VP1 codon deoptimization and high-fidelity substitutions in 3D polymerase as potential vaccine strategies for eliciting immune responses against enterovirus A71.

Enterovirus A71 (EV-A71) can induce severe neurological complications and even fatal encephalitis in children, and it has caused several large outbreaks in Taiwan since 1998. We previously generated VP1 codon-deoptimized (VP1-CD) reverse genetics (rg) EV-A71 viruses (rgEV-A71s) that harbor a high-fidelity (HF) 3D polymerase. These VP1-CD-HF rgEV-A71s showed lower replication kinetics in vitro and decreased virulence in an Institute of Cancer Research (ICR) mouse model of EV-A71 infection, while still retaining their antigenicity in comparison to the wild-type virus. In this study, we aimed to further investigate the humoral and cellular immune responses elicited by VP1-CD-HF rgEV-A71s to assess the potential efficacy of these EV-A71 vaccine candidates. Following intraperitoneal (i.p.) injection of VP1-CD-HF rgEV-A71s in mice, we observed a robust induction of EV-A71-specific neutralizing IgG antibodies in the antisera after 21 days. Splenocytes isolated from VP1-CD-HF rgEV-A71s-immunized mice exhibited enhanced proliferative activities and cytokine production (IL-2, IFN-γ, IL-4, IL-6, and TNF-α) upon re-stimulation with VP1-CD-HF rgEV-A71, as compared to control mice treated with adjuvant only. Importantly, administration of antisera from VP1-CD-HF rgEV-A71s-immunized mice protected against lethal EV-A71 challenge in neonatal mice. These findings highlight that our generated VP1-CD-HF rgEV-A71 viruses are capable of inducing both cellular and humoral immune responses, supporting their potential as next-generation EV-A71 vaccines for combating EV-A71 infection.IMPORTANCEEV-A71 can cause severe neurological diseases and cause death in young children. Here, we report the development of synthetic rgEV-A71s with the combination of codon deoptimization and high-fidelity (HF) substitutions that generate genetically stable reverse genetics (rg) viruses as potential attenuated vaccine candidates. Our work provides insight into the development of low-virulence candidate vaccines through a series of viral genetic editing for maintaining antigenicity and genome stability and suggests a strategy for the development of an innovative next-generation vaccine against EV-A71.

Plasmacytoid Dendritic Cells Enhance T-Independent B Cell Response through a p38 MAPK-STAT1 Axis.

TLR signaling in B cells triggers their activation and differentiation independent of help from T cells. Plasmacytoid dendritic cells (pDCs) cooperate with B cells to boost TLR-stimulated T-independent humoral immunity; however, the molecular mechanisms remain elusive. In this study, we demonstrate that in the mouse system, the adjuvant effects of pDCs also occurred following challenge with pathogens and that follicular (FO) B cells were more sensitive to pDC-induced enhancement than were marginal zone (MZ) B cells. Moreover, pDCs migrated to the FO zones and interacted with FO B cells upon stimulation in vivo. CXCL10, a ligand for CXCR3 expressed on pDCs, was superinduced in the coculture system and facilitated the cooperative activation of B cells. Moreover, pDCs also promoted TLR-stimulated autoantibody production in FO B and MZ B cells. Ingenuity Pathway Analysis and gene set enrichment analysis revealed that type I IFN (IFN-I)-mediated JAK-STAT and Ras-MAPK pathways were highly enriched in R848-stimulated B cells cocultured with pDCs compared with B cells alone. Whereas IFN-I receptor 1 deficiency reduced pDC-enhanced B cell responses, STAT1 deficiency displayed a more pronounced defect. One of the STAT1-dependent but IFN-I-independent mechanisms was TLR-induced STAT1-S727 phosphorylation by p38 MAPK. Serine 727 to alanine mutation attenuated the synergism between pDCs and B cells. In conclusion, we uncover a molecular mechanism for pDC-enhanced B cell response and define a crucial role of the IFN-I/TLR-mediated signaling pathway through a p38 MAPK-STAT1 axis in controlling T-independent humoral immunity and providing a novel therapeutic target for treating autoimmune diseases.

