Orrkornum1460
The neonicotinoid pesticide, imidacloprid (IMI), is frequently detected in the environment and in foods. It is absorbed and metabolized by the intestine; however, its effects on intestinal barrier integrity are not well studied. We investigated whether IMI disrupts the permeability of the intestinal epithelial barrier via in vivo tests on male Wistar rats, in vitro assays using the human intestinal epithelial cell line, Caco-2, and in silico analyses. A repeated oral dose 90-day toxicity study was performed (0.06 mg/kg body weight/day). IMI exposure significantly increased intestinal permeability, which led to significantly elevated serum levels of endotoxin and inflammatory biomarkers (tumor necrosis factor-alpha and interleukin-1 beta) without any variation in body weight. Decreased transepithelial electrical resistance with increased permeability was also observed in 100 nM and 100 μM IMI-treated Caco-2 cell monolayers. Amounts of tight junction proteins in IMI-treated colon tissues and between IMI-treated Caco-2 cells were significantly lower than those of controls. Increased levels of myosin light chain phosphorylation, myosin light chain kinase (MLCK), and p65 subunit of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB p65) phosphorylation were found in IMI-exposed cells compared with control cells. Furthermore, the barrier loss caused by IMI was rescued by the MLCK inhibitor, ML-7, and cycloheximide. Pregnane X receptor (PXR, NR1I2) was inhibited by low-dose IMI treatment. In silico analysis indicated potent binding sites between PXR and IMI. Together, these data illustrate that IMI induces intestinal epithelial barrier disruption and produces an inflammatory response, involving the down-regulation of tight junctions and disturbance of the PXR-NF-κB p65-MLCK signaling pathway. The intestinal barrier disruption caused by IMI deserves attention in assessing the safety of this neonicotinoid pesticide.Cadmium (Cd) and arsenic (As) contamination in paddy soils poses serious health risks to humans. The accumulation of Cd and As in rice (Oryza sativa L.) depends on their bioavailability, which is affected by soil physicochemical properties and soil microbial activities. However, little is known about the intricate interplay between rice plants and their rhizosphere microbes during the uptake of Cd and As. In this study, different bacterial communities were established by sterilizing paddy soils with γ-radiation. A pot experiment using two paddy soils with different levels of contamination was conducted to explore how the bacterial community composition affects Cd and As accumulation in rice plants. The results showed that the sterilization treatment substantially changed the bacterial composition in the rhizosphere, and significantly increased the grain yield (by 33.5-38.3%). The sterilization treatment resulted in significantly decreased concentrations of Cd (by 18.2-38.7%) and As (by 20.3-36.7%) in the grain, straw, and root of rice plants. The accumulation of Cd and As in rice plants was negatively correlated with the relative abundance of sulfate-reducing bacteria and iron-oxidizing bacteria in the rhizosphere. Other specific taxa associated with the accumulation of Cd and As in rice plants were also identified. Our results suggest that regulating the composition of the rhizosphere bacterial community could simultaneously reduce Cd and As accumulation in rice grain and increase the grain yield. These results would be useful for developing strategies to cultivate safe rice crops in areas contaminated with Cd and As.Wastewater treatment plants (WWTPs) in South Africa, like is the case for most WWTPs around the globe albeit capable of removing substantial quantities of microplastics (MPs) and in fact, the treatments become ineffective for those plastic particles less than 100 µm. As a consequence, the receiving water bodies in which the final effluent is discharged becomes highly polluted. The present research is devoted to the analysis of the pervasive MPs in wastewaters of the treatment plant located in the Gauteng Province, South Africa using Pyrolysis - GC-TOF-MS. Based on the results, there were 23 pyrolyzate products with contributions from PVC, PA, PET and PE with abundances of 47.8%, 13.1%, 17.4% and 4.3% respectively. The remaining 17.4% could be attributed as additives in MPs. The SEM images illustrated that the MPs appeared to be inter - wined, fibrous of different thicknesses and lengths. The highly weathered MPs exhibited the rough surface which was noticeably damaged with peeled off layers presumably because of photo-oxidation during the aging process. The vibrational modes of FTIR revealed the presence of the various functional groups in the corresponding polymers of MPs. The thermal studies confirmed the presence of calcium, aluminum and silicon as residues of catalysts or flame retardants or UV stabilizers in MPs or as adsorbates resulting from the surface adsorption from the surroundings. The Py-GC-TOF-MS confirmed the identity of the various fragments related to the MPs monomers.
Lysosomal protein transmembrane 4 beta (LAPTM4B) is selectively expressed in hepatocellular carcinoma (HCC) cells and thus a potential biomarker for diagnosing HCC. In this study, we designed a novel
F-labeled PET probe to non-invasively visualize LAPTM4B expression in mouse model of HCC tumor.
A PET targeting tracer named [
F]FP-LAP2H was radio-synthesized using a LAPTM4B targeting peptide, LAP2H, coupled with 4-nitrophenyl-2-[
F]fluoropropionate ([
F]NFP). Radio-stability, cell uptake, micro PET/CT imaging and ex vivo biodistribution were performed for determining its stability, cell binding specificity, and tumor targeting in vivo.
