Study on the binding characteristics of hydroxylated polybrominated diphenyl ethers and thyroid transporters using the multispectral technique and computational simulation

<p>Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) are a class of toxic environmental pollutants that are persistent, bioaccumulative, and difficult to degrade. Their structure is very similar to the thyroid hormone (T4) and uses the body’s thyroid transporter (TTR) binding to interfere with the endocrine balance, disrupting the body’s normal physiological activity. According to Fourier transform infrared spectroscopy and dynamics simulation of <i>do_dssp</i> module analysis, there are three kinds of OH-PBDEs that can induce TTR secondary structural changes. Fluorescence spectra and UV–Vis spectra show that for the three kinds of OH-PBDEs for TTR, the main methods of quenching are static quenching and non-radiative energy transfer. According to thermodynamic analysis, Δ<i>G</i> < 0, Δ<i>H</i> > 0, and Δ<i>S</i> > 0 combine to show that the hydrophobic interaction is the main driving force of the combination. From the molecular docking analysis, it was found that 4′-hydroxy-2,2′,4,5′- tetrabromodiphenyl ether (4′-OH-BDE49) and 4 hydroxy-2,2′,3,4′,5,6,6′- heptabromodiphenyl ether (4-OH-BDE188) had a cationic–π interaction with TTR, whereas 4 hydroxy-2,2′,3,4,5,5′,6- heptabromodiphenyl ether (4-OH-BDE187) was bonded to TTR by hydrogen bonds to form stable complexes. In this paper, we highlight the consistency of spectroscopic experiments and computer simulations so as to provide a reliable analytical method for the toxicological properties of small molecule contaminants.</p

Additional file 1 of Oligoribonuclease mediates high adaptability of P. aeruginosa through metabolic conversion

Supplementary Material 1: Supplementary Figure S1-S5. Supplementary Table S1-S

Population Genetic Structure of <i>Glycyrrhiza inflata</i> B. (Fabaceae) Is Shaped by Habitat Fragmentation, Water Resources and Biological Characteristics

<div><p>Background</p><p>Habitat fragmentation, water resources and biological characteristics are important factors that shape the genetic structure and geographical distribution of desert plants. Analysis of the relationships between these factors and population genetic variation should help to determine the evolutionary potential and conservation strategies for genetic resources for desert plant populations. As a traditional Chinese herb, <i>Glycyrrhiza inflata</i> B. (Fabaceae) is restricted to the fragmented desert habitat in China and has undergone a dramatic decline due to long-term over-excavation. Determining the genetic structure of the <i>G</i>. <i>inflata</i> population and identifying a core collection could help with the development of strategies to conserve this species.</p><p>Results</p><p>We investigated the genetic variation of 25 <i>G</i>. <i>inflata</i> populations based on microsatellite markers. A high level of population genetic divergence (<i>F</i>_ST = 0.257), population bottlenecks, reduced gene flow and moderate genetic variation (<i>H</i>_E = 0.383) were detected. The genetic distances between the populations significantly correlated with the geographical distances, and this suggests that habitat fragmentation has driven a special genetic structure of <i>G</i>. <i>inflata</i> in China through isolation by distance. STRUCTURE analysis showed that <i>G</i>. <i>inflata</i> populations were structured into three clusters and that the populations belonged to multiple water systems, which suggests that water resources were related to the genetic structure of <i>G</i>. <i>inflata</i>. In addition, the biological characteristics of the perennial species <i>G</i>. <i>inflata</i>, such as its long-lived seeds, asexual reproduction, and oasis ecology, may be related to its resistance to habitat fragmentation. A core collection of <i>G</i>. <i>inflata</i>, that included 57 accessions was further identified, which captured the main allelic diversity of <i>G</i>. <i>inflata</i>.</p><p>Conclusions</p><p>Recent habitat fragmentation has accelerated genetic divergence. The population genetic structure of <i>G</i>. <i>inflata</i> has been shaped by habitat fragmentation, water resources and biological characteristics. This genetic information and core collection will facilitate the conservation of wild germplasm and breeding of this Chinese medicinal plant.</p></div

Analysis of molecular variance (AMOVA) of 25 populations of <i>G</i>. <i>inflata</i>.

