Gene expression profiling of nasal inflammation induced by diesel particles using an in vivo system.

Korean diesel particulate matter 20 (KDP20) is a pollutant comprising a complex mixture of carbon and chemical irritants. Although particulate matter and nasal inflammation are strongly associated, the underlying molecular mechanism based on systematic transcriptome analysis remains unknown. In this study, genome-wide gene expression profiles of mouse nasal tissues were determined following exposure to KDP20 for 5 and 10 days and compared with those of the control (n = 4/group). We identified 758 significant differentially expressed genes (DEGs) and classified them as 5-day-specific, 10-day-specific, and common among groups based on their expression patterns. The terms "regulation of alpha-beta T cell differentiation," "macrophage differentiation," and "cell adhesion mediated by integrin" were significantly enriched in each group. Receiver operating characteristic analysis revealed six genes as potential predictive biomarkers. The differential expression of these six genes was validated using quantitative RT-PCR (n = 3/group). Furthermore, a possible mechanism for nasal inflammation was suggested through the binding analysis between metal ions and genes. The genes identified in this study may play important roles in regulating the mechanism of nasal inflammation induced by diesel particles, especially immune cell regulation, and may function as markers for diesel particle-induced nasal inflammation.

Damage to Olfactory Organs of Adult Zebrafish Induced by Diesel Particulate Matter.

Particulate matter (PM) is an environmental hazard that is associated with various human health risks. The olfactory system is directly exposed to PM; therefore, the influence of PM exposure on olfactory function must be investigated. In this study, we propose a zebrafish olfactory model to evaluate the effects of exposure to diesel particulate matter (DPM), which was labeled Korean diesel particulate matter (KDP20). KDP20 comprises heavy metals and polycyclic aromatic hydrocarbons (PAHs). KDP20 exposed olfactory organs exhibited reduced cilia and damaged epithelium. Olfactory dysfunction was confirmed using an odor-mediated behavior test. Furthermore, the olfactory damage was analyzed using Alcian blue and anti-calretinin staining. KDP20 exposed olfactory organs exhibited histological damages, such as increased goblet cells, decreased cell density, and calretinin level. Quantitative real-time polymerase chain reaction (qRT-PCR) revealed that PAHs exposure related genes (AHR2 and CYP1A) were upregulated. Reactive oxidation stress (ROS) (CAT) and inflammation (IL-1B) related genes were upregulated. Furthermore, olfactory sensory neuron (OSN) related genes (OMP and S100) were downregulated. In conclusion, KDP20 exposure induced dysfunction of the olfactory system. Additionally, the zebrafish olfactory system exhibited a regenerative capacity with recovery conditions. Thus, this model may be used in future investigating PM-related diseases.

New application for assessment of dry eye syndrome induced by particulate matter exposure.

Dry eye syndrome (DES) is a multifactorial condition characterized by insufficient tear lubrication and eye irritation. Air pollutants, including particulate matter (PM), are an emerging threat to human health causing DES and other diseases. However, the pathogenic mechanisms of DES induced by PM exposure remain to be fully elucidated. Recent studies have attempted to create DES animal model using PM exposure. In this study, we explored a novel in vivo exposure model of DES, utilizing an inhalation device (aerosol exposure system) to reproduce the natural exposure to atmospheric PM. Rats were exposed to urban PM (UPM) using this aerosol system for 5 h per day over 5 days. Tear volume in UPM-exposed rats decreased significantly, whereas corneal irregularity and lissamine green staining significantly increased following UPM exposure. Additional effects observed following UPM exposure included apoptosis in the corneal epithelium and a decrease in the number of goblet cells in the conjunctiva. UPM also affected the stability of the tear film by disrupting its mucin-4 layer. In conclusion, aerosol exposure systems have proven effective as assessment tools for DES caused by PM.

Apricot Kernel Extract and Amygdalin Inhibit Urban Particulate Matter-Induced Keratoconjunctivitis Sicca.

