Radiation and chemo-sensitizing effects of DNA-PK inhibitors are proportional in tumors and normal tissues.

Inhibitors of DNA-PK sensitize cancers to radiotherapy and DNA-damaging chemotherapies, with candidates in clinical trials. However, the degree to which DNA-PK inhibitors also sensitize normal tissues remains poorly characterized. In this study we compare tumor growth control and normal tissue sensitization following DNA-PK inhibitors in combination with radiation and etoposide. FaDu tumor xenografts implanted in mice were treated with 10 - 15Gy irradiation ± 3 - 100 mg/kg AZD7648. A dose-dependent increase in time to tumor volume doubling following AZD7648 was proportional to an increase in toxicity scores of the overlying skin. Similar effects were seen in the intestinal jejunum, tongue and FaDu tumor xenografts of mice assessed for proliferation rates at 3.5 days after treatment with etoposide or 5Gy whole body irradiation ± DNA-PK inhibitors AZD7648 or peposertib (M3814). Additional organs were examined for sensitivity to DNA-PK inhibitor activity in ATM-deficient mice, where DNA-PK activity is indicated by surrogate marker γH2AX. Inhibition was observed in heart, brain, pancreas, thymus, tongue and salivary glands of ATM-deficient mice treated with the DNA-PK inhibitors relative to radiation alone. Similar reductions are also seen in ATM-deficient FaDu tumor xenografts where both pDNA-PK and γH2AX staining could be performed. Conclusions: DNA-PK inhibitor-mediated sensitization to radiation and DNA-damaging chemotherapy is not limited to tumor tissues, but also extends to normal tissues sustaining DNA damage. These data are useful for interpretation of the sensitizing effects of DNA damage repair inhibitors, where a therapeutic index showing greater cell-killing effects on cancer cells is crucial for optimal clinical translation.

Structures and growth pathways of AunCln+3- (n ≤ 7) cluster anions.

Gold chloride clusters play an important role in catalysis and materials chemistry. Due to the diversity of their species and isomers, there is still a dearth of structural studies at the molecular level. In this work, anions of AunCln+3 - and AunCln+5 - (n = 2-4) clusters were obtained by laser desorption/ionization mass spectrometry (LDI MS), and the most stable isomers of AunCln+3 - were determined after a thorough search and optimization at the TPSSh/aug-cc-pVTZ/ECP60MDF level. The results indicate that all isomers with the lowest energy have a planar zigzag skeleton. In each species, there is one Au(III) atom at the edge connected with four Cl atoms, which sets it from the other Au(I) atoms. Four growth pathways for AunCln+3 - (n = 2-7) clusters are proposed (labelled R1, R2, R3 and R4). They are all associated with an aurophilic contact and are exothermic. The binding energies tend to stabilize at ∼ -41 kcal/mol when the size of the cluster increases in all pathways. The pathway R1, which connects all the most stable isomers of the respective clusters, is characterized by cluster growth due to aurophilic interactions at the terminal atom of Au(I) in the zigzag chains. In the pathway of R4 involving Au-Au bonding in its initial structures (n ≤ 3), the distance between intermediate gold atoms grows with cluster size, ultimately resulting in the transfer of the intermediate Au-Au bonding into aurophilic interaction. The size effect on the structure and aurophilic interactions of these clusters will be better understood based on these discoveries, potentially providing new insights into the active but elusive chemical species involved in the corresponding catalytic reactions or nanoparticle synthesis processes.

Probing the processing of facial expressions in monkeys via time perception and eye tracking.

