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  • 1
    Online Resource
    Online Resource
    Engineered Sumoylation-Deficient Prdx6 Mutant Protein-Loaded Nanoparticles Provide Increased Cellular Defense and Prevent Lens Opacity
    MDPI AG ; 2021
    In:  Antioxidants Vol. 10, No. 8 ( 2021-08-04), p. 1245-
    Details
    In: Antioxidants, MDPI AG, Vol. 10, No. 8 ( 2021-08-04), p. 1245-
    Abstract: Aberrant Sumoylation-mediated protein dysfunction is involved in a variety of oxidative and aging pathologies. We previously reported that Sumoylation-deficient Prdx6K(lysine)122/142R(Arginine) linked to the TAT-transduction domain gained stability and protective efficacy. In the present study, we formulated wild-type TAT-HA-Prdx6WT and Sumoylation-deficient Prdx6-loaded poly-lactic-co-glycolic acid (PLGA) nanoparticles (NPs) to further enhance stability, protective activities, and sustained delivery. We found that in vitro and subconjuctival delivery of Sumoylation-deficient Prdx6-NPs provided a greater protection of lens epithelial cells (LECs) derived from human and Prdx6−/−-deficient mouse lenses against oxidative stress, and it also delayed the lens opacity in Shumiya cataract rats (SCRs) than TAT-HA-Prdx6WT-NPs. The encapsulation efficiencies of TAT-HA-Prdx6-NPs were ≈56%–62%. Dynamic light scattering (DLS) and atomic force microscopy (AFM) analyses showed that the NPs were spherical, with a size of 50–250 nm and a negative zeta potential (≈23 mV). TAT-HA-Prdx6 analog-NPs released bioactive TAT-HA-Prdx6 (6%–7%) within 24 h. Sumoylation-deficient TAT-HA-Prdx6-NPs provided 35% more protection by reducing the oxidative load of LECs exposed to H2O2 compared to TAT-HA-Prdx6WT-NPs. A subconjuctival delivery of TAT-HA-Prdx6 analog-NPs demonstrated that released TAT-HA-Prdx6K122/142R could reduce lens opacity by ≈60% in SCRs. Collectively, our results demonstrate for the first time that the subconjuctival delivery of Sumoylation-deficient Prdx6-NPs is efficiently cytoprotective and provide a proof of concept for potential use to delay cataract and oxidative-related pathobiology in general.
    Type of Medium: Online Resource
    ISSN: 2076-3921
    URL: Article
    DOI: 10.3390/antiox10081245
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2704216-9
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  • 2
    Online Resource
    Online Resource
    Novel Technique for Retinal Nerve Cell Regeneration with Electrophysiological Functions Using Human Iris-Derived iPS Cells
    MDPI AG ; 2021
    In:  Cells Vol. 10, No. 4 ( 2021-03-28), p. 743-
    Details
    In: Cells, MDPI AG, Vol. 10, No. 4 ( 2021-03-28), p. 743-
    Abstract: Regenerative medicine in ophthalmology that uses induced pluripotent stem cells (iPS) cells has been described, but those studies used iPS cells derived from fibroblasts. Here, we generated iPS cells derived from iris cells that develop from the same inner layer of the optic cup as the retina, to regenerate retinal nerves. We first identified cells positive for p75NTR, a marker of retinal tissue stem and progenitor cells, in human iris tissue. We then reprogrammed the cultured p75NTR-positive iris tissue stem/progenitor (H-iris stem/progenitor) cells to create iris-derived iPS (H-iris iPS) cells for the first time. These cells were positive for iPS cell markers and showed pluripotency to differentiate into three germ layers. When H-iris iPS cells were pre-differentiated into neural stem/progenitor cells, not all cells became positive for neural stem/progenitor and nerve cell markers. When these cells were pre-differentiated into neural stem/progenitor cells, sorted with p75NTR, and used as a medium for differentiating into retinal nerve cells, the cells differentiated into Recoverin-positive cells with electrophysiological functions. In a different medium, H-iris iPS cells differentiated into retinal ganglion cell marker-positive cells with electrophysiological functions. This is the first demonstration of H-iris iPS cells differentiating into retinal neurons that function physiologically as neurons.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells10040743
