Molecular Toxicology of Pyrrolizidine Alkaloids

Pyrrolizidine alkaloids are cytotoxic, carcinogenic, and anti-carcinogenic in vivo and in vitro, and they produce many hazardous effects in humans and animals. Pyrrolizidine alkaloids (PAs) also cross-link with DNA and/or protein. However, whether such cross-linking is important to the toxic action of PAs is not known. In addition, the exact mechanism underlying these DNA cross-links or cytotoxicity is also not clear. In three separate studies, I characterized the nature of PA-induced DNA cross-links and the relationships between PA structures and cross-linking potency. In the first study (Chapter II), I found that cross-linking potency of PA congeners coincided with their abilities to cause cytopathologic effects. Macrocyclic a,p-unsaturated diesters PAs and their pyrrolic metabolites were the most potent inhibitors of colony formation, and inducers of cytopathologic changes and megalocyte formation. The macrocyclic α, β-saturated diester PA and open diesters PAs slightly inhibited colony formation, and slightly changed cell morphology. Retronecine and indicine N-oxide were completely inactive. In the next study (Chapter Ill), I found that pyrrolic macrocyclic metabolites were more potent DNA cross-linkers than their parent compounds as determined by alkaline elution. The pyrroles of the macrocyclic diester PAs were potent DNADNA (inter- and/or intra) cross-linkers in BstEll-digested λ-phage DNA or pBR322 plasmid DNA but dehydroretronecine and indicine N-oxide were not. I also examined which DNA sequences were more susceptible to PA-induced cross-links by using a series of restriction endonucleases to determine sequence specificity. The most favorable cross-linking site for PAs appeared to be 5\u27d(GG) and 5\u27-d(GA) although other sites, 5\u27-d(CC) or 5\u27-d(CG), might be also preferable cross-linking targets. In the next study (Chapter IV), I characterized the nature of DNA-protein interactions induced by PAs, because I found in previous studies that PA-induced cross-links are largely protein associated. In PA or pyrrolic PA exposed cells, cross-linked proteins with molecular weights 40 - 60 kD were detected. Two-dimensional electrophoretic analysis revealed that these proteins were probably acidic in nature. In an in vitro system utilizing pBR322 or Bst Ell-digested λ-phage DNA. dehydrosenecionine induced DNAprotein cross-links with BSA, indicating that such interactions might be related to amino acid composition of protein. These results confirmed that PA-induced DNA cross-links (DNA-DNA, DNA-protein cross-links) are influenced by three structural features: the C1 ,2 unsaturation of pyrrolizidine ring, α, β-unsaturation, and size of the macrocyclic diester ring. The ability to form cross-links was closely related to the known toxic potencies of these PAs. From this research, I also conclude that DNA crosslinking is the most critical event leading to PA-related diseases and that crosslinking is due to pyrrolic metabolites of PAs, not via a common metabolite as was once thought

Accessible Home Environments for People with Functional Limitations: A Systematic Review

The aim of this review is to evaluate the health and social effects of accessible home environments for people with functional limitations, in order to provide evidence to promote well-informed decision making for policy guideline development and choices about public health interventions. MEDLINE and nine other electronic databases were searched between December 2014 and January 2015, for articles published since 2004. All study types were included in this review. Two reviewers independently screened 12,544 record titles or titles and abstracts based on our pre-defined eligibility criteria. We identified 94 articles as potentially eligible; and assessed their full text. Included studies were critically appraised using the Mixed Method Appraisal Tool, version 2011. Fourteen studies were included in the review. We did not identify any meta-analysis or systematic review directly relevant to the question for this systematic review. A narrative approach was used to synthesise the findings of the included studies due to methodological and statistical heterogeneity. Results suggest that certain interventions to enhance the accessibility of homes can have positive health and social effects. Home environments that lack accessibility modifications appropriate to the needs of their users are likely to result in people with physical impairments becoming disabled at home

DEVELOPMENT AND EVALUATION OF A NOVEL TAEKWONDO CHEST PROTECTOR TO IMPROVE MOBILITY WHEN PERFORMING AXE KICKS

The axe kick, in Olympic style taekwondo, has been identified as the most popular scoring technique aimed to the head during full contact competition. The first purpose of this study was to identify and investigate design issues with the current World Taekwondo Federation approved chest protector. A secondary purpose was to develop a novel chest protector addressing the identified design issues and to conduct a biomechanical analysis. Fifteen male elite Taekwondo players were selected to perform three different styles of the axe kick, i.e., front, in-out, and out-in axe kick five times each for a total of 45 kicks. Two-way repeated measures ANOVA showed significant differences between the novel and existing chest protector conditions for vertical height of the toe, downward kicking foot speed, hip flexion angle and ipsilateral shoulder flexion extension range of motion (ROM) (p0.05). These results indicate that the novel chest protector interferes less with both the lower and upper limbs during the performance of the axe kick and provides a more natural, free-moving alternative to the current equipment used

Reciprocal knock-in mice to investigate the functional redundancy of lamin B1 and lamin B2.