Accurately recognizing facial expressions is essential for effective social interactions. Non-human primates (NHPs) are widely used in the study of the neural mechanisms underpinning facial expression processing, yet it remains unclear how well monkeys can recognize the facial expressions of other species such as humans. In this study, we systematically investigated how monkeys process the facial expressions of conspecifics and humans using eye-tracking technology and sophisticated behavioral tasks, namely the temporal discrimination task (TDT) and face scan task (FST). We found that monkeys showed prolonged subjective time perception in response to Negative facial expressions in monkeys while showing longer reaction time to Negative facial expressions in humans. Monkey faces also reliably induced divergent pupil contraction in response to different expressions, while human faces and scrambled monkey faces did not. Furthermore, viewing patterns in the FST indicated that monkeys only showed bias toward emotional expressions upon observing monkey faces. Finally, masking the eye region marginally decreased the viewing duration for monkey faces but not for human faces. By probing facial expression processing in monkeys, our study demonstrates that monkeys are more sensitive to the facial expressions of conspecifics than those of humans, thus shedding new light on inter-species communication through facial expressions between NHPs and humans.

Construction of a UDP-Arabinose Regeneration System for Efficient Arabinosylation of Pentacyclic Triterpenoids.

Glycosylation is an important method of modifying natural products and is usually catalyzed by uridine 5'-diphosphate (UDP)-glycosyltransferase. UDP-ß-l-arabinose (UDP-Ara) confers specific functions to natural products such as pentacyclic triterpenoids. However, UDP-arabinosyltransferase with high regioselectivity toward pentacyclic triterpenoids has rarely been reported. In addition, UDP-Ara is mainly biosynthesized from UDP-α-d-glucose (UDP-Glc) through several reaction steps, resulting in the high cost of UDP-Ara. Herein, UGT99D1 was systematically characterized for specifically transferring one moiety of arabinose to the C-3 position of typical pentacyclic triterpenoids. Subsequently, 15 enzymes from plants, mammals, and microorganisms were characterized, and a four-enzyme cascade comprising sucrose synthase, UDP-Glc dehydrogenase, UDP-α-d-glucuronic acid decarboxylase, and UDP-Glc 4-epimerase was constructed to transform sucrose into UDP-Ara with UDP recycling. This system was demonstrated to efficiently produce the arabinosylated derivative (Ara-BA) of typical pentacyclic triterpenoid betulinic acid (BA). Finally, the in vitro cytotoxicity tests indicated that Ara-BA showed much higher anticancer activities than BA. The established arabinosylation platform shows the potential to enhance the pharmacological activity of natural products.

Dual-mode supramolecular fluorescent probe for rapid and on-site detection of chlorpyrifos in the environment.

Chlorpyrifos (CPF) as a classic organophosphorus pesticide has been widely used in agricultural applications to control insects and worms. CPF in the environment can cause deaths of diverse kinds of aquatic organism and bring a high risk to human health. Therefore, the development of effective analytical method for CPF is of great importance. In this work, a novel dual-mode albumin (ALB)-based supramolecular probe FD@ALB was designed and prepared for rapid detection of CPF in the environment. The limit of detection is 0.57 µM (∼ 0.2 ppm) with a wider detection range up to 200 µM, which is satisfactory for application. The sensing mechanism can be ascribed to CPF-induced phosphorylation of ALB, thus leading to a change in the binding microenvironment of FD dye. Moreover, the paper-based test strips were used in conjunction with the FD@ALB, realizing the portable detection of CPF. This method was demonstrated to be suitable for on-site detection of CPF in various kinds of environmental samples, including water, soil, and food samples, with the aid of a smartphone. To the best of our knowledge, this is the first analytical method achieving a combination of the rapid and ratiometric detection of CPF in the environment.

The combination of in situ photodynamic promotion and ion-interference to improve the efficacy of cancer therapy.

Photodynamic therapy (PDT) is proved to be a promising modality for clinical cancer treatment. However, it also suffers from a key obstacle in association with its oxygen-dependent nature which greatly limits its effective application against hypoxic tumors. Herein, on the basis of the unique property of calcium peroxide (CaO2), we propose an O2-self-supply strategy for the promotion of PDT by combining the in situ O2-generation characteristic of calcium peroxide with the photosensitive nature of porphyrin. A shell of ZIF-8 was synthesized surround the CaO2 core to prevent the CaO2 from premature decomposition and increased the loading of THPP efficiently. Depending on the in situ self-supply of O2, the photosensitizer was able to exhibit an enhanced PDT effect that significantly inhibit the growth of tumor. Moreover, the enrichment of free calcium ions derived from the decomposition of CaO2 under acidic tumor microenvironment also shows the unique ion-interference effect and contributes to the obvious inhibition against tumor growth. This work presents a synergistic strategy for the construction of a photodynamic promotion/ion-interference combined nano-platform which can also serve as an inspiration for the future design of effective nanocomposites in tumor treatment.

