Novel Disinfection Byproducts Formed from the Pharmaceutical Gemfibrozil Are Bioaccumulative and Elicit Increased Toxicity Relative to the Parent Compound in Marine Polychaetes (Neanthes arenaceodentata)

Formation of halogenated disinfection byproducts (DBPs) from pharmaceutically active compounds has been observed in water supply systems following wastewater chlorination. Although research has been limited thus far, several studies have shown that halogenated DBPs may elicit increased toxicity compared to their parent compounds. For example, the lipid regulator gemfibrozil has been shown to form chlorogemfibrozil (Cl-gemfibrozil) and bromogemfibrozil (Br-gemfibrozil) following chlorination, which are more potent antiandrogens in male Japanese medaka (Oryzias latipes) compared to their parent compounds. In the present study, we aimed to characterize the bioaccumulative ability of halogenated gemfibrozil DBPs in marine polychaetes via chronic sediment exposures and, consequently, to assess the chronic and acute toxicity of halogenated gemfibrozil DBPs through sediment (in vivo) and aqueous (in vivo and in silico) toxicity evaluations. Following 28 day sediment exposures, Cl-gemfibrozil and Br-gemfibrozil bioaccumulated within Neanthes arenaceodentata, with both compounds reducing survival and growth. The biota-sediment accumulation factors determined for Cl-gemfibrozil and Br-gemfibrozil were 2.59 and 6.86, respectively. Furthermore, aqueous 96 h toxicity tests with N. arenaceodentata indicated that gemfibrozil DBPs elicited increased toxicity compared to the parent compound. While gemfibrozil had an acute LC50 value of 469.85 +/- 0.096 mg/L, Cl-gemfibrozil and Br-gemfibrozil had LC50 values of 12.34 +/- 0.085 and 9.54 +/- 0.086 mg/L, respectively. Although acute toxicity is relatively low, our results indicate that halogenated gemfibrozil DBPs are bioaccumulative and may elicit effects in apex food web organisms prone to accumulation following lifelong exposures

Heme oxygenase-1 is a potent inhibitor of placental ischemia-mediated endothelin-1 production in cultured human glomerular endothelial cells

Preeclampsia is a pregnancy-specific disorder of maternal hypertension and reduced renal hemodynamics linked to reduced endothelial function. Placental ischemia is thought to be the culprit of this disease, as it causes the release of factors like tumor necrosis factor (TNF)-α that induce vascular endothelin-1 (ET-1) production. Interestingly, placental ischemia-induced hypertension in rats [reduced uterine perfusion pressure (RUPP) model] is abolished by ETA receptor blockade, suggesting a critical role for ET-1. Although it has been found that systemic induction of heme oxygenase (HO)-1 is associated with reduced ET-1 production and attenuated hypertension, it is unclear whether HO-1 directly modulates the increased ET-1 response to placental factors. We tested the hypothesis that HO-1 or its metabolites inhibit ET-1 production in human glomerular endothelial cells induced by serum of RUPP rats or TNF-α. Serum (5%) from RUPP hypertensive (mean arterial blood pressure 119 ± 9 mmHg) vs. normotensive pregnant (NP, 101 ± 6 mmHg, P &lt; 0.001) rats increased ET-1 production (RUPP 168.8 ± 18.1 pg/ml, NP 80.3 ± 22.7 pg/ml, P &lt; 0.001, n = 12/group). HO-1 induction [25 µM cobalt photoporphyrin (CoPP)] abolished RUPP serum-induced ET-1 production (1.6 ± 0.8 pg/ml, P &lt; 0.001), whereas bilirubin (10 µM) significantly attenuated ET-1 release (125.3 ± 5.2 pg/ml, P = 0.005). Furthermore, TNF-α-induced ET-1 production (TNF-α 31.0 ± 8.4 vs. untreated 7.5 ± 0.4 pg/ml, P &lt; 0.001) was reduced by CoPP (1.5 ± 0.8 pg/ml, P &lt; 0.001) and bilirubin (10.5 ± 4.3 pg/ml, P &lt; 0.001). These results suggest that circulating factors released during placental ischemia target the maternal glomerular endothelium to increase ET-1, and that pharmacological induction of HO-1 or bilirubin could be a treatment strategy to block this prohypertensive pathway in preeclampsia. </jats:p

Heme oxygenase attenuates angiotensin II-mediated superoxide production in cultured mouse thick ascending loop of Henle cells