Exposure to particulate matter is a risk factor for various ocular surface diseases, including keratoconjunctivitis sicca (KCS). In this study, we investigated the protective effects of apricot kernel extract (AKE) and its bioactive compound, amygdalin, on KCS induced by exposure to urban particulate matter (UPM). In the in vivo experiments, eye drops containing 0.5 mg/mL AKE (AKE-0.5) or 1 mg/mL AKE (AKE-1) were administered directly into the eyes of female rats after UPM exposure. Additionally, the effect of AKE and amygdalin on matrix metalloproteinases (MMPs) activity and the expressions of inflammatory factors, including tumor necrosis factor (TNF)-α and interleukin (IL)-6, was investigated in conjunctival epithelial cells in vitro. Topical administration of AKE-1 attenuated UPM exposure-induced reduction of tear secretion. Both AKE-0.5 and AKE-1 inhibited UPM exposure-induced corneal epithelial damage and irregularity. AKE also protected against UPM exposure-induced disruption of the mucin-4 layer on the ocular surface. In addition, AKE and amygdalin prevented UPM-induced activation of MMPs and upregulation of TNF-α and IL-6 in conjunctival epithelial cells. Therefore, AKE may have protective effects against UPM exposure-induced KCS via the inhibition of MMPs and inflammation. The pharmacological activities of AKE may be in part due to its bioactive compound, amygdalin.

Aster koraiensis extract prevents diabetes-induced retinal vascular dysfunction in spontaneously diabetic Torii rats.

BACKGROUND: Aster koraiensis extract (AKE) is a standard dietary herbal supplement. The aim of this study is to investigate the inhibitory effects of AKE on diabetes-induced retinal vascular dysfunction in Spontaneously Diabetic Torii (SDT) rats. METHODS: AKE (50 and 100 mg/kg body weight/day) was administered for 16 weeks. The effects of orally administered AKE on blood glucose levels, retinal vascular leakage, apoptosis, and accumulation of advanced glycation end products (AGEs) in the retina were evaluated. RESULTS: SDT rats exhibited hyperglycemia and retinal vascular leakage, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was clearly detected apoptosis in the retinal microvasculature. Immunofluorescence staining revealed the accumulation of AGEs in the retinal vasculature of the SDT rats. However, oral administration of AKE for 16 weeks blocked diabetes-induced blood-retinal barrier (BRB) breakdown and the loss of occludin, which is an important tight junction protein. Apoptosis of retinal vascular cells and AGE accumulation were significantly inhibited after AKE treatment. CONCLUSION: These results indicate that, as a dietary herbal supplement, AKE may have beneficial effects on patients with diabetic retinopathy.

GS-E3D, a new pectin lyase-modified red ginseng extract, inhibited diabetes-related renal dysfunction in streptozotocin-induced diabetic rats.

BACKGROUND: GS-E3D is a newly developed pectin lyase-modified red ginseng extract. The purpose of this study was to investigate the therapeutic effects of GS-E3D on diabetes-related renal dysfunction in streptozotocin-induced diabetic rats. METHOD: GS-E3D (25, 50, and 100 mg/kg body weight per day) was administered for 6 weeks. The levels of blood glucose and hemoglobin A1c, and of urinary albumin, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and advanced glycation end-products (AGEs) were determined. Kidney histopathology, renal accumulation of AGEs, and expression of α-smooth muscle actin (α-SMA) were also examined. RESULTS: Administration of GS-E3D for 6 weeks reduced urinary levels of albumin, 8-OHdG, and AGEs in diabetic rats. Mesangial expansion, renal accumulation of AGEs, and enhanced α-SMA expression were significantly inhibited by GS-E3D treatment. Oral administration of GS-E3D dose-dependently improved all symptoms of diabetic nephropathy by inhibiting renal accumulation of AGEs and oxidative stress. CONCLUSION: The results of this study indicate that the use of GS-E3D as a food supplement may provide effective treatment of diabetes-induced renal dysfunction.

Cnidium officinale extract and butylidenephthalide inhibits retinal neovascularization in vitro and in vivo.