Comparative pharmacokinetics and urinary excretion of arsenic and mercury after oral administration of realgar, cinnabar and AnGongNiuHuang Pill to rats.

Realgar- and cinnabar-containing AnGongNiuHuang Pill (AGNHP) is widely used for treating encephalopathy syndrome. However, it raises great safety concerns due to the adverse effects reported by arsenic or mercury poisoning. Although AGNHP has been generally recognized, little is known about the metabolism of arsenic and mercury and their resulting potential health risk in vivo. Thus, comparative pharmacokinetics and urinary excretion of arsenic and mercury were conducted in rats after oral administration of realgar, cinnabar and AGNHP, respectively. The contents of arsenic and mercury in rat blood and urine were determined by hydride-generation atomic fluorescence spectrometry (HG-AFS) after wet digestion. AGNHP significantly reduced the absorption of arsenic in blood and promoted urinary arsenic excretion. Whereas, it increased the blood mercury absorption and reduced urinary mercury excretion. No significant toxicity was observed in the clinical dose range of AGNHP. However, excessive exposure to arsenic and mercury may still pose risks especially by long-term or excessive medication. The results are helpful for the rational clinical applications of realgar- and cinnabar-containing TCMs.

Formalin-induced pain prolongs sub- to supra-second time estimation in rats.

BACKGROUND: Temporal estimation can be influenced by pain, which is a complex psychological and physiological phenomenon. However, the time range in which perception is most sensitive to pain remains unclear. METHODS: In the present study, we explored the effects of acute inflammatory pain on time perception in the sub- to supra-second (0.6-2.4-s) and supra-second (2-8-s) ranges in rats. Plantar formalin injection was used to induce acute inflammatory pain, and a temporal bisection task was used to measure time perception. Task test sessions were held for five consecutive days (one per day): the day before injection (baseline), immediately after injection, and the three post-injection days. The point of subjective equality (PSE, which reflects the subjective duration) and Weber fraction (which reflects temporal sensitivity) were calculated and analysed. RESULTS: In the 0.6-2.4-s range, the PSE was significantly lower, indicating prolonged subjective duration, in the formalin group relative to the saline group (p = 0.049) immediately after injection. Formalin-induced pain also tended to lengthened time perception in the 0.6-2.4-s range on post-injection days 2 (p = 0.06) and 3 (p = 0.054). In the 2-8-s range, formalin injection did not affect the PSE or Weber fraction. CONCLUSIONS: The enhanced effect of pain on temporal perception in the sub- to supra-second range is observed in this study and this effect is attenuated with the prolongation of estimated time, even in rats.

Improving the activity and thermostability of GH2 ß-glucuronidases via domain reassembly.

Glycoside hydrolase family 2 (GH2) enzymes are generally composed of three domains: TIM-barrel domain (TIM), immunoglobulin-like ß-sandwich domain (ISD), and sugar-binding domain (SBD). The combination of these three domains yields multiple structural combinations with different properties. Theoretically, the drawbacks of a given GH2 fold may be circumvented by efficiently reassembling the three domains. However, very few successful cases have been reported. In this study, we used six GH2 ß-glucuronidases (GUSs) from bacteria, fungi, or humans as model enzymes and constructed a series of mutants by reassembling the domains from different GUSs. The mutants PGUS-At, GUS-PAA, and GUS-PAP, with reassembled domains from fungal GUSs, showed improved expression levels, activity, and thermostability, respectively. Specifically, compared to the parental enzyme, the mutant PGUS-At displayed 3.8 times higher expression, the mutant GUS-PAA displayed 1.0 time higher catalytic efficiency (kcat /Km ), and the mutant GUS-PAP displayed 7.5 times higher thermostability at 65°C. Furthermore, two-hybrid mutants, GUS-AEA and GUS-PEP, were constructed with the ISD from a bacterial GUS and SBD and TIM domain from fungal GUSs. GUS-AEA and GUS-PEP showed 30.4% and 23.0% higher thermostability than GUS-PAP, respectively. Finally, molecular dynamics simulations were conducted to uncover the molecular reasons for the increased thermostability of the mutant.

