
Document type	Journal Article
ISSN	2312-7996
ISSN (online)	2312-7996
DOI	10.15694/mep.2017.000154
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Article: SCD1-Fatty Acid Desaturase Inhibitor MF-438 Alleviates Latent Inflammation Induced by Preservative-Free Prostaglandin Analog Eye Drops.

Pacwa, Anna / Machowicz, Joanna / Wojtyniak, Alicja / Pietrucha-Dutczak, Marita / Toropainen, Elisa / Koskela, Ali / Mrukwa-Kominek, Ewa / Lewin-Kowalik, Joanna / Smedowski, Adrian

Journal of inflammation research

2022 Volume 15, Page(s) 793–806

Abstract: Introduction: Prostaglandin analogs are the first line of treatment in patients with glaucoma. Recently, many preservative-free prostaglandin analogs have been marketed to increase their tolerance in chronic use. However, potentially safer formulations ... ...

Abstract	Introduction: Prostaglandin analogs are the first line of treatment in patients with glaucoma. Recently, many preservative-free prostaglandin analogs have been marketed to increase their tolerance in chronic use. However, potentially safer formulations have been reported to induce inflammation within ocular surface and adnexa, associated with pronounced activation of tissue macrophages. Aim: We aimed to evaluate the effect of a Stearoyl-CoA desaturase-1 (SCD1) inhibitor, MF-438, on the differentiation of monocytes exposed to eye drop detergents, representing saturated fatty acid derivatives. Methods: A culture of human peripheral blood monocytes was exposed to eye drops containing fatty acid derivatives (eye drop detergents), pf-latanoprost (Monoprost Results: The following concentrations of SCD1 (ng/mL) were measured: 7.8±0.3 - pf-latanoprost group; 1.5±0.4 - pf-tafluprost group; 6.8±0.7 - MGHS40 group; 0.4±0.002 - PS80 group; 0.9±0.02 - pf-latanoprost+MF-438 group; 5.4±1.6 - C(-) control; 0.5±0.04 - M1 control; 2.2±0.13 - M2 control. The percentages of macrophages in culture were 33.6%, 17.6%, 33%, 0%, 13.5%, 18.6%, 36.3%, and 39.3% for the pf-latanoprost, pf-tafluprost, MGHS40, PS80, pf-latanoprost+MF-438, C(-), M1, and M2 cultures, respectively. There was a strong correlation between SCD1 concentration and macrophage count in the culture ( Conclusion: Inhibition of SCD1 in monocytes prevents their transformation into macrophages after exposure to saturated fatty acid derivatives contained in eye drops, which may contribute to the limitation of latent inflammation within ocular adnexa and could possibly translate into better tolerability of the topical treatment.
Language	English
Publishing date	2022-02-08
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	2494878-0
ISSN	1178-7031
ISSN	1178-7031
DOI	10.2147/JIR.S347784
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