Ceria nanoparticles: biomedical applications and toxicity. / 二氧化铈纳米颗粒：生物医学应用和毒性.

Ceria nanoparticles (CeO2 NPs) have become popular materials in biomedical and industrial fields due to their potential applications in anti-oxidation, cancer therapy, photocatalytic degradation of pollutants, sensors, etc. Many methods, including gas phase, solid phase, liquid phase, and the newly proposed green synthesis method, have been reported for the synthesis of CeO2 NPs. Due to the wide application of CeO2 NPs, concerns about their adverse impacts on human health have been raised. This review covers recent studies on the biomedical applications of CeO2 NPs, including their use in the treatment of various diseases (e.|g., Alzheimer's disease, ischemic stroke, retinal damage, chronic inflammation, and cancer). CeO2 NP toxicity is discussed in terms of the different systems of the human body (e.|g., cytotoxicity, genotoxicity, respiratory toxicity, neurotoxicity, and hepatotoxicity). This comprehensive review covers both fundamental discoveries and exploratory progress in CeO2 NP research that may lead to practical developments in the future.

Dragonfly visual evolutionary neural network: A novel bionic optimizer with related LSGO and engineering design optimization.

Biological visual systems intrinsically include multiple kinds of motion-sensitive neurons. Some of them have been successfully used to construct neural computational models for problem-specific engineering applications such as motion detection, object tracking, etc. Nevertheless, it remains unclear how these neurons' response mechanisms can be contributed to the topic of optimization. Hereby, the dragonfly's visual response mechanism is integrated with the inspiration of swarm evolution to develop a dragonfly visual evolutionary neural network for large-scale global optimization (LSGO) problems. Therein, a grayscale image input-based dragonfly visual neural network online outputs multiple global learning rates, and later, such learning rates guide a population evolution-like state update strategy to seek the global optimum. The comparative experiments show that the neural network is a competitive optimizer capable of effectively solving LSGO benchmark suites with 2000 dimensions per example and the design of an operational amplifier.

Retinal Microenvironment-Protected Rhein-GFFYE Nanofibers Attenuate Retinal Ischemia-Reperfusion Injury via Inhibiting Oxidative Stress and Regulating Microglial/Macrophage M1/M2 Polarization.

Retinal ischemia is involved in the occurrence and development of various eye diseases, including glaucoma, diabetic retinopathy, and central retinal artery occlusion. To the best of our knowledge, few studies have reported self-assembling peptide natural products for the suppression of ocular inflammation and oxidative stress. Herein, a self-assembling peptide GFFYE is designed and synthesized, which can transform the non-hydrophilicity of rhein into an amphiphilic sustained-release therapeutic agent, and rhein-based therapeutic nanofibers (abbreviated as Rh-GFFYE) are constructed for the treatment of retinal ischemia-reperfusion (RIR) injury. Rh-GFFYE significantly ameliorates oxidative stress and inflammation in an in vitro oxygen-glucose deprivation (OGD) model of retinal ischemia and a rat model of RIR injury. Rh-GFFYE also significantly enhances retinal electrophysiological recovery and exhibits good biocompatibility. Importantly, Rh-GFFYE also promotes the transition of M1-type macrophages to the M2 type, ultimately altering the pro-inflammatory microenvironment. Further investigation of the treatment mechanism indicates that Rh-GFFYE activates the PI3K/AKT/mTOR signaling pathway to reduce oxidative stress and inhibits the NF-κB and STAT3 signaling pathways to affect inflammation and macrophage polarization. In conclusion, the rhein-loaded nanoplatform alleviates RIR injury by modulating the retinal microenvironment. The findings are expected to promote the clinical application of hydrophobic natural products in RIR injury-associated eye diseases.

Neural network architectures for optical channel nonlinear compensation in digital subcarrier multiplexing systems.