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2661518-6
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  • 3
    Online Resource
    Online Resource
    Obligatory Role of AMPK Activation and Antioxidant Defense Pathway in the Regulatory Effects of Metformin on Cellular Protection and Prevention of Lens Opacity
    MDPI AG ; 2022
    In:  Cells Vol. 11, No. 19 ( 2022-09-27), p. 3021-
    Details
    In: Cells, MDPI AG, Vol. 11, No. 19 ( 2022-09-27), p. 3021-
    Abstract: Increasing levels of oxidative-stress due to deterioration of the Nrf2 (NFE2-related factor)/ARE (antioxidant response element) pathway is found to be a primary cause of aging pathobiology. Metformin having anti-aging effects can delay/halt aging-related diseases. Herein, using lens epithelial cell lines (LECs) of human (h) or mouse (m) and aging h/m primary LECs along with lenses as model systems, we demonstrated that Metformin could correct deteriorated Bmal1/Nrf2/ARE pathway by reviving AMPK-activation, and transcriptional activities of Bmal1/Nrf2, resulting in increased antioxidants enzymatic activity and expression of Phase II enzymes. This ensued reactive oxygen species (ROS) mitigation with cytoprotection and prevention of lens opacity in response to aging/oxidative stress. It was intriguing to observe that Metformin internalized lens/LECs and upregulated OCTs (Organic Cation Transporters). Mechanistically, we found that Metformin evoked AMPK activation-dependent increase of Bmal1, Nrf2, and antioxidants transcription by promoting direct E-Box and ARE binding of Bmal1 and Nrf2 to the promoters. Loss-of-function and disruption of E-Box/ARE identified that Metformin acted by increasing Bmal1/Nrf2-mediated antioxidant expression. Data showed that AMPK-activation was a requisite for Bmal1/Nrf2-antioxidants-mediated defense, as pharmacologically inactivating AMPK impeded the Metformin’s effect. Collectively, the results for the first-time shed light on the hitherto incompletely uncovered crosstalk between the AMPK and Bmal1/Nrf2/antioxidants mediated by Metformin for blunting oxidative/aging-linked pathobiology.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells11193021
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
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  • 4
    Online Resource
    Online Resource
    Hydralazine Revives Cellular and Ocular Lens Health-Span by Ameliorating the Aging and Oxidative-Dependent Loss of the Nrf2-Activated Cellular Stress Response
    MDPI AG ; 2023
    In:  Antioxidants Vol. 12, No. 1 ( 2023-01-06), p. 140-
    Details
    In: Antioxidants, MDPI AG, Vol. 12, No. 1 ( 2023-01-06), p. 140-
    Abstract: A major hallmark of aging-associated diseases is the inability to evoke cellular defense responses. Transcriptional protein Nrf2 (nuclear factor erythroid-derived 2-related factor) plays a pivotal role in the oxidative stress response, cellular homeostasis, and health span. Nrf2’s activation has been identified as a therapeutic target to restore antioxidant defense in aging. Here, we demonstrated that FDA-approved drug, hydralazine (Hyd), was a reactivator of the Nrf2/ARE (antioxidant response element) pathway in various ages and types of mouse (m) or human (h) lens epithelial cells (LECs) and mice lenses in-vitro/in-vivo. This led to Hyd-driven abatement of carbonyls, reduced reactive oxygen species (ROS), and reduced 4-HNE/MDA-adducts with cytoprotection, and extended lens healthspan by delaying/preventing lens opacity against aging/oxidative stress. We elucidated that Hyd activated the protective signaling by inducing Nrf2 to traverse from the cytoplasm to the nucleus and potentiated the ARE response by direct interaction of Nrf2 and ARE sequences of the promoter. Loss-of-function study and cotreatment of Hyd and antioxidant, N-acetyl cysteine (NAC) or Peroxiredoxin (Prdx)6, specified that Nrf2/ARE-driven increase in the promoter activity was Hyd-dependent. Our study provides proof-of concept evidence and, thereby, paves the way to repurposing Hyd as a therapeutic agent to delay/prevent aging and oxidative-related disorders.
