Dataset Information

Melatonin Ameliorates Inflammation and Oxidative Stress by Suppressing the p38MAPK Signaling Pathway in LPS-Induced Sheep Orchitis.

ABSTRACT: Gram-negative bacterial infections of the testis can lead to infectious orchitis, which negatively influences steroid hormone synthesis and spermatogenesis. Lipopolysaccharide (LPS), a major component of the Gram-negative bacterial cell wall, acts via toll like receptors 4 (TLR4) to trigger innate immune responses and activate nuclear factor kappa B signaling. The protective mechanisms of melatonin on LPS-induced infectious orchitis have not been reported. Herein, we developed an LPS-induced sheep infectious orchitis model. In this model, the phagocytic activity of testicular macrophages (TM) was enhanced after melatonin treatment. Moreover, we found that melatonin suppressed secretion of TM pro-inflammatory factors by suppressing the p38MAPK pathway and promoting Leydig cell testosterone secretion. Expressions of GTP cyclohydrolase-I and NADPH oxidase-2 were reduced by melatonin while heme oxygenase-1 expression was up-regulated. Thus, melatonin reduced the severity of LPS-induced orchitis by stimulating antioxidant activity. The results of this study provide a reference for the treatment of acute infectious orchitis.

SUBMITTER: Deng SL

PROVIDER: S-EPMC7765110 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Melatonin Ameliorates Inflammation and Oxidative Stress by Suppressing the p38MAPK Signaling Pathway in LPS-Induced Sheep Orchitis.

Deng Shou-Long SL Zhang Bao-Lu BL Reiter Russel J RJ Liu Yi-Xun YX

Antioxidants (Basel, Switzerland) 20201214 12

Gram-negative bacterial infections of the testis can lead to infectious orchitis, which negatively influences steroid hormone synthesis and spermatogenesis. Lipopolysaccharide (LPS), a major component of the Gram-negative bacterial cell wall, acts via toll like receptors 4 (TLR4) to trigger innate immune responses and activate nuclear factor kappa B signaling. The protective mechanisms of melatonin on LPS-induced infectious orchitis have not been reported. Herein, we developed an LPS-induced she ...[more]

PMID: 33327643

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Project description:Background: Rheumatoid arthritis (RA) is a chronic autoimmune disorder, characterized by an increased number of M1-like macrophages in the joints. Polyphyllin I (PPI), one of the main components in the Rhizoma of Paris polyphyllin, displays a selective inhibitory effect on various tumor cells. Here we sought to investigate the anti-rheumatoid arthritis effects and mechanisms of PPI on macrophages in vivo and in vitro. Materials and Methods:In vitro, primary bone marrow-derived macrophages (BMMs) and peritoneal elucidated macrophages (PEMs) were stimulated by lipopolysaccharide (LPS) and Interferon (IFN)-γ and then treated with PPI. We determined the degree of activation of IKKα/β and p65, two key mediators of the NF-κB-mediated inflammatory pathway, by measuring their phosphorylated forms by Western blot. The p65 nuclear localization was detected by immunofluorescent staining. Further, a NF-κB-linked luciferase reporter plasmid, as well as those expressing key mediators of the Toll-like receptor 4 pathway, such as myeloid differentiation primary response 88 (MYD88), interleukin-1 receptor (IL-1R) associated kinase (IRAK)-1, TNF receptor associated factors (TRAF)-6, Transforming growth factor-b-activated kinase 1 (TAK1) and p65, were used to identify the mechanism by which PPI achieves its inhibitory effects on macrophage-mediated inflammation. Moreover, a NF-κB inhibitor, p65-targeted siRNAs, and a p65 plasmid were further used to validate the anti-inflammatory mechanism of PPI. In vivo, PPI (1 mg/kg) was administered intragastrically one time a day for 7 weeks starting on the 42nd day after the first immunization with collagen in a collagen-induced arthritis (CIA) mouse model. Micro-computed Tomography scanning, histological examination, F4/80 and iNOS double immunofluorescent staining and CD4 immunohistochemical staining were performed to determine the effect of PPI treatment on joint structure and inflammation in this model. Results: PPI reduced the inflammatory cytokines production of PEMs stimulated by LPS/IFN-γ, inhibited the phosphorylation of IKKα/β and p65, and prevented p65 nuclear localization. The NF-κB luciferase assay showed that the target of PPI was closely related to the NF-κB pathway. Moreover, NF-κB inhibition, siRNA-mediated knockdown of p65, and p65 overexpression eliminated PPI's inhibitory effect. In addition, PPI attenuated the bone erosion and synovitis, as well as M1-like macrophage and T cell infiltration, in the ankle joint of the CIA model. Conclusion: PPI demonstrated effective amelioration of synovial inflammation in the ankle joint of CIA mice while suppressing NF-κB-mediated production of pro-inflammatory effectors in activated macrophages.

Project description:BackgroundBenign prostatic hyperplasia (BPH) is the most common urologic disease affecting aging men. The pathogenesis of BPH is multi-factorial, and chronic inflammation (CI) might be the central mechanism. Interleukin (IL)-27 signaling has been suggested as a modulator in autoimmune and inflammatory conditions. In this study, we used microarray experiments to analyze gene expression and molecular phenotypic associated with BPH progression, with a particular focus on CI and IL-27/IL-27RA signaling, and verified the microarray data in cell biology experiments.MethodsThirty BPH patients' specimens and clinical parameters were analyzed. BPH patients were divided into two groups based on the average prostate volume (41.5 mL): group 1, ≤40 mL; and group 2, >40 mL. Microarray experiments were conducted to identify differentially expressed genes (DEGs) by applying appropriate biostatistics to normalize and analyze the dataset. The candidate gene (IL27RA) was validated by quantitative reverse transcriptase-PCR (qRT-PCR) and immunohistochemistry (IHC). The interaction of IL27RA with genes involved in canonical inflammation-associated pathways was investigated by cell biology experiments.ResultsEighty-three percent of BPH specimens contained inflammatory infiltrates, and the predominant type was CI. The serum PSA levels and prevalence of CI were higher in group 2. Microarray experiments identified 361 DEGs between these 2 groups. IL27RA was down-regulated and associated with prominent CI in BPH tissues of group 2. Validated by qRT-PCR and IHC, the results showed IL-27RA might modulate CI and progression of BPH. Thus, we investigated the interaction of IL27RA with TLR4, IL6, and IL8, which were involved in inflammation-associated pathways. We found the activation of IL-27RA after IL-27 treatment led to phosphorylation of STAT1 and STAT3 in prostate epithelial cells. By comparative treatments with lipopolysaccharide (LPS), IL-27, or combination, we found that IL-27/IL-27RA signaling suppressed the production of inflammatory cytokines, IL-6 and IL-8, induced by LPS/TLR4 pathway.ConclusionsOur study revealed that down-regulation of IL27RA in prostate tissue was associated with higher prevalence of CI and BPH progression. IL-27/IL-27RA signaling suppressed the LPS/TLR4 pathway. We conclude the IL-27/IL-27RA signaling might modulate CI and provide potential therapeutic strategies to prevent BPH progression.

Dataset Information

Melatonin Ameliorates Inflammation and Oxidative Stress by Suppressing the p38MAPK Signaling Pathway in LPS-Induced Sheep Orchitis.

Publications

Melatonin Ameliorates Inflammation and Oxidative Stress by Suppressing the p38MAPK Signaling Pathway in LPS-Induced Sheep Orchitis.

Similar Datasets

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