Dual-Atom Catalyst with N-Colligated Zn1Co1 Species as Dominant Active Sites for Propane Dehydrogenation.

Dual-atom catalysts (DACs) with paired active sites can provide unique intrinsic properties for heterogeneous catalysis, but the synergy of the active centers remains to be elucidated. Here, we develop a high-performance DAC with Zn1Co1 species anchored on nitrogen-doped carbon (Zn1Co1/NC) as the dominant active site for the propane dehydrogenation (PDH) reaction. It exhibits several times higher turnover frequency (TOF) of C3H8 conversion and enhanced C3H6 selectivity compared to Zn1/NC or Co1/NC with only a single-atom site. Various experimental and theoretical studies suggest that the enhanced PDH performance stems from the promoted activation of the C-H bond of C3H8 triggered by the electronic interaction between Zn1 and Co1 colligated by N species. Moreover, the dynamic sinking of the Zn1 site and rising of the Co1 site, together with the steric effect of the dissociated H species at the bridged N during the PDH reaction, provides a feasible channel for C3H6 desorption through the more exposed Co1 site, thereby boosting the selectivity. This work provides a promising strategy for designing robust hetero DACs to simultaneously increase activity and selectivity in the PDH reaction.

Suppression of annexin A1 and its receptor reduces herpes simplex virus 1 lethality in mice.

Herpes simplex virus 1 (HSV-1)-induced encephalitis is the most common cause of sporadic, fatal encephalitis in humans. HSV-1 has at least 10 different envelope glycoproteins, which can promote virus infection. The ligands for most of the envelope glycoproteins and the significance of these ligands in virus-induced encephalitis remain elusive. Here, we show that glycoprotein E (gE) binds to the cellular protein, annexin A1 (Anx-A1) to enhance infection. Anx-A1 can be detected on the surface of cells permissive for HSV-1 before infection and on virions. Suppression of Anx-A1 or its receptor, formyl peptide receptor 2 (FPR2), on the cell surface and gE or Anx-A1 on HSV-1 envelopes reduced virus binding to cells. Importantly, Anx-A1 knockout, Anx-A1 knockdown, or treatments with the FPR2 antagonist reduced the mortality and tissue viral loads of infected mice. Our results show that Anx-A1 is a novel enhancing factor of HSV-1 infection. Anx-A1-deficient mice displayed no evident physiology and behavior changes. Hence, targeting Anx-A1 and FPR2 could be a promising prophylaxis or adjuvant therapy to decrease HSV-1 lethality.

Acyclovir-resistant HSV-1 isolates among immunocompromised patients in southern Taiwan: Low prevalence and novel mutations.

Herpes simplex virus type 1 (HSV-1) can establish latency in humans and easily relapse in immunocompromised patients, with significant mortality. Treatment with acyclovir (ACV) can result in the emergence of HSV resistance. A total of 440 frozen HSV-1 isolates collected from 318 patients from January 2014 to July 2019 were obtained from National Cheng Kung University Hospital in southern Taiwan. These 440 isolates were subjected to phenotypic studies for ACV-resistance by initial screening with the plaque reduction assay (PRA) and further validation by the DNA reduction assay (DRA). The ACV-resistant strains were further investigated by Sanger sequencing for the full-length UL23 and UL30 genes, which encode thymidine kinase and DNA polymerase, respectively. Hematological malignancies or hematopoietic stem-cell transplantation patients accounted for 56.9% (124/218) among the immunocompromised patients (218/318) in this study. Repeated sampling for HSV testing was 50% (109/218) in immunocompromised patients. Only 1.38% (3/218) of immunocompromised patients and 0.9% (3/318) of all patients developed ACV-resistant HSV-1 as measured by phenotypic screening assays. It is noteworthy that a novel Y248D mutation in the UL23 gene from an immunocompromised patient was found by both PRA and DRA. In 3D protein predicting analysis, uncharged Y248 was located at an alpha-helix and substituted by negative-charged D248, which may alter the function of viral thymidine kinase. Besides, three unreported mutations related to natural polymorphism were found in virus isolates from two immunocompetent patients, including 683-688 deletion, R227H, and A351D in the UL30 gene. These data show that the prevalence of ACV-resistant HSV-1 among immunocompromised patients in southern Taiwan is low. These results will be helpful for the clinical management and treatment of HSV infections.