Lamins B1 and B2 (B-type lamins) have very similar sequences and are expressed ubiquitously. In addition, both Lmnb1- and Lmnb2-deficient mice die soon after birth with neuronal layering abnormalities in the cerebral cortex, a consequence of defective neuronal migration. The similarities in amino acid sequences, expression patterns, and knockout phenotypes raise the question of whether the two proteins have redundant functions. To investigate this topic, we generated "reciprocal knock-in mice"-mice that make lamin B2 from the Lmnb1 locus (Lmnb1(B2/B2)) and mice that make lamin B1 from the Lmnb2 locus (Lmnb2(B1/B1)). Lmnb1(B2/B2) mice produced increased amounts of lamin B2 but no lamin B1; they died soon after birth with neuronal layering abnormalities in the cerebral cortex. However, the defects in Lmnb1(B2/B2) mice were less severe than those in Lmnb1-knockout mice, indicating that increased amounts of lamin B2 partially ameliorate the abnormalities associated with lamin B1 deficiency. Similarly, increased amounts of lamin B1 in Lmnb2(B1/B1) mice did not prevent the neurodevelopmental defects elicited by lamin B2 deficiency. We conclude that lamins B1 and B2 have unique roles in the developing brain and that increased production of one B-type lamin does not fully complement loss of the other

Association between shift work and obesity among female nurses: Korean Nurses’ Survey

Background: Shift work has been hypothesized as a risk factor for obesity. In this study, we investigated the association between current shift work and body mass index (BMI) among female nurses in Korea. The relationship between duration of shift work and BMI of the participants was also evaluated. Methods: This cross-sectional survey evaluated participants in the Korean Nurses’ Survey, conducted from October to December 2011, using web-based self-administered questionnaires. A total of 9,989 nurses were included among 10,000 who registered on the survey web site (5,287 shift workers and 4,702 non-shift workers). Current shift workers were divided into tertiles of shift work duration (0.08–3.00 years, n = 1,732; 3.08–6.75 years, n = 1,731; and 6.83–38.00 years, n = 1,686). The BMI thresholds of overweight and obesity were ≥23 kg/m2 and ≥25 kg/m2, respectively. Data were analyzed using SPSS software. Results: Mean participant age was 33.2 ± 8.6 years and the mean BMI was 20.9 ± 2.5 kg/m2. There were statistically significant differences in current smoking status, regular drinking habit, dietary habits, regular exercise, sleep problems and self-perceived health status according to duration of shift work. The overall prevalence of overweight/obesity (18.6%) and obesity (7.4%) increased significantly as shift work duration increased from the lowest to highest tertile (P for trend <0.001). Multivariate logistic regression analysis revealed no association between current shift work and BMI. However, after adjusting for potential confounders, the participants with the longest duration of shift work were 1.63 (95% CI, 1.22–2.17) times more likely to be overweight or obese than those with the shortest duration. There was a significant positive association between obesity and shift work duration in the unadjusted analysis; however, it was attenuated and no longer significant in the multivariate model. Conclusions: The duration of shift work was positively associated with prevalence of overweight/obesity in nurses in Korea. Although these findings need to be confirmed in prospective studies, they suggest that special attention should be paid to female nurses with a long duration of shift work

Symptom Bother, Physical and Mental Stress, and Health-related Quality of Life in Women with Overactive Bladder Syndrome