Dual-path modulation of hydrogen peroxide to ameliorate hypoxia for enhancing photodynamic/starvation synergistic therapy.

The common existence of hypoxia within the tumor microenvironment severely restricts the efficacy of photodynamic therapy (PDT), which is attributed to the fact that the PDT process is strongly oxygen (O2) dependent. Here, a multifunctional composite (named CPCG), which combines polyethylene glycol (PEG) functionalized cerium oxide nanoparticles (CeO2) with photosensitizer chlorin e6 (Ce6) and glucose oxidase (GOx), is reported for generating O2 within the tumor microenvironment by the dual-path hydrogen peroxide (H2O2)-modulated ways to ameliorate hypoxia, thereby enhancing the PDT efficiency. This process is realized based on the dual enzyme-like activity of CeO2. The first modulated way is to transform the superoxide anion (O2˙-) into H2O2 by the superoxide dismutase-like activity of CeO2. The second modulated way is to decompose glucose into H2O2 through the catalysis of GOx. Subsequently, H2O2 generated from the above dual modulated ways can further produce O2via the catalase-like activity of CeO2. Additionally, the depletion of glucose could impede the nutrient supply to obtain starvation therapy. Both in vitro and in vivo experiments indicate that the CPCG composite could enhance the efficacy of photodynamic/starvation synergistic therapy. Therefore, this strategy offers great potential to modulate the O2 level in the tumor microenvironment for better therapeutic outcomes, and can act as a promising candidate in photodynamic/starvation synergistic therapy.

Molecular dynamics exploring of atmosphere components interacting with lung surfactant phospholipid bilayers.

Sulfur dioxide (SO2), nitrogen oxide (NO2) and ozone (O3) in the atmosphere are significantly correlated with various respiratory and cardiovascular diseases. High doses of each of these gases or a mixture can change the physical and chemical properties of the lung membrane, thus leading to an increased pulmonary vascular permeability and structural failure of the alveolar cell membrane. In the present study, detailed molecular dynamic (MD) modeling was applied to investigate the effects of SO2, NO2, O3 and mixtures of these gases on the dipalmitoyl phosphatidylcholine (DPPC) phospholipid bilayer. The results showed that several key physical properties, including the mass density, lipid ordering parameter, lipid diffusion, and electrostatic potential of the cell membrane, have been changed by the binding of different compounds. This resulted in significant variations and more disorder in the DPPC bilayer. The multiple analyses of membrane properties proved the toxicity of NO2, O3, and SO2 to the DPPC bilayer, providing a theoretical basis for the experimental phenomenon that SO2, NO2 and O3 can cause lung cell apoptosis. For the single systems, the damage to DPPC bilayer caused by O3 was more serious than NO2 and SO2. More importantly, the MD simulations using the mixtures of SO2, NO2, and O3 showed a much greater decline of membrane fluidity and the aggravation of membrane damage than the single systems, indicating a synergistic effect when NO2, SO2, and O3 coexisted in the atmosphere, which could lead to much more severe damage and greater toxicities to the lung.

Exploring toxicity of perfluorinated compounds through complex network and pathway modeling.