Appraisal of guidelines for managing contrast medium in patients with metformin: consensuses, controversies, and gaps.

OBJECTIVES: The current guidelines contain substantial inconsistency regarding the use of metformin concomitantly with contrast media. The objective of this study is to appraise the guidelines and summarize the agreements and differences among recommendations. METHODS: Our search focused on English language guidelines published between 2018 and 2021. Guidelines for the management of contrast media in patients with continuous metformin were included. Guidelines were assessed using the Appraisal of Guidelines for Research and Evaluation II instrument. RESULTS: Six guidelines out of 1134 fulfilled the inclusion criteria with an AGREE II score of 79.2% (IQR 72.7 to 85.1%). There was good overall quality of the guidelines, with six considered "strongly recommended." CPGs scored poorly in "Clarity of Presentation" and "Applicability," with scores of 75.9% and 76.4%, respectively. The intraclass correlation coefficients were excellent in each domain. There are some guidelines (33.3%) that recommend discontinuation of metformin in patients with an eGFR of < 30 mL/min/1.73 m2, while some guidelines (16.7%) suggest the threshold of renal function should be eGFR < 40 mL/min/1.73 m2. CONCLUSIONS: Most guidelines recommend withdrawing metformin before using contrast agents in diabetic patients with severely impaired kidney function but disagree on the renal function thresholds. Furthermore, the gaps regarding discontinuing metformin with moderate renal impairment (30 mL/min/1.73 m2 < eGFR < 60 mL/min/1.73 m2) must be considered in future studies. KEY POINTS: • Guidelines involving metformin and contrast agents are reliable and optimal. • Most guidelines advocate discontinuing metformin before using contrast agents in diabetic patients with advanced renal failure, but there are controversial suggestions regarding kidney function thresholds. • The gaps regarding the time of discontinuation of the metformin with moderate renal impairment (30 mL/min/1.73 m2 < eGFR < 60 mL/min/1.73 m2) must be considered in the extensive RCT studies.

Surface Chemistry and Catalytic Reactivity of Borocarbonitride in Oxidative Dehydrogenation of Propane.

Borocarbonitride (BCN) materials are newly developed oxidative dehydrogenation catalysts that can efficiently convert alkanes to alkenes. However, BCN materials tend to form bulky B2 O3 due to over-oxidation at the high reaction temperature, resulting in significant deactivation. Here, we report a series of super stable BCN nanosheets for the oxidative dehydrogenation of propane (ODHP) reaction. The catalytic performance of the BCN nanosheets can be easily regulated by changing the guanine dosage. The control experiment and structural characterization indicate that the introduction of a suitable amount of carbon could prevent the formation of excessive B2 O3 from BCN materials and maintain the 2D skeleton at a high temperature of 520 °C. The best-performing catalyst BCN exhibits 81.9 % selectivity towards olefins with a stable propane conversion of 35.8 %, and the propene productivity reaches 16.2 mmol h-1 g-1 , which is much better than hexagonal BN (h-BN) catalysts. Density functional theory calculation results show that the presence of dispersed rather than aggregated carbon atoms can significantly affect the electronic microenvironment of h-BN, thereby boosting the catalytic activity of BCN.

Absence of the lectin-like domain of thrombomodulin reduces HSV-1 lethality of mice with increased microglia responses.

