Molecular SPECT/CT Profiling of Claudin18.2 Expression In Vivo: Implication for Patients with Gastric Cancer.

Zolbetuximab (IMAB362), a monoclonal antibody targeting Claudin18.2 (CLDN 18.2), demonstrates a significant clinical benefit in patients with advanced gastroesophageal cancers. The noninvasive assessment of CLDN18.2 expression through molecular imaging offers a potential avenue for expedited monitoring and the stratification of patients into risk groups. This study elucidates that CLDN18.2 is expressed at a noteworthy frequency in primary gastric cancers and their metastases. The iodogen method was employed to label IMAB362 with 123I/131I. The results demonstrated the efficient and reproducible synthesis of 123I-IMAB362, with a specific binding affinity to CLDN18.2. Immuno-single-photon emission computed tomography (SPECT) imaging revealed the rapid accumulation of 123I-IMAB362 in gastric cancer xenografts at 12 h, remaining stable for 3 days in patient-derived tumor xenograft models. Additionally, tracer uptake of 123I-IMAB362 in MKN45 cells surpassed that in MKN28 cells at each time point, with tumor uptake correlating significantly with CLDN18.2 expression levels. Positron emission tomography/computed tomography imaging indicated that tumor uptake of 18F-FDG and the functional/viable tumor volume in the 131I-IMAB362 group were significantly lower than those in the 123I-IMAB362 group on day 7. In conclusion, 123I-IMAB362 immuno-SPECT imaging offers an effective method for direct, noninvasive, and whole-body quantitative assessment of tumor CLDN18.2 expression in vivo. This approach holds promise for accelerating the monitoring and stratification of patients with gastric cancer.

Biotin-conjugated Ru(II) complexes with AIE characteristics as mitochondria-targeted photosensitizers for enhancing photodynamic therapy by disrupting cellular redox balance.

The potential use of Ru(II) complexes as photosensitizers (PSs) in photodynamic therapy (PDT) has gained significant attention. In comparison with fluorophores with aggregation-caused quenching (ACQ), fluorophores with aggregation-induced emission (AIE) characteristics exhibit sustained fluorescence and dispersibility in aqueous solutions. PSs with AIE characteristics have received much attention in recent years. Herein, we reported two novel biotin-conjugated Ru(II) polypyridyl complexes (Ru1 and Ru2) with AIE characteristics. When exposed to 460 nm (10 mW cm-2) light, Ru1 and Ru2 exhibited outstanding photostability and photocatalytic activity. Ru1 and Ru2 could efficiently generate singlet oxygen and induce pUC19 DNA photolysis when exposed to 460 nm light. Interestingly, both Ru1 and Ru2 also functioned as catalysts for NADH oxidation when exposed to 460 nm light. The presence of biotin fragments in Ru1 and Ru2 enhanced the specific uptake of these complexes by tumor cells. Both complexes showed minimal toxicity to selected cells in the dark. Nevertheless, the phototoxicity of both complexes significantly increased upon 460 nm light irradiation for 15 min. Further experiments revealed that Ru2 primarily accumulated in mitochondria and might bind to mitochondrial DNA. Under 460 nm light irradiation, Ru2 induced the generation of reactive oxygen species (ROS) and NADH depletion disrupting intracellular redox homeostasis in A549 cells, activating the mitochondrial apoptosis pathway resulting in up-regulation of apoptotic marker caspase-3, effectively damaged A549 cell DNA and arrested A549 cell cycle in the S phase. In vivo anti-tumor experiments were conducted to assess the effects of Ru2 on tumor growth in A549 tumor-bearing mice. The results showed that Ru2 effectively inhibited tumor growth under 460 nm light irradiation conditions. These findings indicate that Ru2 has great potential as a targeted photosensitizer for mitochondrial targeting imaging and photodynamic therapy of tumors.

In vitro and in vivo antitumor activity of novel half-sandwich ruthenium complexes containing quinoline derivative ligands.