    Type of Medium: Online Resource
    ISSN: 2076-3921
    URL: Article
    DOI: 10.3390/antiox12010140
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2704216-9
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  • 5
    Online Resource
    Online Resource
    Sulforaphane-Induced Klf9/Prdx6 Axis Acts as a Molecular Switch to Control Redox Signaling and Determines Fate of Cells
    MDPI AG ; 2019
    In:  Cells Vol. 8, No. 10 ( 2019-09-27), p. 1159-
    Details
    In: Cells, MDPI AG, Vol. 8, No. 10 ( 2019-09-27), p. 1159-
    Abstract: Sulforaphane (SFN), an activator of transcription factor Nrf2 (NFE2-related factor), modulates antioxidant defense by Nrf2-mediated regulation of antioxidant genes like Peroxiredoxin 6 (Prdx6) and affects cellular homeostasis. We previously observed that dose levels of SFN are crucial in determining life or death of lens epithelial cells (LECs). Herein, we demonstrated that higher doses of SFN ( 〉 6 μM) activated death signaling by overstimulation of Nrf2/ARE (antioxidant response element)-mediated Kruppel-like factor (Klf9) repression of Prdx6 expression, which increased reactive oxygen species (ROS) load and cell death. Mechanistically, Klf9 bound to its repressive Klf9 binding elements (RKBE; 5-CA/GCCC-3) in the Prdx6 promoter, and repressed Prdx6 transcription. Under the condition of higher dose of SFN, excessive Nrf2 abundance caused death signaling by enforcing Klf9 activation through ARE (5-RTGAYnnnGC-3) in Klf9 promoter that suppress antioxidant genes such as Prdx6 via a Klf9-dependent fashion. Klf9-depletion showed that Klf9 independently caused ROS reduction and subsequent cell survival, demonstrating that Klf9 upregulation caused cell death. Our work revealed the molecular mechanism of dose-dependent altered activity of SFN in LECs, and demonstrated that SFN activity was linked to levels of Nrf2/Klf9/Prdx6 axis. We proposed that in the development of therapeutic interventions for aging/oxidative disorders, combinations of Klf9-ShRNA and Nrf2 inducers may prove to be a promising strategy.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells8101159
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
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  • 6
    Online Resource
    Online Resource
    Role of Decorin in the Lens and Ocular Diseases
    MDPI AG ; 2022
    In:  Cells Vol. 12, No. 1 ( 2022-12-24), p. 74-
    Details
    In: Cells, MDPI AG, Vol. 12, No. 1 ( 2022-12-24), p. 74-
    Abstract: Decorin is an archetypal member of the small leucine-rich proteoglycan gene family and is involved in various biological functions and many signaling networks, interacting with extra-cellular matrix (ECM) components, growth factors, and receptor tyrosine kinases. Decorin also modulates the growth factors, cell proliferation, migration, and angiogenesis. It has been reported to be involved in many ischemic and fibrotic eye diseases, such as congenital stromal dystrophy of the cornea, anterior subcapsular fibrosis of the lens, proliferative vitreoretinopathy, et al. Furthermore, recent evidence supports its role in secondary posterior capsule opacification (PCO) after cataract surgery. The expression of decorin mRNA in lens epithelial cells in vitro was found to decrease upon transforming growth factor (TGF)-β-2 addition and increase upon fibroblast growth factor (FGF)-2 addition. Wound healing of the injured lens in mice transgenic for lens-specific human decorin was promoted by inhibiting myofibroblastic changes. Decorin may be associated with epithelial–mesenchymal transition and PCO development in the lens. Gene therapy and decorin administration have the potential to serve as excellent therapeutic approaches for modifying impaired wound healing, PCO, and other eye diseases related to fibrosis and angiogenesis. In this review, we present findings regarding the roles of decorin in the lens and ocular diseases.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells12010074
