Hollow CeO2-Based Nanozyme with Self-Accelerated Cascade Reactions for Combined Tumor Therapy.

Nanozymes have obvious advantages in improving the efficiency of cancer treatment. However, due to the lack of tissue specificity, low catalytic efficiency, and so on, their clinical applications are limited. Herein, the nanoplatform CeO2@ICG@GOx@HA (CIGH) with self-accelerated cascade reactions is constructed. The as-prepared nanozyme shows the superior oxidase (OXD)-like, superoxide dismutase (SOD)-like, catalase (CAT)-like and peroxidase (POD)-like activities. At the same time, under 808 nm near-infrared (NIR) irradiation, the photodynamic and photothermal capabilities are also significantly enhanced due to the presence of indocyanine green (ICG). We demonstrate that the nanozyme CIGH can efficiently accumulate in the tumor and exhibit amplified cascade antitumor effects with negligible systemic toxicity through the combination of photodynamic therapy (PDT), photothermal therapy (PTT), chemodynamic therapy (CDT) and starvation therapy. The nanozyme prepared in this study provides a promising candidate for catalytic nanomedicines for efficient tumor therapy.

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.

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.

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.

General anesthetics have differential inhibitory effects on gap junction channels and hemichannels in astrocytes and neurons.

Astrocytes represent a major non-neuronal cell population actively involved in brain functions and pathologies. They express a large amount of gap junction proteins that allow communication between adjacent glial cells and the formation of glial networks. In addition, these membrane proteins can also operate as hemichannels, through which "gliotransmitters" are released, and thus contribute to neuroglial interaction. There are now reports demonstrating that alterations of astroglial gap junction communication and/or hemichannel activity impact neuronal and synaptic activity. Two decades ago we reported that several general anesthetics inhibited gap junctions in primary cultures of astrocytes (Mantz et al., (1993) Anesthesiology 78(5):892-901). As there are increasing studies investigating neuroglial interactions in anesthetized mice, we here updated this previous study by employing acute cortical slices and by characterizing the effects of general anesthetics on both astroglial gap junctions and hemichannels. As hemichannel activity is not detected in cortical astrocytes under basal conditions, we treated acute slices with the endotoxin LPS or proinflammatory cytokines to induce hemichannel activity in astrocytes, which in turn activated neuronal hemichannels. We studied two extensively used anesthetics, propofol and ketamine, and the more recently developed dexmedetomidine. We report that these drugs have differential inhibitory effects on gap junctional communication and hemichannel activity in astrocytes when used in their respective, clinically relevant concentrations, and that dexmedetomidine appears to be the least effective on both channel functions. In addition, the three anesthetics have similar effects on neuronal hemichannels. Altogether, our observations may contribute to optimizing the selection of anesthetics for in vivo animal studies.

[The relationship of SIRT3 with cellular metabolism and cardiovascular diseases].

Protein deacetylases play an extremely crucial role in cellular biological processes and have been categorized into four families (HDACⅠ, HDACⅡ, HDACⅢ and HDACⅣ) in human. Of them, HDACⅢ, also known as the Sir2 (Silent information regulator 2) family, contains seven members, SIRT1-7, each exhibiting different cellular localization and biological function. As a major mitochondrial deacetylase, SIRT3 not only modulates cellular metabolism, but also plays important roles in apoptosis, tumor growth, aging and a number of other diseases. In this review, we summarize recent findings related to SIRT3 with an emphasis on its biological functions in regulating cell metabolism and its possible roles in cardiovascular diseases.

Eventually periodic solutions of a max-type difference equation.

We study the following max-type difference equation xn = max{A(n)/x(n-r), x(n-k)}, n = 1,2,…, where {A(n)} n=1 (+∞) is a periodic sequence with period p and k, r ∈ {1,2,…} with gcd(k, r) = 1 and k ≠ r, and the initial conditions x(1-d), x(2-d),…, x 0 are real numbers with d = max{r, k}. We show that if p = 1 (or p ≥ 2 and k is odd), then every well-defined solution of this equation is eventually periodic with period k, which generalizes the results of (Elsayed and Stevic (2009), Iricanin and Elsayed (2010), Qin et al. (2012), and Xiao and Shi (2013)) to the general case. Besides, we construct an example with p ≥ 2 and k being even which has a well-defined solution that is not eventually periodic.