A series of half-sandwich ruthenium complexes containing quinoline derivative ligands was synthesized, which had excellent antitumor toxicity toward a variety of cell lines and could localize lysosomes. The damage of lysosomes promotes the release of cathepsin B and initiates downstream apoptotic cascade signals. The increase in reactive oxygen species (ROS) caused by the decrease in mitochondrial membrane potential (ΔΨm) synergistically amplified the damage degree of lysosomes. In addition, the complex could inhibit cell transfer and clone formation. In vivo results showed that the complex had excellent biological effects in tested mouse samples as the body weight of mice did not change much during the treatment, and the mean tumor volume was significantly lower than the control group.

De Novo Mutations Contributes Approximately 7% of Pathogenicity in Inherited Eye Diseases.

Purpose: The purpose of this study was to describe genotype-phenotype associations and novel insights into genetic characteristics in a trio-based cohort of inherited eye diseases (IEDs). Methods: To determine the etiological role of de novo mutations (DNMs) and genetic profile in IEDs, we retrospectively reviewed a large cohort of proband-parent trios of Chinese origin. The patients underwent a detailed examination and was clinically diagnosed by an ophthalmologist. Panel-based targeted exome sequencing was performed on DNA extracted from blood samples, containing coding regions of 792 IED-causative genes and their flanking exons. All participants underwent genetic testing. Results: All proband-parent trios were divided into 22 subgroups, the overall diagnostic yield was 48.67% (605/1243), ranging from 4% to 94.44% for each of the subgroups. A total of 108 IED-causative genes were identified, with the top 24 genes explaining 67% of the 605 genetically solved trios. The genetic etiology of 6.76% (84/1243) of the trio was attributed to disease-causative DNMs, and the top 3 subgroups with the highest incidence of DNM were aniridia (n = 40%), Marfan syndrome/ectopia lentis (n = 38.78%), and retinoblastoma (n = 37.04%). The top 10 genes have a diagnostic yield of DNM greater than 3.5% in their subgroups, including PAX6 (40.00%), FBN1 (38.78%), RB1 (37.04%), CRX (10.34%), CHM (9.09%), WFS1 (8.00%), RP1L1 (5.88%), RS1 (5.26%), PCDH15 (4.00%), and ABCA4 (3.51%). Additionally, the incidence of DNM in offspring showed a trend of correlation with paternal age at reproduction, but not statistically significant with paternal (P = 0.154) and maternal (P = 0.959) age at reproduction. Conclusions: Trios-based genetic analysis has high accuracy and validity. Our study helps to quantify the burden of the full spectrum IED caused by each gene, offers novel potential for elucidating etiology, and plays a crucial role in genetic counseling and patient management.

Design, synthesis, and LFA-1/ICAM-1 antagonist activity evaluation of Lifitegrast analogues.

The interaction between Lymphocyte function-associated antigen 1 (LFA-1) and intercellular-adhesion molecule-1 (ICAM-1) plays important roles in the cell-mediated immune response and inflammation associated with dry eye disease. LFA-1/ICAM-1 antagonists can be used for the treatment of dry eye disease, such as Lifitegrast which has been approved by the FDA in 2016 as a new drug for the treatment of dry eye disease. In this study, we designed and synthesized some new structure compounds that are analogues to Lifitegrast, and their biological activities were evaluated by in vitro cell-based assay and also by in vivo mouse dry eye model. Our results demonstrated that one of these analogues of Lifitegrast (compound 1b) showed good LFA-1/ICAM-1 antagonist activity in in vitro assay; meanwhile, it also significantly reduced ocular surface epithelial cells damage, increased goblet cell density in dry eye mouse and highly improved the symptoms of dry eye mouse. Graphical abstract.

Esculetin protects human corneal epithelial cells from oxidative stress through Nrf-2 signaling pathway.

