Papers - Nakazawa, Yosuke

TRPV1 attenuates epithelial-mesenchymal transition via calpain-protein tyrosine phosphatase pathway in lens epithelial cells

Nakazawa Y., Nishizawa F., Kawata S., Sugiyama Y., Nagai N., Yamamoto N., Funakoshi-Tago M.

Experimental Eye Research 258   110435 2025.09

ISSN  00144835

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TRPV1, which is widely expressed throughout the body, is a non-selective cation channel activated by capsaicin. We previously reported that TRPV1 activation suppressed TGFβ2-induced epithelial-mesenchymal transition (EMT) by inhibiting Epidermal Growth Factor Receptor (EGFR) phosphorylation in lens epithelial cells (Sugiyama et al., 2021). However, the detailed molecular mechanism remains unclear. In this study, we focused on the calpain–protein tyrosine phosphatase (PTP) pathway to elucidate the detailed mechanism underlying TRPV1-induced EMT suppression. Calpain and PTP inhibitors mitigated the suppressive effect of capsaicin on TGFβ2-induced EMT in vitro and ex vivo. Finally, we shown that CalpainS1 and PTPN9 overexpression abrogated the effect of capsaicin on EMT in lens epithelial cells. Our findings indicate that calpain and PTP proteins are good candidates for preventing EMT after cataract surgery.

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De novo <i>CDKN1C</i> variant in Beckwith-Wiedermann spectrum with atypical complications

Moriura, Y; Nishio, Y; Ichimura, S; Noda, H; Tanahashi, Y; Yamamoto, H; Nakazawa, Y; Oso, T; Sato, Y; Takenouchi, T; Saitoh, S; Muramatsu, Y; Ogi, T

HUMAN GENOME VARIATION 12 ( 1 ) 9 2025.05

ISSN  2054-345X

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Antagonistic effects of PU.1 on Gfi-1B-induced erythroid colony formation in human cord blood cells

Manabe N., Sakurai T., Kihara-Negishi F., Nakazawa Y., Yamada T., Iwama A., Oikawa T.

Cellular and molecular biology (Noisy-le-Grand, France) 71 ( 3 ) 48 - 56 2025.04

ISSN  0145-5680

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Gfi-1B is a hematopoietic transcription factor essential for growth and differentiation of the erythroid/megakaryocytic lineages, and PU.1 is a master regulator for myeloid development. Herein, we demonstrate that PU.1 interacted with Gfi-1B in vivo by immunoprecipitation assay. GST pull-down assays showed that the binding sites were located in the Ets domain of PU.1 and the zinc finger domain of Gfi-1B. Luciferase reporter assays revealed that PU.1 and Gfi-1B antagonized each other's transcriptional activity in a dose-dependent manner. The transduction of Gfi-1B alone in human cord blood progenitor cells strongly enhanced erythroid colony formation. However, the transduction of PU.1 along with Gfi-1B in the progenitors significantly inhibited erythroid colony formation. Co-expression of Gfi-1B with a mutant PU.1, which bound to Gfi-1B but not to GATA1, another erythroid master regulator, also inhibited Gfi-1B-induced erythroid colony formation. Our results suggest that the function of Gfi-1B in the growth and differentiation of erythroid cells is antagonized by the expression of PU.1.

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Pharmacological Behavior of Propylene Glycol/Polyvinyl Alcohol Hydrogel Incorporating Indomethacin Nanocrystals in the Skin

Otake H., Ogata F., Nakazawa Y., Misra M., Tsubaki M., Kawasaki N., Nagai N.

Gels 11 ( 4 )  2025.04

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Background: We previously reported that carbopol hydrogels incorporating indomethacin nanoparticles (IMC NPs) improved the low permeability and bioavailability of skin formulations in transdermal drug delivery systems. However, the combination of NPs with other types of hydrogels has not been sufficiently explored to date. Therefore, this study investigated propylene glycol (PG)/polyvinyl alcohol (PVA) hydrogel as an alternative base to carbopol hydrogel for incorporating IMC NPs. Methods: IMC NPs were prepared using bead milling treatment, and these NPs were incorporated into PG/PVA hydrogel (IMC-NP@PG/PVA hydrogel). The IMC concentration was measured using the HPLC method, and seven-week-old Wistar rats were used to evaluate skin absorption. Results: Bead milling reduced the IMC particle size in the PG/PVA hydrogels to the nanoscale (30–200 nm) without altering its crystalline form. The IMC-NP@PG/PVA hydrogel exhibited enhanced uniformity, solubility, and drug release compared to the IMC microparticle-loaded PG/PVA hydrogel (IMC-MP@PG/PVA hydrogel), with a 1.44-fold greater area under the concentration–time curve. Transdermal permeability studies revealed that IMC-NP@PG/PVA had 2.36-fold higher absorption than the IMC-MP@PG/PVA hydrogel, with dissolved IMC permeating the skin. Pharmacokinetics in the rats showed significantly increased plasma levels, absorption rates, and bioavailability for IMC-NP@PG/PVA, demonstrating its superior delivery efficiency. Moreover, the skin absorption of IMC-NP@PG/PVA was higher than that of carbopol hydrogel. Conclusions: These findings highlight the potential of PG/PVA hydrogels as an effective base for transdermal drug delivery systems based on NPs.

