Aflatoxin B1 (AFB1) has been postulated to be a hepatocarcinogen in humans, possibly by causing p53 mutations at codon 249. AFB1 is metabolized via the phase I and II detoxification pathways; hence, genetic variation at those loci may predict susceptibility to the effects of AFB1. To test this hypothesis, genetic variation in two AFB1 detoxification genes, epoxide hydrolase (EPHX) and glutathione S-transferase Ml (GSTM1), was contrasted with the presence of serum AFB,-albumin adducts, the presence of hepatocellular carcinoma (HCC), and with p53 codon 249 mutations. Mutant alleles at both loci were significantly overrepresented in individuals with serum AFB1-albumin adducts in a crosssectional study. Mutant alleles of EPHX were significantly overrepresented in persons with HCC, also in a case-control study. The relationship of EPHX to HCC varied by hepatitis B surface antigen status and indicated that a synergistic effect may exist. p53 codon 249 mutations were observed only among HCC patients with one or both high-risk genotypes. These results indicate that individuals with mutant genotypes at EPHX and GSTM1 may be at greater risk of developing AFB1 adducts, p53 mutations, and HCC when exposed to AFB1. Hepatitis B carriers with the high-risk genotypes may be an even greater risk than carriers with low-risk genotypes. These findings support the existence of genetic susceptibility in humans to the environmental carcinogen AFB1 and indicate that there is a synergistic increase in risk of HCC with the combination of hepatitis B virus infection and susceptible genotype.Primary hepatocellular carcinoma (HCC) is a tumor that occurs at high frequencies in east Asia and subSaharan Africa. In those areas of the world, chronic infection with the hepatitis B-virus (HBV) is the best described risk factor; however, only 20-25% of HBV carriers develop HCC. Exposure to the mycotoxin aflatoxin B1 (AFB1) has also been suggested to increase HCC risk (1), in part because in vitro experiments have demonstrated that AFB1 mutagenic metabolites bind to DNA and are capable of inducing G-to-T transversions (2).In certain areas of the HCC endemic regions, an unusual mutational hot spot has been reported in the p53 tumor suppressor gene (3)(4)(5)(6)(7)(8). This mutation, at the third base of codon 249 in exon 7, is an AGG-to-AGT transversion (arginine to serine). HCCs from other areas of the world have been reported to have markedly lower frequencies of codon 249 mutations (9-16). The geographic distribution of these mutations and the similarity to the transversions produced in vitro by AFB1 suggested to investigators that exposure to AFB1 caused the mutations (3, 4). Recent demonstration of the preferential mutability of codon 249 by rat liver microsome-activated AFB1 in HepG2 cells has supported the hypothesis (17).While rates of chronic HBV infection and AFB1 exposure are both elevated in HCC endemic areas, HCC rates in those regions of Asia are an order of magnitude higher than are the rates in areas of Africa with comparable e...

Psoralen and angelicin are two effective compounds isolated from psoraleae, a traditional Chinese medicine. They have a wide range of applications for bone disease treatment and immune modulation. In this study, we explored their new applications for the treatment of periodontal diseases. This study aimed to investigate the effects of psoralen and angelicin on Porphyromonas gingivalis growth and P. gingivalis-derived lipopolysaccharide (Pg-LPS)-induced inflammation, and further to evaluate their effects on osteogenesis. Finally, the effects of angelicin on a mouse model of periodontitis were also investigated. The results showed that psoralen and angelicin had beneficial dose-dependent effects regarding the inhibition of planktonic P. gingivalis and biofilms of P. gingivalis. There were no significant differences in the viability of monocyte-like THP-1 cells and human periodontal ligament cells (hPDLCs) treated with either psoralen or angelicin compared to the untreated control cells. Psoralen and angelicin also markedly decreased the mRNA expression and release of inflammatory cytokines (interleukin [IL]-1β and IL-8) by THP-1 cells in a dose-dependent manner. They significantly enhanced the alkaline phosphatase (ALP) activity of hPDLCs and up-regulated the expression of osteogenic proteins (runt-related transcription factor 2 [RUNX2], distal-less homeobox 5 [DLX5], and osteopontin [OPN]). Angelicin significantly attenuated alveolar bone loss and inflammation response in the mice with periodontitis. In conclusion, our data demonstrated that psoralen and angelicin could inhibit the growth of planktonic P. gingivalis and P. gingivalis biofilm. It is also the first report on the anti-inflammatory effect of psoralen and angelicin against Pg-LPS. They also had an osteogenesis-potentiating effect on hPDLCs. The in vivo study also indicated the effect of angelicin regarding protection against periodontitis. Our study highlighted the potential ability of psoralen and angelicin to act as novel natural agents to prevent and treat periodontitis.