<p>Analysis of molecular variance (AMOVA) of 25 populations of <i>G</i>. <i>inflata</i>.</p

Summary of the genetic values of 25 populations of <i>G</i>. <i>inflata</i> based on 20 SSR loci.

<p>Summary of the genetic values of 25 populations of <i>G</i>. <i>inflata</i> based on 20 SSR loci.</p

Scatter plots of the pairwise genetic distance (<i>F</i>_ST / (1-<i>F</i>_ST)) versus the geographical distance (km) of all sampled populations of <i>G</i>. <i>inflata</i>.

<p>A significant positive relationship (<i>r</i> = 0.5, <i>P</i> < 0.01) was observed between the genetic distance (<i>F</i>_ST / (1-<i>F</i>_ST)) and geographical distance of <i>G</i>. <i>inflata</i> populations in China.</p

Geographic locations and genetic structure analyses of the 25 <i>G</i>. <i>inflata</i> populations in China.

<p>The 25 <i>G</i>. <i>inflata</i> populations distributed in the Hexi Corridor of Gansu province, the Hami Basin and the Tarim Basin of Xinjiang province. The spatial genetic structure assignment of wild <i>G</i>. <i>inflata</i> occurred at <i>K</i> = 3. The three colours represent three clusters that strongly matched the geographic distribution. The first cluster of populations (blue) was distributed in the Hami Basin and Hexi Corridor. The populations that were collected from the south and north rims of the Tarim Basin belonged to the second cluster (green). The third cluster populations (red) came from the west rim of the Tarim Basin.</p

Comparison of the sampling efficiencies between the M-strategy (M-Method) and random strategy.

<p>The inflection point represents the optimal core collection size (57 accessions) that captures all 176 alleles of <i>G</i>. <i>inflata</i> in China.</p

Genetic diversity within samples of the core collections of <i>G</i>. <i>inflata</i> classified according to the number of allele and the Shannon index (<i>I</i>).

<p>Genetic diversity within samples of the core collections of <i>G</i>. <i>inflata</i> classified according to the number of allele and the Shannon index (<i>I</i>).</p

Role of P‑Glycoprotein on the Brain Penetration and Brain Pharmacodynamic Activity of the MEK Inhibitor Cobimetinib

Cobimetinib is a MEK inhibitor currently in clinical trials as an anticancer agent. The objectives of this study were to determine in vitro and in vivo if cobimetinib is a substrate of P-glycoprotein (P-gp) and/or breast cancer resistance protein (Bcrp1) and to assess the implications of efflux on cobimetinib pharmacokinetics (PK), brain penetration, and target modulation. Cell lines transfected with P-gp or Bcrp1 established that cobimetinib was a substrate of P-gp but not a substrate of Bcrp1. In vivo, after intravenous and oral administration of cobimetinib to FVB (wild-type; WT), <i>Mdr1a/b­(−/−)</i>,<i> Bcrp1 (−/−)</i>, and <i>Mdr1a/b­(−/−)/Bcrp­(−/−)</i> knockout (KO) mice, clearance was similar in WT (35.5 ± 16.7 mL/min/kg) and KO animals (22.0 ± 3.6 to 27.6 ± 5.2 mL/min/kg); oral exposure was also similar between WT and KO animals. After an oral 10 mg/kg dose of cobimetinib, the mean total brain to plasma ratio (Kp) at 6 h postdose was 0.3 and 0.2 in WT and <i>Bcrp1­(−/−)</i> mice, respectively. In <i>Mdr1a/b­(−/−)</i> and <i>Mdr1<i>a</i>/1b/Bcrp1­(−/−)</i> KO mice and WT mice treated with elacridar (a P-gp and BCRP inhibitor), Kp increased to 11, 6, and 7, respectively. Increased brain exposure in <i>Mdr1a/b­(−/−)</i> and <i>Mdr1<i>a</i>/1b/Bcrp1­(−/−)</i> KO and elacridar treated mice was accompanied by up to ∼65% suppression of the target (pErk) in brain tissue, compared to WT mice. By MALDI imaging, the cobimetinib signal intensity was relatively high and was dispersed throughout the brain of <i>Mdr1<i>a</i>/1b/Bcrp1­(−/−)</i> KO mice compared to low/undetectable signal intensity in WT mice. The efflux of cobimetinib by P-gp may have implications for the treatment of patients with brain tumors/metastases