Effects of shift work on sleep quality and cardiovascular function in Taiwanese police officers

This study aimed to investigate the effects of shift work on sleep quality, cardiovascular function, and physical activity (PA) levels in Taiwanese police officers. Twenty-one male police officers aged 26.9 ± 4.1 years old located in Taipei voluntarily participated in this study. The participants completed the resting heart rate (HR) and hemodynamic variables (e.g. blood pressure, BP) before and after day-time (DTW) and night-time (NTW) shift work phases (5 working days and 2 resting days for each phase). Additionally, an actigraphy was administered to measure PA and sleep patterns in the last 3 working days. The average total sleep time and sleep efficiency were 278.5 ± 79. 6 min and 72.9 ± 10%, respectively, in the NTW phases, which were significantly lower than that in the DTW phases. A comparison of the PA characteristics between the two phases revealed that a lower proportion of moderate-vigorous PA (1.2 ± 0.8%) and a greater proportion of sedentary behaviour PA (74.8 ± 6.4%) was found in the NTW phases. The results of hemodynamic measures demonstrated that the police officers have significantly elevated systolic BP by 3.3% and diastolic BP by 3.9% after the NTW phases. Furthermore, the NTW phases exhibited a significantly higher percentage change ratio of systolic BP and diastolic BP compared to the DTW phases. Compared with the DTW phases, the NTW phase was significantly more likely to report higher decreasing parasympathetic-related HR variability with a range of −5.9% to −7.8%. In conclusion, night-time shift work resulted in negative physiological changes leading to adverse effects on the health and well-being of Taiwanese police officers.</p

Bioactive Isoprenoid-Derived Natural Products from a Dongsha Atoll Soft Coral Sinularia erecta

Four new isoprenoids, including two norcembranoids sinulerectols A and B (<b>1</b> and <b>2</b>), a cembranoid sinulerectol C (<b>3</b>), and a degraded cembranoid sinulerectadione (<b>4</b>), along with three known isoprenoids, an unnamed norcembrene (<b>5</b>), sinularectin (<b>6</b>), and ineleganolide (<b>7</b>), and a known nitrogen-containing compound (<i>Z</i>)-<i>N</i>-[2-(4-hydroxyphenyl)­ethyl]-3-methyldodec-2-enamide (<b>8</b>), were isolated from an extract of the marine soft coral Sinularia erecta. The structure of sinularectin (<b>6</b>) was revised, too. Compounds <b>3</b>, <b>4</b>, and <b>8</b> exhibited inhibitory activity against the proliferation of a limited panel of cancer cell lines, whereas <b>1</b>, <b>2</b>, and <b>8</b> displayed potent anti-inflammatory activity in fMLP/CB-stimulated human neutrophils

Targeting the EGFR/PCNA Signaling Suppresses Tumor Growth of Triple-Negative Breast Cancer Cells with Cell-Penetrating PCNA Peptides

<div><p>Tyrosine 211 (Y211) phosphorylation of proliferation cell nuclear antigen (PCNA) coincides with pronounced cancer cell proliferation and correlates with poor survival of breast cancer patients. In epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-resistant cells, both nuclear EGFR (nEGFR) expression and PCNA Y211 phosphorylation are increased. Moreover, the resistance to EGFR TKI is a major clinical problem in treating EGFR-overexpressing triple-negative breast cancer (TNBC). Thus, effective treatment to combat resistance is urgently needed. Here, we show that treatment of cell-penetrating PCNA peptide (CPPP) inhibits growth and induces apoptosis of human TNBC cells. The Y211F CPPP specifically targets EGFR and competes directly for PCNA tyrosine Y211 phosphorylation and prevents nEGFR from binding PCNA <i>in vivo</i>; it also suppresses tumor growth by sensitizing EGFR TKI resistant cells, which have enhanced nEGFR function and abrogated classical EGFR membrane signaling. Furthermore, we identify an active motif of CPPP, RFLNFF (RF6 CPPP), which is necessary and sufficient to inhibit TKI-resistant TNBC cell growth of orthotopic implanted tumor in mice. Finally, the activity of its synthetic retro-inverted derivative, D-RF6 CPPP, on an equimolar basis, is more potent than RF6 CPPP. Our study reveals a drug candidate with translational potential for the future development of safe and effective therapeutic for EGFR TKI resistance in TNBC.</p> </div

A proposed model of CPPP in TNBC treatment.

