An Antagonism Joint Action of Lead and Di-2-Ethylhexyl Phthalate Explains an Improved Ability of Learning and Memory after Combined Exposure in Weaning Rats

Lead and di-2-ethylhexyl phthalate (DEHP) are widely distributed in the environment, and their neurotoxicity has caused a widespread concern. The complexity of environmental exposure provides the possibility of their combined exposure. The present study aims to describe a joint neurotoxicity and clarify the potential mechanism after combined exposure to lead and DEHP. A 2 × 3 factorial design was used to analyze either single effects or their interaction by a subchronic lead and DEHP exposure model of the male weaning rats. Similar to the previous study, lead or DEHP single exposure showed an increased neurotoxicity. Interestingly, our neurobehavioral test showed the rats in the combined exposure groups had a better ability of learning and memory compared with the single-exposure ones. It seemed to reflect an antagonism joint action in neurotoxicity after combined exposure. The content of dehydroepiandrosterone (DHEA) in serum and the mRNA level of brain-derived neurotrophic factor (Bdnf) in the hippocampus showed a similar trend to the ability of learning and memory. However, there was insufficient evidence to support the joint action on some indexes of oxidative stress such as malondialdehyde (MDA), the ratio of reduced glutathione(GSH) to oxidized glutathione(GSSG), γglutamylcysteine synthetase (γ-GCS), glutathione-s transferase (GST), and nuclear factor E2-related factor 2 (Nrf2) mRNA expression in the hippocampus. In a word, our current study reminded a unique antagonism joint action of neurotoxicity after combined exposure to lead and DEHP, which may contribute to understanding some shallow mechanism of the joint toxicity due to the complexity of environmental pollutant exposure.

     

Co-treatment with interferon-γ and 1-methyl tryptophan ameliorates cardiac fibrosis through cardiac myofibroblasts apoptosis

Molecular and Cellular Biochemistry - Electron transfer occurs through heme-Fe across the cytochrome c protein. The current models of long range electron transfer pathways in proteins include...     

Lidocaine Attenuates Cognitive Impairment After Isoflurane Anesthesia by Reducing Mitochondrial Damage

Mitochondrial dysfunction has been proposed to be one of the earliest triggering events in isoflurane-induced neuronal damage. Lidocaine has been demonstrated to attenuate the impairment of cognition in aged rats induced by isoflurane in our previous study. In this study, we hypothesized that lidocaine could attenuate isoflurane anesthesia-induced cognitive impairment by reducing mitochondrial damage. H4 human neuroglioma cells and 18-month-old male Fischer 344 rats were exposed to isoflurane or isoflurane plus lidocaine. Cognitive function was tested at 14 days after treatment by the Barnes Maze test in male Fischer 344 rats. Morphology was observed under electron microscope, and mitochondrial transmembrane potential, electron transfer chain (ETC) enzyme activity, complex-I–IV activity, immunofluorescence and flow cytometry of annexin V-FITC binding, TUNEL assay, and Western blot analyses were applied. Lidocaine attenuated cognitive impairment caused by isoflurane in aged Fischer 344 rat. Lidocaine was effective in reducing mitochondrial damage, mitigating the decrease in mitochondrial membrane potential (Δ_Ψm), reversing isoflurane-induced changes in complex activity in the mitochondrial electron transfer chain and inhibiting the apoptotic activities induced by isoflurane in H4 cells and Fischer 344 rats. Additionally, lidocaine suppressed the ratio of Bax (the apoptosis-promoting protein) to Bcl-2 (the apoptosis-inhibiting protein) caused by isoflurane in H4 cells. Lidocaine proved effective in attenuating isoflurane-induced POCD by reducing mitochondrial damage.

     

Chronic Sleep Restriction Induces Aβ Accumulation by Disrupting the Balance of Aβ Production and Clearance in Rats

Amyloid-β (Aβ) plays an important role in Alzheimer’s disease (AD) pathogenesis, and growing evidence has shown that poor sleep quality is one of the risk factors for AD, but the mechanisms of sleep deprivation leading to AD have still not been fully demonstrated. In the present study, we used wild-type (WT) rats to determine the effects of chronic sleep restriction (CSR) on Aβ accumulation. We found that CSR-21d rats had learning and memory functional decline in the Morris water maze (MWM) test. Meanwhile, Aβ₄₂ deposition in the hippocampus and the prefrontal cortex was high after a 21-day sleep restriction. Moreover, compared with the control rats, CSR rats had increased expression of β-site APP-cleaving enzyme 1 (BACE1) and sAPPβ and decreased sAPPα levels in both the hippocampus and the prefrontal cortex, and the BACE1 level was positively correlated with the Aβ₄₂ level. Additionally, in CSR-21d rats, low-density lipoprotein receptor-related protein 1 (LRP-1) levels were low, while receptor of advanced glycation end products (RAGE) levels were high in the hippocampus and the prefrontal cortex, and these transporters were significantly correlated with Aβ₄₂ levels. In addition, CSR-21d rats had decreased plasma Aβ₄₂ levels and soluble LRP1 (sLRP1) levels compared with the control rats. Altogether, this study demonstrated that 21 days of CSR could lead to brain Aβ accumulation in WT rats. The underlying mechanisms may be related to increased Aβ production via upregulation of the BACE1 pathway and disrupted Aβ clearance affecting brain and peripheral Aβ transport.