Perfluorinated compounds (PFCs) have serious impacts on human health, which could interfere with the body's signal pathways and affect the normal hormone balance of humans. PFCs were reported to bind to many proteins causing a series of biological effects. It was quite possible that the in vivo action of PFCs was not a single target or a single pathway, suggesting the toxic effect was due to the disturbance of protein or gene network, not limited to the modification of a single target protein or gene. Thus, a PFCs-targets interaction network was constructed and the significant differences in the characteristics of complex networks between the branched PFCs and linear PFCs were observed. A molecular dynamics simulation proved that binding ability of the branched PFCs to the target protein was much weaker than that of the linear PFCs, explaining why the branched PFCs presented significantly difference from the linear PFCs in terms of complex network characteristics. In addition, four target genes were identified as the central node genes of the network. The four target genes were proved to present certain influences on some diseases, which suggested a high correlation between PFCs to these diseases, including obesity, hepatocellular carcinoma and diabetes. The present work was helpful to develop new approaches to identify the key toxic targets of compounds and to explore the toxicity effects on pathways. AbbreviationsARandrogen receptorBPAbisphenol AESR1estrogen receptor 1ESR2estrogen receptor 2GLTPglycolipid transfer proteinHbFthe fetal hemoglobinHBG1hemoglobin subunit γ-1hERαhuman ERαHSD17B1hydroxysteroid 17-ß dehydrogenase 1KEGGKenya encyclopedia of genes and genomesMDmolecular dynamics simulationPFCsperfluorinated compoundsPFOAperfluorooctanoic acidPFOSperfluorooctane sulfonatePOPspersistent organic pollutantsRMSDroot-mean-square deviationSHBGsex hormone binding globulinSPC/Eextended simple point charge modelTRthyroid hormone receptorCommunicated by Ramaswamy H. Sarma.

Formalin-induced and neuropathic pain altered time estimation in a temporal bisection task in rats.

Time perception is an important ability that is related closely to humans' and animals' daily activities. It can be distorted by various emotional states. In human studies, experimental pain has been shown to prolong the perception of time. However, related animal studies are lacking. In this study, we used a temporal bisection task to investigate how acute inflammatory pain (induced by hind-paw formalin injection) and chronic neuropathic pain [induced by spinal nerve ligation (SNL)] affected time perception in rats. Rats were trained to recognize "short" (1200-ms) and "long" (2400-ms) anchor-duration pure tones and were rewarded for corresponding lever presses. During testing, rats perceived a series of intermediate-duration and anchor-duration pure tones, and selected levers corresponding to the "short" and "long" tones. After formalin injection, rats gave more "long" lever-press responses than after saline injection. The point of subjective equality after formalin injection also increased, suggesting that formalin-induced acute pain extended time perception. In contrast, rats that had undergone SNL gave fewer "long" lever-press responses compared with the sham surgery group. This animal study suggests that formalin-induced pain and neuropathic pain may have different effects on time perception.

Scalable Synthesis of Micromesoporous Iron-Nitrogen-Doped Carbon as Highly Active and Stable Oxygen Reduction Electrocatalyst.

Micromesoporous metal-nitrogen-doped carbons have attracted incremental attention owning to their high activities for the electrocatalyzing oxygen reduction reaction (ORR). However, scalable synthesis of micromesoporous metal-nitrogen-doped carbons having superior electrocatalytic activity and stability remains a challenge. Here, an iron-nitrogen-doped carbon with highly electrocatalytic properties was simply prepared by ZnCl2 activation of an in situ polymerized iron-containing polypyrrole (PPy@FeClx) at high temperature. High yields of polypyrrole (∼98 wt %) and iron-nitrogen-doped carbon (∼47 wt %) could be reached. The eutectic state of FeClx-ZnCl2 and its derived ZnFe2O4 maskant played important roles in making micromesopores, scattering iron atoms, and trapping nitrogen atoms, leading to numerous micromesopore defects, a larger specific surface area, a more nitrogen doping content, and active sites for the material. The electrochemical tests and Zn-air battery measurements showed that the micromesoporous iron-nitrogen-doped carbon could achieve much positive onset and half-wave potentials at 0.98 and 0.90 V, respectively, as well as a large current density (6.06 mA/cm2) and good cycling stability. The combination of the iron-nitrogen doping and micromesopore defects by the eutectic salt activation method provided an effective way to scalable synthesize iron-nitrogen-doped carbon as highly active and stable oxygen reduction electrocatalytsts.

