JaeWook Yang

l-Kynurenine-induced apoptosis in human NK cells is mediated by reactive oxygen species

Recent studies have shown that indoleamine 2,3-dioxygenase (IDO) plays a pivotal role in the modulation of immune response against tumor and virus infection. Here we demonstrate the pro-apoptotic effect of L-kynurenine, a tryptophan catabolite of IDO, on human NK cell line, NK92 MI. Treatment with L-kynurenine dose-dependently induced growth inhibition and apoptosis in NK92 MI cells. Treatment with the antioxidant NAC completely protected cells from L-kynurenine-induced apoptosis. Moreover, we found that treatment with Z-VAD-fmk and ZB4 slightly inhibited L-kynurenine-induced apoptosis, suggesting that L-kynurenine-induced apoptosis in NK cells occurs primarily through an ROS mediated pathway. We observed that the presence of NAC blocks cytochrome c release and activation of caspase-3 during L-kynurenine-induced apoptosis. Overall, we conclude that L-kynurenine resulting from IDO can cause cell death via ROS pathway in NK cells. Our findings provide a new insight into the interaction between NK cells and IDO positive cancer cells in regulating immune responses.

The association between conjunctival MALT lymphoma and Helicobacter pylori.

Background/aims: Helicobacter pylori is well known to be responsible for gastric mucosa-associated lymphoid tissue (MALT) lymphoma. This study evaluates whether H pylori is also responsible for conjunctival MALT lymphoma and which strain of H pylori is associated with conjunctival MALT lymphoma. Methods: Fifteen cases of conjunctival MALT lymphoma were investigated. Eight biopsies of normal conjunctiva were also investigated as controls. The specimens were investigated for the presence of H pylori DNA with polymerase chain reaction (PCR) using 16S rDNA primer. When the PCR using 16S rDNA was positive for H pylori, the specimens were analysed for the virulent gene with PCR using vacA s1/2 primer and vacA m1/2 primer. Results: H pylori DNA was identified in all 15 specimens of conjunctival MALT lymphomas and none of the controls. Of these 15 H pylori positive lymphoma specimens, the vacA s1 and vacA m2 alleles were detected in two, and only vacA s1 allele was detected in 11. Conclusions: H pylori is thought to play a role in the pathogenesis of conjunctival MALT lymphoma, and H pylori with vacA s1 allele appears to be a virulent strain for conjunctival MALT lymphoma.

Progressive cribriform and zosteriform hyperpigmentation--the late onset linear and whorled nevoid hypermelanosis.

To the Editor We report the case of a healthy 16-year-old male with progressively increasing brown macules arranged in a zosteriform pattern on the left abdomen and back. The lesion appeared at the age of 15 and has been enlarged since then. He had no history of any preceding eruption or injury to the area. He had no evidence of internal diseases. His family had no history of skin abnormalities. He was not taking any medications. Physical examination revealed linear, cribriform, brown macular pigmentation arranged in a zosteriform pattern on the left abdomen and back (fig. 1). All macules were uniformly tan. Laboratory studies, including complete blood cell count, liver and renal function tests and serum electrolyte, had negative results. A skin boipsy specimen from the abdomen revealed increased pigmentation within the basal keratinocytes. There were a few dermal melanophages. No nevus cells were present (fig. 2). Fontana-Masson stain showed an increase in melanin in the basal keratinocytes. The diagnosis of progressive cribriform and zosteriform hyperpigmentation – the late onset linear and whorled nevoid hypermelanosis was made. No treatments were given. Progressive cribriform and zosteriform hyperpigmentation was first described by Rower and colleagues in 1978. 1 The following criteria were suggested: (1) uniformly tan cribriform macular pigmentation in a zosteriform distribution; (2) a histologic pattern that consisted of a mild increase in melanin pigment in the basal cell layer and complete absence of nevus cells; (3) no history of rash, injury, or inflammation to suggest postinflammatory hyperpigmentation; (4) onset well after birth with gradual extension – age at onset was in the second decade of life in every case; and (5) lack of other associated cutaneous or internal abnormalities. 1 Linear and whorled nevoid hypermelanosis was first described by Kalter and colleagues in 1988. 2 It is characterized by swirls and streaks of macular hyperpigmentation along the lines of Blaschko. It usually appears early during the first year of life. In some patients, the lesions are quite stable, while in others they spread but then stabilize by the age of 2–3. The linear hyperpigmentation tends to persist indefinitely. Occasionally, there are associated systemic abnormalities. 2 Somatic mosaicism that develops during embryogenesis appears to be the underlying aetiology. The linear nature of the pigmented bands probably reflects the clonal migration and proliferation of embryonic melanocyte precursors (melanoblasts). 3 Recently, linear and whorled nevoid hypermelanosis have been used to encompass a wide spectrum of clinical entities, ranging from the congenital or perinatal form of Kalter and colleagues to the segmentary and delayed form of Rower and colleagues, for which there is a tendency to use the term progressive cribriform and zosteriform hyperpigmentation. 4 We report herein a case of progressive cribriform and zosteriform hyperpigmentation – the late onset linear and whorled nevoid hypermelanosis which is not associated with systemic abnormalities.