BACKGROUND: Retinal neovascularization, which is the pathological growth of new blood vessels, is associated with retinopathy of prematurity, neovascular age-related macular degeneration, diabetic retinopathy and retinal vein occlusion. In this study, we evaluated the effect of an extract of Cnidium officinale Makino (COE) and its bioactive compound, butylidenephthalide (BP), on the migration and tube formation of human umbilical vein endothelial cells (HUVECs), and on retinal pathogenic neovascularization in the oxygen-induced retinopathy (OIR) mouse model. METHOD: The HUVECs were incubated with COE and BP (0.1-10 µg/ml). The mice were exposed to 75 % oxygen for 5 days starting on the 7(th) postnatal day (P7-P12). Then, the mice were returned to room air and intraperitoneally injected with COE (100 mg/kg) and BP (5 mg/kg) once per day for 5 days (P12-P16). On P17, we measured retinal neovascularization and analyzed the angiogenesis-related proteins expression using protein arrays. RESULTS: COE and BP inhibit the HUVECs migration and the tube formation in a dose-dependent manner. In addition, COE significantly decreased retinal neovascularization in the OIR mice. COE reduced the expression levels of AREG, ANG, DLL4, Endostatin, IGFBP-2 and VEGF. Additionally, BP also inhibited the retinal neovascularization and down-regulated the expression of AREG, ANG, DLL4 and VEGF. CONCLUSION: These results suggest that COE and BP exerts antiangiogenic effects on retinal neovascularization by inhibiting the expression of AREG, ANG, DLL4 and VEGF, indicating that antiangiogenic activities of COE may be in part due to its bioactive compound, BP.

HL-217, a new topical anti-angiogenic agent, inhibits retinal vascular leakage and pathogenic subretinal neovascularization in Vldlr⁻/⁻ mice.

HL-217 is a new synthetic angiogenesis inhibitor. Platelet derived growth factor (PDGF) is a vasoactive factor and has been implicated in proliferative retinopathies. In this study, we examined the mechanism of action and efficacy of topical application of HL-217 on subretinal neovascularization in very low-density lipoprotein receptor knockout (Vldlr(-/-)) mice. In three-week-old male Vldlr(-/-) mice, HL-217 (1.5 or 3mg/ml) was administered twice per day for 4 weeks by topical eye drop instillation. Neovascular areas were then measured. We used a protein array to evaluate the expression levels of angiogenic factors. The inhibitory effect of HL-217 on the PDGF-BB/PDGFRß interaction was evaluated in vitro. The neovascular area in the Vldlr(-/-) mice was significantly reduced by HL-217. Additionally, HL-217 decreased the expression levels of PDGF-BB protein and VEGF mRNA. Moreover, HL-217 dose-dependently inhibited the PDGF-BB/PDGFRß interaction (IC50=38.9 ± 0.7 µM). These results suggest that HL-217 is a potent inhibitor of PDGF-BB. HL-217, when applied topically, is an effective inhibitor of subretinal neovascularization due to its ability to inhibit the pro-angiogenic effects of PDGF-BB.

Inhibitory effect of Samul-tang on retinal neovascularization in oxygen-induced retinopathy.

BACKGROUND: Retinal neovascularization is a common cause of vision loss in proliferative diabetic retinopathy, retinopathy of prematurity and age-related macular degeneration. Samul-tang (SMT) is a widely used traditional herbal medicine in East Asia and is also known as Shimotsu-to in Japanese and Si-Wu decoction in Chinese. This study was designed to evaluate the inhibitory effect of SMT on retinal pathogenic angiogenesis in a mouse model of oxygen-induced retinopathy (OIR). METHOD: The mice were exposed to a 75% concentration of oxygen for five days, starting on postnatal day 7 (P7-P12). The mice were then exposed to room air and were intraperitoneally injected with SMT (10 mg/kg or 50 mg/kg) once per day for five days (P12-P16). On P17, we measured retinal neovascularization and evaluated both the expression of angiogenesis-related proteins and changes in the gene expression level in the mRNA. RESULTS: SMT reduced the area of the central retina and reduced retinal neovascularization in OIR mice. The protein array revealed that SMT reduced the level of SDF-1 protein expression. Quantitative real-time PCR revealed that the HIF-1α, SDF-1, CXCR4 and VEGF mRNA levels in the retinas of OIR mice were elevated compared with those of normal control mice. However, SMT decreased the levels of HIF-1α, SDF-1, CXCR4 and VEGF mRNA in OIR mice. CONCLUSION: We are the first to elucidate that SMT inhibits the retinal pathogenic angiogenesis induced by ischemic retinopathy in OIR mice. SMT significantly inhibited retinal neovascularization by downregulating HIF-1α, SDF-1, CXCR4 and VEGF. Based on the results of our study, SMT could be a useful herbal medicine for treating ischemic retinopathy.