BACKGROUND: Herpes simplex virus 1 (HSV-1) can induce fatal encephalitis. Cellular factors regulate the host immunity to affect the severity of HSV-1 encephalitis. Recent reports focus on the significance of thrombomodulin (TM), especially the domain 1, lectin-like domain (TM-LeD), which modulates the immune responses to bacterial infections and toxins and various diseases in murine models. Few studies have investigated the importance of TM-LeD in viral infections, which are also regulated by the host immunity. METHODS: In vivo studies comparing wild-type and TM-LeD knockout mice were performed to determine the role of TM-LeD on HSV-1 lethality. In vitro studies using brain microglia cultured from mice or a human microglia cell line to investigate whether and how TM-LeD affects microglia to reduce HSV-1 replication in brain neurons cultured from mice or in a human neuronal cell line. RESULTS: Absence of TM-LeD decreased the mortality, tissue viral loads, and brain neuron apoptosis of HSV-1-infected mice with increases in the number, proliferation, and phagocytic activity of brain microglia. Moreover, TM-LeD deficiency enhanced the phagocytic activity of brain microglia cultured from mice or of a human microglia cell line. Co-culture of mouse primary brain microglia and neurons or human microglia and neuronal cell lines revealed that TM-LeD deficiency augmented the capacity of microglia to reduce HSV-1 replication in neurons. CONCLUSIONS: Overall, TM-LeD suppresses microglia responses to enhance HSV-1 infection.

From EGFR kinase inhibitors to anti-inflammatory drugs: Optimization and biological evaluation of (4-(phenylamino)quinazolinyl)-phenylthiourea derivatives as novel NF-κB inhibitors.

The transcription factor NF-κB is a pivotal mediator of chronic inflammatory and autoimmune diseases. Based on our previously published dual EGFR/NF-κB inhibitors, we designed and synthesized new thiourea quinazoline derivatives that retained only the NF-κB inhibitory activity. Several congeners displayed a strong suppression of NF-κB activity in a reporter gene assay, yet low cytotoxicity, and were further evaluated in differentiated macrophage-like THP-1 cells. The compounds exhibited a strong inhibition of IL-6 and, less potently, of TNFα release, which was accompanied by a selective induction of macrophage cell death. The mode of action was investigated with a selected inhibitor, 18, revealing that the translocation of p65/RelA to the nucleus but not its release from the IκB complex was inhibited. Eventually, 18 was identified as the first small molecule inhibitor affecting only the phosphorylation of p65-Ser468 but not of Ser536, which may be causally related to the retention of NF-κB in the cytoplasm. Altogether, our novel NF-κB inhibitors seem applicable for the suppression of cytokine release and the additional selective depletion of activated macrophages in various inflammatory diseases.

JAK2-Mediated Phosphorylation of Stress-Induced Phosphoprotein-1 (STIP1) in Human Cells.

Stress-induced phosphoprotein-1 (STIP1)-a heat shock protein (HSP)70/HSP90 adaptor protein-is commonly overexpressed in malignant cells, where it controls proliferation via multiple signaling pathways, including JAK2/STAT3. We have previously shown that STIP1 stabilizes the protein tyrosine kinase JAK2 in cancer cells via HSP90 binding. In this study, we demonstrate that STIP1 may act as a substrate for JAK2 and that phosphorylation of tyrosine residues 134 and 152 promoted STIP1 protein stability, induced its nuclear-cytoplasmic shuttling, and promoted its secretion into the extracellular space. We also found that JAK2-mediated STIP1 phosphorylation enhanced cell viability and increased resistance to cisplatin-induced cell death. Conversely, interference STIP1 with JAK2 interaction-attained either through site-directed mutagenesis or the use of cell-penetrating peptides-decreased JAK2 protein levels, ultimately leading to cell death. On analyzing human ovarian cancer specimens, JAK2 and STIP1 expression levels were found to be positively correlated with each other. Collectively, these results indicate that JAK2-mediated phosphorylation of STIP-1 is critical for sustaining the JAK2/STAT3 signaling pathway in cancer cells.