Dry eye formation often originates from oxidative damage to the ocular surface, which can be caused by external environment or internal pathologic factors. Esculetin (6, 7-dihydroxycoumarin) is a natural product found in many plants, and has been reported to have multiple pharmacological activities. The objective of our present study is to investigate if esculetin could protect the corneal epithelial cells from oxidative damages and its underlying antioxidant molecular mechanisms. Our experimental results demonstrated that pretreatment with esculetin markedly increased the cell viability while decreased the apoptosis in H2O2-treated human corneal epithelial (HCE) cells, by regulating Bcl-2, Bax and caspase-3 protein expressions and by altering the imbalance of activities of intracellular reactive oxygen species (ROS) and superoxide dismutase (SOD). Our data revealed that esculetin played an antioxidant role not only through its antioxidant activity, but also by highly inducing Nrf-2 translocation to the nucleus, which in turn, enhanced Nrf2 signaling regulated antioxidant genes (HO-1, NQO1, GCLM, SOD1 and SOD2) mRNA expression levels in H2O2-treated HCE cells. In the present study, the protective effects of esculetin on the corneal epithelium were also confirmed by a murine desiccating stress induced dry eye model in vivo. These data illustrated, for the first time, that esculetin may have the ability to protect human corneal epithelial cells from oxidative damages through its scavenging of free radical properties and through the activation of Nrf2 signaling.

Tribulus terrestris Ameliorates Oxidative Stress-Induced ARPE-19 Cell Injury through the PI3K/Akt-Nrf2 Signaling Pathway.

Oxidative stress on retinal pigment epithelial (RPE) cells has been confirmed to play a crucial role in the development and progression of age-related macular degeneration (AMD) or other retinal degenerative diseases. Tribulus terrestris (TT) is a Chinese traditional herb medicine, which has been used for the treatment of ocular diseases for many centuries. In this study, we investigated the underlying mechanisms of TT and examined its ability to protect and restore the human retinal pigment epithelial cells (ARPE-19) against H2O2-induced oxidative stress. Our data show that 200 µg/mL of ethanol extract of Tribulus terrestris (EE-TT) significantly increased the cell viability and prevented the apoptosis of H2O2-treated ARPE-19 cells through the regulation of Bcl2, Bax, cleaved caspase-3, and caspase-9. Treatment with EE-TT also significantly decreased the upregulated reactive oxygen species (ROS) activities and increased the downregulated superoxide dismutase (SOD) activities induced by H2O2 in ARPE-19 cells. Additionally, H2O2 at 1 mM significantly decreased the mRNA expression levels of Nrf2, CAT, SOD1, SOD2, HO-1, GST-pi, NQO1, and GLCM in ARPE-19 cells; however, treatment with EE-TT reversed the downregulated mRNA expression levels of all these genes induced by H2O2. Furthermore, treatment with 200 µg/mL EE-TT alone for 24 h significantly increased Nrf2, HO-1, NQO1, and GCLM mRNA expressions in ARPE-19 cells when compared with untreated control cells. Pretreatment with the inhibitor of PI3K/Akt signaling (LY294002) completely blocked these EE-TT-upregulated mRNA expressions and abolished the improvement of cell viability in H2O2-treated ARPE-19 cells. These findings all suggest that Tribulus terrestris has significant antioxidant effects on oxidative stressed ARPE-19 cells through regulating PI3K/Akt-Nrf2 signaling pathway.

Portable Handheld Slit-Lamp Based on a Smartphone Camera for Cataract Screening.