Vaccinium myrtillus extract prevents or delays the onset of diabetes--induced blood-retinal barrier breakdown.

Many dietary supplements have been sold through advertising their large number of beneficial effects. The aim of this study was to determine whether bilberries (Vaccinium myrtillus) help to prevent diabetes-induced retinal vascular dysfunction in vivo. V. myrtillus extract (VME; 100 mg/kg) was orally administered to streptozotocin-induced diabetic rats for 6 weeks. All diabetic rats exhibited hyperglycemia, and VME did not affect the blood glucose levels and body weight during the experiments. In the fluorescein-dextran angiography, the fluorescein leakage was significantly reduced in diabetic rats treated with VME. VME treatment also decreased markers of diabetic retinopathy, such as retinal vascular endothelial growth factor (VEGF) expression and degradation of zonula occludens-1, occludin and claudin-5 in diabetic rats. In conclusion, VME may prevent or delay the onset of early diabetic retinopathy. These findings have important implications for prevention of diabetic retinopathy using a dietary bilberry supplement.

Effect of Guibi-Tang, a Traditional Herbal Formula, on Retinal Neovascularization in a Mouse Model of Proliferative Retinopathy.

Ocular pathologic angiogenesis is an important causative risk factor of blindness in retinopathy of prematurity, proliferative diabetic retinopathy, and neovascular macular degeneration. Guibi-tang (GBT) is a frequently used oriental herbal formula in East Asian countries, and is also called Qui-pi-tang in Chinese and Kihi-To in Japanese. In the present study, we investigated the preventive effect of GBT on retinal pathogenic neovascularization in a mouse model of oxygen-induced retinopathy (OIR). C57BL/6 mice were exposed to 75% hyperoxia for five days on postnatal day 7 (P7). The mice were then exposed to room air from P12 to P17 to induce ischemic proliferative retinopathy. GBT (50 or 100 mg/kg/day) was intraperitoneally administered daily for five days (from P12 to P16). On P17, Retinal neovascularization was measured on P17, and the expression levels of 55 angiogenesis-related factors were analyzed using protein arrays. GBT significantly decreased retinal pathogenic angiogenesis in OIR mice, and protein arrays revealed that GBT decreased PAI-1 protein expression levels. Quantitative real-time PCR revealed that GBT reduced vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2), and plasminogen activator inhibitor 1 (PAI-1) mRNA levels in OIR mice. GBT promotes potent inhibitory activity for retinal neovascularization by decreasing VEGF, FGF2, and PAI-1 levels.

Sipjeondaebo-tang, a traditional herbal formula, inhibits retinal neovascularization in a mouse model of oxygen-induced retinopathy.