PURPOSE: The objective of this study was to identify the relationships among symptom bother, physical and mental stress and health-related quality of life (HRQoL) in women with overactive bladder (OAB) syndrome. METHODS: The participants were 106 women who were diagnosed with OAB (urgency, urge urinary incontinence, frequency, and/or nocturia) at P university hospital. Data were collected from Dec 23, 2011 to Aug 31, 2012. RESULTS: The mean score for symptom bother was 43.1 points, for physical stress, 12.8 which was slightly higher than mental stress (11.8), and for HRQoL, 63.9. For symptom type, there were statistically significant differences in the symptom bother (F=8.67, p&amp;lt;.001) and HRQL (F=3.32, p= .023). The Symptom bother of OAB was positively correlated with physical stress (r=.23, p= .014) and mental stress (r=.33, p&amp;lt;.001) and negatively correlated with the subscales of HRQoL; coping (r=-.66, p&amp;lt;.001), concern (r=-.71, p&amp;lt;.001), sleep (r=-.59, p&amp;lt;.001), and social interaction (r=-.58, p&amp;lt;.001). CONCLUSION: From the results, bother symptom was associated with physical, mental stress and HRQoL. These results suggest that nursing intervention programs for OAB should be developed not only to relieve the symptoms but also to reduce stress and improve the quality of life

Preparation and Evaluation of PEGylated and Folate-PEGylated Liposomes Containing Paclitaxel for Lymphatic Delivery

This study attempted to prepare polyethylene-glycol modified (PEGylated) and folate-PEGylated liposomes containing paclitaxel (Ptx) in order to reduce the toxicity and improve the bioavailability and biocompatibility by targeting drugs to the lymphatics using cancer cell specific ligand folate to prevent metastasis via the lymphatic system. Liposomes were prepared by lipid film hydration method using PEG and folate-PEG as surface modifiers. The mean particle size and encapsulation efficiency of liposomes were 114±6.81 nm and 81±2.3% for PEGylated liposome and 122±4.87 nm and 88±2.0% for folate-PEGylated liposome, respectively. According to stability test, it could be confirmed that PEGylated and folate-PEGylated liposomes were stable for at least 5 days. After intravenous administration of the PEGylated and folate-PEGylated liposomes to rats, the CLt (total clearance) and t1/2 (half-life) were significantly different (P<0.05) compared with those of PADEXOL Inj. In targeting efficiency, calculated as the concentration ratio of Ptx in lymph nodes and plasma, there was significant increase in targeting efficiency at lymph nodes (P<0.05). From these results, we could conclude that the prepared Ptx-containing PEGylated and folate-PEGylated liposomes are good candidates for the targeted delivery of the drug to lymphatic system

Retina-Inspired Carbon Nitride-Based Photonic Synapses for Selective Detection of UV Light

Photonic synapses combine sensing and processing in a single device, so they are promising candidates to emulate visual perception of a biological retina. However, photonic synapses with wavelength selectivity, which is a key property for visual perception, have not been developed so far. Herein, organic photonic synapses that selectively detect UV rays and process various optical stimuli are presented. The photonic synapses use carbon nitride (C3N4) as an UV-responsive floating-gate layer in transistor geometry. C3N4 nanodots dominantly absorb UV light; this trait is the basis of UV selectivity in these photonic synapses. The presented devices consume only 18.06 fJ per synaptic event, which is comparable to the energy consumption of biological synapses. Furthermore, in situ modulation of exposure to UV light is demonstrated by integrating the devices with UV transmittance modulators. These smart systems can be further developed to combine detection and dose-calculation to determine how and when to decrease UV transmittance for preventive health care.

Preparation and evaluation of solid-self-emulsifying drug delivery system containing paclitaxel for lymphatic delivery

Solid-self-emulsifying drug delivery system (S-SEDDS) of paclitaxel (Ptx) was developed by the spray drying method with the purpose of improving the low bioavailability (BA) of Ptx. 10% oil (ethyl oleate), 80% surfactant mixture (Tween 80: Carbitol, 90: 10, w/w), and 10% cosolvent (PEG 400) were chosen according to their solubilizing capacity. The mean droplet size, zeta potential, and encapsulation efficiency of the prepared S-SEDDS were 16.9 &plusmn; 1.53 nm, 12.5 &plusmn; 1.66 mV, and 56.2 &plusmn; 8.1%, respectively. In the S-SEDDS, Ptx presents in the form of molecular dispersion in the emulsions or is distributed in an amorphous state or crystalline with very small size. The prepared S-SEDDS formulation showed 70 and 75% dissolution in 60 and 30 min in dissolution medium pH 1.2 and 6.8, respectively. Significant increase (P &le; 0.05) in the peak concentration (C m a x), the area under the curve (A U C 0 - &infin;), and the lymphatic targeting efficiency of Ptx was observed after the oral administration of the Ptx-loaded S-SEDDS to rats (20 mg/kg as Ptx). Our research suggests the prepared Ptx-loaded S-SEDDS can be a good candidate for the enhancement of BA and targeting drug delivery to the lymphatic system of Ptx