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Article ; Online: mTOR inhibitors potentially reduce TGF-β2-induced fibrogenic changes in trabecular meshwork cells

Nozomi Igarashi / Megumi Honjo / Makoto Aihara

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 10

Abstract: Abstract We examined the effects of mTOR inhibitors on the fibrotic response induced by transforming growth factor-beta2 (TGF-β2) in cultured human trabecular meshwork (hTM) cells. TGF-β2-induced expression of fibronectin, collagen type I, alpha 1 chain ( ...

Abstract	Abstract We examined the effects of mTOR inhibitors on the fibrotic response induced by transforming growth factor-beta2 (TGF-β2) in cultured human trabecular meshwork (hTM) cells. TGF-β2-induced expression of fibronectin, collagen type I, alpha 1 chain (COL1A1), and alpha-smooth muscle actin (αSMA) in hTM cells was examined in the presence or absence of mTOR inhibitors using quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry. The migration rates of hTM cells were examined in the presence of TGF-β2 with or without mTOR inhibitors. An in vitro study showed that the expression of fibronectin, COL1A1, and αSMA was upregulated by TGF-β2 treatment of hTM cells; such upregulation was significantly suppressed by mTOR inhibitors. The inhibitors significantly reduced the migration rate of TGF-β2-stimulated hTM cells. mTOR inhibitors may usefully reduce the fibrotic response of hTM cells and we may have to explore if it is also effective in in vivo model.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2021-07-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Effect of pigmentation intensity of trabecular meshwork cells on mechanisms of micropulse laser trabeculoplasty

Shota Shimizu / Megumi Honjo / Koichiro Sugimoto / Michiaki Okamoto / Makoto Aihara

Scientific Reports, Vol 12, Iss 1, Pp 1-

2022 Volume 11

Abstract: Abstract The intraocular pressure (IOP)-lowering mechanisms of micropulse laser trabeculoplasty (MLT) remain unclear. The present study was performed to investigate the mechanism of action of MLT, and to determine whether the pigmentation intensity of ... ...

Abstract	Abstract The intraocular pressure (IOP)-lowering mechanisms of micropulse laser trabeculoplasty (MLT) remain unclear. The present study was performed to investigate the mechanism of action of MLT, and to determine whether the pigmentation intensity of trabecular meshwork (TM) cells is associated with the treatment effects. Primary human TM cells were exposed to melanin granules to artificially introduce different levels of pigmentation. Micropulse (MP) laser irradiation was performed, and interleukin (IL)-1α/β, matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMPs), and extracellular matrix (ECM) protein expression were evaluated by RT-qPCR and immunocytochemistry. IL-1α/β and MMP-1, -3, and -9 mRNA expression were significantly upregulated at 4 and 24 h after MP laser irradiation, respectively, but there were no significant changes in TIMP expression. The extent of these upregulation was greater in cells with strong pigmentation intensity. Protein expressions of fibronectin and collagen I were significantly decreased in cells with strong staining intensity. These results suggested that MP laser irradiation alter the MMP/TIMP ratio and enhance ECM turnover, resulting in increased outflow of aqueous humor. The pigmentation intensity of the TM tissues may affect the treatment efficacy of MLT, because TM cells with strong staining intensity showed a significantly enhanced response to MP laser irradiation.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Effects of selective EP2 receptor agonist, omidenepag, on trabecular meshwork cells, Schlemm’s canal endothelial cells and ciliary muscle contraction

Natsuko Nakamura / Megumi Honjo / Reiko Yamagishi / Nozomi Igarashi / Rei Sakata / Makoto Aihara

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 16

Abstract: Abstract This study investigated the effects of omidenepag (OMD), a novel selective EP2 receptor agonist, on human trabecular meshwork (HTM) cells, monkey Schlemm’s canal endothelial (SCE) cells, and porcine ciliary muscle (CM) to clarify the mechanism ... ...