Microstructure and Mechanical Properties of Novel High-Strength, Low-Activation Wx(TaVZr)100-x (x = 5, 10, 15, 20, 25) Refractory High Entropy Alloys.

In this work, novel high-strength, low-activation Wx(TaVZr)100-x (x = 5, 10, 15, 20, 25) refractory high entropy alloys (RHEAs) were prepared by vacuum arc melting. Their microstructure, compressive mechanical properties, hardness, and fracture morphology were investigated and analyzed. The results show that the RHEAs possess a disordered BCC phase, ordered Laves phase, and Zr-rich HCP phase. Their dendrite structures were observed, and the distribution of dendrites became gradually more dense with an increase in W content. The RHEAs demonstrate high strength and hardness, with these properties being higher than in most reported tungsten-containing RHEAs. For example, the typical W20(TaVZr)80 RHEA has a yield strength of 1985 MPa and a hardness of 636 HV, respectively. The improvement in terms of strength and hardness are mainly due to solid solution strengthening and the increase in dendritic regions. During compression, with the increase in the applied load, the fracture behavior of RHEAs changed from initial intergranular fractures to a mixed mode combining both intergranular and transgranular fractures.

Recent Advances in W-Containing Refractory High-Entropy Alloys-An Overview.

During the past decade, refractory high-entropy alloys (RHEA) have attracted great attention of scientists, engineers and scholars due to their excellent mechanical and functional properties. The W-containing RHEAs are favored by researchers because of their great application potential in aerospace, marine and nuclear equipment and other high-temperature, corrosive and irradiated fields. In this review, more than 150 W-containing RHEAs are summarized and compared. The preparation techniques, microstructure and mechanical properties of the W-containing RHEAs are systematically outlined. In addition, the functional properties of W-containing RHEAs, such as oxidation, corrosion, irradiation and wear resistance have been elaborated and analyzed. Finally, the key issues faced by the development of W-containing RHEAs in terms of design and fabrication techniques, strengthening and deformation mechanisms, and potential functional applications are proposed and discussed. Future directions for the investigation and application of W-containing RHEAs are also suggested. The present work provides useful guidance for the development, processing and application of W-containing RHEAs and the RHEA components.

On the WEDM of WNbMoTaZrx (x = 0.5, 1) Refractory High Entropy Alloys.

As a potential candidate for the next generation of high-temperature alloys, refractory high entropy alloys (RHEAs) have excellent mechanical properties and thermal stability, especially for high-temperature applications, where the processing of RHEAs plays a critical role in engineering applications. In this work, the wire electrical discharge machining (WEDM) performance of WNbMoTaZrx (x = 0.5, 1) RHEAs was investigated, as compared with tungsten, cemented carbide and industrial pure Zr. The cutting efficiency (CE) of the five materials was significantly dependent on the melting points, while the surface roughness (Ra) was not. For the RHEAs, the CE was significantly affected by the pulse-on time (ON), pulse-off time (OFF) and peak current (IP), while the surface roughness was mainly dependent on the ON and IP. The statistical analyses have shown that the CE data of RHEAs have relatively-smaller Weibull moduli than those for the Ra data, which suggests that the CE of RHEAs can be tuned by optimizing the processing parameters. However, it is challenging to tune the surface roughness of RHEAs by tailoring the processing parameters. Differing from the comparative materials, the WEDMed surfaces of the RHEAs showed dense spherical re-solidified particles at upper recast layers, resulting in larger Ra values. The proportion of the upper recast layers can be estimated by the specific discharge energy (SDE). Following the WEDM, the RHEAs maintained the main BCC1 phase, enriched with the W and Ta elements, while the second BCC2 phase in the Zr1.0 RHEA disappeared. Strategies for achieving a better WEDMed surface quality of RHEAs were also proposed and discussed.

Prediction of Flight Status of Logistics UAVs Based on an Information Entropy Radial Basis Function Neural Network.