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Changes in Protein Expression in Warmed Human Lens Epithelium Cells Using Shotgun Proteomics

Otake H., Yamamoto T., Yamamoto N., Nakazawa Y., Miyata Y., Taga A., Sasaki H., Nagai N.

Medicina (Lithuania) 61 ( 2 )  2025.02

ISSN  1010660X

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Background and Objectives: In previous studies, we reported that the assessment of the cumulative thermal dose in the crystalline lens, conducted through computational modeling utilizing a supercomputer and the biothermal transport equation, exhibited a significant association with the incidence of nuclear cataracts. In this study, we have investigated the types of proteins that expressed underlying 35.0 °C (normal-temp) and 37.5 °C (warming-temp) by using the shotgun liquid chromatography (LC) with tandem mass spectrometry (MS/MS)-based global proteomic approach. Materials and Methods: We have discussed the changes in protein expression in warmed iHLEC-NY2 cells using Gene Ontology analysis and a label-free semiquantitative method based on spectral counting. Results: In iHLEC-NY2, 615 proteins were detected, including 307 (49.9%) present in both lenses cultured at normal-temp and warming-temp, 130 (21.1%) unique to the lens cultured at normal-temp, and 178 (29.0%) unique to the lens cultured at warming-temp. Furthermore, LC–MS/MS analysis showed that warming decreased the expression of actin, alpha cardiac muscle 1, actin-related protein 2, putative tubulin-like protein alpha-4B, ubiquitin carboxyl-terminal hydrolase 17-like protein 1, ubiquitin-ribosomal protein eL40 fusion protein, ribosome biogenesis protein BMS1 homolog, histone H2B type 1-M, and histone H2A.J. in iHLEC-NY2. Conclusions: The decreases in the specific protein levels of actin, tubulin, ubiquitin, ribosomes, and histones may be related to cataract development under warming conditions. This investigation could provide a critical framework for understanding the correlation between temperature dynamics and the development of nuclear cataracts.

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Semiquantitative analysis of protein expression in heated rat lens using shotgun proteomics.

Otake H, Masuda S, Yamamoto T, Miyata Y, Nakazawa Y, Yamamoto N, Taga A, Sasaki H, Nagai N

Molecular medicine reports 31 ( 1 )  2025.01

ISSN  1791-2997

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Previous studies have reported that a strong correlation between the estimated cumulative thermal exposure in the crystalline lens and the incidence of nuclear cataracts; however, the precise relationship between temperature and cataracts remains to be fully elucidated. In the present study, the shotgun liquid chromatography/mass spectroscopy-based global proteomic approach was applied to investigate cataract-inducing factors in lens cultured at normal (35.0°C) and slightly warmer (37.5°C) conditions. In the rat lens, 190 proteins (total) were identified. Of these, 48 proteins (25.3%) were found in lenses cultured at both 35.0°C and 37.5°C. Moreover, 85 proteins (44.7%) were unique to lenses cultured at 35.0°C, while 57 proteins (30.0%) were unique to lenses cultured at 37.5°C. Protein expression changes in rat lenses cultured at 37.5°C were examined using a label-free semiquantitative approach that uses spectral counting and Gene Ontology analysis. Filensin and vimentin protein expression, key factors in maintaining lens structure, were decreased. These findings may serve as a valuable indicator for elucidating the relationship between temperature and the onset of nuclear cataracts.

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Dermal formulation based on carbopol and Gum Arabic improves skin retention of indomethacin.