Theoretical insights into layered IrO2 for the oxygen evolution reaction.

Here we present the density functional theory-based exploration of layered IrO2 polymorphs for the oxygen evolution reaction, as well as a data-driven geometric descriptor for catalytic activity. The layer edges are identified as promising active site motifs with not only low theoretical overpotential but also intriguing structural flexibility and to break the universal energetic scaling through torsional distortion.

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.

pH-responsive oxygen self-sufficient smart nanoplatform for enhanced tumor chemotherapy and photodynamic therapy.

Premature drug release in chemotherapy and hypoxic conditions in photodynamic therapy (PDT) are perplexing problems in tumor treatment. Thus, it is of great significance to develop the novel therapeutic system with controllable drug release and effective oxygen generation. Herein, a pH-responsive oxygen self-sufficient smart nanoplatform (named DHCCC), integrating hollow mesoporous silica nanoparticles (HMSNs), chitosan (CS), doxorubicin hydrochloride (DOX), chlorin e6 (Ce6) and catalase (CAT), is fabricated to enhance the tumor therapeutic efficacy efficiently through avoiding premature drug release and mitigating hypoxia of tumor microenvironment (TME). The drug DOX can be efficiently loaded into the HMSNs with large cavity and be controllable released because of the pH responsiveness of CS to the weak acidic TME, thereby elevating the chemotherapy efficacy. Meanwhile, CAT can catalyze the decomposition of endogenous hydrogen peroxide in situ generating oxygen to alleviate the hypoxia and enhance the PDT efficiency considerably. In vitro and in vivo results demonstrate that the combined chemo-photodynamic therapy based on the DHCCC nanoplatform exerts more effective antitumor efficacy than chemotherapy or PDT alone. The current study provides a promising inspiration to construct the pH-responsive oxygen self-sufficient smart nanomedicine with potentials to prevent premature drug leakage and overcome hypoxia for efficient tumor therapy.

Radiation and Chemo-Sensitizing Effects of DNA-PK Inhibitors Are Proportional in Tumors and Normal Tissues.

Inhibitors of DNA-dependent protein kinase (PRKDC; 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 to 15 Gy irradiation ± 3 to 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 5 Gy 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 the 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. DNA-PK inhibitor-mediated sensitization to radiation and DNA-damaging chemotherapy are not only 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.

Laryngeal mask airway does not reduce postoperative nasal bleeding outside the operation room after intranasal surgery.

BACKGROUND: The aim of this study was to detect the effect of the laryngeal mask airway (LMA) versus the endotracheal tube (ETT) on postoperative nasal bleedings in and outside the operation room (OR) after intranasal surgery. METHODS: 134 patients undergoing elective intranasal surgeries were randomly allocated to receive LMA or ETT during general anesthesia. The incidence, episodes, and severity of nasal bleeding were evaluated in the OR and within the postoperative 24 hours in the ward. Furthermore, medical assistance and severe complications were assessed. RESULTS: THE overall incidence of postoperative nasal bleeding throughout the observation period was similar between the two groups. The LMA reduced nasal bleeding in the OR. However, outside the OR, the incidence of the first episode of postoperative nasal bleeding in the LMA group was higher than that in the ETT group (difference: -26.5%; 95% CI: -42.2% to -10.7%; P < 0.001). In the LMA group, more patients needed medical assistance (P = 0.029), and the number of assistance was also higher (P = 0.027) in the ward. No severe complications occurred during the observation period. CONCLUSION: The LMA does not alleviate nasal bleeding conditions and even increases the demands of medical service outside the OR after intranasal surgery, although it reduces epistaxis during extubation.

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.

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.

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.

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.

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.

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.

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.