     

Intrinsic Effects of Gold Nanoparticles on Oxygen–Glucose Deprivation/Reperfusion Injury in Rat Cortical Neurons

This study aimed to investigate the potential effects of gold nanoparticles (Au-NPs) on rat cortical neurons exposed to oxygen–glucose deprivation/reperfusion (OGD/R) and to elucidate the corresponding mechanisms. Primary rat cortical neurons were exposed to OGD/R, which is commonly used in vitro to mimic ischemic injury, and then treated with 5- or 20-nm Au-NPs. We then evaluated cell viability, apoptosis, oxidative stress, and mitochondrial respiration in these neurons. We found that 20-nm Au-NPs increased cell viability, alleviated neuronal apoptosis and oxidative stress, and improved mitochondrial respiration after OGD/R injury, while opposite effects were observed for 5-nm Au-NPs. In terms of the underlying mechanisms, we found that Au-NPs could regulate Akt signaling. Taken together, these results show that 20-nm Au-NPs can protect primary cortical neurons against OGD/R injury, possibly by decreasing apoptosis and oxidative stress, while activating Akt signaling and mitochondrial pathways. Our results suggest that Au-NPs may be potential therapeutic agents for ischemic stroke.

     

First-principles investigations on structural stability,elastic and electronic properties of Co7M6 (M= W,Mo, Nb) µ phases

The structural, elastic and electronic properties of Co₇M₆ (M?=?W, Mo, Nb) μ phases were investigated by first-principles calculations based on the density functional theory (DFT). The calculated cohesive energy indicates that Co₇M₆ (M?=?W, Mo, Nb) μ phases are thermodynamically stable. Besides, Co₇W₆ owns a higher structural stability than that of Co₇Mo₆ and Co₇Nb₆. The obtained elastic constant demonstrates that Co₇M₆ (M?=?W, Mo, Nb) are mechanically stable. With Voigt-Reuss-Hill (VRH) approximation, the elastic bulk modulus (B), shear modulus (G), Young's modulus (E) and Poisson's ratio (ν) were derived. The ductility and plasticity as well as the elastic anisotropy of the three phases were discussed in details. Finally, the density of states and charge density difference were also analysed to reveal the underlying mechanism of structural stability and the elastic properties.     

Activation of NFKB-JMJD3 signaling promotes bladder fibrosis via boosting bladder smooth muscle cell proliferation and collagen accumulation

Chronic cystitis is characterized by the hyperplasia and fibrosis of the bladder wall as well as attenuated compliance of the bladder. To further unravel its underlying molecular mechanism, the role of NFκB-JMJD3 signaling pathway in cystitis induced bladder fibrosis was investigated. Jmjd3 and Col1/3 expression was detected in a cystitis mouse model that was developed by intraperitoneal injection of cyclophosphamide (CYP). Human bladder smooth muscle cells (hBSMCs) were stimulated in vitro with lipopolysaccharide (LPS), and the cell proliferation and collagen accumulation were detected using EdU, CCK8, flow cytometry, qPCR, western blotting and immunofluorescence assays. Furthermore, the effects of NFκB and JMJD3 on cell proliferation and collagen accumulation were investigated using its selective antagonists, JSH23 and GSK-J4, respectively. CYP induced cystitis significantly increased Jmjd3, Col1 and Col3 expression in the bladder muscle cells. Furthermore, LPS stimulation markedly activated NFκB signaling and elevated JMJD3 expression in hBSMCs, and the activation of NFκB-JMJD3 signaling significantly promoted cell proliferation and collagen accumulation by upregulating CCND1 and COL1/3 expression, respectively. Our study reveals the critical role of NFκB-JMJD3 signaling in cystitis induced bladder reconstruction by regulating hBSMC proliferation and extracellular matrix (ECM) deposition, and these findings provide an avenue for effective treatment of patients with cystitis.