Otake H, Fumihiko O, Nakazawa Y, Misra M, Tsubaki M, Kawasaki N, Nagai N

PloS one 20 ( 6 ) e0326051 2025

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ニルバジピンナノサスペンション点眼による眼組織への 薬物送達：経口投与時における薬物挙動との比較

門脇玲太, 明和亮伍, 岩井誓治, 永田万由美, 松島博之, 中澤洋介, 山本直樹, 佐々木　洋, 長井紀章

日本白内障学会誌 (日本白内障学会)  36   95 - 99 2024.06

Research paper (scientific journal), Joint Work

亜セレン酸誘発白内障モデルの混濁過程における 水晶体弾性力の変化

門脇玲太, 浅井拓己, 出口粧央里, 大竹裕子, 岡本紀夫, 中澤洋介, 佐々木　洋, 長井紀章

日本白内障学会誌 (日本白内障学会)  36   104 - 109 2024.06

Research paper (scientific journal), Joint Work, Accepted

Identification of Ascorbate Free Radical Reductase in the Lens

Mikako Oka, Masayasu Bando, Yosuke Nakazawa, Hiroko Ushikubo, Takashi Yoshikado, Kenji Okada, Koji Chiba, Makoto Takehana

The Journal of the Japanese Society for Cataract Research (Japanese Society for Cataract Research)  36   113 - 122 2024.06

Research paper (scientific journal), Joint Work, Accepted

Design of an Oral Tablet Containing Furosemide Nanoparticles with Elevated Bioavailability.

Nagai N, Ogata F, Kadowaki R, Deguchi S, Otake H, Nakazawa Y, Misra M, Kawasaki N

Journal of oleo science (Journal of oleo science)  73 ( 4 ) 563 - 571 2024

ISSN  1345-8957

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The solubility and permeability of the Biopharmaceutics Classification System (BCS) class IV drugs, such as furosemide (FUR), are low. Thus, the oral bioavailability of these drugs needs to be augmented. Here, we aimed to design orally disintegrating tablets containing FUR nanoparticles to improve bioavailability after oral administration. The FUR nanoparticles were generated by bead-milling in water containing 0.5% methylcellulose and 0.5% 2-hydroxypropyl-β-cyclodextrin (w/w%). Particle size was approximately 47-350 nm (mean particle size, 188 nm). An orally disintegrating tablet (FUR-NP tablet) comprising FUR nanoparticles (1%) was successfully produced by employing suspensions outlined above that incorporated additives (4% D-mannitol, 0.4% polyvinylpyrrolidone, and 16% gum Arabic, w/w%), followed by freeze-drying. The FUR-NP tablet disaggregated after only 5 s in water, liberating nano-sized FUR particles (172 nm). Experiments using rats showed the absorption of the FUR-NP tablet was significantly improved by comparison with a FUR tablet containing microparticles. In summary, the orally disintegrating tablet containing FUR nanoparticles markedly enhanced the bioavailability of FUR. We anticipate this formulation will also improve the bioavailability of other BCS class IV drugs.

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Therapeutic Effects of Rebamipide Nanocrystals as Carbopol Gel Formulation Containing Gum Arabic in a Hamster Model of Oral Mucositis

Otake H., Masuda S., Kadowaki R., Ogata F., Nakazawa Y., Yamamoto N., Kawasaki N., Nagai N.

Journal of Oleo Science 73 ( 12 ) 1479 - 1491 2024

ISSN  13458957

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Severe oral mucositis is a major cause of a low quality of life in patients; however, the therapeutic effect of traditional treatments is insufficient. Therefore, we designed a carbopol gel based on rebamipide nanocrystals (REB NCs) and gum arabic (GA-REB@NP), and investigated its efficacy in accelerating wound healing in a hamster model of oral mucositis. REB NCs were prepared by bead milling, and GA-REB@NP were prepared by incorporating REB NCs into a carbopol gel. The REB sizes were measured using a SALD-7100 and NanoSight LM10, and both powder X-ray diffraction and differential thermal analysis were used to analyze the crystalline form. Drug release from the gel formulations and therapeutic effects were evaluated using hamsters. The particles of milled-REB without GA were microsized, whereas the particle size of milled-REB with GA was in the range of 30–180 nm, and the crystalline form was similar to that of REB with or without bead milling. Next, we evaluated the characteristics of GA-REB@NP. The particle size of REB in GA-REB@NP was in the range of 45–200 nm, and drug release from GA-REB@NP was higher than that from the gel incorporating REB microcrystals (GA-REB@MP). In addition, REB nanoparticles were released from GA-REB@NP. Moreover, inhibitors of both clathrin-(dynasore) and caveolae-dependent endocytosis (nystatin) attenuated the enhanced REB levels in the cheek pouches of hamsters treated with GA-REB@NP. GA-REB@NP also enhanced the healing of the wound area compared with GA-REB@MP in hamsters injected with acetic acid. We prepared GA-REB@NP, which provided high REB delivery into the cheek pouch tissue via endocytosis. Additionally, we demonstrated that wound healing in acetic acid-injected hamsters was promoted by the application of GA-REB@NP.