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
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  • 7
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    Online Resource
    Switching of Redox Signaling by Prdx6 Expression Decides Cellular Fate by Hormetic Phenomena Involving Nrf2 and Reactive Oxygen Species
    MDPI AG ; 2022
    In:  Cells Vol. 11, No. 8 ( 2022-04-08), p. 1266-
    Details
    In: Cells, MDPI AG, Vol. 11, No. 8 ( 2022-04-08), p. 1266-
    Abstract: Changes in intracellular reactive oxygen species (ROS) levels due to remodeling of antioxidant defense can affect the status of biological homeostasis in aging/oxidative stress. Peroxiredoxin 6 (Prdx6), an antioxidant gene downstream target for the Nrf2 pathway, plays a role in regulating ROS homeostasis. Using aging human (h) lens epithelial cells (LECs) or Prdx6-deficient (Prdx6−/−) mouse (m) LECs, here we showed that dichlorofluorescein (DCF) oxidation or H2O2 were strictly controlled by Prdx6. We observed that a moderate degree of oxidative stress augmented Nrf2-mediated Prdx6 expression, while higher doses of H2O2 (≥100 µM) caused a dramatic loss of Prdx6 expression, resulting in increased DCF oxidation and H2O2 amplification and cell death. Mechanistically, at increased oxidative stress, Nrf2 upregulated transcriptional factor Klf9, and that Klf9 bound to the promoter and repressed the Prdx6 gene. Similarly, cells overexpressing Klf9 displayed Klf9-dependent Prdx6 suppression and DCF oxidation with H2O2 amplification, while ShKlf9 reversed the process. Our data revealed that H2O2 and DCF oxidation levels play a hormetical role, and the Nrf2-Klf9-Prdx6 pathway is pivotal for the phenomena under the conditions of oxidative load/aging. On the whole, the results demonstrate that oxidative hormetical response is essentially based on levels of oxidative triggering and the status of Klf9-Prdx6 pathway activation; thus, Klf9 can be considered as a therapeutic target for hormetic shifting of cellular defense to improve protective resilience to oxidative stress.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells11081266
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
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  • 8
    Online Resource
    Online Resource
    Enhancement of Amyloid β1–43 Production in the Lens Epithelium of Japanese Type 2 Diabetic Patients
    MDPI AG ; 2020
    In:  Biomedicines Vol. 8, No. 4 ( 2020-04-13), p. 87-
    Details
    In: Biomedicines, MDPI AG, Vol. 8, No. 4 ( 2020-04-13), p. 87-
    Abstract: We investigated whether the accumulation of amyloid β-protein (Aβ) is enhanced in the lenses of diabetic patients. Lens epithelium samples were collected from Japanese patients during cataract surgery, and the Aβ levels and gene expression of Aβ-producing and -degrading enzymes in the samples were measured by ELISA and real-time RT-PCR, respectively. The Aβ1–43 levels in lenses of non-diabetic patients were low (0.11 pmol/g protein), while the levels in lenses of diabetic patients were significantly (6-fold) higher. Moreover, the Aβ1–43/total-Aβ ratio in the lenses of diabetic patients was also significantly higher than non-diabetic patients (p 〈 0.05). In addition, the mRNA levels for Aβ-producing enzymes were also enhanced in the lenses of diabetic patients. In contrast to the results for Aβ-producing enzymes, the mRNAs for the Aβ-degrading enzymes in the lenses of diabetic patients were significantly lower than in non-diabetic patients (p 〈 0.05). Furthermore, Aβ1–43/total-Aβ ratio in lenses was found to increase with plasma glucose level. In conclusion, these results suggest that high glucose levels cause both an increase in Aβ production and a decrease in Aβ degradation, and these changes lead to the enhancement in Aβ1–43 accumulation in the lenses of diabetic patients. These findings are useful for developing therapies for diabetic cataracts and for developing anti-cataract drugs.