Heme oxygenase (HO)-1 induction can attenuate the development of angiotensin II (ANG II)-dependent hypertension. However, the mechanism by which HO-1 lowers blood pressure is not clear. The goal of this study was to test the hypothesis that induction of HO-1 can reduce the ANG II-mediated increase in superoxide production in cultured thick ascending loop of Henle (TALH) cells. Studies were performed on an immortalized cell line of mouse TALH (mTALH) cells. HO-1 was induced in cultured mTALH cells by treatment with cobalt protoporphyrin (CoPP, 10 μM) or hemin (50 μM) or by transfection with a plasmid containing the human HO-1 isoform. Treatment of mTALH cells with 10−9 M ANG II increased dihydroethidium (DHE) fluorescence (an index of superoxide levels) from 35.5 ± 5 to 136 ± 18 relative fluorescence units (RFU)/μm2. Induction of HO-1 via CoPP, hemin, or overexpression of the human HO-1 isoform significantly reduced ANG II-induced DHE fluorescence to 64 ± 5, 64 ± 8, and 41 ± 4 RFU/μm2, respectively. To determine which metabolite of HO-1 is responsible for reducing ANG II-mediated increases in superoxide production in mTALH cells, cells were preincubated with bilirubin or carbon monoxide (CO)-releasing molecule (CORM)-A1 (each at 100 μM) before exposure to ANG II. DHE fluorescence averaged 80 ± 7 RFU/μm2 after incubation with ANG II and was significantly decreased to 55 ± 7 and 53 ± 4 RFU/μm2 after pretreatment with bilirubin and CORM-A1. These results demonstrate that induction of HO-1 in mTALH cells reduces the levels of ANG II-mediated superoxide production through the production of both bilirubin and CO

The Effect of Vojta's Reflex Locomotion on the Stability of Patients with Hereditary Polyneuropathy

This thesis deals with the influence of Vojta's reflex locomotion on stability of the pacients suffering from hereditary neuropathy. In the review of knowledges there is presented the part about hereditary neuropathies, it's classification, clinical symptoms and diagnostics. The second part of the review is about the stability and it's determination. The last part is dedicated to Vojta's reflex locomotion. In experimental part, there is presented studies, which evaluates the influence of Vojta's reflex locomotion on the sensitive functiones (discrimination, texture perception, vibration perception) and the postural stability (using Balance Master system) in the two groups of the pacients suffering from hereditary neuropathy. The first groupe was measured before and after Vojta's therapy and the second groupe (control one) was measured in the same way, but without therapy. Consequently, the basic statistic indicators of gained set of data were calculated. As a conclusion, there has been some changes before and after therapy in sensitive functiones (vibrations perception, discrimination) and postural function and one test of postural stability in the group of patients threated with Vojta's reflex therapy, compared to control group. Powered by TCPDF (www.tcpdf.org

Biochemical Mechanisms for Geographical Adaptations to Novel Toxin Exposures in Butterflyfish

Some species of butterflyfish have had preyed upon corals for millions of years, yet the mechanism of butterflyfish specialized coral feeding strategy remains poorly understood. Certain butterflyfish have the ability to feed on allelochemically rich soft corals, e.g. Sinularia maxima. Cytochrome P450 (CYP) is the predominant enzyme system responsible for the detoxification of dietary allelochemicals. CYP2-like and CYP3A-like content have been associated with butterflyfish that preferentially consumes allelochemically rich soft corals. To investigate the role of butterflyfish CYP2 and CYP3A enzymes in dietary preference, we conducted oral feeding experiments using homogenates of S. maxima and a toxin isolated from the coral in four species of butterflyfish with different feeding strategies. After oral exposure to the S. maxima toxin 5-episinulaptolide (5ESL), which is not normally encountered in the Hawaiian butterflyfish diet, an endemic specialist, Chaetodon multicinctus experienced 100% mortality compared to a generalist, Chaetodon auriga, which had significantly more (3-6 fold higher) CYP3A-like basal content and catalytic activity. The specialist, Chaetodon unimaculatus, which preferentially feed on S. maxima in Guam, but not in Hawaii, had 100% survival, a significant induction of 8-12 fold CYP3A-like content, and an increased ability (2-fold) to metabolize 5ESL over other species. Computer modeling data of CYP3A4 with 5ESL were consistent with microsomal transformation of 5ESL to a C15-16 epoxide from livers of C. unimaculatus. Epoxide formation correlated with CYP3A-like content, catalytic activity, induction, and NADPH-dependent metabolism of 5ESL. These results suggest a potentially important role for the CYP3A family in butterflyfish-coral diet selection through allelochemical detoxification

Effects of dietary exposure to <i>S</i>.<i>maxima</i> tissue homogenate on the hepatic content CYP2K1-like and CYP2M1-like (A, B) and catalytic activity (C) of and CYP2 in four species of butterflyfish.

<p>Different letters indicate significant (P ≤ 0.05) differences between untreated and treated fish (N = 6–8).</p

NADPH-dependent clearance and transformation of 5ESL to 5ESLO in liver microsomes from four species of butterflyfish and recombinant human CYP3A4.

<p>Different letters indicate significant (P ≤ 0.05) differences between species* indicated signifcnat differences between control and pretreated <i>C</i>. <i>unimaculatus</i> (P ≤ 0.05) (N = 6–8).</p