Retinal neovascularization is a common pathology in age-related macular degeneration, retinopathy of prematurity and proliferative diabetic retinopathy. Platelet derived growth factor (PDGF) is a vasoactive factor and has been implicated in proliferative retinopathies. Oxygen-induced retinopathy in the mouse is the standard experimental model of proliferative retinopathies. Sipjeondaebo-tang (SDT) is the most widely used traditional herbal formula in East Asia, also known as Shi-Quan-Da-Bu-Tang in Chinese and Juzen-taiho-to in Japanese. SDT has been known to exert anti-angiogenic activities in several tumor models, but the role of SDT in proliferative retinopathies remains unclear. Thus, the object of the present study is to examine the mechanism of action and efficacy of SDT on retinal neovascularization in oxygen-induced ischemic retinopathy (OIR) mice. Neonatal mice at postnatal day 7 (P7) were exposed to 75% concentration of oxygen for 5 days (P7-P12), and then returned to room air from P12 to P17 to induce retinal neovascularization. SDT were administered once per day for 5 consecutive days (P12-P16) by intraperitoneal injection. Retinal neovascularization was measured at P17. We used a protein array to evaluate the expression levels of angiogenic factors. Inhibitory activity of SDT on PDGF-BB/PDGFRß interaction was evaluated in vitro. Retinal neovascularization in the OIR mice was significantly decreased by SDT. SDT decreased the expression levels of PDGF-BB protein and VEGF mRNA. Moreover, SDT dose-dependently inhibited PDGF-BB/PDGFRß interaction (IC50 = 388.82 ± 7.31 µg/ml). In conclusion, SDT is a potent inhibitor of retinal neovascularization through inhibiting the pro-angiogenic effect of PDGF-BB.

Root of Polygonum cuspidatum extract reduces progression of diabetes-induced mesangial cell dysfunction via inhibition of platelet-derived growth factor-BB (PDGF-BB) and interaction with its receptor in streptozotocin-induced diabetic rats.

BACKGROUND: Platelet-derived growth factor-BB (PDGF-BB) is highly expressed in the renal tissues of patients with diabetic nephropathy, and it plays an important role in the initiation and progression of diabetic nephropathy. The aim of this study was to evaluate the protective effects of root of Polygonum cuspidatum extract (PCE) on early renal glomerular proliferation in streptozotocin (STZ)-induced diabetic rats. METHODS: PCE (100, 350 mg/kg/day) was administered to diabetic rats for 16 weeks. Blood glucose and albuminuria were measured. Renal histology, α-smooth muscle actin (α-SMA), and proliferating cell nuclear antigen (PCNA) expression levels were also examined. RESULTS: After 16 weeks of treatment with PCE, severe hyperglycemia and albuminuria were observed in the diabetic rats. The expressions levels of α-SMA and PCNA proteins were significantly increased in the glomeruli of the diabetic rats. The expression levels of PDGF-BB and its receptor expressions were greatly increased in the glomeruli of the diabetic rats. However, PCE markedly reduced albuminuria in the diabetic rats. PCE inhibited α-SMA and PCNA up-regulation and ameliorated PDGF-BB and PEGFR-ß protein expression in the diabetic rats. In addition, the binding of PDGF-BB/PDGFR-ß was inhibited by PCE as shown by an in vitro assay. CONCLUSIONS: These results suggest that PCE has an inhibitory effect on mesangial proliferation in diabetic renal tissues via the inhibition of the interaction of PDGF-BB with its receptor. PCE may have beneficial effects in preventing the progression of diabetic nephropathy.

Dynamic Photonic Janus Colloids with Axially Stacked Structural Layers.

Diblock copolymer (dBCP) particles capable of dynamic shape and color changes have gained significant attention due to their versatility in programmable shapes and intricate nanostructures. However, their application in photonic systems remains limited due to challenges in achieving a sufficient number of defect-free photonic layers over a tens-of-micrometer scale. In this study, we present a pioneering demonstration of photonic dBCP particles featuring over 300 axially stacked photonic layers with responsive color- and shape-transforming capabilities. Our approach leverages the complex interplay between the macrophase separation of multiple incompatible components and the microphase separation of dBCP from solvent-evaporative microemulsions. Specifically, continuous phase separation of silicone oil from polystyrene-block-poly(2-vinylpyridine) (PS-b-P2VP), triggered by solvent evaporation, promotes the anisotropic growth of PS-b-P2VP layers. This results in the formation of Janus colloids, where an oil droplet merges with a nanostructured polymer cone and lamellar structures align along the long axis of the cone. We highlight the capability to precisely adjust the particle morphology and the corresponding orientation, dispersion, and structural color window by modulating both the molecular weight of PS-b-P2VP and the volume ratio between PS-b-P2VP and silicone oil. Furthermore, reversible swelling/deswelling of photonic colloids is visualized and correlated with their structural colors. Finally, we demonstrate the potential of this study by presenting a multicolor-patterned array of photonic colloids, highlighting the possibilities for applications in smart photonic ink and devices.

