We synthesize the current literatures and use the power of meta-analysis to examine trends on association between hormone replacement therapy (HRT) and the risk of breast cancer (BC). We performed a comprehensive literature search using PubMed, EMBASE, and Web of Science from their inception until Jan 2017. Prospective studies that provided adjusted risk estimates of HRT and BC risk were eligible. Categorical and dose-response meta-analyses followed the PRISMA were conducted using random effects model and restricted cubic spline model, respectively. Forty-seven publications from thirty-five unique studies were included, involving 3,898,376 of participants and 87,845 of BC cases. Compared with non-users, RR for current estrogen-only therapy (ET) users was 1.14 (95% confidence interval (CI) = 1.05–1.22), and for per year increases was 1.02 (95% CI = 1.02–1.02). Moreover, RR for current estrogen plus progestin therapy (EPT) users was 1.76, (95% CI = 1.56–1.96), and for per year increases was 1.08 (95% CI = 1.08–1.08). Dose-response analyses revealed 8–10 years’ onset peaks, and indicated residual increased BC risk remained after stopping use of ET regimen rather than for EPT. Effect-modifiers like BMI, duration of use, race/ethnicity, routes of administration were recognized. In Conclusions, current use of EP or EPT and ever use of tibolone are associated with an elevated risk of BC. Compared with slim HRT users and non-users, lower BC risks were found among overweight/obese HRT users and former EPT users, respectively. Both ET and EPT users are associated with higher risk of lobular BC than ductal BC, and more ER-positive than negative BC cases were detected among EPT users.
1-Methylpyrene (1-MP) is a widespread pollutant that is carcinogenic in animals following metabolic activation. Previous studies have shown that benzylic hydroxylation of 1-MP, catalyzed by multiple CYP isoforms, gives rise to 1-hydroxymethylpyrene (1-HMP), which becomes bioreactive following further metabolism by various sulfotransferase (SULT) isoforms. However, the mutagenic and chromosome damaging effects of 1-MP and 1-HMP in mammalian cells have not been investigated. In this study a Chinese hamster V79-derived cell line expressing both human CYP2E1 and human SULT1A1 was used to investigate the ability of 1-MP and 1-HMP to induce cytotoxicity (using the CCK-8 assay), micronuclei and Hprt gene mutations. The role of each enzyme was investigated through co-exposure in the presence of an enzyme inhibitor. We found that at concentrations of 0.5-4 μM and 5-20 μM, under conditions where no reduction in cell viability/growth occurred, 1-HMP and 1-MP induced micronuclei in V79-hCYP2E1-hSULT1A1 cells in a concentration-dependent manner; however, both compounds were inactive in V79 cells. Similarly, they both caused an increase in Hprt mutant frequency in V79-hCYP2E1-hSULT1A1 cells in these concentration ranges, with 1-MP impairing cell viability/growth at 10 μM and above in the mutagenicity assay. The compounds were again both inactive in V79 cells. The effects of 1-HMP in V79-hCYP2E1-hSULT1A1 cells were blocked or reduced by addition of pentachlorophenol (PCP), a SULT1 inhibitor; the genotoxicity of 1-MP was significantly reduced by either 1-aminobenotrazole, a CYP2E1 inhibitor, or PCP. The results suggest that human CYP2E1 and SULT1A1 cooperate to activate 1-MP and cause genotoxicity in mammalian cells.
Kazal-type serine proteinase inhibitors are found in a large number of living organisms and play crucial roles in various biological and physiological processes. Although some Kazal-type serine protease inhibitors have been identified in leeches, none has been reported from Hirudinaria manillensis, which is a medically important leech. In this study, a novel Kazal-type trypsin inhibitor was isolated from leech H. manillensis, purified and named as bdellin-HM based on the sequence similarity with bdellin-KL and bdellin B-3. Structural analysis revealed that bdellin-HM was a 17,432.8 Da protein and comprised of 149 amino acid residues with six cysteines forming three intra-molecular disulfide bonds. Bdellin-HM showed similarity with the Kazal-type domain and may belong to the group of “non-classical” Kazal inhibitors according to its CysI-CysII disulfide bridge position. Bdellin-HM had no inhibitory effect on elastase, chymotrypsin, kallikrein, Factor (F) XIIa, FXIa, FXa, thrombin and plasmin, but it showed a potent ability to inhibit trypsin with an inhibition constant (Ki) of (8.12 ± 0.18) × 10−9 M. These results suggest that bdellin-HM from the leech of H. manillensis plays a potent and specific inhibitory role towards trypsin.
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