Background Periodontitis is one of the most common oral diseases and is a potential risk factor for systemic diseases. In this study, we aimed to investigate the association between periodontitis and learning and memory impairment. Methods We established a periodontitis model by topical application of Porphyromonas gingivalis lipopolysaccharide ( P. gingivalis -LPS) into the palatal gingival sulcus of the maxillary first molars of 10-week-old male rats for a 10-week period. We assessed alveolar bone resorption using micro–computed tomography analysis and learning and memory ability using the Morris water maze test. We determined the levels of cytokines [interleukin (IL)-1β, IL-6, IL-8, and IL-21] and LPS in the peripheral blood and cortex, as well as toll-like receptor 4 (TLR4)/NF-κB signaling pathway activation, using reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and western blot. We determined activation of microglia and astrocytes, expression of Aβ1-42, APP and Tau by immunohistochemistry. Finally, we measured the expression of amyloid precursor protein (APP) and its key secretases, as well as the Aβ1-40/1-42 ratio, by RT-PCR, western blot, and ELISA. Results We found that periodontitis induced learning and memory impairment in the rats. Further, we observed that it induced significant alveolar bone resorption. There was an increase in the levels of inflammatory cytokines and LPS. Moreover, we confirmed TLR4/NF-κB signaling pathway activation. We also observed activated microglia and astrocytes with enlarged cell bodies and irregular protrusions. Finally, we observed the promotion of β- and γ-secretases APP processing. Conclusion Our findings indicated that periodontitis was associated with learning and memory impairment, probably induced by neuroinflammation via activating the TLR4/NF-κB signaling pathway. Furthermore, abnormal APP processing could be involved in this progress.

Vertical heterojunction NiO/β n-Ga2O/n+ Ga2O3 rectifiers employing NiO layer extension beyond the rectifying contact for edge termination exhibit breakdown voltages (VB) up to 4.7 kV with a power figure-of-merits, VB2/RON of 2 GW·cm−2, where RON is the on-state resistance (11.3 mΩ cm2). Conventional rectifiers fabricated on the same wafers without NiO showed VB values of 840 V and a power figure-of-merit of 0.11 GW cm−2. Optimization of the design of the two-layer NiO doping and thickness and also the extension beyond the rectifying contact by TCAD showed that the peak electric field at the edge of the rectifying contact could be significantly reduced. The leakage current density before breakdown was 144 mA/cm2, the forward current density was 0.8 kA/cm2 at 12 V, and the turn-on voltage was in the range of 2.2–2.4 V compared to 0.8 V without NiO. Transmission electron microscopy showed sharp interfaces between NiO and epitaxial Ga2O3 and a small amount of disorder from the sputtering process.

Background Increasing evidence suggests a causal link between periodontitis and cognitive disorders. Systemic inflammation initiated by periodontitis may mediate the development of cognitive impairment. Our study aims to investigate the effect of ligature-induced periodontitis on cognitive function and the role of signal transducers and activators of transcription 3 (STAT3) in this process. Materials and methods Ligature-induced periodontitis was established, and the rats were treated intraperitoneally with/without the pSTAT3 inhibitor cryptotanshinone (CTS). Alveolar bone resorption and periodontal inflammation were detected by micro-computed tomography analysis and histopathological evaluation. Locomotor activity and cognitive function were evaluated by the open field test and the Morris water maze test, respectively. The activation of microglia and astrocytes in the hippocampus and cortex was assessed by immunohistochemistry (IHC). The expression of interleukins (IL-1β, IL-6, IL-8, IL-21) in both the periphery and cortex was evaluated by RT-PCR and ELISA. The expression of TLR/NF-κB and ROS cascades was evaluated by RT-PCR. The expression of pSTAT3 and the activation of the STAT3 signaling pathway (JAK2, STAT3, and pSTAT3) in the periodontal tissue and cortex were assessed by IHC and Western blot. The expression of amyloid precursor protein (APP) and its key secretases was evaluated by RT-PCR. The level of amyloid β-protein (Aβ) and the ratio of Aβ1-40/1-42 were measured via ELISA in the plasma and cortex while IHC was used to detect the level of Aβ1-42 in the brain. Results In periodontal ligature rats, significant alveolar bone resorption and local inflammatory cell infiltration were present. Apparent increases in inflammatory cytokines (IL-1β, IL-6, IL-8, and IL-21) were detected in peripherial blood and brain. Additionally, spatial learning and memory ability was impaired, while locomotor activity was not affected. Activated microglia and astrocytes were found in the cortex and hippocampus, presenting as enlarged cell bodies and irregular protrusions. Levels of TLR/NF-kB, PPAR and ROS were altered. The STAT3 signaling pathway was activated in both the periodontal tissue and cortex, and the processing of APP by β- and γ-secretases was promoted. The changes mentioned above could be relieved by the pSTAT3 inhibitor CTS. Conclusions Ligature-induced periodontitis in rats resulted in systemic inflammation and further abnormal APP processing, leading to cognitive impairments. In this progress, the activation of the STAT3 signaling pathway may play an important role by increasing inflammatory load and promoting neuroinflammation.

The band alignment of sputtered NiO on β-Ga2O3 was measured by x-ray photoelectron spectroscopy for post-deposition annealing temperatures up to 600 °C. The band alignment is type II, staggered gap in all cases, with the magnitude of the conduction and valence band offsets increasing monotonically with annealing temperature. For the as-deposited heterojunction, ΔE V = −0.9 eV and ΔE C = 0.2 eV, while after 600 °C annealing the corresponding values are ΔE V = −3.0 eV and ΔE C = 2.12 eV. The bandgap of the NiO was reduced from 3.90 eV as-deposited to 3.72 eV after 600 °C annealing, which accounts for most of the absolute change in ΔE V−ΔE C. Differences in thermal budget may be at least partially responsible for the large spread in band offsets reported in the literature for this heterojunction. Other reasons could include interfacial disorder and contamination. Differential charging, which could shift peaks by different amounts and could potentially be a large source of error, was not observed in our samples.

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