Comparison of experimental porous silicone implants and porous silicone implants

BackgroundTo investigate the extent and pattern of fibrovascular ingrowth of porous silicone sphere implants compared to porous polyethylene implants.MethodsExperimental porous silicone sphere implants and porous polyethylene implants were implanted in the left socket of 20 New Zealand white rabbits after enucleation. Fibrovascular ingrowth and maturation was evaluated at 4 weeks and 8 weeks after implantation by histopathologic examination and scanning electron microscope.ResultsAt 4 weeks after surgery, porous polyethylene implants showed deeper fibrovascular ingrowth than porous silicone sphere implants; 42.4% versus 34.2% of radius of the implants respectively (p = 0.047). However there was no significant difference in the depth of fibrovascular ingrowth between the two groups at 8 weeks after implantation, although porous polyethylene implants showed deeper fibrovascular ingrowth than porous silicone sphere implants; 71.6% versus 63.6% (p = 0.102).ConclusionsPorous silicone orbital implants demonstrated a comparable extent of fibrovascular ingrowth to that for porous polyethylene implants. Therefore, this new porous silicone sphere implant may be a good candidate to substitute for current porous implants at a lower cost.

The 15-deoxy-δ12,14-prostaglandin J2 inhibits LPS‑stimulated inflammation via enhancement of the platelet‑activating factor acetylhydrolase activity in human retinal pigment epithelial cells

A well-recognized natural ligand of PPARγ, 15-deoxy-δ(12,14)-prostaglandin J(2) (15d-PGJ(2)) possesses immunomodulatory properties. The aim of this study was to elucidate whether 15d-PGJ(2) was able to attenuate lipopolysaccharide (LPS)-induced inflammatory responses in human retinal pigment epithelial (RPE) cells, which are involved in ocular immune responses. In addition, we examined whether the platelet activating factor (PAF) is associated with the anti-inflammatory activity of 15d-PGJ(2). ARPE19 cells treated with varying concentrations of 15d-PGJ(2) and a PAF antagonist (CV3988) were used in this study. The activity of PAF-acetylhydrolase (PAF-AH) was assayed by treatment with 15d-PGJ(2) and CV3988 in the presence of LPS. 15d-PGJ(2) and CV3988 inhibited the LPS-induced mRNA expression and protein production of interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) in ARPE19 cells. These effects resulting from 15d-PGJ(2) were not abrogated by the PPARγ antagonist, indicating that the actions were PPARγ-independent. Furthermore, 15d-PGJ(2) and CV3988 enhanced the PAF-AH activity. Additionally, 15d-PGJ(2) inhibited the phosphorylation of the extracellular signal-regulated kinase (ERK) and the activation of nuclear transcription factor-κB (NF-κB). These results demonstrated that 15d-PGJ(2) reduced LPS-stimulated inflammatory responses in ARPE19 cells by enhancing the PAH-AH activity. These results suggest that 15d-PGJ(2) may have potent anti-inflammatory activity against ocular inflammation.

Caffeic acid phenethyl ester inhibits the inflammatory effects of interleukin-1β in human corneal fibroblasts.

Abstract Context: Expression of various inflammatory mediators in corneal fibroblasts contributes to corneal inflammation. Objective: The purpose of this study was to assess the possible effects of caffeic acid phenethyl ester (CAPE) on the expression of inflammatory mediators during an inflammatory response in human corneal fibroblasts. Materials and methods: The levels of interleukin (IL)-6, monocyte chemotactic protein (MCP)-1, and intercellular adhesion molecule-1 (ICAM-1) from IL-1β-exposed human corneal fibroblasts were measured with enzyme-linked immunosorbent assays (ELISA). The regulatory mechanisms of CAPE on cellular signaling pathways were examined using Western blot and electrophoretic mobility shift assays. A functional validation was carried out by evaluating the inhibitory effects of CAPE on neutrophil and monocyte migration in vitro. Results: CAPE inhibited the expression of IL-6, MCP-1 and ICAM-1 induced by the pro-inflammatory cytokine IL-1β in corneal fibroblasts. The activation of AKT and NF-κB by IL-1β was markedly inhibited by CAPE, whereas the activity of mitogen-activated protein kinases (MAPKs) was not affected. CAPE significantly suppressed the IL-1β-induced migration of differentiated (d)HL-60 and THP-1 cells. Discussion: These anti-inflammatory effects of CAPE may be expected to inhibit the infiltration of leukocytes into the corneal stroma in vivo.