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High ambient temperature may induce presbyopia via TRPV1 activation

Nakazawa Y., Kuno Y., Shimada H., Nagai N., Hiramatsu N., Takeda S., Yamamoto N., Funakoshi-Tago M., Sasaki H.

Medical Molecular Morphology 57 ( 4 ) 268 - 276 2024

ISSN  18601480

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The prevalence of presbyopia and nuclear cataracts (NUC) is reported to be higher in tropical areas than that in other regions, suggesting a potential influence of high temperatures on lens health. Transient receptor potential vanilloid (TRPV) channels play a crucial role in detecting ambient temperatures across various species, with TRPV1 and TRPV4 expressed in lens epithelial cells. In this study, we investigated whether ambient temperatures affect TRPV1 and TRPV4 activity in the lens, potentially contributing to the development of presbyopia and NUC. We conducted experiments using cultured human lens epithelial cell lines under different temperature conditions. Our results revealed that the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) and p38 pathways, downstream molecules of TRPV1, were activated, while Src family kinase, a downstream molecule of TRPV4, was inhibited at 37.5 °C culture compared to 35.0 °C. Confocal microscope images demonstrated higher expression of TRPV1 in 3D-structured cells under high-temperature culture conditions. Additionally, in organ culture lenses, higher elasticity was observed at elevated temperatures compared to that at lower temperatures. These results suggest that high ambient temperatures may induce lens sclerosis via TRPV1 activation, potentially contributing to the development of presbyopia and NUC.

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Suppression of Neuroinflammation by Coffee Component Pyrocatechol via Inhibition of NF-κB in Microglia.

Murata T, Tago K, Miyata K, Moriwaki Y, Misawa H, Kobata K, Nakazawa Y, Tamura H, Funakoshi-Tago M

International journal of molecular sciences (International Journal of Molecular Sciences)  25 ( 1 )  2023.12

ISSN  16616596

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According to numerous studies, it has been epidemiologically suggested that habitual coffee intake seems to prevent the onset of neurodegenerative diseases. In this study, we hypothesized that coffee consumption suppresses neuroinflammation, which is closely related to the development of neurodegenerative diseases. Using microglial BV-2 cells, we first found that the inflammatory responses induced by lipopolysaccharide (LPS) stimulation was diminished by both coffee and decaffeinated coffee through the inhibition of an inflammation-related transcription factor, nuclear factor-κB (NF-κB). Pyrocatechol, a component of roasted coffee produced by the thermal decomposition of chlorogenic acid, also exhibited anti-inflammatory activity by inhibiting the LPS-induced activation of NF-κB. Finally, in an inflammation model using mice injected with LPS into the cerebrum, we observed that intake of pyrocatechol as well as coffee decoctions drastically suppressed the accumulation of microglia and the expression of interleukin-6 (IL-6), tumor necrosis factor α (TNFα), CCL2, and CXCL1 in the inflammatory brain. These observations strongly encourage us to hypothesize that the anti-inflammatory activity of pyrocatechol as well as coffee decoction would be useful for the suppression of neurodegeneration and the prevention of the onsets of Alzheimer’s (AD) and Perkinson’s diseases (PD).

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Recovery from indomethacin-induced gastrointestinal bleeding by treatment with teprenone

Deguchi, S; Iwakami, A; Tujigiwa, M; Otake, H; Mano, Y; Yamamoto, N; Nakazawa, Y; Misra, M; Nagai, N

JOURNAL OF PHARMACEUTICAL HEALTH CARE AND SCIENCES (Journal of Pharmaceutical Health Care and Sciences)  9 ( 1 ) 44 2023.11