In this work, we propose to use various artificial neural network (ANN) structures for modeling and compensation of intra- and inter-subcarrier fiber nonlinear interference in digital subcarrier multiplexing (DSCM) optical transmission systems. We perform nonlinear channel equalization by employing different ANN cores including convolutional neural networks (CNN) and long short-term memory (LSTM) layers. First, we develop a fiber nonlinearity compensation for DSCM systems based on a fully-connected network across all subcarriers. In subsequent steps, and borrowing from the perturbation analysis of fiber nonlinearity, we gradually upgrade proposed designs towards modular structures with better performance-complexity advantages. Our study shows that putting proper macro structures in design of ANN nonlinear equalizers in DSCM systems can be crucial in development of practical solutions for future generations of coherent optical transceivers.

Pyridine-appended disulfidephospholipids enable exceptionally high drug loading and stability as a robust liposomal platform.

Low drug loading and instability of liposomes are two main challenges in the clinic. Herein, a liposomal platform from alternative pyridine-appended disulfidephospholipid (Pyr-SS-PC) was developed for delivering camptothecin (CPT) with high loading and stability. These Pyr-SS-PC lipids with π-π stacking open a general gate in the delivery of aromatic ring-containing drugs.

Retinal cell-targeted liposomal ginsenoside Rg3 attenuates retinal ischemia-reperfusion injury via alleviating oxidative stress and promoting microglia/macrophage M2 polarization.

Retinal ischemia-reperfusion (RIR) injury remains a major challenge that is detrimental to retinal cell survival in a variety of ocular diseases. However, current clinical treatments focus on a single pathological mechanism, making them unable to provide comprehensive retinal protection. A variety of natural products including ginsenoside Rg3 (Rg3) exhibit potent antioxidant and anti-inflammatory activities. Unfortunately, the hydrophobicity of Rg3 and the presence of various intraocular barriers limit its effective application in clinical settings. Hyaluronic acid (HA)- specifically binds to cell surface receptors, CD44, which is widely expressed in retinal pigment epithelial cells and M1-type macrophage. Here, we developed HA-decorated liposomes loaded with Rg3, termed Rg3@HA-Lips, to protect against retinal damage caused by RIR injury. Treatment with Rg3@HA-Lips significantly inhibited the oxidative stress induced by RIR injury. In addition, Rg3@HA-Lips promoted the transition of M1-type macrophage to the M2 type, ultimately reversing the pro-inflammatory microenvironment. The mechanism of Rg3@HA-Lips was further investigated and found that they can regulateSIRT/FOXO3a, NF-κB and STAT3 signaling pathways. Together with as well demonstrated good safety profiles, this CD44-targeted platform loaded with a natural product alleviates RIR injury by modulating the retinal microenvironment and present a potential clinical treatment strategy.

Reactive oxygen species-responsive mitochondria-targeted liposomal quercetin attenuates retinal ischemia-reperfusion injury via regulating SIRT1/FOXO3A and p38 MAPK signaling pathways.

Retinal ischemia-reperfusion (RIR) injury is involved in the pathogenesis of various vision-threatening diseases. The overproduction of reactive oxygen species (ROS) is thought to be the main cause of RIR injury. A variety of natural products, including quercetin (Que), exhibit potent antioxidant activity. However, the lack of an efficient delivery system for hydrophobic Que and the presence of various intraocular barriers limit the effective retinal delivery of Que in clinical settings. In this study, we encapsulated Que into ROS-responsive mitochondria-targeted liposomes (abbreviated to Que@TPP-ROS-Lips) to achieve the sustained delivery of Que to the retina. The intracellular uptake, lysosome escape ability, and mitochondria targeting ability of Que@TPP-ROS-Lips were evaluated in R28 retinal cells. Treating R28 cells with Que@TPP-ROS-Lips significantly ameliorated the decrease in ATP content, ROS generation, and increase in the release of lactate dehydrogenase in an in vitro oxygen-glucose deprivation (OGD) model of retinal ischemia. In a rat model, the intravitreal injection of Que@TPP-ROS-Lips 24 h after inducing retinal ischemia significantly enhanced retinal electrophysiological recovery and reduced neuroinflammation, oxidative stress, and apoptosis. Que@TPP-ROS-Lips were taken up by retina for at least 14 days after intravitreal administration. Molecular docking and functional biological experiments revealed that Que targets FOXO3A to inhibit oxidative stress and inflammation. Que@TPP-ROS-Lips also partially inhibited the p38 MAPK signaling pathway, which contributes to oxidative stress and inflammation. In conclusion, our new platform for ROS-responsive and mitochondria-targeted drug release shows promise for the treatment of RIR injury and promotes the clinical application of hydrophobic natural products.

