Lactational exposure to environmentally relevant benzo(a)pyrene causes astrocytic activation and anxiety-like behavior in male mice.

Previous studies have shown the adversely neurodevelopmental effects of exposure to benzo(a)pyrene (BaP) at early life stage. However, it is unclear the effects of lactational exposure to environmentally relevant BaP on anxiety-like behavior and the molecular mechanisms related. In this study, lactational exposure to 1 and 10 µg/kg bw BaP from postnatal day 3-21 caused anxiety-like behavior and alterations of the expressions of the neurodevelopment and anxiety-related genes in adolescence male mice using O cycle maze. Moreover, BaP exposure increased the expression level of glial fibrillary acidic protein, a typical marker of astrocytes, in hippocampus of male offspring. The release of pro-inflammatory cytokines interleukin 6 and tumor necrosis factor α was also elevated in BaP-treated offspring. Further, lactational exposure to BaP decreased the level of glutathione and the expressions of antioxidant genes (Thioredoxin 1 and Glutaredoxin 2) in male offspring. Our study demonstrated that environmentally relevant BaP lactational exposure caused anxiety-like behavior in male offspring involved in astrocytic activation, neuroinflammation, and antioxidant capability dysfunction.

Downregulation of mitochondrial cyclooxygenase-2 inhibits the stemness of nasopharyngeal carcinoma by decreasing the activity of dynamin-related protein 1.

Cancer stem cells (CSCs) are a small subset of malignant cells, possessing stemness, with strong tumorigenic capability, conferring resistance to therapy and leading to the relapse of nasopharyngeal carcinoma (NPC). Our previous study suggested that cyclooxygenase-2 (COX-2) would be a novel target for the CSCs-like side population (SP) cells in NPC. In the present study, we further found that COX-2 maintained the stemness of NPC by enhancing the activity of mitochondrial dynamin-related protein 1 (Drp1), a mitochondrial fission mediator, by studying both sorted SP cells from NPC cell lines and gene expression analyses in NPC tissues. Using both overexpression and knockdown of COX-2, we demonstrated that the localization of COX-2 at mitochondria promotes the stemness of NPC by recruiting the mitochondrial translocation of p53, increasing the activity of Drp1 and inducing mitochondrial fisson. Inhibition of the expression or the activity of Drp1 by siRNA or Mdivi-1 downregulates the stemness of NPC. The present study also found that inhibition of mitochondrial COX-2 with resveratrol (RSV), a natural phytochemical, increased the sensitivity of NPC to 5-fluorouracil (5-FU), a classical chemotherapy drug for NPC. The underlying mechanism is that RSV suppresses mitochondrial COX-2, thereby reducing NPC stemness by inhibiting Drp1 activity as demonstrated in both the in vitro and the in vivo studies. Taken together, the results of this study suggest that mitochondrial COX-2 is a potential theranostic target for the CSCs in NPC. Inhibition of mitochondrial COX-2 could be an attractive therapeutic option for the effective clinical treatment of therapy-resistant NPC.

Protein phosphatase 2A-B55δ enhances chemotherapy sensitivity of human hepatocellular carcinoma under the regulation of microRNA-133b.

BACKGROUND: Hepatocellular carcinoma (HCC) remains a major public health problem worldwide. The identification of effective chemotherapeutic targets for advanced HCC patients is urgently required. In this study, we investigated the role of protein phosphatase 2A-B55δ subunit (PP2A-B55δ, encoded by the PPP2R2D gene) and related mechanisms affecting chemotherapy sensitivity of HCC. METHODS: Experimental approaches for measuring the levels of PPP2R2D mRNA and B55δ protein in HCC included bioinformatics analyses, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting (WB), immunofluorescence and immunohistochemistry assays. Cell cycle, migration, colony formation, apoptosis, and cell proliferation assays in stable PPP2R2D-knockdown and -overexpression cell lines in vitro, and tumorigenicity assays in vivo, were performed to explore the function of B55δ in cisplatin (cDDP) chemotherapy of HCC. Bioinformatics prediction, luciferase reporter assays, qRT-PCR, WB, and cell cycle analyses were used to reveal the regulatory relationship between microRNA-133b (miR-133b) and PPP2R2D expression. miR-133b mimic and inhibitor were used to elucidate the regulatory mechanism. RESULTS: Our studies showed that PPP2R2D expression was down-regulated in both HCC tumors and HCC cell lines. Treatment with cDDP increased the amount of B55δ protein. Artificially increasing the expression of B55δ counteracted cyclin-dependent kinase 1 activation, modulated transitions of the cell cycle, and increased the suppressive effect of cDDP on cell migration, colony formation, apoptosis, and proliferation in vitro and tumor growth in vivo, thus enhancing therapeutic efficiency. In contrast, knockdown of B55δ partially inhibited the effect of cDDP chemotherapy. miR-133b was shown to regulate PPP2R2D expression by binding to the 3'-untranslated region of PPP2R2D mRNA. The miR-133b/PPP2R2D signaling pathway affects the effectiveness of cDDP chemotherapy. CONCLUSIONS: PP2A-B55δ, regulated by miR-133b, enhances the sensitivity of HCC to cDDP chemotherapy. Our data indicate that PP2A-B55δ might be a novel and attractive target for increasing chemotherapy sensitivity of HCC.

[Changes of historical Paragonimus metacercaria infection rates of freshwater crabs in Yongjia County].

OBJECTIVE: To understand the changes of Paragonimus metacercaria infection rates of freshwater crabs in Paragonimus endemic areas and explore the causes in Yongjia County, Zhejiang Province, China. METHODS: A field investigation was carried out. The freshwater crabs were collected and the metacercaria were separated from the crabs. The infection rates, infectiosities and infection indexes were calculated and the results were vertically compared with the historical findings. The causes of the changes were discussed. RESULTS: Compared with those in 1980, the average infection rate in original endemic areas decreased from 59.71% to 21.50% (P < 0.05), while the infection density decreased from 1.09/g to 0.23/g (P < 0.05). The infection index decreased obviously. In Hesheng Village, it decreased from 4.05 to 0.01 (P < 0.01), in Wuchi Village, it was from 37.90 to 2.91 (P <0.01), and in Daruoyan Scinic area,it was from 5.85 to 0.03 (P < 0.01). Two endemic areas disappeared but two new endemic areas (Sihai Village and Sunshan Village) were found, and in Sunshan Village, the metacercaria infection rate was 100%, the infection density and infection index were 21.30/g and 3 402.68 respectively, which meant it was a super high endemic focus. CONCLUSION: The Paragonimus metacercaria infection rate in crabs is lower than before in Yongjia County, but some super high epidemic focus of paragonimiasis still exists. Therefore, we still should strengthen the control measures.