Effects of silk fibroin in murine dry eye

The study aimed to investigate the effects of silk fibroin in a mouse model of dry eye. The experimental dry eye mouse model was developed using more than twelve-weeks-old NOD.B10.H2b mice exposing them to 30–40% ambient humidity and injecting them with scopolamine hydrobromide for 10 days. Tear production and corneal irregularity score were measured by the instillation of phosphate buffered saline or silk fibroin. Corneal detachment and conjunctival goblet cell density were observed by hematoxylin and eosin or periodic acid Schiff staining in the cornea or conjunctiva. The expression of inflammatory markers was detected by immunohistochemistry in the lacrimal gland. The silk group tear production was increased, and corneal smoothness was improved. The corneal epithelial cells and conjunctival goblet cells were recovered in the silk groups. The expression of inflammatory factors was inhibited in the lacrimal gland of the silk group. These results show that silk fibroin improved the cornea, conjunctiva, and lacrimal gland in the mouse model of dry eye. These findings suggest that silk fibroin has anti-inflammatory effects in the experimental models of dry eye.

Inhibitory effects of the platelet-activating factor receptor antagonists, CV-3988 and Ginkgolide B, on alkali burn-induced corneal neovascularization

Abstract Purpose: Platelet-activating factor (PAF) has been found in various ocular tissues; the activity of PAF depends on the binding to its specific receptor, PAF-receptor. We investigated the therapeutic effects of PAF-receptor antagonists (CV-3988 and Ginkgolide B) on alkali burn-induced corneal neovascularization (CNV). Methods: CNV was induced by applying a 0.2 N sodium hydroxide (3 µl, NaOH) solution directly on mice corneas. CV-3988 (1 mM/10 µl) and Ginkgolide B (1 mM/10 µl) were administered topically on the corneas three times daily for three consecutive days. CNV was evaluated under a slit-lamp microscope. Corneas were processed for histological, immunohistochemical and reverse transcription polymerase chain reaction analysis. Human umbilical vein endothelial cells were used for the migration and tube formation assay. Results: Application of CV-3988 and Ginkgolide B inhibited CNV caused by alkali burn. CV-3988 and Ginkgolide B attenuated the expression of PAF-receptor mRNA. Alkali injury induced a massively increased intraocular mRNA expression of an angiogenic factor in cornea tissues, whereas these increments were attenuated by the application of CV-3988 and Ginkgolide B. Conclusions: CV-3988 and Ginkgolide B reversed opacity and neovascularization in alkali burn-induced corneas. Our findings suggest that CV-3988 and Ginkgolide B may be therapeutically useful in the treatment of CNV and inflammation.

Therapeutic Efficacy of Nanocomplex of Poly(Ethylene Glycol) and Catechin for Dry Eye Disease in a Mouse Model

Purpose We investigated the possibility of the nanocomplex of poly(ethylene glycol) (PEG) and catechin as a new biomedical material to treat dry eye disease. Methods NOD.B10.H2b mice were exposed to an air draft and injected with scopolamine for 10 days. Ten days later, the mice were treated with normal saline (n = 11), 1% catechin (n = 11), 1% PEG (n = 11), and 1% catechin/PEG nanocomplex solution mixture containing catechin and PEG at weight ratios of 1:1 (CP1, n = 11), 1:5 (CP5, n = 11), and 1:10 (CP10, n = 11). All treatments were administered five times a day for 10 days. We estimated the effect of PEG/catechin nanocomplexes on inflammation, tear production, epithelium stabilization, and goblet cell density. Results Desiccation stress significantly decreased tear production and increased the corneal irregularity score. Furthermore, desiccation stress markedly increased the detached epithelium and decreased the numbers of conjunctival goblet cells. In addition, the expression of proinflammatory-related factors was markedly induced by desiccation stress in the lacrimal glands. However, the PEG/catechin nanocomplex effectively induced an increase in tear production, stabilization of the corneal epithelium, and an increase in conjunctival goblet cells and anti-inflammatory improvements in a PEG dose-dependent manner. Conclusions In this study, we found that PEG may increase bioavailability of catechin. Therefore, the PEG/catechin nanocomplex can be used as a new biomedical material to treat dry eye disease through stabilization of the tear film and inhibition of inflammation.

RGN-259 (thymosin β4) improves clinically important dry eye efficacies in comparison with prescription drugs in a dry eye model.

This study evaluated the clinical activity of RGN-259 (thymosin β4) in comparison with cyclosporine A (CsA), diquafosol (DQS), and lifitegrast (LFA) in a murine model of dry eye. The model was NOD.B10-H2b mice in a 30–40% humidified environment together with daily scopolamine hydrobromide injections for 10 days. After desiccation stress, all drugs were evaluated after 10 treatment days. RGN-259 increased tear production similar to that in the DQS- and LFA-treated mice while CsA was inactive. RGN-259 improved corneal smoothness and decreased fluorescein staining similar to that of LFA group while CsA and DQS were inactive. Corneal epithelial detachment was reduced by RGN-259, and DQS and LFA showed similar activity but the CsA was inactive. RGN-259 increased conjunctival goblet cells and mucin production comparable to that seen with CsA, while DQS and LFA were inactive. RGN-259 reduced the over-expression of inflammatory factors comparable to that with CsA and LFA, while DQS was inactive. RGN-259 increased mucin production comparable to that observed with CsA, while DQS and LFA were inactive. In conclusion, RGN-259 promoted recovery of mucins and goblet cells, improved corneal integrity, and reduced inflammation in a dry eye mouse model and was equal to or more effective than prescription treatments.