ROS generation and p-38 activation contribute to montmorillonite-induced corneal toxicity in vitro and in vivo.

BACKGROUND: Montmorillonite (Mt) and its derivatives are now widely used in industrial and biomedical fields. Therefore, safety assessments of these materials are critical to protect human health after exposure; however, studies on the ocular toxicity of Mt are lacking. In particular, varying physicochemical characteristics of Mt may greatly alter their toxicological potential. To explore the effects of such characteristics on the eyes, five types of Mt were investigated in vitro and in vivo for the first time, and their underlying mechanisms studied. RESULTS: The different types of Mt caused cytotoxicity in human HCEC-B4G12 corneal cells based on analyses of ATP content, lactate dehydrogenase (LDH) leakage, cell morphology, and the distribution of Mt in cells. Among the five Mt types, Na-Mt exhibited the highest cytotoxicity. Notably, Na-Mt and chitosan-modified acidic Na-Mt (C-H-Na-Mt) induced ocular toxicity in vivo, as demonstrated by increases corneal injury area and the number of apoptotic cells. Na-Mt and C-H-Na-Mt also induced reactive oxygen species (ROS) generation in vitro and in vivo, as indicated by 2',7'-dichlorofluorescin diacetate and dihydroethidium staining. In addition, Na-Mt activated the mitogen-activated protein kinase signaling pathway. The pretreatment of HCEC-B4G12 cells with N-acetylcysteine, an ROS scavenger, attenuated the Na-Mt-induced cytotoxicity and suppressed p38 activation, while inhibiting p38 activation with a p38-specific inhibitor decreased Na-Mt-induced cytotoxicity. CONCLUSIONS: The results indicate that Mt induces corneal toxicity in vitro and in vivo. The physicochemical properties of Mt greatly affect its toxicological potential. Furthermore, ROS generation and p38 activation contribute at least in part to Na-Mt-induced toxicity.

Nanoparticles loaded with pharmacologically active plant-derived natural products: Biomedical applications and toxicity.

Pharmacologically active natural products have played a significant role in the history of drug development. They have acted as sources of therapeutic drugs for various diseases such as cancer and infectious diseases. However, most natural products suffer from poor water solubility and low bioavailability, limiting their clinical applications. The rapid development of nanotechnology has opened up new directions for applying natural products and numerous studies have explored the biomedical applications of nanomaterials loaded with natural products. This review covers the recent research on applying plant-derived natural products (PDNPs) nanomaterials, including nanomedicines loaded with flavonoids, non-flavonoid polyphenols, alkaloids, and quinones, especially their use in treating various diseases. Furthermore, some drugs derived from natural products can be toxic to the body, so the toxicity of them is discussed. This comprehensive review includes fundamental discoveries and exploratory advances in natural product-loaded nanomaterials that may be helpful for future clinical development.

Potential Biochemical Pesticide-Synthesis of Neofuranocoumarin and Inhibition the Proliferation of Spodoptera frugiperda Cells through Activating the Mitochondrial Pathway.

