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[Display omitted] Noninfective uveitis is a major cause of vision impairment, and corticosteroid medication is a mainstay clinical strategy that causes severe side effects. Rapamycin (RAPA), a potent immunomodulator, is a promising treatment for noninfective uveitis. However, because high and frequent dosages are required, it is a great challenge to implement its clinical translation for noninfective uveitis therapy owing to its serious toxicity. In the present study, we engineered an injectable microparticulate drug delivery system based on biodegradable block polymers (i.e., polycaprolactone-poly (ethylene glycol)-polycaprolactone, PCEC) for efficient ocular delivery of RAPA via a subconjunctival injection route and investigated its therapeutic efficacy in an experimental autoimmune uveitis (EAU) rat model. RAPA-PCEC microparticles were fabricated using the emulsion-evaporation method and thoroughly characterized using scanning electron microscopy, fourier transform infrared spectroscopy, X-ray diffraction, and differential scanning calorimetry. The formed microparticles exhibited slow in vitro degradation over 28 days, and provided both in vitro and in vivo sustained release of RAPA over 4 weeks. Additionally, a single subconjunctival injection of PCEC microparticles resulted in high ocular tolerance. More importantly, subconjunctival injection of RAPA-PCEC microparticles significantly attenuated the clinical signs of EAU in a dose-dependent manner by reducing inflammatory cell infiltration (i.e., CD45+ cells and Th17 cells) and inhibiting microglial activation. Overall, this injectable microparticulate system may be promising vehicle for intraocular delivery of RAPA for the treatment of noninfective uveitis. [ABSTRACT FROM AUTHOR]

Ricin toxin (RT) is a potent toxin derived from castor beans and has a high risk of mortality following inhalation-induced acute lung injury (ALI). Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor β superfamily and acts as a protective effect in diverse inflammatory diseases. Yet, the role of GDF15 in ALI has not been evaluated. In this study, we investigated the intrinsic role of Gdf15 in ALI induced by intratracheal inoculation of a 1.5 × LD 50 (lethal dose for 50%) of aerosolized RT in Gdf15 knockout (KO) mice compared to wild-type (WT) mice. In this model, Gdf15 deletion significantly increased pathology in lung tissues for RT-induced ALI in mice, led to significantly decreased body weights and survival rates and increased expression of inflammatory-related cytokine and chemokine levels at 24 and 72 h post-exposure. Infiltration of myeloid cells in lung tissue were quantified using flow cytometry. Although a similar infiltration pattern of inflammatory cells was observed in Gdf15 KO and WT groups, Gdf15 KO mice had elevated levels of neutrophils and decreased levels of Ly6Clo monocytes (cells with distinct destructive and protective roles, respectively) in the early stage of ALI. Gene expression profiles revealed similar effects as observed through RNA-seq. Bioinformatics analysis confirmed that pro-inflammatory signaling pathways were activated and the expression of inflammatory genes was significantly up-regulated after RT exposure compared to the corresponding baseline control in Gdf15 KO and WT mice. Compared to WT mice, inflammatory genes were more pronounced in Gdf15 KO groups after RT exposure. To our knowledge, this study presents the first research to systematically evaluate the role of Gdf15 in RT-induced ALI. These results collectively uncovered an immune response signature in lung tissues and reveal a critical role of Gdf15 in this ALI mice model. Our findings expose novel opportunities to investigate the contribution of GDF15 for the treatment of lung inflammatory diseases. [Display omitted] • Gdf15 deletion exacerbates lung pathological damage after ricin exposure. • Gdf15 deletion leads to increased expression of inflammation-associated cytokines. • Gdf15 deletion alters immune cell infiltration and accumulation in the lung. • Gdf15 deletion increases NF-κB activity and upregulates inflammatory genes. [ABSTRACT FROM AUTHOR]

• CEL prophylactically and therapeutically attenuated the experimental autoimmune uveitis. • CEL treatment effectively suppressed the pathological Th17 response by targeting STAT3-IL17 pathway. • CEL altered the gut microbial community of EAU rats by reducing the relative abundance of pathogenic bacteria and simultaneously enriching the relative abundance of beneficial bacteria. • CEL treatment reshaped the gut metabolites in the EAU rats. Extensive research has revealed the favorable effects of celastrol (CEL) against various diseases, but the role of CEL in autoimmune uveitis remains unexplored. We first assessed the prophylactical and therapeutical effects of CEL on autoimmune uveitis via rat experimental autoimmune uveitis model. After network pharmacology, functional enrichment and molecular docking analyses, we predicted the potential target of CEL and validated its effect on EAU by clinical and histopathological scores, Evans blue staining, immunofluorescence assay and western blotting. Then we evaluated the role of CEL in the gut environment by 16S rRNA sequencing and untargeted metabolomic analysis. We confirmed that CEL treatment suppressed the pathological TH17 response, inhibited the migration of inflammatory cells, and preserved the integrity of BRB via targeting STAT3-IL17 pathway. Furthermore, CEL was found to reduce the relative abundance of opportunistic pathogenic bacteria including Clostridium_sensu_stricto_1 , Parasutterella and GCA-900066575 , and enrich the relative abundance of beneficial Oscillospirales and Ruminococcus_torques_group in EAU rats by fecal 16S rRNA sequencing. Meanwhile, CEL treatment reshaped the gut metabolites in the EAU rats by increasing the relative concentrations of cholic acid, progesterone and guggulsterone, and decreasing the relative levels of isoproterenol, creatinine and phenylacetylglutamine. CEL exerts its ameliorative effects on the experimental autoimmune uveitis through the dual mechanisms of targeting STAT3 and reprofiling the gut microenvironment. [ABSTRACT FROM AUTHOR]