PURPOSE: As part of plans to provide help to people in remote and poor areas who have no medical resources, a portable slit-lamp based on a smartphone was proposed. This would help in early screening of cataract diseases. METHODS: This means a microlens is designed that would work with a phone's camera. The phone's photo taking function is used in capturing the image of the eyes lens to replace the observation system of the desktop slit-lamp. A simplified slit light band was designed. In order for the light source part to meet the portable requirements of the slit-lamp, the adjustable and diffused light functions of the ligaments were removed in this design. Furthermore, the images collected by the smartphone are uploaded to the deep learning cataract screening system, which can achieve real-time and effective screening of cataract. RESULTS: Unlike the desktop slit-lamp, which needs skilled personnel to operate, this device can be easily operated by less-skilled or inexperienced doctors. This eliminates the concerns of inaccurate diagnosis based on the use of unskilled professionals. Due to the portability, ease of use, and simplicity in obtaining crystal images of this device, it serves as a promising platform for nonhospital screening and telemedicine. CONCLUSIONS: In this paper, we invented a small portable device for screening cataract. This device is to make screening and diagnosis of cataract in remote areas very fast and effective. It will also solve the problem of inadequate specialized doctors and equipment in those areas as well. Translational Relevance. Smartphones can be used with portable slit-lamps to capture the images of the lens.

Lysosome-targeted chemotherapeutics: Anticancer mechanism of N-heterocyclic carbene iridium(III) complex.

N-heterocyclic carbenes-modified half-sandwich iridium(III) complex [(η5-C5Me4C6H4C6H5)Ir(C^C)Cl]PF6 (C1) (where C^C is a N-heterocyclic carbene ligand) can effectively prevent the proliferation of human cervical cancer cells. Here, this study aims to investigate the in-deep anticancer effects of this complex on non-small cell lung cancer cells and explore the underlying molecular mechanism. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay showed that iridium(III) complex had potent cytotoxicity studies towards non-small cell lung cancer cells (A549), human lung squamous cells (L78), human cervical cancer cells (Hela) and human bronchial epithelial cells (BEAS-2B). Colocalization and cellular uptake studies were analyzed by confocal microscopy. Notably, C1 targeted lysosomes and entered the cancer cells partially through an energy-dependent pathway, inducing the release of cathepsins and other proteins. These proteins regulated lysosomal-mitochondrial dysfunction, thus leading to the release of cytochrome c (cyt c), which amplified apoptotic signals by activating many downstream pathways such as caspase pathways to promote cell apoptosis. The results showed that the inhibitory mechanism of this organometallic iridium(III) complex may involve caspase-associated apoptosis initiated by the lysosomal-mitochondrial pathway.

Health risk assessment and bioaccessibilities of heavy metals for children in soil and dust from urban parks and schools of Jiaozuo, China.

Urban parks and schools sever as the mainly activity areas for children, but risk assessment posed by heavy metals (HMs) from soil and dust in these area has rarely been investigated. In this study, six urban parks and seven schools in Jiaozuo, China, were taken as research objects to understand the contamination level and bioaccessibility of HMs from soil and dust in urban parks and schools. The results indicated that Zn, Cu, Pb, Cd, As, Ni and Co from soil and dust were above the background values, especially Zn and Cd in dust, and As and Cd in soil. Serious Cd pollution was discovered, and respective Cd concentrations in soil and dust were 17.83 and 7.52 times the background value. Additionally, the average concentration and bioaccessibility of Zn, Mn, Pb, Cd, Cr, Ni and Co in dust were both higher than in soil. High concentration and high bioaccessibility of HMs in dust suggested that HMs contamination were serious and universal in Jiaozuo. The concentrations of most HMs were higher in the gastric phase, except for Cu and Cd which remained higher in the intestinal phase. Both in the gastric phase and intestinal phase, Mn, As and Cd in soil and dust both have high bioaccessibility which all exceed 10%. The carcinogenic and non-carcinogenic risks base on the total HMs for children (soil: 7.93, 1.96E-05; dust: 6.44, 3.58E-05) were greater than those for adults (soil: 6.35E-01, 1.32E-05; dust: 5.06E-01, 2.42E-05), and urban parks and schools posed high potential risk for children. Therefore, assessment the risk posed by HMs contamination of soil and dust in urban parks and schools is vital and urgent for children.

Adaptive response of reproduction to high-altitude hypoxic stress by altering mRNA expression of hypoxia-inducible factors in female yaks (Bos grunniens).

