Polystyrene microplastics induced nephrotoxicity associated with oxidative stress, inflammation, and endoplasmic reticulum stress in juvenile rats

IntroductionUnintended intake of microplastic particles has been demonstrated to exert adverse health effects, however, studies on relevant nephrotoxicity in juvenile mammals are lacking.MethodsTherefore, we investigated the potential nephrotoxicity of oral-exposed polystyrene microplastics (PSMPs) (1,000 nm, 2.0 mg/kg/d) for 28 days in juvenile rats. Levels of oxidative stress, inflammation, and endoplasmic reticulum (ER) stress in kidneys were analyzed.Results and discussionResults revealed that PSMPs noticeably decreased the growth rate of bodyweight, and organ index of the kidney, cardiac, and ovary. The intestinal injury caused by PSMPs exposure was also observed, which was distinctly alleviated with N-acetyl-cysteine (NAC) and Salubrinal (Sal) treatment compared with the single PSMPs group. PSMPs caused histological lesions of the kidney via disrupting the serum blood urea nitrogen (BUN), creatinine (CRE), and pro-inflammatory mediators IL-1β, IL-6, and TNF-α. Furthermore, PSMPs exposure induced ER stress and inflammation presumably potentially mediated by oxidative stress in kidneys of rats. Eventually, PSMPs also promoted renal cells apoptosis, manifested as an obvious increase in the number of positive cells for the dUTP nick end labeling of Terminal deoxynucleotidyl transferase, which also can be confirmed by the elevated expression of genes associated with apoptosis Bcl-2, Bax, Caspase-12, Caspase-9, Caspase-3, and IHC score of Caspase-12 in the PSMPs group. Supplementation of NAC and Sal not only ameliorated the PSMPs-induced oxidative stress and ER stress but also the inflammation and apoptosis in the kidney. Collectively, this study suggested that PSMPs caused nephrotoxicity in juvenile rats potentially through oxidative damage and ER stress, which call for greater efforts to be taken on regulating the PSMPs ingestion in children

The relationship between IGF1 and the expression spectrum of miRNA in the placenta of preeclampsia patients

Objectives: Pre-eclampsia (PE) affects many women worldwide and remains the leading cause of morbidity and mortality in neonatal and maternal settings. Abnormal expression of placental microRNAs (miRNAs) may be associated with PE. Material and methods: This study was conducted to the relationship between IGF1 and the expression spectrum of miRNA in the placenta of preeclampsia patient. The expression of miRNA in placental tissue was compared between pre-eclampsia (n = 6) and normal pregnant women (n = 5) miRNA targets were studied by computer simulation and functional assays. The role of miRNA was verified in trophoblast cell lines by apoptosis assay and invasion assay. Results: There was a significant increase in miRNAs in the placenta of women with pre-eclampsia compared with patients with normal pregnancy. Luciferase assay confirmed direct regulation of miRNA. Conclusions: The expression of IGF1 and miRNA was significantly increased in the placenta of patients with pre-eclampsia

Unequal Perylene Diimide Twins in a Quadruple Assembly

Natural light-harvesting (LH) systems can divide identical dyes into unequal aggregate states, thereby achieving intelligent "allocation of labor". From a synthetic point of view, the construction of such kinds of unequal and integrated systems without the help of proteinaceous scaffolding is challenging. Here, we show that four octatetrayne-bridged ortho-perylene diimide (PDI) dyads (POPs) self-assemble into a quadruple assembly (POP)4 both in solution and in the solid state. The two identical PDI units in each POP are compartmentalized into weakly coupled PDIs (P520) and closely stacked PDIs (P550) in (POP)4 . The two extreme pools of PDI chromophores were unambiguously confirmed by single-crystal X-ray crystallography and NMR spectroscopy. To interpret the formation of the discrete quadruple assembly, we also developed a two-step cooperative model. Quantum-chemical calculations indicate the existence of multiple couplings within and across P520 and P550, which can satisfactorily describe the photophysical properties of the unequal quadruple assembly. This finding is expected to help advance the rational design of dye stacks to emulate functions of natural LH systems.</p

Pharmacokinetics/pharmacodynamics of polymyxin B in patients with bloodstream infection caused by carbapenem-resistant Klebsiella pneumoniae

Introduction: Polymyxin B is a last-line therapy for carbapenem-resistant microorganisms. However, a lack of clinical pharmacokinetic/pharmacodynamic (PK/PD) data has substantially hindered dose optimization and breakpoint setting.Methods: A prospective, multi-center clinical trial was undertaken with polymyxin B [2.5 mg/kg loading dose (3-h infusion), 1.25 mg/kg/12 h maintenance dose (2-h infusion)] for treatment of carbapenem-resistant K. pneumoniae (CRKP) bloodstream infections (BSI). Safety, clinical and microbiological efficacy were evaluated. A validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was applied to determine the concentrations of polymyxin B in blood samples. Population pharmacokinetic (PK) modeling and Monte Carlo simulations were conducted to examine the susceptibility breakpoint for polymyxin B against BSI caused by CRKP.Results: Nine patients were enrolled and evaluated for safety. Neurotoxicity (5/9), nephrotoxicity (5/9), and hyperpigmentation (1/9) were recorded. Blood cultures were negative within 3 days of commencing therapy in all 8 patients evaluated for microbiological efficacy, and clinical cure or improvement occurred in 6 of 8 patients. Cmax and Cmin following the loading dose were 5.53 ± 1.80 and 1.62 ± 0.41 mg/L, respectively. With maintenance dosing, AUCss,24 h was 79.6 ± 25.0 mg h/L and Css,avg 3.35 ± 1.06 mg/L. Monte Carlo simulations indicated that a 1 mg/kg/12-hourly maintenance dose could achieve &gt;90% probability of target attainment (PTA) for isolates with minimum inhibitory concentration (MIC) ≤1 mg/L. PTA dropped substantially for MICs ≥2 mg/L, even with a maximally recommended daily dose of 1.5 mg/kg/12-hourly.Conclusion: This is the first clinical PK/PD study evaluating polymyxin B for BSI. These results will assist to optimize polymyxin B therapy and establish its breakpoints for CRKP BSI