Abstract	Abstract This study investigated the effects of omidenepag (OMD), a novel selective EP2 receptor agonist, on human trabecular meshwork (HTM) cells, monkey Schlemm’s canal endothelial (SCE) cells, and porcine ciliary muscle (CM) to clarify the mechanism of intraocular pressure (IOP) reduction involving conventional outflow pathway. In HTM and SCE cells, the effects of OMD on transforming growth factor-β2 (TGF-β2)-induced changes were examined. The expression of actin cytoskeleton and extracellular matrix (ECM) proteins, myosin light chain (MLC) phosphorylation in HTM cells were evaluated using real-time quantitative PCR, immunocytochemistry, and western blotting. The expression of barrier-related proteins, ZO-1 and β-catenin, and permeability of SCE cells were evaluated using immunocytochemistry and transendothelial electrical resistance. The CM contraction was determined by contractibility assay. OMD significantly inhibited expression of TGF-β2 induced mRNA, protein, and MLC-phosphorylation on cytoskeletal and ECM remodeling in the HTM dose dependently. In SCE cells, OMD suppressed TGF-β2-induced expression of the barrier-related proteins and decreased SCE monolayer permeability. OMD at 3 µM significantly inhibited CM contraction, however, the effect was not significant at lower concentrations. IOP lowering effect of OMD through conventional outflow pathway is exerted by increasing outflow facilities with the modulation of TM cell fibrosis and SCE cell permeability.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2021-08-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Contribution of prostanoid FP receptor and prostaglandins in transient inflammatory ocular hypertension

Reiko Yamagishi-Kimura / Megumi Honjo / Makoto Aihara

Scientific Reports, Vol 8, Iss 1, Pp 1-

2018 Volume 7

Abstract: Abstract We explored the involvement of FP receptor and endogenous prostaglandins (PGs) in transient ocular hypertension (OH) induced by PGE2 or PGF2α in mouse eyes. PGE2 and PGF2α were topically applied to induce transient OH in Wild-type (WT) and FP-, ... ...

Abstract	Abstract We explored the involvement of FP receptor and endogenous prostaglandins (PGs) in transient ocular hypertension (OH) induced by PGE2 or PGF2α in mouse eyes. PGE2 and PGF2α were topically applied to induce transient OH in Wild-type (WT) and FP-, EP1-, EP2-, and EP3-deficient (knockout [KO]) mice. To suppress endogenous PG production, the non-steroidal anti-inflammatory drug nepafenac was applied topically before treatment. PGE2 and PGF2α induced significant OH in the WT, FPKO, and EP1–3KO mice compared to the control 30 min after instillation, and the increase in IOP at 30 or 60 min after instillation in FPKO mice was significantly higher than that in the WT mice. The effects of PGF2α on the increase in IOP were significantly weaker than those of PGE2, especially in EP1KO and EP3KO mice. Transient OH induced by PGE2 and PGF2α was significantly attenuated by nepafenac treatment in FPKO mice. Transient OH was induced by PGE2 and PGF2α in WT, FPKO, and EP1–3KO mice, which was enhanced in FPKO mice. This OH was significantly diminished by nepafenac treatment in FPKO mice, suggesting that FP receptor may have an important naïve physiological role in the eye, and could regulate IOP elevation during PG-associated ocular inflammation.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2018-07-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Diagnostic ability and sectoral structure–function relationship of circumpapillary and macular superficial vessel density in early glaucomatous eyes

Kaho Akiyama / Hitomi Saito / Shiroaki Shirato / Aiko Iwase / Koichiro Sugimoto / Takashi Fujishiro / Hiroshi Murata / Rei Sakata / Megumi Honjo / Makoto Aihara

Scientific Reports, Vol 12, Iss 1, Pp 1-

2022 Volume 8

Abstract: Abstract This study aimed to evaluate the diagnostic ability and sectoral structure function relationship of circumpapillary vessel density (cpVD) and macular vessel density (mVD) with optical coherence tomography angiography (OCTA) in early glaucomatous ...

Abstract	Abstract This study aimed to evaluate the diagnostic ability and sectoral structure function relationship of circumpapillary vessel density (cpVD) and macular vessel density (mVD) with optical coherence tomography angiography (OCTA) in early glaucomatous (EG) eyes. 224 EG eyes of 167 patients (mean deviation (MD) > − 6 dB) and 70 normal eyes of 70 subjects were enrolled in this retrospective cross-sectional study. All patients underwent OCT and OCTA scanning. Diagnostic abilities were evaluated with area under receiver operating characteristic curves (AUROC). Structure function relationships of superior, inferior and Garway-Heath sectoral values with its corresponding visual field (VF) sensitivity were determined using linear mixed models. AUROCs were 0.798, 0.621, 0.876 and 0.835 for cpVD, mVD, circumpapillary retinal nerve fiber layer thickness (cpRNFLT) and ganglion cell-inner plexiform layer, respectively. AUROC of cpVD was significantly lower than cpRNFLT (P = 0.010) and higher than mVD (P < 0.001). All Garway-Heath sectors of cpVD significantly correlated with its corresponding VF sensitivity except for the nasal sector. MVD also showed significant structure function relationship and the correlations were stronger in the perifoveal region (6 mm annulus) than in the parafoveal region (3 mm annulus). CpVD demonstrated moderate diagnostic ability and both cpVD and mVD demonstrated significant association with VF sensitivity in EG eyes.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Optic disc cupping characteristics of normal pressure hydrocephalus patients with normal-tension glaucoma

Nozomi Igarashi / Megumi Honjo / Shotaro Asano / Kiyoshi Takagi / Makoto Aihara

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 9

Abstract: Abstract We examined the potential association of idiopathic normal pressure hydrocephalus (iNPH) with the generation of normal-tension glaucoma (NTG), to explore possible relationships between intracranial pressure (ICP) and the presence of glaucoma, ... ...