Hypoxia-inducible factors (HIFs) are oxygen-dependent transcriptional activators, but there is little information about their role in yak (Bos grunniens) reproduction. The present study, for the first time, investigated the adaptive mechanism of yak reproduction to high-altitude hypoxic stress by comparing the expression of HIF mRNAs between female yaks at high-altitude and cattle at low-altitude. Hypothalamus, anterior pituitary, oviduct, ovary and uterus tissue samples were collected from five adult female yaks and cattle. mRNA expression was determined by the quantitative real-time polymerase chain reaction. Both HIF-1α and HIF-2α were expressed in all five tissues examined from both species, albeit at different levels. In yaks, the highest mRNA levels of HIF-1α and HIF-2α occurred in the oviduct and anterior pituitary, respectively. Both HIF-1α and HIF-2α mRNA levels were higher in yaks than in cattle (p < 0.01). These data provide evidence that adaptation of reproduction to hypoxic conditions is associated with a greater expression of HIF-1α and HIF-2α in the reproductive axis of female yaks than cattle.

Theranostic Lysosomal Targeting Anticancer and Antimetastatic Agents: Half-Sandwich Iridium(III) Rhodamine Complexes.

Two rhodamine-modified half-sandwich Ir(III) complexes with the general formula [(Cpx)Ir(CN) Cl] were synthesized and characterized, where Cpx is 1-biphenyl-2,3,4,5-tetramethylcyclopentadienyl (Cpxbiph). Both complexes showed potent anticancer activity against A549, HeLa, and HepG2 cancer cells and normal cells, and altered ligands had an effect on proliferation resistance. The complex enters cells through energy dependence, and because of the different ligands, not only could it affect the anticancer ability of the complex but also could affect the degree of complex lysosome targeting, lysosomal damage, and further prove the antiproliferative mechanism of the complex. Excitingly, antimetastatic experiments demonstrated that complex 1 has the ability to block the migration of cancer cells. Furthermore, although the complex did not show a stronger ability to interfere with the coenzyme NAD+/NADH pair by transfer hydrogenation, the intracellular reactive oxygen species (ROS) content has shown a marked increase. NF-κB activity is increased by ROS regulation, and the role of ROS-NF-κB signaling pathway further induces apoptosis. Moreover, cell flow experiments also demonstrated that complex 1 blocked the cell cycle in S phase, but the complex did not cause significant changes in the mitochondrial membrane potential.

Triphenylamine-appended cyclometallated iridium(III) complexes: Preparation, photophysical properties and application in biology/luminescence imaging.

Four triphenylamine (TPA)-appended cyclometallated iridium(III) complexes were designed and synthesized. Photophysical properties of these complexes were studied, and density functional theory (DFT) was utilized to analyze the influence of the ancillary ligands (TPA-modified bipyridine) to these complexes. The introduction of TPA units could effectively adjust the lipid solubility of complexes (logP), and endowed complexes with potential bioactivity (anticancer, antibacterial and bactericidal activity), especially in the field of anticancer (the best value of IC50 is 4.34±0.01µM). Interestingly, complexe 4 show some selectivity for cancer cells versus normal cells. Meanwhile, complexes could effectively prevent the metastasis of cancer cells. Complexes can be transported by serum albumin and followed by the static quenching mechanism (Kq: 1013M-1s-1), disturb cell cycle at G0/G1 phase, and induce apoptosis. The favorable fluorescence property confirmed these complexes followed by an energy-dependent cellular uptake mechanism, effectively accumulated in lysosomes (PCC: >0.95) and induced lysosomal damage, and eventually leaded to cell death. Our study demonstrates that these complexes are potential anticancer agents with dual functions, including metastasis inhibition and lysosomal damage.

New Organometallic Tetraphenylethylene⋠Iridium(III) Complexes with Antineoplastic Activity.