Furanocoumarins, the secondary metabolites of plants, are considered to be natural insecticides and fungicides because they prevent the invasion of plant pathogenic microorganisms and the predation of herbivorous insects. In this study, novel 2-arylfuranocoumarin derivatives were designed to synthesize by condensation, esterification, bromination, and Wittig reaction. The results showed an excellent photosensitive activity of 2-thiophenylfuranocoumarin (I34). Cell Counting Kit-8 detected that I34 could inhibit the proliferation of Spodoptera frugiperda (Sf9) cells in a time- and concentration-dependent manner under ultraviolet A (UV-A) light for 3 min. The inverted microscope revealed that cells treated with I34 swelled, the membrane was ruptured, and apoptotic bodies appeared. The flow cytometry detected that I34 could induce apoptosis of Sf9 cells, increase the level of intracellular reactive oxygen species (ROS), decrease the mitochondrial membrane potential, and block cell cycle arrest in the G2/M phase. Transmission electron microscopy detected cell mitochondrial cristae damage, matrix degradation, and mitochondrial vacuolation. Further enzyme activity detection revealed that the enzyme activities of apoptosis-related proteins caspase-3 and caspase-9 increased significantly (p < 0.05). Finally, Western blotting analysis detected that the phosphorylation level of Akt and Bad and the expression of the apoptosis inhibitor protein Bcl-XL were inhibited, cleaved-PARP and P53 were increased, and cytochrome C was released from the mitochondria into the cytoplasm. Moreover, under UV-A irradiation, I34 promoted the increase in ROS in Sf9 cells, activated the mitochondrial apoptotic signal transduction pathway, and finally, inhibited cell proliferation. Thus, novel furanocoumarins exhibit a potential application prospect as a biochemical pesticide.

Silica nanoparticles: Biomedical applications and toxicity.

Silica nanoparticles (SiNPs) are composed of silicon dioxide, the most abundant compound on Earth, and are used widely in many applications including the food industry, synthetic processes, medical diagnosis, and drug delivery due to their controllable particle size, large surface area, and great biocompatibility. Building on basic synthetic methods, convenient and economical strategies have been developed for the synthesis of SiNPs. Numerous studies have assessed the biomedical applications of SiNPs, including the surface and structural modification of SiNPs to target various cancers and diagnose diseases. However, studies on the in vitro and in vivo toxicity of SiNPs remain in the exploratory stage, and the toxicity mechanisms of SiNPs are poorly understood. This review covers recent studies on the biomedical applications of SiNPs, including their uses in drug delivery systems to diagnose and treat various diseases in the human body. SiNP toxicity is discussed in terms of the different systems of the human body and the individual organs in those systems. This comprehensive review includes both fundamental discoveries and exploratory progress in SiNP research that may lead to practical developments in the future.

Mechanistic study of silica nanoparticles on the size-dependent retinal toxicity in vitro and in vivo.

BACKGROUND: Silica nanoparticles (SiO2 NPs) are extensively applied in the biomedical field. The increasing medical application of SiO2 NPs has raised concerns about their safety. However, studies on SiO2 NP-induced retinal toxicity are lacking. METHODS: We investigated the retinal toxicity of SiO2 NPs with different sizes (15 and 50 nm) in vitro and in vivo along with the underlying mechanisms. The cytotoxicity of SiO2 NPs with different sizes was assessed in R28 human retinal precursor cells by determining the ATP content and LDH release. The cell morphologies and nanoparticle distributions in the cells were analyzed by phase-contrast microscopy and transmission electron microscopy, respectively. The mitochondrial membrane potential was examined by confocal laser scanning microscopy. The retinal toxicity induced by SiO2 NPs in vivo was examined by immunohistochemical analysis. To further investigate the mechanism of retinal toxicity induced by SiO2 NPs, reactive oxygen species (ROS) generation, glial cell activation and inflammation were monitored. RESULTS: The 15-nm SiO2 NPs were found to have higher cytotoxicity than the larger NPs. Notably, the 15-nm SiO2 NPs induced retinal toxicity in vivo, as demonstrated by increased cell death in the retina, TUNEL-stained retinal cells, retinal ganglion cell degeneration, glial cell activation, and inflammation. In addition, The SiO2 NPs caused oxidative stress, as demonstrated by the increase in the ROS indicator H2DCF-DA. Furthermore, the pretreatment of R28 cells with N-acetylcysteine, an ROS scavenger, attenuated the ROS production and cytotoxicity induced by SiO2 NPs. CONCLUSIONS: These results provide evidence that SiO2 NPs induce size-dependent retinal toxicity and suggest that glial cell activation and ROS generation contribute to this toxicity.