Reward Processing under Chronic Pain from the Perspective of "Liking" and "Wanting": A Narrative Review.

The therapeutic goals of patients with chronic pain are not only to relieve pain but also to improve the quality of life. Chronic pain negatively affects various aspects of daily life, such as by decreasing the motivation to work and reward sensitivity, which may lead to difficulties in daily life or even unemployment. Human and animal studies have shown that chronic pain damages reward processing; the exploration of associated internal mechanisms may aid the development of treatments to repair this damage. Incentive salience theory, used widely to describe reward processing, divides this processing into "liking" (reward-induced hedonic sensory impact) and "wanting" (reward-induced motivation) components. It has been employed to explain pathological changes in reward processing induced by psychiatric disorders. In this review, we summarize the findings of studies of reward processing under chronic pain and examine the effects of chronic pain on "liking" and "wanting." Evidence indicates that chronic pain compromises the "wanting" component of reward processing; we also discuss the neural mechanisms that may mediate this effect. We hope that this review aids the development of therapies to improve the quality of life of patients with chronic pain.

Sibling astrocytes share preferential coupling via gap junctions.

Astrocytes are organized as communicating cellular networks where each cell is connected to others via gap junctions. These connections are not pervasive and there is evidence for the existence of subgroups composed by preferentially connected cells. Despite being unclear how these are established, we hypothesized lineage might contribute to the establishment of these subgroups. To characterize the functional coupling of clonally related astrocytes, we performed intracellular dye injections in clones of astrocytes labeled with the StarTrack method. This methodology revealed sibling astrocytes are preferentially connected when compared to other surrounding astrocytes. These results suggest the role of the developmental origin in the organization of astrocytes as intercellular networks.

Mild Hyperthermia-Enhanced Enzyme-Mediated Tumor Cell Chemodynamic Therapy.

The heterogeneity and diversity of tumors seriously attenuate the curative outcome of single treatment modes. Combined therapy has been demonstrated to be a promising candidate to enhance therapeutic efficacy compared with monotherapy. As an emerging therapeutic strategy, chemodynamic therapy (CDT) has drawn extensive attention in recent years. However, the therapeutic efficiency of CDT is still unsatisfying because the level of intracellular hydrogen peroxide (H2O2) restricts the production of hydroxyl radicals (•OH). In this study, a novel curative strategy which combines glucose oxidase (GOx)-mediated Fe3O4-based Fenton reaction and multiwalled carbon nanotube (MWNT)-produced mild hyperthermia enhancer is proposed, achieving a mild hyperthermia-enhanced enzyme-mediated tumor cell CDT. GOx can catalyze the conversion of glucose into gluconic acid and H2O2, which can elevate acidity in the tumor microenvironment and boost Fe3O4-based Fenton reaction, producing a myriad of •OH to induce tumor cell death. Furthermore, by using the theory that a temperature rise expedites the kinetics of a chemical reaction, producing a higher reaction rate and more resultants per unit time, we integrate MWNTs in this therapy system, which generate mild hyperthermia so as to accelerate the Fenton reaction for increasing the productivity of •OH. Therefore, an amplified CDT can be realized. The therapy platform, mild hyperthermia-enhanced GOx-mediated CDT, provides an effective treatment for cancer and takes CDT a step further.

Understanding the interaction of single-walled carbon nanotube (SWCNT) on estrogen receptor: A combined molecular dynamics and experimental study.