Iridium(III) complexes have attracted more and more attention in the past few years because of their potential antineoplastic activity. In this study, four IrIII complexes of the types [(η5 -Cpx )Ir(N^N)Cl]PF6 (complexes 1 and 2) and [Ir(Phpy)2 (N^N)]PF6 (complexes 3 and 4) have been synthesized and characterized. They exhibit potential antineoplastic activity towards A549 cells, especially in the case of complex 1 [IC50 =(3.56±0.5) µm], which was nearly six times as effective as cisplatin [(21.31±1.7) µm]. Additionally, these complexes show some selectivity towards cancer cells over normal cells. They could be transported by serum albumin (binding constants were changed from 0.37×105 to 81.71×105 m-1 ). IrIII complexes 1 and 2 could catalyze the transformation of nicotinamide adenine dinucleotide reduced form (NADH) into NAD+ (turnover numbers 43.2, 11.9] and induce the accumulation of reactive oxygen species, thus confirming their antineoplastic mechanism of oxidation, whereas the cyclometalated complexes 3 and 4 were able to target the lysosome [Pearson co-localization coefficient (PCC)=0.73], cause lysosomal damage, and induce apoptosis. Understanding the mechanism of action would help further structure-activity optimization on these IrIII complexes as emerging cancer therapeutics.

Differences in the risk assessment of soil heavy metals between newly built and original parks in Jiaozuo, Henan Province, China.

Differences in the concentrations of heavy metals between newly built and original parks remain incompletely understood. In this work, two newly built and four original parks in Jiaozuo, China, were taken as research objects. Using the geo-accumulation index, ecological risk assessment index and human health risk model, differences in heavy metal pollution between the two types of parks were determined. In the surveyed region, five heavy metals, namely, Zn, Cu, As, Ni and Co, polluted the environment. Serious As pollution was discovered, and respective As concentrations in the soils of newly built and original parks were 5.9 and 3 times the background value. The concentrations of Zn, Mn, As, Pb, Cr and Ni in newly built parks were higher than those in the four original parks, although the concentrations of Cu and Co between the two types of parks were not significantly different. The carcinogenic and non-carcinogenic risks of these metals in newly built parks (adults: 4.27E-05, 1.08; children: 2.53E-04, 8.94) were greater than those in original parks (adults: 2.57E-05, 0.67; children: 1.52E-04, 5.39), and newly built parks posed higher potential risk than original parks. Therefore, the concentration of heavy metals in soil must be assessed before former industrial sites are transformed into parks.

Rhodamine-modified fluorescent half-sandwich iridium and ruthenium complexes: potential application as bioimaging and anticancer agents.

Most half-sandwich metal anticancer complexes are non-fluorescent, which results in an uncertain mechanism of action (MoA). We designed and synthesized eight fluorescent half-sandwich iridium (Ir) and ruthenium (Ru) complexes by introducing rhodamine derivatives into the N^N-chelating ligand. These complexes have features of bio-imaging and anticancer agents and may merit future development as novel anticancer agents.

Mst1 facilitates hyperglycemia-induced retinal pigmented epithelial cell apoptosis by evoking mitochondrial stress and activating the Smad2 signaling pathway.