Size-Dependent Cytotoxicity and Reactive Oxygen Species of Cerium Oxide Nanoparticles in Human Retinal Pigment Epithelia Cells.

PURPOSE: The use of cerium oxide nanoparticles (CeO2 NPs), a lanthanide element oxide and bivalent compound, has been growing continuously in industry and biomedicine. Due to their wide application, the potential human health problems of CeO2 NPs have attracted attention, but studies on the toxicity of this compound to human eyes are lacking. This study investigated the cytotoxicity and reactive oxygen species (ROS) of CeO2 NPs in human retinal pigment epithelial cells (ARPE-19 cells). METHODS: Using the transmission electron microscope (TEM), the size distribution and shape of CeO2 NPs were characterized. To explore the effect of CeO2 NP size on ophthalmic toxicity in vitro, three sizes (15, 30 and 45 nm) of CeO2 NPs were investigated using ATP content measurement, LDH release measurement and cell proliferation assay in ARPE-19 cells. ROS values and mitochondrial membrane potential depolarization were evaluated by H2DCF-DA staining and JC-1 staining. Morphology changes were detected using a phase-contrast microscope. RESULTS: The cytotoxicity of 15 nm CeO2 NPs was found to be the highest and hence was further explored. Treatment with 15 nm CeO2 NPs caused the morphology of ARPE-19 cells to change in a dose- and time-dependent manner. Moreover, the treatment induced excessive ROS generation and mitochondrial membrane potential depolarization. In addition, cytotoxicity was attenuated by the application of a ROS scavenger N-acetyl-L- cysteine (NAC). CONCLUSION: CeO2 NPs induced cytotoxicity in ARPE-19 cells and excessive production of ROS and decreasing mitochondrial membrane potential. The Overproduction of ROS partially contributes to CeO2 NP-induced cytotoxicity.

Artificial fly visual joint perception neural network inspired by multiple-regional collision detection.

The biological visual system includes multiple types of motion sensitive neurons which preferentially respond to specific perceptual regions. However, it still keeps open how to borrow such neurons to construct bio-inspired computational models for multiple-regional collision detection. To fill this gap, this work proposes a visual joint perception neural network with two subnetworks - presynaptic and postsynaptic neural networks, inspired by the preferentialperception characteristics of three horizontal and vertical motion sensitive neurons. Related to the neural network and three hazard detection mechanisms, an artificial fly visual synthesized collision detection model for multiple-regional collision detection is originally developed to monitor possible danger occurrence in the case where one or more moving objects appear in the whole field of view. The experiments can clearly draw two conclusions: (i) the acquired neural network can effectively display the characteristics of visual movement, and (ii) the collision detection model, which outperforms the compared models, can effectively perform multiple-regional collision detection at a high success rate, and only takes about 0.24s to complete the process of collision detection for each virtual or actual image frame with resolution 110×60.

Highly selective enrichment of radioactive cesium from solution by using zinc hexacyanoferrate(III)-functionalized magnetic bentonite.