Abstract	Abstract We examined the potential association of idiopathic normal pressure hydrocephalus (iNPH) with the generation of normal-tension glaucoma (NTG), to explore possible relationships between intracranial pressure (ICP) and the presence of glaucoma, and to compare disc morphology of NTG patients with or without iNPH. We investigated 20 iNPH patients, examined the prevalence of glaucoma, and compared the optic discs of NTG patients with iNPH (n = 11) and age-matched NTG patients without iNPH (n = 16). All data were collected prior to the treatment of iNPH, to eliminate the possibility that the treatment may have contributed to the progression of NTG. The diagnoses of NTG were made using visual field data, intraocular pressure measurements, fundoscopy, and optical coherence tomography (OCT). Using OCT, the optic nerve disc depth was also measured. The ICP was higher in the iNPH with NTG compared to iNPH without NTG (p = 0.0425), and the cupping depths of the discs of NTG patients with iNPH were significantly shallower compared with those of NTG patients without iNPH (p = 0.0097). Based on the difference in cupping depth, NTG patients with iNPH may have a different morphology from typical glaucoma patients, which could in turn reflect a different pathogenesis compared to NTG patients without iNPH.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2019-02-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Structural Changes and Astrocyte Response of the Lateral Geniculate Nucleus in a Ferret Model of Ocular Hypertension

Takashi Fujishiro / Megumi Honjo / Hiroshi Kawasaki / Ryo Asaoka / Reiko Yamagishi / Makoto Aihara

International Journal of Molecular Sciences, Vol 21, Iss 4, p

2020 Volume 1339

Abstract: We investigated structural changes and astrocyte responses of the lateral geniculate nucleus (LGN) in a ferret model of ocular hypertension (OH). In 10 ferrets, OH was induced via the injection of cultured conjunctival cells into the anterior chamber of ... ...

Abstract	We investigated structural changes and astrocyte responses of the lateral geniculate nucleus (LGN) in a ferret model of ocular hypertension (OH). In 10 ferrets, OH was induced via the injection of cultured conjunctival cells into the anterior chamber of the right eye; six normal ferrets were used as controls. Anterograde axonal tracing with cholera toxin B revealed that atrophic damage was evident in the LGN layers receiving projections from OH eyes. Immunohistochemical analysis with antibodies against NeuN, glial fibrillary acidic protein (GFAP), and Iba-1 was performed to specifically label neurons, astrocytes, and microglia in the LGN. Significantly decreased NeuN immunoreactivity and increased GFAP and Iba-1 immunoreactivities were observed in the LGN layers receiving projections from OH eyes. Interestingly, the changes in the immunoreactivities were significantly different among the LGN layers. The C layers showed more severe damage than the A and A1 layers. Secondary degenerative changes in the LGN were also observed, including neuronal damage and astrocyte reactions in each LGN layer. These results suggest that our ferret model of OH is valuable for investigating damages during the retina−brain transmission of the visual pathway in glaucoma. The vulnerability of the C layers was revealed for the first time.
Keywords	lgn ; ferret ; glaucoma ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2020-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Apolipoprotein M Inhibits Angiogenic and Inflammatory Response by Sphingosine 1-Phosphate on Retinal Pigment Epithelium Cells

Ryo Terao / Megumi Honjo / Makoto Aihara

International Journal of Molecular Sciences, Vol 19, Iss 1, p

2017 Volume 112

Abstract: Sphingosine 1-phosphate (S1P) is a potent lipid mediator that modulates inflammatory responses and proangiogenic factors. It has been suggested that S1P upregulates choroidal neovascularization (CNV) and may be deeply involved in the pathogenesis of ... ...

