The cause of chronic inflammatory periodontitis, which leads to the destruction of periodontal ligament and alveolar bone, is multifactorial. An increasing number of studies have shown the clinical significance of NLRP3-mediated low-grade inflammation in degenerative disorders, but its causal linkage to age-related periodontitis has not yet been elucidated. In this study, we investigated the involvement of the NLRP3 inflammasome and the therapeutic potential of NLRP3 inhibition in age-related alveolar bone loss by using in vivo and in vitro models. The poor quality of alveolar bones in aged mice was correlated with caspase-1 activation by macrophages and elevated levels of IL-1β, which are mainly regulated by the NLRP3 inflammasome, in periodontal ligament and serum, respectively. Aged mice lacking Nlrp3 showed better bone mass than age-matched wild-type mice via a way that affects bone resorption rather than bone formation. In line with this finding, treatment with MCC950, a potent inhibitor of the NLRP3 inflammasome, significantly suppressed alveolar bone loss with reduced caspase-1 activation in aged mice but not in young mice. In addition, our in vitro studies showed that the addition of IL-1β encourages RANKL-induced osteoclastogenesis from bone marrow–derived macrophages and that treatment with MCC950 significantly suppresses osteoclastic differentiation directly, irrelevant to the inhibition of IL-1β production. Our results suggest that the NLRP3 inflammasome is a critical mediator in age-related alveolar bone loss and that targeting the NLRP3 inflammasome could be a novel option for controlling periodontal degenerative changes with age.
Doxorubicin in combination with other cytotoxic drugs has clinical advantages. However, doxorubicin-induced cardiotoxicity negatively impacts clinical utility and outcomes. Cardiotoxicity can result from increased oxidative stress or from a local cytochrome P450 mediated increase in 20-hydroxy-5, 8, 11, 14-eicosatetraenoic acid (20-HETE). Oleanolic acid (OA) is a natural pentacyclic triterpenoid with free radical scavenging, cardioprotective, and P450-mediated cyclooxygenase-upregulating properties. We investigated co-delivery of liposomal OA and doxorubicin in a HepG2 model of hepatocellular carcinoma (HCC). OA attenuated the cardiotoxicity induced by doxorubicin without compromising its anticancer activity. Apoptosis assays revealed that co-delivery of DOX and OA produced a synergistic anticancer effect. However, the drugs had antagonistic effects on cardiomyocytes. Female BALB/c nude mice treated with OA-and DOX-loaded liposomes (ODLs) exhibited reduced tumor growth, stable body weight, and stable organ indices. Reduced 20-HETE production suggested ODLs had limited cardiotoxicity. No changes in biochemical or histopathological markers were observed in mice treated with ODLs. Tailored co-delivery of OA and DOX may thus be an effective therapeutic strategy for treating HCC.
1 Interleukin-12 (IL-12) plays a central role in the immune system by driving the immune response towards T helper 1 (Th1) type responses characterized by high IFN-g and low IL-4 production. In this study we investigated whether retinoid-mediated inhibition of interleukin-12 production in mouse macrophages could regulate cytokine pro®le of antigen (Ag)-primed CD4 + Th cells. 2 Pretreatment with retinoids (9-cis-RA, all-trans-RA, TTNPB) signi®cantly inhibited IL-12 production by mouse macrophages stimulated with lipopolysaccharide (LPS) or heated-killed Listeria monocytogenes (HKL). Retinoid-pretreated macrophages reduced their ability to induce IFN-g and increased the ability to induce IL-4 in Ag-primed CD4 + T cells. 3 Addition of recombinant IL-12 to cultures of retinoid-pretreated macrophages and CD4 + T cells restored IFN-g production in CD4 + T cells. 4 The in vivo administration of 9-cis-RA resulted in the inhibition of IL-12 production by macrophages stimulated in vitro with either LPS or HKL, leading to the inhibition of Th1 cytokine pro®le (decreased IFN-g and increased IL-4 production) in CD4 + T cells. 5 These ®ndings may explain some known e ects of retinoids including the inhibition of encephalitogenicity, and point to a possible therapeutic use of retinoids in the Th1-mediated immune diseases such as autoimmune diseases.
This study investigated the potential adverse effects of amitraz on the initiation and maintenance of pregnancy in Sprague-Dawley rats as well as its effects on embryo-fetal development after maternal exposure during the entire pregnancy period. Amitraz was administered to pregnant rats by gavage from days 1 to 19 of gestation at dose levels of 0, 3, 10, and 30 mg/kg/day. All dams underwent a caesarean section on day 20 of gestation and their fetuses were examined for any external, visceral, and skeletal abnormalities. At 30 mg/kg, maternal toxicity manifested as an increase in the incidence of abnormal clinical signs and a lower body weight gain and food intake. Developmental toxicity included an increase in the fetal death rate, a decrease in the litter size, and a reduction in the fetal body weight. In addition, there was an increase in the incidence of fetal external, visceral, and skeletal abnormalities. At 10 mg/kg, maternal toxicity observed included a decrease in the body weight gain and a decrease in food intake. In addition, minimal developmental toxicity, including a decrease in the fetal body weight, an increase in the visceral and skeletal aberrations, and a delay in fetal ossification. There were no signs of either maternal toxicity or developmental toxicity at 3 mg/kg. These results show that amitraz administered during the entire pregnancy period in rats is embryotoxic and teratogenic at the maternally toxic dose (i.e., 30 mg/kg/day) and is minimally embryotoxic at a minimally maternally toxic dose (i.e., 10 mg/kg/day). Under these experimental conditions, the no-observed-adverse-effect level of amitraz for both dams and embryo-fetal development is estimated to be 3 mg/kg/day.
1 Transcription factors such as NF-kB provide powerful targets for drugs to use in the treatment of cancer. In this report parthenolide (PT), a sesquiterpene lactone of herbal remedies such as feverfew (Tanacetum parthenium) with NF-kB inhibitory activity, markedly increased the degree of human leukaemia HL-60 cell dierentiation when simultaneously combined with 5 nM 1a,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ). PT by itself did not induce HL-60 cell dierentiation. 2 Cyto¯uorometric analysis indicated that PT stimulated 1,25-(OH) 2 D 3 -induced dierentiation of HL-60 cells predominantly into monocytes. 3 Pretreatment of HL-60 cells with PT before the 1,25-(OH) 2 D 3 addition also potentiated the 1,25-(OH) 2 D 3 -induced HL-60 cell dierentiation in both a dose-and a time-dependent manner, in which the enhanced levels of cell dierentiation closely correlated with the inhibitory levels of NF-kB binding activity by PT. 4 In contrast, santonin, a sesquiterpene lactone without an inhibitory activity of NF-kB binding to the kB sites, did not enhance the 1,25-(OH) 2 D 3 -induced HL-60 cell dierentiation. 5 In transfection experiments, PT enhanced 1,25-(OH) 2 D 3 -induced VDRE-dependent promoter activity. Furthermore, PT restored 1,25-(OH) 2 D 3 -induced VDRE-dependent promoter activity inhibited by TNF-a, an activator of NF-kB signalling pathway. 6 These results indicate that PT strongly potentiates the 1,25-(OH) 2 D 3 -induced HL-60 cell dierentiation into monocytes via the inhibition of NF-kB activity and provide evidence that inhibition of NF-kB activation can be a pre-requisite to the ecient entry of promyelocytic leukaemia cells into a dierentiation pathway.
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