Aiming at addressing the problems of short battery life, low payload and unmeasured load ratio of logistics Unmanned Aerial Vehicles (UAVs), the Radial Basis Function (RBF) neural network was trained with the flight data of logistics UAV from the Internet of Things to predict the flight status of logistics UAVs. Under the condition that there are few available input samples and the convergence of RBF neural network is not accurate, a dynamic adjustment method of RBF neural network structure based on information entropy is proposed. This method calculates the information entropy of hidden layer neurons and output layer neurons, and quantifies the output information of hidden layer neurons and the interaction information between hidden layer neurons and output layer neurons. The structural design and optimization of RBF neural network were solved by increasing the hidden layer neurons or disconnecting unnecessary connections, according to the connection strength between neurons. The steepest descent learning algorithm was used to correct the parameters of the network structure to ensure the convergence accuracy of the RBF neural network. By predicting the regression values of the flight status of logistics UAVs, it is demonstrated that the information entropy-based RBF neural network proposed in this paper has good approximation ability for the prediction of nonlinear systems.

Doxycycline Ameliorates the Severity of Experimental Proliferative Vitreoretinopathy in Mice.

After successful surgeries for patients with rhegmatogenous retinal detachment, the most common cause of retinal redetachment is proliferative vitreoretinopathy (PVR), which causes severe vision impairment and even blindness worldwide. Until now, the major treatment for PVR is surgical removal of the epiretinal membrane, while effective treatment to prevent PVR is still unavailable. Therefore, we investigated the potential of doxycycline, an antibiotic in the tetracycline class, to treat PVR using a mouse model. We used the human retinal pigment epithelial cell line, ARPE-19, for in vitro and in vivo studies to test doxycycline for PVR treatment. We found that doxycycline suppressed the migration, proliferation, and contraction of ARPE-19 cells with reduced p38 MAPK activation and total MMP activity. Intravitreal doxycycline and topical tetracycline treatment significantly ameliorated the PVR severity induced by ARPE-19 cells in mice. PVR increased the expression of MMP-9 and IL-4 and p38 MAPK phosphorylation and modestly decreased IL-10. These effects were reversed by doxycycline and tetracycline treatment in the mouse retina. These results suggest that doxycycline will be a potential treatment for PVR in the future.

Microglia Reduce Herpes Simplex Virus 1 Lethality of Mice with Decreased T Cell and Interferon Responses in Brains.

Herpes simplex virus 1 (HSV-1) infects the majority of the human population and can induce encephalitis, which is the most common cause of sporadic, fatal encephalitis. An increase of microglia is detected in the brains of encephalitis patients. The issues regarding whether and how microglia protect the host and neurons from HSV-1 infection remain elusive. Using a murine infection model, we showed that HSV-1 infection on corneas increased the number of microglia to outnumber those of infiltrating leukocytes (macrophages, neutrophils, and T cells) and enhanced microglia activation in brains. HSV-1 antigens were detected in brain neurons, which were surrounded by microglia. Microglia depletion increased HSV-1 lethality of mice with elevated brain levels of viral loads, infected neurons, neuron loss, CD4 T cells, CD8 T cells, neutrophils, interferon (IFN)-ß, and IFN-γ. In vitro studies demonstrated that microglia from infected mice reduced virus infectivity. Moreover, microglia induced IFN-ß and the signaling pathway of signal transducer and activator of transcription (STAT) 1 to inhibit viral replication and damage of neurons. Our study reveals how microglia protect the host and neurons from HSV-1 infection.

The cellular immunophenotype expression of influenza A virus and influenza B virus infection in children.