Advances in Molecular Quantum Chemistry Contained in the Q-Chem 4 Program Package

A summary of the technical advances that are incorporated in the fourth major release of the Q-Chem quantum chemistry program is provided, covering approximately the last seven years. These include developments in density functional theory methods and algorithms, nuclear magnetic resonance (NMR) property evaluation, coupled cluster and perturbation theories, methods for electronically excited and open-shell species, tools for treating extended environments, algorithms for walking on potential surfaces, analysis tools, energy and electron transfer modelling, parallel computing capabilities, and graphical user interfaces. In addition, a selection of example case studies that illustrate these capabilities is given. These include extensive benchmarks of the comparative accuracy of modern density functionals for bonded and non-bonded interactions, tests of attenuated second order Møller–Plesset (MP2) methods for intermolecular interactions, a variety of parallel performance benchmarks, and tests of the accuracy of implicit solvation models. Some specific chemical examples include calculations on the strongly correlated Cr2 dimer, exploring zeolite-catalysed ethane dehydrogenation, energy decomposition analysis of a charged ter-molecular complex arising from glycerol photoionisation, and natural transition orbitals for a Frenkel exciton state in a nine-unit model of a self-assembling nanotube

Software for the frontiers of quantum chemistry:An overview of developments in the Q-Chem 5 package

This article summarizes technical advances contained in the fifth major release of the Q-Chem quantum chemistry program package, covering developments since 2015. A comprehensive library of exchange–correlation functionals, along with a suite of correlated many-body methods, continues to be a hallmark of the Q-Chem software. The many-body methods include novel variants of both coupled-cluster and configuration-interaction approaches along with methods based on the algebraic diagrammatic construction and variational reduced density-matrix methods. Methods highlighted in Q-Chem 5 include a suite of tools for modeling core-level spectroscopy, methods for describing metastable resonances, methods for computing vibronic spectra, the nuclear–electronic orbital method, and several different energy decomposition analysis techniques. High-performance capabilities including multithreaded parallelism and support for calculations on graphics processing units are described. Q-Chem boasts a community of well over 100 active academic developers, and the continuing evolution of the software is supported by an “open teamware” model and an increasingly modular design

Substituent Effect on Vibrationally Resolved Absorption Spectra and Exciton Dynamics of Dipyrrolonaphthyridinedion Aggregates

Dipyrrolonaphthyridinedion (DPND) thin films exhibit interesting photo-physical properties and singlet fission (SF) processes. A recent experimental work found that the alkyl substitution in DPND skeleton has the remarkable influence on the characteristics of electronic absorption spectra and SF rates. Here, we theoretically elucidate the microscopic mechanism of the substituent effect on the optical properties and exciton dynamics of materials by combining the electronic structure calculations and the quantum dynamics simulations. The results show that the alkyl substituent has a minor effect on the single molecular properties, but dramatically changes these of DPND aggregates via varying the intermolecular interactions. The aggregates of DPND with and without alkyl side chains exhibit the more-likely of characters of H-type aggregations. In the former (DPND6), the weak degree of mixing of intramolecular localized excited (LE) states and intermolecular charge transfer (CT) states makes the low-energy absorption band possess the predominant optical absorption, while in the latter (DPND), the CT and LE states are close in energy, together with their strong interaction, resulting in the substantial state-mixing, so that its two low-energy absorption bands have nearly equal oscillator strengths and a wide energy spacing of more than 0.5 eV. The simulation of exciton dynamics elucidates that the photo-initiated states in both aggregates cannot generate the free charge carrier because of the lack of enough driving forces. However, the population exchanges between LE and CT states in DPND aggregates are much faster than in DPND6 aggregates, indicating the different SF behaviors, consistent with the experimental observation

pH Accelerates the Long-Range Electron Transfer for Lignin Degradation via Second-Sphere H-Bonding Interactions

pH plays versatile roles in both biology and chemistry. For instance, pH can regulate the long-range electron transfer (ET) in many proteins. However, the mechanistic basis of many pH-dependent long-range ET processes remain unclear. In this study, we unravel the critical role of pH in accelerating the long-range ET in lignin peroxidase (LiP) using QM/MM MD simulations and the nonadiabatic ET and PCET theories. As a key enzyme involved in lignin degradation, LiP accomplishes the one-electron oxidation of lignin via two consecutive long-range ET reactions: the first one involves ET from Trp171 to the active species of Compound I, affording the Trp171 radical species, while the second one involves ET from the lignin substrate to the Trp171 radical, affording the lignin cation radical species. Our study demonstrates that pH can remarkably modulate the mechanism and kinetics of both ET reactions. Specifically, in the absence of the pH buffer of tartaric acid, our study shows that the first ET leads to a neutral Trp• radical, agreeing with the EPR experiments. Surprisingly, the addition of the tartaric acid stabilizes the Trp-H•+ cation radical via second-sphere H-bonding interactions and accelerates the ET rate for lignin oxidation by several orders of magnitude. These findings are consistent with the experimental information available, which not only expand our understanding on pH-dependent ET reactions in both biology and chemistry, but also provide valuable insights on tryptophan-mediated biological ET reactions