Neurodegenerative pathways and metabolic changes in the hippocampus and cortex of mice exposed to urban particulate matter: Insights from an integrated interactome analysis.

Recently, urban particulate matter (UPM) exposure has been associated with the development of brain disorders. This study uses bioinformatic analyses to elucidate the molecular unexplored mechanisms underlying the effects of UPM exposure on the brain. Mice are exposed to UPM (from 3 days to 20 weeks), and their behavioral patterns measured. We measure pathology and gene expression in the hippocampus and cortical regions of the brain. An integrated interactome of genes is established, which enriches information on metabolic processes. Using this network, we isolate the core genes that are differentially expressed in the samples. We observe cognitive loss and pathological changes in the brains of mice at 16 or 20 weeks of exposure. Through network analysis of core-differential genes and measurement of pathway activity, we identify differences in the response to UPM exposure between the hippocampus and cortex. However, neurodegenerative disease pathways are implicated in both tissues following short-term exposure to UPM. There were also significant changes in metabolic function in both tissues depending on UPM exposure time. Additionally, the cortex of UPM-exposed mice shows more similarities with psychiatric disorders than with neurodegenerative diseases. The connectivity map database is used to isolate genes contributing to changes in expression due to UPM exposure. New approaches for inhibiting or preventing the brain damage caused by UPM exposure can be developed by targeting the functions and selected genes identified in this study.

Cirsium japonicum mitigates allergic nasal inflammation by regulating NRF2-mediated mucin production: Systematic transcriptome and molecular docking analyses.

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Anti-inflammatory and anti-allergic effects of Cheonwangbosim-dan water extract: An in vitro and in vivo study.

Ethnopharmacological relevance: Cheonwangbosim-dan is a traditional herbal prescription that is widely used to improve or treat physical and mental illnesses in East Asian countries.Aim of the study: The aim of the present study was to investigate the preventive and protective effects of a Cheonwangbosim-dan water extract (CBDW) against allergic inflammation using in vitro and in vivo models. Materials and methods: BEAS-2B and MC/9 cells were treated with various concentrations of CBDW and stimulated with different inducers of inflammatory mediators. The production of various inflammatory mediators was subsequently evaluated. BALB/c mice were sensitized and challenged by repeated application of ovalbumin (OVA). CBDW was administered by oral gavage once daily for 10 consecutive days. We assessed the number of inflammatory cells and production of Th2 cytokines in bronchoalveolar lavage fluid (BALF), the plasma levels of total and OVA-specific immunoglobulin E (IgE), and histological changes in lung tissue. Results: Our findings showed that CBDW significantly decreased the levels of various inflammatory mediators (eotaxin-1, eotaxin-3, RANTES, LTC4, TNF-α, MMP-9, 5-LO, ICAM-1, and VCAM-1) in vitro, significantly reduced the accumulation of total inflammatory cells, the production of Th2 cytokines (IL-5 and IL-13), the levels of IgE (total and OVA-specific) in vivo, and remarkably inhibited histological changes (infiltration of inflammatory cells and goblet cell hyperplasia) in vivo. Conclusions: These results suggest that CBDW possesses anti-inflammatory and anti-allergic properties by lowering allergic inflammation.

Gleditsia sinensis Lam. aqueous extract attenuates nasal inflammation in allergic rhinitis by inhibiting MUC5AC production through suppression of the STAT3/STAT6 pathway.