BACKGROUND: The innate immune response is the primary defense against influenza virus infection. METHODS: This is a prospective study carried out in children <18 years of age who were diagnosed with influenza A or influenza B infection. Demographic and clinical data, laboratory findings and cell immunophenotypes on first presentation were compared. RESULTS: With respect to immunophenotype, influenza A infection resulted in a higher fraction of CD14+ and CD4+IL-17A+cells compared to children infected with influenza B. By contrast, influenza B infection resulted in a comparatively higher percentage of double-negative CD4-CD8- lymphocyte subsets. Influenza A infection was associated with comparatively higher percentages of CD4+CD25highFoxp3+ and CD4+CD25lowFoxp3+ cells. By contrast, the percentage of CD8+CD25high and CD8+CD25low cells was similar among patients with influenza A infection and influenza B infection. CONCLUSIONS: An improved understanding of the fraction of regulatory T cells with influenza virus infections may provide further understandings on immune responses.

Period-mismatched sine dual-interface grating for optical absorption in silicon thin-film solar cells.

Crystalline silicon thin-film solar cells with period-mismatched sine dual-interface gratings are proposed. Several structural parameters of the front and rear gratings, such as heights, periods, and duty ratios, are optimized using the finite-difference time-domain method. The mechanisms of absorption enhancement are also illustrated by analyzing the optical and electrical performance in thin-film solar cells with different grating arrangements. Numerical results indicate that the period-mismatched sine dual-interface grating structure shows obvious improvement in absorption efficiency and is more suitable for grating structures with small period. The short-circuit current density of the period-mismatched dual-interface sine grating structure is improved to 18.89mA/cm2, an increase of 41.39% as compared with the planar structure. The research findings can be utilized to guide the design of grating structures for thin-film solar cells.

Chitosan Oligosaccharides Suppress Nuclear Factor-Kappa B Activation and Ameliorate Experimental Autoimmune Uveoretinitis in Mice.

We investigated the therapeutic potential and mechanism of chitosan oligosaccharides (COS) for experimental autoimmune uveoretinitis (EAU) in mice. EAU was induced in C57/BL6 mice by injection of human interphotoreceptor retinoid-binding protein (IRBP) peptides. At the same time, a high or low dose (20 or 10 mg/kg) of COS or phosphate-buffered saline (PBS) was given to mice daily after EAU induction. We found that mouse EAU is ameliorated by the high-dose COS treatment when compared with PBS treatment. In the retinas of high-dose COS-treated mice, the nuclear translocation of NF-κB subunit (p65) was suppressed, and the expression of several key EAU inflammatory mediators, IFN-γ, TNF-α, IL-1α, IL-4, IL-5, IL-6, IL-10, IL-17 and MCP-1 was lowered. These results suggest that COS may be a potential treatment for posterior uveitis.

Suppression of the Reactive Oxygen Response Alleviates Experimental Autoimmune Uveitis in Mice.

Reactive oxygen species (ROS) are produced by host phagocytes and play an important role in antimicrobial actions against various pathogens. Autoimmune uveitis causes blindness and severe visual impairment in humans at all ages worldwide. However, the role of ROS in autoimmune uveitis remains unclear. We used ROS-deficient (Ncf1-/-) mice to investigate the role of ROS in experimental autoimmune uveitis (EAU). Besides, we also used the antioxidant N-acetylcysteine (NAC) treatment to evaluate the effect of suppression of ROS on EAU in mice. The EAU disease scores of Ncf1-/- mice were significantly lower than those of wild-type mice. EAU induction increased the levels of cytokines (interleukin (IL)-1α, IL-1ß, IL-4, IL-6, IL-12, IL-17, and tumor necrosis factor (TNF)-α) and chemokines (monocyte chemoattractant protein (MCP)-1) in the retinas of wild-type mice but not in those of Ncf1-/- mice. EAU induction enhanced the level of NF-κB activity in wild-type mice. However, the level of NF-κB activity in Ncf1-/- mice with EAU induction was low. Treatment with the antioxidant NAC also decreased the severity of EAU in mice with reduced levels of oxidative stress, inflammatory mediators, and NF-κB activation in the retina. We successfully revealed a novel role of ROS in the pathogenesis of EAU and suggest a potential antioxidant role for the treatment of autoimmune uveitis in the future.