<p>The schematic illustrates the potential mechanism of CPPP in treatment of TKI-sensitive and -resistant TNBC. (A) In TNBC, both the classical EGFR membrane signaling and nuclear EGFR-mediated phosphorylation of PCNA at Y211 exist for cell proliferation. CPPP disrupts the nuclear EGFR-mediated PCNA phosphorylation at Y211, leading to suppression of proliferation. (B) In EGFR TKI-resistant TNBC, EGFR TKIs abrogate the classical EGFR membrane signaling, and thus elevate nuclear translocation of EGFR to phosphorylate more PCNA at Y211, triggering more second compartment of proliferation. CPPP attenuates more nuclear EGFR-mediated cell proliferation through repression of Y211 phosphorylation in the presence of EGFR TKIs.</p

The cytotoxic effect of different CPPP derivatives in TNBC cells.

<p>(A) The schematic illustrates the amino acid sequence of each CPPP derivative. (B–C) MDA-MB 468 cells were individually treated with 50 µM of each CPPP derivative for 24 h, and then the relative cell viability (B) and Annexin V-positive cells (C) were determined. (E–F) MDA-MB 468 (E) or MDA-MB 231 (F) cells were treated with indicated concentrations of RF6 CPPP or D-RF6 CPPP for 24 h, and the relative cell viability was examined. (G) The percentage of the apoptotic cells from each TNBC cell line after 24 h treatment with 15 µM of Mock (PBS), Scramble and D-RF6 were determined by flow cytometry of Annexin V-positive cells. The bars indicate mean ± S.D.; **, p<0.01; ***, p<0.001 by <i>t</i>-test.</p

The phosphorylation of PCNA at Y211 and the cytotoxic effects of CPPP in normal breast cell line and TNBC cells.

<p>(A) Total cell lysate from MCF10A normal breast cell line or MDA-MB 468 and MDA-MB 231 TNBC cell lines were extracted, the protein levels of EGFR and total PCNA were determined by immunoblotting (IB). The Y211 phosphorylation of PCNA was examined by immunoprecipitation (IP) with anti-p-Y211 antibody and followed by IB against PCNA. (B) Each TNBC cell line was treated with indicated concentration of scrambled (Scramble) or Y211 CPPP (Y211F) peptides for 24 h. The relative cell viability was measured by WST-1 assay. (C) The percentage of the apoptotic cells from each TNBC cell line after 24 h treatment with 15 µM of Mock (PBS), Scramble and Y211F were determined by flow cytometry of Annexin V-positive cells. The bars indicate mean ± S.D. *, p<0.05; ***, p<0.001 by <i>t</i>-test.</p

The cytotoxic effect of CPPP in TKI-resistant TNBC cells.

<p>(A) Cell lysate from non-nuclear and nuclear fractions were isolated from parental (P), Iressa-resistant (IR) or Tarceva-resistant (TR) MDA-MB 468 cells. The protein level of EGFR in each fraction was examined by IB. α-tubulin and lamin B were used as the markers of non-nuclear and nuclear fraction, respectively. (B) The association between nEGFR and PCNA in chromatin lysate from P-, IR- and TR-TNBC cells were verified by IP with IgG or anti-PCNA antibody. (C) The amount of p-Y211 on PCNA in each TNBC line was examined. A comparison of the relative intensity p-Y211 in IR- or TR-TNBC cells to the parental TNBCs is shown at the bottom. (D) Total cell lysate from P-, IR- and TR-TNBC cells were isolated. The protein level of indicated proteins were examined by IB. (E–F) The P-, IR-, or TR-TNBC cells were treated with 15 µM Y211F CPPP for 24 h and the relative cell viability (E) and Annexin V-positive cells (F) were determined. The bars indicate mean ± S.D. **, p<0.01; ***, p<0.001 by <i>t</i>-test.</p

The effect of CPPP on tumor growth <i>in vivo</i>.

<p>(A) Approximately 1×10⁷ MDA-MB 468 cells were subcutaneously injected into the flanks of nude mice. When the tumors were palpable, mice were randomly divided into 4 groups and treated with PBS (Control), scrambled peptide for RF6 (Scramble), RF6 CPPP, or D-RF6 CPPP (200 nmol/mouse) by intratumoral injection. Tumor volume was measured the tumor volume at the indicated time point. (B) The weight of each of the harvested tumors from (A) was measured after treatment. (C) Approximately 1×10⁷ Iressa-resistant MDA-MB 468 (MDA-MB 468/IR) cells were injected into the mammary fat pad on either side of SCID mice. When the tumors were palpable, mice were randomly divided into 3 groups and treated with PBS (Control), scrambled peptide for D-RF6 (Scramble), or D-RF6 CPPP (200 nmol/mouse) by intratumoral injection. Tumor volume was measured the tumor volume at the indicated time point. (D) The weight of each of the harvested tumors from (C) was measured after treatment. The curves and bars indicate mean ± S.D.; *, p<0.05; **, p<0.01; ***, p<0.001 by <i>t</i>-test. (E) Extracted tumor tissue lysates from (D), the protein levels of EGFR, p-Y211, PCNA and cleaved-caspase-3 were determined by IB.</p