    Type of Medium: Online Resource
    ISSN: 2227-9059
    URL: Article
    DOI: 10.3390/biomedicines8040087
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2720867-9
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  • 9
    Online Resource
    Online Resource
    Role of Decorin in Posterior Capsule Opacification and Eye Lens Development
    MDPI AG ; 2021
    In:  Cells Vol. 10, No. 4 ( 2021-04-09), p. 863-
    Details
    In: Cells, MDPI AG, Vol. 10, No. 4 ( 2021-04-09), p. 863-
    Abstract: Decorin (DCN) is involved in a variety of physiological and pathological processes. Epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) has been proposed as a major cause for the development of posterior capsule opacification (PCO) after cataract surgery. We investigated the plausible target gene(s) that suppress PCO. The expression of Dcn was significantly upregulated in rat PCO tissues compared to that observed in the control using a microarray-based approach. LECs treated with fibroblast growth factor (FGF) 2 displayed an enhanced level of DCN expression, while LECs treated with transforming growth factor (TGF)β-2 showed a decrease in DCN expression. The expression of tropomyosin 1 (Tpm1), a marker of lens EMT increased after the addition of TGFβ-2 in human LEC; however, upregulation of Tpm1 mRNA or protein expression was reduced in human LECs overexpressing human DCN (hDCN). No phenotypic changes were observed in the lenses of 8- and 48-week-old transgenic mice for lens-specific hDCN (hDCN-Tg). Injury-induced EMT of the mouse lens, and the expression patterns of α smooth muscle actin, were attenuated in hDCN-Tg mice lenses. Overexpression of DCN inhibited the TGFβ-2-induced upregulation of Tpm1 and EMT observed during wound healing of the lens, but it did not affect mouse lens morphology until 48 weeks of age. Our findings demonstrate that DCN plays a significant role in regulating EMT formation of LECs and PCO, and suggest that for therapeutic intervention, maintenance of physiological expression of DCN is essential to attenuate EMT progression and PCO formation.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells10040863
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
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  • 10
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    Online Resource
    Roles of TGF β and FGF Signals in the Lens: Tropomyosin Regulation for Posterior Capsule Opacity
    MDPI AG ; 2018
    In:  International Journal of Molecular Sciences Vol. 19, No. 10 ( 2018-10-09), p. 3093-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 19, No. 10 ( 2018-10-09), p. 3093-
    Abstract: Transforming growth factor (TGF) β and fibroblast growth factor (FGF) 2 are related to the development of posterior capsule opacification (PCO) after lens extraction surgery and other processes of epithelial–mesenchymal transition (EMT). Oxidative stress seems to activate TGF β1 largely through reactive oxygen species (ROS) production, which in turn alters the transcription of several survival genes, including lens epithelium-cell derived growth factor (LEDGF). Higher ROS levels attenuate LEDGF function, leading to down-regulation of peroxiredoxin 6 (Prdx6). TGF β is regulated by ROS in Prdx6 knock-out lens epithelial cells (LECs) and induces the up-regulation of tropomyosins (Tpms) 1/2, and EMT of LECs. Mouse and rat PCO are accompanied by elevated expression of Tpm2. Further, the expression of Tpm1/2 is induced by TGF β2 in LECs. Importantly, we previously showed that TGF β2 and FGF2 play regulatory roles in LECs in a contrasting manner. An injury-induced EMT of a mouse lens as a PCO model was attenuated in the absence of Tpm2. In this review, we present findings regarding the roles of TGF β and FGF2 in the differential regulation of EMT in the lens. Tpms may be associated with TGF β2- and FGF2-related EMT and PCO development.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms19103093
    Language: English
    Publisher: MDPI AG
    Publication Date: 2018
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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