Realizing highly effective and selective enrichment of radioactive Cs(I) in complex environmental systems and exploring the microscale adsorption mechanism of Cs(I) on adsorbing material is the key point for developing highly efficient materials for Cs(I) adsorption. In addition, the low cytotoxicity of materials is essential for practical applications and environmental protection. In this study, the controlled assembly of bentonite carrier with a highly selective substance of Cs(I) is prepared by in-situ synthesis method in order to construct a low-toxic functional clay material with high adsorption capacity and selectivity of Cs(I) in complex environmental systems. The efficiency of the zinc hexacyanoferrate(III)-grafted magnetic bentonite (denoted as ZHF/MB) composite was evaluated in adsorption isotherm studies, kinetics analyses, and selectivity tests by using the batch technique. The toxicity of the ZHF/MB composite was evaluated through in vitro cytotoxicity assays using human hepatic cells (HepG2 cells). The results revealed that the ZHF/MB composite had not only a higher adsorption capacity (1.638 mmol/g, 60 °C) for Cs+ ions than a number of other natural and manmade materials but also no cytotoxicity in human cells. In addition, the ZHF/MB composite showed excellent selectivity for Cs+ with a removal efficiency of over 90% from solution (m/V = 0.4 g/L, [Mn+]initial = 10 mg/L, Mn+= Cs+, Ni2+,Sr2+, Co2+). The promising safe toxicology profile, remarkable Cs+ adsorption efficiency, and excellent selectivity of the ZHF/MB composite demonstrate its great potential for using as a decorporation agent for radioactive cesium remediation. The implementation of this research will provide new adsorption materials and method for radioactive Cs(I) waste management.

Allosteric inhibition of CRISPR-Cas9 by bacteriophage-derived peptides.

BACKGROUND: CRISPR-Cas9 has been developed as a therapeutic agent for various infectious and genetic diseases. In many clinically relevant applications, constitutively active CRISPR-Cas9 is delivered into human cells without a temporal control system. Excessive and prolonged expression of CRISPR-Cas9 can lead to elevated off-target cleavage. The need for modulating CRISPR-Cas9 activity over time and dose has created the demand of developing CRISPR-Cas off switches. Protein and small molecule-based CRISPR-Cas inhibitors have been reported in previous studies. RESULTS: We report the discovery of Cas9-inhibiting peptides from inoviridae bacteriophages. These peptides, derived from the periplasmic domain of phage major coat protein G8P (G8PPD), can inhibit the in vitro activity of Streptococcus pyogenes Cas9 (SpCas9) proteins in an allosteric manner. Importantly, the inhibitory activity of G8PPD on SpCas9 is dependent on the order of guide RNA addition. Ectopic expression of full-length G8P (G8PFL) or G8PPD in human cells can inactivate the genome-editing activity of SpyCas9 with minimum alterations of the mutation patterns. Furthermore, unlike the anti-CRISPR protein AcrII4A that completely abolishes the cellular activity of CRISPR-Cas9, G8P co-transfection can reduce the off-target activity of co-transfected SpCas9 while retaining its on-target activity. CONCLUSION: G8Ps discovered in the current study represent the first anti-CRISPR peptides that can allosterically inactivate CRISPR-Cas9. This finding may provide insights into developing next-generation CRISPR-Cas inhibitors for precision genome engineering.

Roles of Exosomes in Ocular Diseases.

Exosomes, nanoscale vesicles with a diameter of 30 to 150 nm, are composed of a lipid bilayer, protein, and genetic material. Exosomes are secreted by virtually all types of cells in the human body. They have key functions in cell-to-cell communication, immune regulation, inflammatory response, and neovascularization. Mounting evidence indicates that exosomes play an important role in various diseases, such as cancer, cardiovascular diseases, and brain diseases; however, the role that exosomes play in eye diseases has not yet been rigorously studied. This review covers current exosome research as it relates to ocular diseases including diabetic retinopathy, age-related macular degeneration, autoimmune uveitis, glaucoma, traumatic optic neuropathies, corneal diseases, retinopathy of prematurity, and uveal melanoma. In addition, we discuss recent advances in the biological functions of exosomes, focusing on the toxicity of exosomes and the use of exosomes as biomarkers and drug delivery vesicles. Finally, we summarize the primary considerations and challenges to be taken into account for the effective applications of exosomes.

Real-time measurement of a probabilistic-shaped 200Gb/s DP-16QAM transceiver.