Abstract	Sphingosine 1-phosphate (S1P) is a potent lipid mediator that modulates inflammatory responses and proangiogenic factors. It has been suggested that S1P upregulates choroidal neovascularization (CNV) and may be deeply involved in the pathogenesis of exudative age-related macular degeneration (AMD). Recent studies have suggested that apolipoprotein M (ApoM), a carrier protein for S1P, modulates the biological properties of S1P in the pathogenesis of atherosclerosis. However, the role of ApoM/S1P in AMD has not been explored. We investigated the effect of S1P on proangiogenic factors in human retinal pigment epithelium (RPE) cell lines in vitro. S1P promoted the expression of vascular endothelial growth factor in RPE cells. Hypoxia inducible factor-1α expression was also upregulated. These S1P-induced enhancements in growth factors and chemotactic cytokines in RPE cells were significantly inhibited by ApoM treatment. Additionally, in vivo experiments using a laser-induced CNV murine model demonstrated that intravitreal ApoM injection significantly reduced the progression of CNV formation. Although the detailed mechanisms remain to be elucidated, the present results provide a novel potential therapeutic target for AMD, and demonstrate a suppressive role for ApoM and S1P in the pathology of CNV progression.
Keywords	sphingosine 1-phosphate ; sphingolipids and inflammation ; S1P-receptors ; apolipoprotein M ; high-density lipoprotein ; choroidal neovascularization ; age-related macular degeneration ; vascular endothelial growth factor ; hypoxia inducible factor ; interleukin-8 ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2017-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The association between structure-function relationships and cognitive impairment in elderly glaucoma patients

Megumi Honjo / Jiro Numaga / Tadashi Hara / Ryo Asaoka

Scientific Reports, Vol 7, Iss 1, Pp 1-

2017 Volume 9

Abstract: Abstract Accurate measurement of visual field (VF) is important in accessing glaucoma, however this may not be achieved in patients with dementia or mild cognitive impairment (CI). We investigated the association between CI and structure-function ... ...

Abstract	Abstract Accurate measurement of visual field (VF) is important in accessing glaucoma, however this may not be achieved in patients with dementia or mild cognitive impairment (CI). We investigated the association between CI and structure-function relationships in elderly glaucoma patients. The study included 94 eyes of 51 glaucoma patients aged ≥75 years with no diagnoses of dementia. CI was assessed using the Mini Mental State Examination (MMSE). Using the leave-one-out cross-validation, the mean deviation (MD) of the Humphrey 30-2 VF was predicted from measurements of optical coherence tomography, and the relationship between the squared prediction error and the MMSE score, together with age, fixation loss (FL), false positive (FP), and false negative (FN) percentages that were analyzed using the linear mixed model. A high prevalence of MCI or dementia was observed in the elderly population. The squared prediction error value of the MD was 17.0 ± 21.1 (mean ± standard deviation). The squared prediction error increased with decreasing MMSE total score, but age, FL, FP, and FN were not related. Careful consideration is needed when interpreting the VF results of these patients, because VF can be over- or underestimated, as suggested by the decreased structure-function relationships.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2017-08-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Effect of postoperative corticosteroids on surgical outcome and aqueous autotaxin following combined cataract and microhook ab interno trabeculotomy

Megumi Honjo / Reiko Yamagishi / Nozomi Igarashi / Chui Yong Ku / Makoto Kurano / Yutaka Yatomi / Koji Igarashi / Makoto Aihara

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 14

Abstract: Abstract To evaluate the effect of postoperative corticosteroids on surgical outcome and autotaxin (ATX) levels after microhook ab interno trabeculotomy combined with cataract surgery (μLOT-CS), prospective, consecutive non-randomized case series ... ...

Abstract	Abstract To evaluate the effect of postoperative corticosteroids on surgical outcome and autotaxin (ATX) levels after microhook ab interno trabeculotomy combined with cataract surgery (μLOT-CS), prospective, consecutive non-randomized case series comparing outcomes of 30 eyes with primary open angle glaucoma was performed. The aqueous ATX, intraocular pressure (IOP) and glaucoma medications were monitored for 3 months postoperatively. An in-vivo mouse μLOT model was generated. In vitro, ATX and fibrotic changes induced by dexamethasone (Dex) treatment following scratch (S) in cultured human trabecular meshwork (hTM) cells were assessed by immunofluorescence, immunoenzymatic assay, and RT-qPCR. Postoperative ATX at 1 week and the number of antiglaucoma medications at 3 months were significantly lower in non-steroid group, and steroid use was the only variable significantly associated with postoperative medications at 3 months in multiregression analyses. In vitro, ATX activity was significantly upregulated in the Dex + S group, and αSMA was significantly upregulated in the Dex and Dex + S groups. Fibronectin and COL1A1 were significantly upregulated in the S group. μLOT-CS decreased IOP and medications in the overall cohort, and non-use of postoperative steroids resulted in a smaller number of postoperative medications. Limiting postoperative steroids in μLOT may minimize IOP elevation and postoperative fibrosis.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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