Hyperglycemia induces retinal pigmented epithelial cell apoptosis and mitochondrial stress via poorly understood mechanisms. The goal of our current study is to explore whether mammalian sterile 20-like kinase 1 (Mst1) is involved in the pathogenesis of hyperglycemia-mediated retinal pigmented epithelial cell apoptosis by triggering mitochondrial abnormalities and activating the Smad2 signaling pathway. Retinal pigmented epithelial ARPE-19 cells were presented with a high-glucose challenge in vitro. Cell viability and apoptosis were measured via western blotting, ELISAs, and immunofluorescence assays. Mitochondrial function was detected via JC-1 staining, mitochondrial ROS flow cytometry, western blotting, and ELISAs. Loss- and gain-of-function assays were performed via cell transfection and transduction with Mst1 siRNA and Smad2 adenovirus, respectively. The results indicated that hyperglycemia treatment upregulated the levels of Mst1, an effect that was accompanied by an increase in ARPE-19 cell apoptosis. Loss of Mst1 attenuated hyperglycemia-induced cell apoptosis, and this effect seemed to be associated with mitochondrial protection. In response to hyperglycemia stimulus, mitochondrial stress was noted in ARPE-19 cells, including mitochondrial ROS overproduction, mitochondrial respiratory metabolism dysfunction, mitochondrial fission/fusion imbalance, and mitochondrial apoptosis activation. Further, we provided evidence to support the crucial role played by Smad2 in promoting Mst1-mediated cell apoptosis and mitochondrial stress. Overexpression of Smad2 abrogated the beneficial effects of Mst1 deletion on ARPE-19 cell viability and mitochondrial protection. Altogether, our results identified Mst1 as a novel mediator controlling the fate of retinal pigmented epithelial cells and mitochondrial homeostasis via the Smad2 signaling pathway. Based on this finding, strategies to repress Mst1 upregulation and block Smad2 activation are vital to alleviate hyperglycemia-mediated retinal pigmented epithelial cell damage.

Triphenyltin(IV) acylhydrazone compounds: Synthesis, structure and bioactivity.

Four new triphenyltin(IV) acylhydrazone compounds of the type Ph3SnCH2CH2CONHN=R (where Ph = phenyl; R = isopropyl, isobutyl, cyclopentyl and cyclooctyl) were synthesized and characterized by elemental analysis, infrared spectrum (IR), nuclear magnetic resonance spectrum (NMR) and mass spectrum (MS). The crystal structures were determined and showed that tin atoms were four-coordinated and adopted a pseudo-tetrahedron configuration. Tin(IV) compounds show excellent bovine serum albumin (BSA) binding properties, and can oxidize nicotinamide-adenine dinucleotid (NADH) to generate reactive oxygen species (ROS), which inducing apoptosis effectively. Bioassay results indicated that tin(IV) compounds have stronger cytotoxic activity against A549 human lung cancer cells compared with cis-platin used clinically, and showing some selectivity.

Protection of Kaempferol on Oxidative Stress-Induced Retinal Pigment Epithelial Cell Damage.

The protection of retinal pigment epithelium (RPE) injury plays an important role in the prevention of or in delaying the pathological progress of retinal degeneration diseases, like age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa. Oxidative stress has been identified as a major inducer of RPE injury, which eventually could lead to a loss of vision. Kaempferol is a natural flavonoid widely distributed in many edible plants, fruits, and traditional medicines and has been reported to have antioxidant, anti-inflammatory, anticancer, and antimicrobial activities. The present study demonstrates that the total antioxidant capacity of kaempferol is approximately two times stronger than that of lutein which is also a natural antioxidant that is widely used in the prevention or treatment of AMD. Our data indicates that kaempferol protects human RPE cells (ARPE-19) from hydrogen peroxide- (H2O2-) induced oxidative cell damage and apoptosis through the signaling pathways involving Bax/Bcl-2 and caspase-3 molecules proofed by real-time PCR and Western blot results. Kaempferol also inhibits the upregulated vascular endothelial growth factor (VEGF) mRNA expression levels induced by H2O2 in ARPE-19 cells and affects the oxidation and antioxidant imbalanced system in ARPE-19 cells treated by H2O2 through the regulations of both the activities of reactive oxygen species (ROS) and superoxide dismutase (SOD). Furthermore, our in vivo experimental results show that in sodium iodate-induced retinal degeneration rat model, kaempferol could protect sodium iodate-induced pathological changes of retina tissue and retinal cells apoptosis as well as the upregulated VEGF protein expression in RPE cells. In summary, these novel findings demonstrate that kaempferol could protect oxidative stressed-human RPE cell damage through its antioxidant activity and antiapoptosis function, suggesting that kaempferol has a potential role in the prevention and therapeutic treatment of AMD or other retinal diseases mediated by oxidative stress.