Continuous real-time measurements are demonstrated from a 200Gb/s format configurable CFP transceiver that uses dual-polarization probabilistic-shaped 16QAM (DP-PS16QAM) modulation. Placed in a 50GHz coherent DWDM transmission system, DP-PS16QAM achieves a back-to-back 1.8dB OSNR gain over uniform DP-16QAM. It also transports over 1940km with EDFA-only amplification, thus doubling propagation distance of uniform DP-16QAM. Furthermore, a 1Tb/s super-channel consisting of five 200Gb/s DP-PS16QAM sub-carriers is placed in a 200GHz grid, and it achieves over 1600km transmission and 5b/s/Hz SE with a raw SE at 6.86b/s/Hz.

ROS generation and JNK activation contribute to 4-methoxy-TEMPO-induced cytotoxicity, autophagy, and DNA damage in HepG2 cells.

4-Methoxy-TEMPO, a derivative of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), is a stable nitroxide radical and is generally used in organic and pharmaceutical syntheses for the oxidation of alcohols. Previously, we reported the involvement of reactive oxygen species (ROS) and c-Jun N-terminal kinases (JNK) in TEMPO-induced apoptosis in mouse L5178Y cells. In this study, we investigated 4-methoxy-TEMPO induced toxicity in human HepG2 hepatoma cells and its underlying mechanisms. Treatments with 4-methoxy-TEMPO (0.5-5 mM for 2-6 h) caused oxidative stress as demonstrated by increased intensity of the ROS indicator H2DCF-DA, decreased levels of glutathione. 4-Methoxy-TEMPO treatment also induced DNA damage as characterized by increased levels of DNA tail intensity in the Comet assay, increased phosphorylation of related proteins including γ-H2A.X, p-Chk1, and p-Chk2, and activation of MAPK signaling pathways. In addition, 4-methoxy-TEMPO also induced autophagy as demonstrated by the conversion of LC3B-I to II, decreased level of p62, and the appearance of GFP-LC3B punctae. To investigate the crosstalk between different signaling pathways, pretreatment of HepG2 with N-acetylcysteine, an ROS scavenger, attenuated 4-methoxy-TEMPO-induced DNA damage, suppressed JNK activation, and diminished autophagy induction. Furthermore, inhibiting JNK activation by a JNK-specific inhibitor, SP600125, decreased DNA damage levels induced by 4-methoxy-TEMPO. These results suggest that multiple mechanisms including ROS generation, DNA damage, and MAPK activation contribute to 4-methoxy-TEMPO-induced toxicity.

Preventive effect of chrysin on experimental autoimmune uveitis triggered by injection of human IRBP peptide 1-20 in mice.

Uveitis is a common cause of blindness worldwide. Experimental autoimmune uveitis (EAU) is an animal model of noninfectious uveitis. Chrysin (5,7-dihydroxyflavone) is a member of the flavonoid family and has anti-inflammatory effects. We immunized C57BL/6J mice with human interphotoreceptor retinoid-binding protein peptide 1-20 to induce EAU. Chrysin was administered intragastrically at 25 mg/kg daily to the chrysin-treated mice from 3 days before immunization to 21 days after immunization. Vehicle was administered to the mice in the control group according to the same protocol. Lower clinical and histopathological scores, increased integrity of the blood-retinal barrier (BRB) and higher expression of tight junction proteins were observed in the chrysin-treated mice. Chrysin significantly decreased the proportions of Th1, Th17 and CD4+CD3+CD62L+ Th0 cells, and increased the proportion of Treg cells. Both macrophage infiltration and the expression of inducible nitric oxide synthase in the retina were efficiently inhibited by chrysin treatment. In chrysin-treated mice, the expression of interferon-γ, interleukin (IL)-17A, IL-6, IL-1ß and tumor necrosis factor-α was reduced in the retina, whereas higher levels of transforming growth factor-ß were detected. Furthermore, NF-κBp65 was downregulated after chrysin treatment. In conclusion, as an anti-inflammatory molecule, chrysin exerts a preventive effect on EAU by modulating the balance among helper T-cell subsets and suppressing ocular inflammation, thereby maintaining the integrity of the BRB.