Considering the large-scale production of diversified nanomaterials, it is paramount importance to unravel the structural details of interactions between nanoparticles and biological systems, and thus to explore the potential adverse impacts of nanoparticles. Estrogen receptors (ER) is one of the most important receptor of human reproductive system and the binding of carbon nanotubes to estrogen receptors was the possible trigger leading to the reproductive toxicity of carbon nanotubes. Thus, with single-walled carbon nanotube (SWCNT) treated as model nanomaterials, a combination of in vivo experiments, spectroscopy assay and molecular dynamic modeling was applied to help us unravel some important issues on the binding characterization between SWCNT and the ligand binding domain (LBD) of ER alpha (ERα). The fluorescence assay and molecular dynamics simulations together validated the binding of SWCNT to ERα, suggesting the possible molecular initiating event. As a consequence, SWCNT binding led to a conformational change on tertiary structure levels and hydrophobic interaction was recognized as the driving force governing the binding behavior between SWCNT and LBD of ERα. A in vivo process presented that the exposure of SWCNT increased ERα expression from 26.43 pg/ml to 259.01 pg/ml, suggesting a potential estrogen interference effects of SWCNT. Our study offers insight on the binding of SWCNT and ERα LBD at atomic level, helpful to accurately evaluate the potential health risks of SWCNT.

The role of dopamine D1- and D2-like receptors related to muscarinic M1 receptors in impulsive choice in high-impulsive and low-impulsive rats.

The non-selective muscarinic receptor agonist oxotremorine-M has been found to decrease impulsive choice in high-impulsive (HI) rats and increase impulsive choice in low-impulsive (LI) rats, but little is known about the muscarinic M1 receptor agonist N-desmethylclozapine (NDMC). This study investigated effects of NDMC on impulsive choice, and the effect of co-administration of NDMC with the dopamine D1-like receptor antagonist SCH 23390 or D2-like receptor antagonist raclopride on impulsive choice in HI and LI rats, characterized by basal levels of impulsive choice in a delay-discounting task. The results revealed that NDMC (1 and 2 mg/kg) significantly increased impulsive choice in HI, but not LI rats. SCH 23390 significantly promoted impulsive choice in HI rats at 0.01 mg/kg, and in LI rats at 0.0075 and 0.01 mg/kg. Moreover, SCH 23390 (0.005 and 0.0075 mg/kg) significantly inhibited the increase in impulsive choice induced by NDMC (1 mg/kg) in HI rats, whereas the increase in impulsive choice produced by SCH 23390 (0.0075 mg/kg) was significantly reversed by NDMC (1 mg/kg) in LI rats. Raclopride (0.04, 0.08, and 0.12 mg/kg) did not affect choice in both HI and LI rats, but significantly antagonized the increase in impulsive choice induced by NDMC (1 mg/kg) in HI rats. These findings suggest that D1- and D2-like receptors might be involved in different effects of the M1 receptor agonist on impulsive choice between HI and LI rats.

Exploring the membrane toxicity of decabromodiphenyl ethane (DBDPE): Based on cell membranes and lipid membranes model.

Decabromodiphenyl ethane (DBDPE) is widely used in industry as an alternative to the decabromodiphenyl ether (BDEs). The large-scale use of DBDPE could lead to rapid growth of the human accumulation level of DBDPE. However, the biophysics of accumulation of DBDPE in cell membranes, as one of determinants of DBDPE metabolism is not clear. In the present study, detailed observations of cell lactate dehydrogenase (LDH) and reactive oxygen species (ROS) levels measurements proved that the DBDPE exposure to cell could result in significant cell membrane damage by concentration-dependent manners. The fluorescence anisotropy analysis supported the evidence that high concentration DBDPE bound decreased membrane fluidity significantly. Besides it, a detailed molecular dynamic (MD) simulation was approached to investigate the effects of DBDPE on the DPPC (dipalmitoyl phosphatidylcholine) phospholipid bilayer, which was constructed as the model of cell membrane. The molecular dynamic simulation revealed that DBDPE molecules can easily enter the membrane from the aqueous phase. Under the concentration of a threshold, the DBDPE molecules tended to aggregate inside the DPPC bilayer and caused pore formation. The bound of high concentration of DBDPE could result in significant variations in DPPC bilayer with a less dense, more disorder and rougher layer. The knowledge about DBDPEs interactions with lipid membranes is fundamentally essential to understand the in vivo process of DBDPE and the physical basis for the toxicity of DBDPE in cell membranes.