The ratio of M1/M2 macrophages in epicardial adipose tissue of CAD patients is changed compared with that in non-CAD patients. Human coronary atherosclerosis is associated with macrophage polarization in epicardial adipose tissue.
Here we review epidemiologic studies dealing with the dietary intake and the body burden of polychlorinated dibenzo-p-dioxins (PCDDs)/polychlorinated dibenzo-furans (PCDFs)/ polychlorinated biphenyls (PCBs) in the general population, and potential adverse health effects of these substances, especially on the risk of diabetes mellitus and endometriosis, and on thyroid function and the neurodevelopment of infants. The mean or median intake of dioxin-related compounds among the general populations of various countries is lower than the maximum tolerable daily intake (TDI) set by the WHO in 1998 (4pg TEQ/kg/day). However, there have been few reports on the distribution of intake and the proportion of subjects whose exposure levels exceed the maximum TDL. At present, it remains unclear whether background exposure to dioxin-related compounds is associated with increased risk of diabetes (because of lack of longitudinal studies), endometriosis (because of lack of studies with sufficient statistical power), or altered thyroid function (because of inconsistent results on humans). Consistent results have been reported for the association between exposure to background levels of PCBs/dioxins, especially trans-placental PCBs, and defective neurodevelopment of infants in the U.S. and Europe. Thus, efforts should be made to further decrease the body burden among women of reproductive age by reducing the release of PCDDs/PCDFs/PCBs into the environment.
The antitumor activity of pladienolide B, a novel splicing inhibitor, against gastric cancer is totally unknown and no predictive biomarker of pladienolide B efficacy has been reported. We investigated the antitumor activity of pladienolide B and its derivative on gastric cancer cell lines and primary cultured cancer cells from carcinomatous ascites of gastric cancer patients. The effect of pladienolide B and its derivative on six gastric cancer cell lines was investigated using a MTT assay and the mean IC50 values determined to be 1.6 ± 1.2 (range, 0.6–4.0) and 1.2 ± 1.1 (range, 0.4–3.4) nM, respectively, suggesting strong antitumor activity against gastric cancer. The mean IC50 value of pladienolide B derivative against primary cultured cells from 12 gastric cancer patients was 4.9 ± 4.7 nM, indicative of high antitumor activity. When 18 SCID mice xenografted with primary cultured cells from three patients were administered the pladienolide B derivative intraperitoneally, all tumors completely disappeared within 2 weeks after treatment. Histological examination revealed a pathological complete response for all tumors. In the xenograft tumors after treatment with pladienolide B derivative, immature mRNA were detected and apoptotic cells were observed. When the expressions of cell-cycle proteins p16 and cyclin E in biopsied gastric cancer specimens were examined using immunohisctochemistry, positivities for p16 and cyclin E were significantly and marginally higher, respectively, in the low-IC50 group compared with the high-IC50 group, suggesting the possibility that they might be useful as predictive biomarkers for pladienolide B. In conclusion, pladienolide B was very active against gastric cancer via a mechanism involving splicing impairment and apoptosis induction.
Paraquat has previously been shown to cause the oxidative damage to DNA in variety of cells and tissues. However, although paraquat‐evoked strand breaks has been extensively studied to assess the DNA damage, the effect of paraquat on base modifications, another marker for the oxidative damage, has not yet been investigated. To further characterize paraquat‐evoked DNA damage, the effect of paraquat on 8‐hydroxy‐deoxyguanosine (8‐OH‐dG) formation in various rat organs was examined. Paraquat markedly increased 8‐OH‐dG contents in various organs, particularly in brain, lung and heart, and this increase reached the maximum levels at 5 days after the drug administration. In contrast, the formation of 8‐hydroxy‐guanosine (8‐OH‐G), a marker for the oxidative damage to RNA, was not significantly affected by paraquat. These results indicate that paraquat causes base modifications as well as strand breaks as a consequence of the oxidative damage to DNA.
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