Accepted,  ISSN  2055-0294

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Background: Gastrointestinal injuries caused by nonsteroidal anti-inflammatory drugs (NSAIDs) is a serious side effect in patients with rheumatoid arthritis (RA). However, effective therapeutic strategies have yet to be established. In this study, we investigated the therapeutic effects of teprenone (TEP), a gastric mucosal protective drug, on NSAID-induced gastrointestinal injuries in rats with RA (AA rats). Methods: Gastrointestinal injury was induced by oral administration of indomethacin (IMC), a typical NSAID. TEP was orally administered after IMC-induced gastrointestinal bleeding, and the stomach, jejunum, and ileum were excised. Results: On day 14 of IMC administration, lesion areas in the stomach, jejunum, and ileum were significantly larger in AA rats than in normal rats. When TEP was orally administered to AA rats, the lesion areas in the stomach, jejunum, and ileum significantly decreased compared with those in control rats (IMC-induced AA rats). Therefore, we measured NOS2 mRNA and NO levels, which were significantly decreased in rats with IMC-induced AA after treatment with TEP. Conclusions: These results suggest that the oral administration of TEP may be useful for the treatment of NSAID-induced gastrointestinal injuries in patients with RA.

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Piezo1 channel causes lens sclerosis via transglutaminase 2 activation.

Doki Y, Nakazawa Y, Sukegawa M, Petrova RS, Ishida Y, Endo S, Nagai N, Yamamoto N, Funakoshi-Tago M, Donaldson PJ

Experimental eye research (Experimental Eye Research)  237   109719 2023.11

Lead author, Corresponding author, Accepted,  ISSN  0014-4835

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Presbyopia is caused by age-related lenticular hardening, resulting in near vision loss, and it occurs in almost every individual aged ≥50 years. The lens experiences mechanical pressure during for focal adjustment to change its thickness. As lenticular stiffening results in incomplete thickness changes, near vision is reduced, which is known as presbyopia. Piezo1 is a mechanosensitive channel that constantly senses pressure changes during the regulation of visual acuity, and changes in Piezo1 channel activity may contribute to presbyopia. However, no studies have reported on Piezo1 activation or the onset of presbyopia. To elucidate the relevance of Piezo1 activation and cross-linking in the development of presbyopia, we analysed the function of Piezo1 in the lens. The addition of Yoda1, a Piezo1 activator, induced an increase in transglutaminase 2 (TGM2) mRNA expression and activity through the extra-cellular signal-regulated kinase (ERK) 1/2 and c-Jun-NH2-terminal kinase1/2 pathways. In ex vivo lenses, Yoda1 treatment induced γ-crystallin cross-linking via TMG2 activation. Furthermore, Yoda1 eye-drops in mice led to lenticular hardening via TGM2 induction and activation in vivo, suggesting that Yoda1-treated animals could serve as a model for presbyopia. Our findings indicate that this presbyopia-animal model could be useful for screening drugs for lens-stiffening inhibition.

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The citrus flavonoid, nobiletin inhibits neuronal inflammation by preventing the activation of NF-κB.

Murata T, Ishiwa S, Lin X, Nakazawa Y, Tago K, Funakoshi-Tago M

Neurochemistry international (Neurochemistry International)  171   105613 2023.09

Accepted,  ISSN  0197-0186

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Nobiletin (5,6,7,8,3′,4′-hexamethoxyflavone) is one of the flavonoids found in shikuwasa, a popular citrus fruit in Okinawa, Japan. It exerts various pharmacological effects, such as anti-tumor, antioxidant, and anti-inflammatory activities. We herein investigated whether nobiletin attenuated lipopolysaccharide (LPS)-induced inflammatory responses in the murine microglial cell line BV-2 and neuroinflammation in mice induced by an intracerebral injection of LPS. In BV-2 cells, nobiletin significantly inhibited the LPS-induced production of nitric oxide (NO) and prostaglandin E2 (PGE2) by preventing the mRNA expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), respectively. Nobiletin also inhibited the LPS-induced mRNA expression of CCL2, CXCL1, IL-6, and TNFα. Nobiletin markedly attenuated the transcriptional activity of the NF-κB p65 subunit without affecting the degradation of IκBα or the nuclear localization of the NF-κB p65 subunit. Nobiletin also inhibited the LPS-induced activation of JNK, but not ERK or p38, in BV-2 cells. Furthermore, the administration of nobiletin significantly suppressed the accumulation of microglia and induction of the mRNA expression of CCL2, CXCL1, IL-6, and TNFα in the murine brain induced by injecting LPS into the striatum. Collectively, these results suggest the potential of nobiletin as a candidate anti-inflammatory drug for the prevention of neuroinflammation.

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Hesperetin treatment attenuates glycation of lens proteins and advanced‑glycation end products generation.

