Rebamipide Increases the Mucin-Like Glycoprotein Production in Corneal Epithelial Cells

Shinohara

Experimental and Therapeutic Medicine

et al. 2017

Abstract. It has been demonstrated that topical administration of rebamipide, which is an antiulcer agent, increases the mucin level of the tear film and ameliorates ocular surface conditions such as lid wiper epitheliopathy. The aim of the present study was to analyze the changes in goblet cell number, cell proliferation, and epidermal growth factor receptor (EGFR) induced by topical rebamipide addition to the lid wiper of humans. A total of 30 eyelid tissue samples were obtained during involutional entropion surgeries, fixed in paraformaldehyde, embedded in paraffin and divided into two groups: Rebamipide or non-rebamipide. The tissues in the rebamipide group were obtained from patients who had a medical history of topical rebamipide use prior to surgery. The number of goblet cells was counted under light microscopy. A total of 22 eyelid tissue samples were further examined using immunohistochemistry with anti-Ki-67 and anti-EGFR antibodies to evaluate cell proliferation and EGFR expression, respectively. Histologically, the lid wiper and palpebral conjunctiva were clearly identified in the tissues. The number of goblet cells was significantly higher in the rebamipide group compared with the non-rebamipide group (P= 0.0367). There was no significant difference in lid wiper cell proliferation between the rebamipide and non-rebamipide groups. Immunohistochemistry revealed that EGFR levels in the lid wiper epithelial cells were significantly higher in the rebamipide group compared with the non-rebamipide group (P=0.0237). These results suggest that topical rebamipide application increases the number of goblet cells in the lid wiper, which in turn upregulates the expression of EGFR. These findings may be clinically relevant and provide a therapeutic basis for the treatment of ocular disease such as dry eye and lid wiper epitheliopathy.

Section: Discussionsupporting

confidence: 67%

Effect of topical rebamipide on goblet cells in the lid wiper of human conjunctiva

Shinohara

Experimental and Therapeutic Medicine

et al. 2017

“…It implies that alterations to the glycans in vivo through dysfunctional post-translational processing or enzymatic digestion of mucin glycans can result in defi cient mucus layers. Drugs such as rebamipide are currently investigated for their capacity to boost mucin production and help restore proper hydration of the mucosa, [ 46 ] but a topical treatment of the mucus with polymers could be a viable alternative. We show that although the simple addition of PEG to the fl uid phase of the lubricant has no effect, immobilizing PEG to the adsorbed mucins greatly enhances hydration and lubrication.…”

Section: Discussionmentioning

confidence: 99%

Modulating Mucin Hydration and Lubrication by Deglycosylation and Polyethylene Glycol Binding

Crouzier

Boettcher

Geonnotti

et al. 2015

Adv Materials Inter

glycoproteins, a family of high molecular weight and densely glycosylated biopolymers. Those mucins can act as an infection shield by trapping various viruses in the biopolymer matrix [ 1 ] and they reduce bacterial adhesion to surfaces. [ 2,3 ] Mucins also form highly hydrated and lubricative layers that protect the underlying epithelium from dehydration and shear stress that emerge during eye blinking or when swallowing food. Water typically accounts for up to 95% of the total mass in the mucus gel. [ 4,5 ] Shifts in the mucus water content correlate with substantial changes of the mucus barrier function [6][7][8] and result in important pathological disorders such as dry mouth [ 9 ] and dry eye. [ 10 ] Mucin-associated glycans contribute up to 80% of the molecular weight of mucins [ 11 ] and contain highly hydrated hydroxyl groups. Differences in the amount and composition of glycans from mucins extracted from pig stomachs and mucins from bovine submaxillary glands correlate with their capacity to adsorb water. [ 12 ] However, other properties such as protein composition also differ between these two mucin species, precluding the establishment of a defi nitive link between the presence of mucin glycans and hydration.Mucins, and other well-hydrated molecules such as zwitterionic polymers, polysaccharides, and polyelectrolytes are generally good boundary lubricants when adsorbed [ 13,14 ] or assembled in brush structures [15][16][17][18] on surfaces. Hence, mucin-associated glycans could also be essential for the lubricative function of mucus. In a related system, the mucin-like macromolecule lubricin showed a signifi cant decrease in lubricity when its associated glycans were removed. [ 19 ] Moreover, the lubricity of salivary fi lms, which contain mucins, has also been correlated with the total amount of glycosylation present in the fi lm. However, also here, the complexity of saliva composition precluded the identifi cation of the specifi c role of mucin glycosylation. [ 20 ] Hence, there is a need for a more defi ned experimental system to determine if mucin glycosylation is essential to the hydration and lubrication properties of mucins.This study explores the role of glycosylation in mucin hydration and lubricity, using mucin coatings as a simplifi ed model system. Such mucin coatings can reconstitute levels of surface hydration [ 21,22 ] and lubrication [23][24][25] similar to those found in native mucus. Our data show that the removal of mucin-bound glycans results in a signifi cant reduction in hydration and lubricity of the mucin-coated surface. We show that the hydration and lubricity of deglycosylated mucins can be partially A key property of mucin glycoproteins is their exceptional capacity to hydrate and lubricate surfaces. In vivo, mucins assemble into mucus hydrogels that cover the epithelium and protect it from dehydration and shear stress. A better understanding of the origin of these properties could lead to new treatment strategies for patients with poor mucus coverage, defective mucus produ...

CHEMICAL & PHARMACEUTICAL BULLETIN

“…The aim of this study was to evaluate taste-masking effect of CGA on bitter drugs using taste sensor measurements and surface plasmon resonance (SPR) analysis of CGA-drug interactions. Six different bitter drugs were used: amlodipine besylate (AMD), [19][20][21] diphenhydramine hydrochloride (DPH), 22) donepezil hydrochloride (DNP), 6) rebamipide (RBM), 18,23,24) diclofenac sodium (DCF) 25) and etodolac (ETD). 25) These drugs are well-established as bitter medicines and are widely used in clinical practice.…”

Section: Taste-masking Effect Of Chlorogenic Acid (Cga) On Bitter Drumentioning

confidence: 99%

Taste-Masking Effect of Chlorogenic Acid (CGA) on Bitter Drugs Evaluated by Taste Sensor and Surface Plasmon Resonance on the Basis of CGA–Drug Interactions

Shiraishi

Haraguchi

Nakamura

et al. 2017

The purpose of this study was to evaluate the taste-masking effects of chlorogenic acid (CGA) on bitter drugs using taste sensor measurements and surface plasmon resonance (SPR) analysis of CGA-drug interactions. Six different bitter drugs were used: amlodipine besylate (AMD), diphenhydramine hydrochloride (DPH), donepezil hydrochloride (DNP), rebamipide (RBM), diclofenac sodium (DCF) and etodolac (ETD). Taste sensor outputs were significantly inhibited by the addition of CGA to all drugs. The inhibition ratio of the taste sensor output decreased in the following order DPH>DNP>AMD≈DCF≈RBM≈ETD. The association rate constant (k a ) for the interaction between drugs and CGA as evaluated by SPR measurement also decreased in the following order DPH>DNP>AMD>DCF≈ETD≈RBM. It was suggested that basic drugs (AMD, DNP, DPH) associate more easily with CGA than acidic drugs (DCF, RBM, ETD). The inhibition ratios (%) of the taste sensor output of bitter drugs caused by CGA and the association rate constants (k a ) between the drugs and CGA were significantly correlated (r s 0.886, p<0.05, Spearman's correlation test). Our findings suggest that the taste-masking effects of CGA are due to its direct association with the drugs. CGA may therefore be a useful taste-masking agent for basic drugs.