Herein, we report a facile method for converting carboxylate-containing indomethacin (Idm) into a cyclooxygenase-2 (COX-2) selective inhibitor via the amidation of an unnatural peptide sequence (Nal-Nal-Asp). The resulting indomethacin amides (i.e., Idm-Nal-Nal-Asp) have high selectivity for COX-2, and can self-assemble into a one-component supramolecular hydrogel that acts as a 'self-delivery' system for boosting anti-inflammatory efficacy. Self-assembled Idm-Nal-Nal-Asp hydrogel robustly inhibits COX-2 expression in lipopolysaccharide (LPS)-activated Raw 264.7 macrophages while also exhibits superior anti-inflammatory and antioxidant activities via reactive oxygen species (ROS)-related NF-κB and Nrf2/HO-1 pathways. Moreover, a rabbit model of endotoxin-induced uveitis (EIU) reveals that the Idm-Nal-Nal-Asp hydrogel outperforms clinically used 0.1 wt% diclofenac sodium eye drops in terms of in vivo anti-inflammatory efficacy via topical instillation route. As a rational approach to designing and applying COX-2 selective inhibitors, this work presents a simple method for converting non-selective nonsteriodal anti-inflammatory drugs (NSAIDs) into highly selective COX-2 inhibitors that can self-assemble into supramolecular hydrogel for anti-inflammation applications. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective(s): The aim of this study is to explore the potential neuroprotective effects of Ginkgolide B (GB), a main terpene lactone and active component in Ginkgo biloba, in hypoxia-induced neuronal damage, and to further investigate its possible mechanisms. Materials and Methods: 54 Sprague-Dawley rats were randomly divided into three groups: the untreated control group (n=18); the hypoxia group (n=18; exposed to 6000 m simulated plateau altitude for six days); and the GB group (n=18; intragastric administration of 12 mg/kg GB three days prior to rapid adaption to 6000 m and on the first two days of hypoxia). After hypoxia exposure for six days, we dissected out the brain hippocampi and performed hematoxylin and eosin staining, Nissl staining, and TUNEL staining. Homogenates of the hippocampi were used to test the oxidative stress indices including malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and catalase. Bax and caspase-3 expression in the hippocampal tissue was measured using qRT-PCR. Results: Treatment with GB before exposure to hypoxia could protect neural cells and increase the number of Nissl bodies. TUNEL and qRT-PCR results demonstrated that GB treatment could decrease apoptotic cells in different areas of the hippocampus. Antioxidant defense systems such as SOD, GSH, and catalase were decreased (P<0.05), and the concentration of MDA was reduced significantly in the hippocampi of rats of the GB group (P<0.05). Conclusion: GB could alleviate hypoxia-induced neuronal damage in rat hippocampus by inhibiting oxidative stress and apoptosis. [ABSTRACT FROM AUTHOR]

[Display omitted] Noninfectious (autoimmune and immune-mediated) uveitis is one of the primary diseases leading to blindness in the world. Due to the limitation of current first-line drugs for clinical uveitis, novel drugs and targets against uveitis are urgently needed. Ganciclovir (GCV), an FDA-approved antiviral drug, is often used to treat cytomegalovirus-induced retinitis in clinical patients. Recently, GCV was found to suppress neuroinflammation via targeting STING signaling because the STING pathway plays a pivotal role in autoimmune diseases. However, until now, the effect of GCV on non-infectious uveitis has never been explored. In this work, using the rat experimental autoimmune uveitis (EAU) model, we first found STING to be highly expressed in infiltrating cells (CD68+, CD45+, and CD4+) and retinal glial cells (Iba1+ and GFAP+) of the immunized retina. More importantly, GCV treatment can significantly suppress the initiation and progression of EAU by inhibiting infiltration of Th17 and inflammatory cells into the retina. Mechanistically, we found that GCV could reverse the levels of pro-inflammatory factors (such as IL-1β) and chemokine-related factors (such as Cxcr3), possibly via targeting the STING pathway. The present results suggest that GCV may be considered as a novel therapeutic strategy against human uveitis. [ABSTRACT FROM AUTHOR]