Doki Y, Nakazawa Y, Morishita N, Endo S, Nagai N, Yamamoto N, Tamura H, Funakoshi-Tago M

Molecular medicine reports (Molecular Medicine Reports)  27 ( 5 )  2023.05

Lead author, Corresponding author, Accepted,  ISSN  1791-2997

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Advanced glycation end products (AGEs) in lens proteins increase with aging, thus inducing cataracts and/or presbyopia. Hesperetin (Hst), which is an abundant plant flavanone largely derived from citrus species, and its derivatives attenuate cataracts and presbyopia in vivo and in vitro; however, no reports have described its effects on AGE formation in lens proteins. The present study demonstrated that AGEs in lens proteins increase with age in mice. Additionally, it showed that Hst can prevent AGEs and N(ϵ)-carboxymethyl-lysine generation and modification of lens proteins using in vitro in human lens epithelial cell lines and ex vivo in mouse lens organ cultures. Furthermore, treatment with Hst prevented lens hardening and decreased chaperone activity in lens proteins. These results suggested that Hst and its derivatives are good candidates for the prevention of presbyopia and cataracts.

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Orally disintegrating tablets containing famotidine nanoparticles provide high intestinal absorbability via the energy-dependent endocytosis pathway

Nagai N., Ogata F., Kadowaki R., Deguchi S., Otake H., Nakazawa Y., Nagata M., Sasaki H., Kawasaki N.

Frontiers in Bioengineering and Biotechnology (Frontiers in Bioengineering and Biotechnology)  11   1167291 2023

Accepted,  ISSN  2296-4185

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The permeability of the Biopharmaceutics Classification System (BCS) class III drugs are low, and their oral bioavailability needs to be improved. In this study, we attempted to design oral formulations containing famotidine (FAM) nanoparticles to overcome the limitations of BCS class III drugs. Dispersions containing FAM nanoparticles with a particle size of approximately 50–220 nm were produced by the bead-milling treatment. Moreover, we succeeded in preparing an orally disintegrating tablet containing FAM nanoparticles using the dispersions described above, additives (D-mannitol, polyvinylpyrrolidone, and gum arabic), and freeze-dry treatment (FAM-NP tablet). The FAM-NP tablet was disaggregated 3.5 s after addition to purified water, and the FAM particles in the redispersion of the FAM-NP tablet stored for 3 months were nano-sized (141 ± 6.6 nm). The ex-vivo intestinal penetration and in vivo absorption of FAM in rats applied with the FAM-NP tablet were significantly higher than those in rats applied with the FAM tablet containing microparticles. In addition, enhanced intestinal penetration of the FAM-NP tablet was attenuated by an inhibitor of clathrin-mediated endocytosis. In conclusion, the orally disintegrating tablet containing FAM nanoparticles improved low mucosal permeability and low oral bioavailability and overcame these issues of BCS class III drugs as oral formulations.

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Aquaporins contribute to vacuoles formation in Nile grass type II diabetic rats

Aihara K., Nakazawa Y., Takeda S., Hatsusaka N., Onouchi T., Hiramatsu N., Nagata M., Nagai N., Funakoshi-Tago M., Yamamoto N., Sasaki H.

Medical Molecular Morphology (Medical Molecular Morphology)  56 ( 4 ) 274 - 287 2023

Lead author, Corresponding author, Accepted,  ISSN  18601480

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Regulation of ion and water microcirculation within the lens is tightly controlled through aquaporin channels and connexin junctions. However, cataracts can occur when the lens becomes cloudy. Various factors can induce cataracts, including diabetes which is a well-known cause. The most common phenotype of diabetic cataracts is a cortical and/or posterior subcapsular opacity. In addition to the three main types and two subtypes of cataracts, a vacuole formation is frequently observed; however, their origin remains unclear. In this study, we focused on the aquaporins and connexins involved in diabetes-induced cataracts and vacuoles in Nile grass type II diabetes. The results showed that the expression of aquaporin 0 and aquaporin 5 increased, and that of connexin 43 decreased in diabetic rat lenses. Additionally, aquaporin 0 and 5 were strongly localized in peripheral of vacuoles, suggesting that aquaporins are involved in vacuoles formation. Transillumination photography revealed large vacuoles at the tip of the Y-suture in the anterior capsule of the diabetic lens, and several small vacuoles were observed in the posterior capsule. Within the vacuoles, cytoplasmic degradation and aggregation of fibrous material were observed. Our findings suggest that aquaporins are potential candidate proteins for preventing vacuole formation.

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