Allergic rhinitis (AR), a chronic respiratory inflammatory disease, is among the most common chronic diseases reported worldwide. Mucus hypersecretion is a critical feature of AR pathogenesis. Although the Gleditsia sinensis extract has several beneficial effects on human health, its effects on allergic inflammation have not yet been investigated. In this study, we examined the effects of G. sinensis aqueous extract (GSAE) on nasal inflammation in an ovalbumin (OVA)-induced AR mouse model. GSAE was administered orally for 1 week and then the clinical nasal symptoms were evaluated. The levels of histamine, OVA-specific immunoglobulin (Ig) E, and interleukin (IL)-13 were measured in the serum using an enzyme-linked immunosorbent assay (ELISA). Inflammatory cells were then counted in the nasal lavage fluid (NALF) and histopathology in the nasal epithelium was evaluated. STAT3/STAT6 phosphorylation was examined in primary human nasal epithelial cells (HNEpCs) using western blot analysis. Oral administration of GSAE to OVA-induced AR mice alleviated nasal clinical symptoms and reduced OVA-specific immunoglobulin E, interleukin (IL)-13, and histamine levels. The accumulation of eosinophils in nasal lavage fluid, nasal mucosa, mast cells, goblet cells, and mucin 5AC (MUC5AC) in the nasal epithelium was also inhibited by GSAE. Treatment with GSAE inhibited the production of MUC5AC in IL-4/IL-13-stimulated primary human nasal epithelial cells through the signal transducer and activator of transcription (STAT)3/STAT6 signaling pathway. These results indicated that GSAE reduces nasal inflammation suggesting that it is a potential treatment option for AR.

Cycloartane-type triterpenes from the leaves of Homonoia riparia with VEGF-induced angiogenesis inhibitory activity.

Six new cycloartane-type triterpenes (1-6), 24-methylenecycloartane-3ß,6ß,7ß-triol (1), 24-methylenecycloartane-3ß,6ß,7ß,16ß-tetraol (2), 24-methylenecycloartane-3ß,6ß,16ß-triol (3), 24-methylenecycloartane-3ß,7ß,16ß-triol 3-O-ß-d-xylopyranoside (4), 24-methylenecycloartane-3ß,6ß,16ß-triol 3-O-ß-d-xylopyranoside (5), and 24-methylenecycloartane-3ß,6ß,7ß-triol 3-O-ß-d-xylopyranoside (6), were isolated from the leaves of Homonoia riparia, together with one known compound, 24-methylenecycloartane-3ß,6ß,7ß,16ß-tetraol 3-O-ß-d-xylopyranoside (7). The structures of the new triterpenes were established by spectroscopic studies and from chemical evidence, and the inhibitory effects of compounds 1 and 3-7 on VEGF-induced vascular permeability were examined in vivo in rats using the Miles assay. In addition, the inhibitory effect of 7 on VEGF-induced tube formation by HUVECs in vitro was investigated.

Methylglyoxal induces hyperpermeability of the blood-retinal barrier via the loss of tight junction proteins and the activation of matrix metalloproteinases.

BACKGROUND: One of the early signs of diabetic retinopathy is the alteration of the blood-retinal barrier (BRB), which may involve the breakdown of endothelial cell tight junctions. Methylglyoxal (MGO) is a cytotoxic metabolite that is produced from glycolysis in vivo. Elevated levels of MGO are observed in a number of pathological conditions, including neurodegenerative disorders and diabetic complications. Herein, we hypothesize that increased levels of MGO disrupt the tight junction protein known as occludin protein by matrix metalloproteinases (MMPs), leading to breakage of the BRB. METHODS: MGO was intravitreally injected into eyes of rats. BRB leakage, MMPs activity, and occludin were investigated in intravitreally MGO-injected eyes. RESULTS: When normoglycemic rats were intravitreally injected with 400 µM MGO, there was widespread leakage of fluorescein isothiocyanate-bovine serum albumin (FITC-BSA) from the retinal vasculature when compared to control retinas. In addition, MGO-injected retinas demonstrated increases of both activity and expression of MMP-2 and MMP-9, and the degradation of occludin was found in the MGO-injected retinas. CONCLUSIONS: The results suggest that the activation of MMPs by elevated levels of MGO in the retina may facilitate an increase in vascular permeability by a mechanism involving proteolytic degradation of occludin. These findings may have implications for the role of MGO in the pathogenesis of diabetic retinopathy.