BACKGROUND AND PURPOSEInflammation is involved in the development and/or progression of many diseases including diabetic complications. Investigations on novel anti-inflammatory agents may offer new approaches for the prevention of diabetic nephropathy. Our previous bioscreening of synthetic analogues of curcumin revealed C66 as a novel anti-inflammatory compound against LPS challenge in macrophages. In this study, we hypothesized that C66 affects high glucose (HG)-induced inflammation profiles in vitro and in vivo and then prevents renal injury in diabetic rats via its anti-inflammatory actions.
EXPERIMENTAL APPROACHPrimary peritoneal macrophages (MPM), prepared from C57BL/6 mice, were treated with HG in the presence or absence of C66. Diabetes was induced in Sprague-Dawley rats with streptozotocin, and the effects of C66 (0.2, 1.0 or 5.0 mg·kg -1 ), administered daily for 6 weeks, on plasma TNF-a levels and expression of inflammatory genes in the kidney were assessed.
KEY RESULTSPretreatment of MPMs with C66 reduced HG-stimulated production of TNF-a and NO, inhibited HG-induced IL-1b, TNF-a, IL-6, IL-12, COX-2 and iNOS mRNA transcription, and the activation of JNK/NF-kB signalling. In vivo, C66 inhibited the increased plasma TNF-a levels and renal inflammatory gene expression, improved histological abnormalities and fibrosis of diabetic kidney, but did not affect the hyperglycaemia in these diabetic rats.
CONCLUSIONS AND IMPLICATIONSThe anti-inflammatory effects of C66 are mediated by inhibiting HG-induced activation of the JNK/NF-kB pathway, rather than by reducing blood glucose in diabetic rats. This novel compound is a potential anti-inflammatory agent and might be beneficial for the prevention of diabetic nephropathy.
Major anti-inflammatory agents, steroids and cyclooxygenase, were proved to have serious side effects. Here, a series of chalcone derivatives were synthesized and screened for anti-inflammatory activities. QSAR study revealed that the presence of electron-withdrawing groups in B-ring and electron-donating groups in A-ring of chalcones was important for inhibition of LPS-induced IL-6 expression. Further, compounds 22, 23, 26, 40, and 47 inhibited TNF-α and IL-6 release in a dose-dependent manner and decreased LPS-induced TNF-α, IL-1β, IL-6, IL-12, and COX-2 mRNA production. Mechanistically, compounds 23 and 26 interfered with JNK/NF-κB signaling and dose-dependently prevented ERK and p38 activation. In addition, 23 and 26 exhibited a significant protection against LPS-induced death and were able to block high glucose-activated cytokine profiles in macrophages. Together, these data show a series of anti-inflammatory chalcones with potential therapeutic effects in inflammatory diseases.
BackgroundEnterovirus 71 (EV71) is a major causative agent of hand, foot and mouth disease, which has been prevalent in Asia–Pacific regions, causing significant morbidity and mortality in young children. Antibodies elicited by experimental EV71 vaccines could neutralize infection in vitro and passively protect animal models from lethal challenge, indicating that neutralizing antibodies play an essential role in protection. However, how neutralizing antibodies inhibit infection in vitro remains unclear.Methods/FindingsIn the present study, we explored the mechanisms of neutralization by antibodies against EV71 virus-like particles (VLPs). Recombinant VLPs of EV71 genotype C4 were produced in insect cells using baculovirus vectors. Immunization with the VLPs elicited a high-titer, EV71-specific antibody response in mice. Anti-VLP mouse sera potently neutralized EV71 infection in vitro. The neutralizing antibodies in the anti-VLP mouse sera were found to target mainly an extremely conserved epitope (FGEHKQEKDLEYGAC) located at the GH loop of the VP1 protein. The neutralizing anti-VLP antisera were able to inhibit virus binding to target cells efficiently. In addition, post-attachment treatment of virus-bound cells with the anti-VLP antisera also neutralized virus infection, although the antibody concentration required was higher than that of the pre-attachment treatment.ConclusionsCollectively, our findings represent a valuable addition to the understanding of mechanisms of EV71 neutralization and have strong implications for EV71 vaccine development.
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