The effects of perfluorononanoic acid (PFNA) on the immune system and its mechanism of action in mice have not been elucidated. Thus, BALB/c mice were exposed to the PFNA (0, 1, 3, or 5 mg/kg/day) for fourteen days. Exposure to PFNA led to a decrease in body weight and in the weight of the lymphoid organs. Cell cycle arrest and apoptosis were observed in the spleen and thymus following PFNA exposure. In the thymus, PFNA mostly modulated CD4+CD8+ thymocytes, whereas the F4/80+, CD11c+, and CD49b+ cells were major targets in the spleen. Although concanavalin A-induced T lymphocyte blastogenesis was not altered by PFNA, production of interleukin (IL)-4 and interferon-gamma by splenic lymphocytes was remarkably impaired. The levels of cortisol and adrenocorticotrophic hormone in sera were increased; however, the expression of glucocorticoid receptor in the thymus was unchanged. In addition, expression of the peroxisome proliferator-activated receptors (PPAR-alpha and PPAR-gamma) and IL-1beta were upregulated significantly in the thymus at a dose of 1 mg PFNA/kg/day. No significant changes in expression of the inhibitory protein IkappaBalpha and IkappaBalpha kinase were observed. Together, these results suggest that PFNA exerts toxic effects on lymphoid organs and T cell and innate immune cell homeostasis in mice and that these effects may result from the activation of PPAR-alpha, PPAR-gamma, and the hypothalamic-pituitary-adrenal axis. Interestingly, at the transcriptional level, the nuclear factor-kappa B signaling pathway appears to be uninvolved in the immunotoxic potential of PFNA.
Various investigations have demonstrated that human fibroblast-like synoviocytes rheumatoid arthritis (HFLS-RA) take part in the chronic inflammatory responses and RA progression. Inhibition of synovium activation and inflammatory processes may represent a therapeutic target to alleviate RA. Paeonol, a major natural product, has many biological and pharmacological activities. However, its protective effects against RA considering HFLS-RA have not been explored. In this study, anti-inflammatory effects of paeonol were detected in interleukin-1β (IL-1β)-treated HFLS-RA. Our results demonstrated that paeonol had no effect on cell survival and IL-1β-induced proliferation in HFLS-RA. Pretreatment with paeonol significantly suppressed the production of pro-inflammatory TNF-α, IL-6 and IL-1β, and the expressions of matrix metalloproteinase-1/-3 in vitro and in vivo. Mice treated with paeonol (10 mg/kg) remarkablely attenuated arthritic symptoms based on clinical arthritis scores and histopathology in collagen-induced arthritis mice. Furthermore, the TLR4 expression and NF-κB p65 activation were inhibited by paeonol in vitro and in vivo. Our findings illustrated that paeonol had significantly suppressed inflammation effects in synovial tissues and RA progression. The potential mechanism might be based on the attenuation TLR4-NF-κB activation. These collective results indicated that paeonol might be a promising therapeutic agent for alleviating RA progress through inhibiting inflammations and NF-κB signalling pathway.
During the traumatic brain injury (TBI), improved expression of circulatory miR-21 serves as a diagnostic feature. Low levels of exosome-miR-21 in the brain can effectively improve neuroinflammation and blood–brain barrier (BBB) permeability, reduce nerve apoptosis, restore neural function and ameliorate TBI. We evaluated the role of macrophage derived exosomes-miR-21 (M-Exos-miR-21) in disrupting BBB, deteriorating TBI, and Rg1 interventions. IL-1 β -induced macrophages (IIM)-Exos-miR-21 can activate NF- κ B signaling pathway and induce the expressions of MMP-1, -3 and -9 and downregulate the levels of tight junction proteins (TJPs) deteriorating the BBB. Rg1 reduced miR-21-5p content in IIM-Exos (RIIM-Exos). The interaction of NMIIA–HSP90 controlled the release of Exos-miR-21, this interaction was restricted by Rg1. Rg1 could inhibit the Exos-miR-21 release in peripheral blood flow to brain, enhancing TIMP3 protein expression, MMPs proteolysis, and restricting TJPs degradation thus protected the BBB integrity. Conclusively, Rg1 can improve the cerebrovascular endothelial injury and hold the therapeutic potential against TBI disease.
Concentrations of perfluorononanoate (PFNA) suggest an obvious increase in the environment, wildlife, and humans. However, the potential toxicity of PFNA still remains to be fully elucidated. Our present work is directed toward evaluating specific thyroid endpoints, and studying the long-term and the trans-generational effects of PFNA on zebrafish. Zebrafish (Danio rerio) were exposed to different concentrations of PFNA (0, 0.05, 0.1, 0.5, and 1 mg/l) from their early life stages (F(0), 23 day post-fertilization dpf), and the exposure period lasted for 180 days. At the end of the exposure period, thyroid follicle histology and plasma thyroid hormone levels in male zebrafish were evaluated as direct endpoints for the specific thyroid toxicities, while gene expression relative to the hypothalamus-pituitary-thyroid axis was also investigated to study the underlying mechanisms. In addition, offspring embryos (F(1)) from the PFNA exposure parental zebrafish was reared in water either without PFNA or under continual exposure to PFNA for an additional 180 days to investigate effects of multi-generational exposures on the circulating T(3) levels and thyroid-associated gene expression. Our results demonstrate significantly elevated plasma T(3) levels were observed in both F(0) and F(1) adults, as well as PFNA-induced histological changes in the thyroid follicles of F(0) male zebrafish. In the liver, the abundance of gene transcript encoding the protein transthyretin (TTR) was significantly induced, while the expression of UDP-glucuronosyltransferases in F(0) adult males was inhibited. The induced thyroid-disrupting effects also demonstrated a trans-generational effect that was reflected by altered gene expression related to thyroid hormone (TH) synthesis and metabolism in F(1) larvae. Our results provide the first evidence for the thyroid-disrupting effects of long-term PFNA exposure in zebrafish.
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