[
F]FP-LAP2H was successfully synthesized with radiochemical yields of 6-14% (decay-corrected yield) and molar activity of 10-44 GBq/μmol. The tracer showed stable (~90%) in phosphate-buffered saline, pH 7.4, and in human serum (~80%) for 2 h. In vitro cell uptake studies indicated the radioactivity accumulation in HCC cells was LAPTM4B protein-specific. Micro PET/CT demonstrated that implanted LAPTM4B positive HepG2 and BEL7402 tumors could be clearly visualized. The ex vivo biodistribution studies demonstrated that the tumor/liver ratio were 1.80 ± 0.65 and 2.09 ± 0.68 in implanted HepG2 and BEL7402 tumors respectively. Savolitinib Negative control and blocking experiments revealed that the radioactivity uptake in the HCC tumor was LAPTM4B protein-specific.
[
F]FP-LAP2H appears to be a potential PET tracer for imaging LAPTM4B-positive HCC tumor. Further endeavors need to do to improve tumor/liver ratio.
[18F]FP-LAP2H appears to be a potential PET tracer for imaging LAPTM4B-positive HCC tumor. Further endeavors need to do to improve tumor/liver ratio.
Childhood cancer survival currently exceeds 80 % five years after diagnosis in high-income countries. In this study, we aimed to describe long-term trends and to investigate socioeconomic and spatial disparities in childhood cancer survival.
The study included 28,073 cases recorded in the French National Registry of Childhood Cancers from 2000 to 2015. Contextual census data (deprivation indices, population density, spatial accessibility to general practitioners) were allocated to each case based on the residence at diagnosis. Overall survival (OS) and conditional 10-year OS for 5-year survivors were estimated for all cancers combined and by diagnostic group and subgroup. Comparisons were conducted by sex, age at diagnosis, period of diagnosis, and contextual indicators. Hazard ratios for death were estimated using Cox models.
All cancers combined, the OS reached 82.8 % [95 % CI 82.4-83.3] at 5 years and 80.8 % [95 % CI 80.3-81.3] at 10 years. Conditional 10-year OS of 5-year survivors reached 97.5 % [95 % CI 97.3-97.7] and was higher than 95 % for all subgroups except osteosarcomas and most subgroups of the central nervous system. In addition to disparities by sex, age at diagnosis, and period of diagnosis, we observed a slight decrease in survival for cases living in the most deprived areas at diagnosis, not consistent across diagnostic groups.
Our results confirm the high 5-year survival for childhood cancer and show an excellent 10-year conditional survival of 5-year survivors. Additional individual data are needed to clarify the factors underlying the slight decrease in childhood cancer survival observed in the most deprived areas.
Our results confirm the high 5-year survival for childhood cancer and show an excellent 10-year conditional survival of 5-year survivors. Additional individual data are needed to clarify the factors underlying the slight decrease in childhood cancer survival observed in the most deprived areas.Isoniazid (INH) is the first-line anti-tubercular drug that is used both for the prophylaxis as well as the treatment of tuberculosis (TB). The patients with TB are more vulnerable to secondary infections and other health complications, hence, they are usually administered a cocktail of drugs. This increases the likelihood of drug-drug interactions (DDIs). INH is clinically proven to interact with drugs like phenytoin, carbamazepine, diazepam, triazolam, acetaminophen, etc. Most of such clinical observations have been supported by in vitro inhibition studies involving INH and cytochrome P450 (CYP) enzymes. A few published in vitro studies have explored the CYP2E1 inhibition potential of INH to explain its interactions with acetaminophen and other CY2E1 substrates, such as chlorzoxazone, but none of them were able to demonstrate any significant inhibition of the enzyme by the drug. It was reported that metabolites of INH, such as acetylhydrazine and hydrazine, were bioactivated by CYP2E1, highlighting that perhaps the drug metabolites were responsible for the mechanism based inhibition (MBI) of the enzyme. Therefore, the purpose of this investigation was to explore CYP2E1 enzyme inhibition potential of INH and its four major metabolites, viz., acetylisoniazid, isonicotinic acid, acetylhydrazine and hydrazine, using human liver microsomes (HLM). Additionally, we determined the fraction unbound in microsomal incubation (fumic) for all the five compounds using equilibrium dialysis assay. We observed that INH and its metabolites had lower propensity for microsomal binding, and the metabolites also lacked the potential to inhibit CYP2E1 enzyme, either by direct inhibition or through MBI. This suggests involvement of some other mechanism to explain interactions of INH with CY2E1 substrates, signifying need of further exploration.Irisflorentin is one of the bioactive constituents from the root of Belamcanda chinensis (L.) DC, which displayed anti-inflammatory and anti-tumor activities. In this work, the in vitro metabolism of irisflorentin was investigated using liver microsomes and hepatocytes. The metabolites were identified by ultra-high performance liquid chromatography combined with quadrupole/orbitrap tandem mass spectrometry. Under the current conditions, a total of 11 metabolites were detected and structurally identified according to accurate masses, fragment ions and retention times. Metabolite M10, identified as 6,7-dihydroxy-5,3',4',5'-tetramethoxy isoflavone, was biosynthesized and unambiguously characterized by nuclear magnetic resonance spectroscopy. The metabolic pathways of irisflorentin included oxidation, demethylation and glucuronidation. M10 was the most abundant metabolite in all tested species. Further phenotyping studies revealed that α-naphthoflavone and ketoconazole displayed significant inhibitory effect on the formation of M10.
