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To investigate the effect and potential mechanism of 3,3'-diindolylmethane (DIM) on ferroptosis against gastric cancer, cells proliferation, lipid reactive oxygen species (ROS) and GSH level were measured in the BGC-823 gastric cancer cells after DIM treatment. Western blotting was used to detect the expression of SLC7A11, GPX4, IP3R and BAP1. Results showed that DIM could induce ferroptosis in the BGC-823 gastric cancer cells via upregulating lipid-ROS level and decreasing GSH generation. Besides, DIM also significantly reduced the protein level of SLC7A11 and GPX4, which was an important regulator of ferroptosis. In addition, DIM promoted the protein level of BAP1 and IP3R in a concentration-dependent manner in the BGC-823 gastric cancer cells. The knockdown of BAP1 could reduce IP3R level and DIM-induced ferroptosis of gastric cancer cells. Taken together, these results indicated that DIM could induce ferroptosis to exert anti-cancer effects via BAP1-IP3R axis, suggesting its effective therapeutic potential in gastric cancer.

Identifying novel agents for cancer treatment is critical because of obstacles with anticancer drug resistance and lack of drug effectiveness. Intracellular calcium ion (Ca

Multi-component combination therapy of cancer is currently a hot spot in the field of cancer treatment research. In this study, a WS2 nanosheet was selected as the substrate material and modified with a cell-like membrane biomimetic liposome (WS2-lipid). The lipid-modified WS2 nanomaterials were successfully prepared with good stability and biocompatibility. Its good photothermal characteristics and high drug loading amount were utilized to achieve a comprehensive chemo and photothermal therapeutic effect. The results showed that the lipid coating strongly enhanced the stability of the WS2 nanosheets before and after DOX loading and the WS2-lipid had a good photothermal performance and drug loading amount. According to the cellular results, WS2-lipid was able to be taken up by MCF-7 cells. Both photothermo-therapy and chemotherapy had a concentration dependent cytotoxicity on MCF-7 cells, and the combined application of both methods had an improved cytotoxicity. In addition, in vivo photothermal experiments indicated that lipid modification could promote intratumoral accumulation of the material. Thus, WS2-lipid can be used as a good nano-platform for phototherapy and chemotherapy combination therapy and has good application prospects in cancer therapy.

Dibromoacetonitrile (DBAN) and dichloroacetonitrile (DCAN) are haloacetonitriles (HANs) produced as by-products of chloramine disinfection of drinking water and can cause neurotoxicity. The molecular pathways leading to HAN-induced neuronal cell death remain unclear. The nuclear factor erythroid 2-related factor 2 (Nrf2) is an important regulator of oxidation reactions. We explored the role of the sequestosome 1 (p62)-Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 pathway in DBAN- and DCAN-induced mouse hippocampal neuronal (HT22) cell injury. DBAN and DCAN reduced cell viability, increased lactate dehydrogenase release rate, and promoted apoptosis. Over the same treatment time, DBAN at lower concentrations caused cell injury, suggesting that DBAN is more cytotoxic than DCAN. DBAN and DCAN triggered oxidative stress by reducing intracellular glutathione and increasing reactive oxygen species concentrations. DBAN and DCAN activated the Nrf2 pathway. Furthermore, Nrf2 inhibitors (all-trans retinoic acid) attenuated DBAN- and DCAN-induced toxicity, whereas Nrf2 activators (tert-Butylhydroquinone) achieved the opposite effect. This indicates that activation of the Nrf2 pathway mediates DBAN- and DCAN-induced cell injury. Notably, the expression of p62, a noncanonical pathway that mediates Nrf2 activation, increased, whereas the expression of Keap1, another regulator of Nrf2, decreased. We noted that high p62 expression activated the Nrf2 pathway, and p62 was regulated through Nrf2, forming a positive feedback loop. N-acetyl-L-cysteine, a mercaptan substance, protected against DBAN- and DCAN-induced toxicity and inhibited the Nrf2 pathway. In summary, Nrf2 pathway inhibition and mercaptan supplementation prevent DBAN- and DCAN-induced HT22 cell injury, accordingly, targeting them is a potential approach to preventing HAN-induced neurotoxicity.

Vascular dysfunction and bacterial infection are key factors for the non-healing of diabetic ulcers. Growth factors and antibiotics seem to effectively target both issues. However, the short half-life and high cost of growth factors and the antibiotics resistance of bacteria greatly limit their further widespread applications. Novel strategies or agents with both angiogenic and antibacterial activities are urgently desirable. Copper peroxide (CuO2) nanodots were reported to be decomposed into Cu2+ and H2O2 under mild acid conditions (pH 5.5). Considering that both decomposed products are acknowledged antibacterial agents (Cu2+, H2O2) and angiogenesis activator (Cu2+), we believe that CuO2 nanodots are suitable for diabetic ulcer treatment because the pathological environment of infected chronic wounds is mildly acidic with pH 5.5-5.6. As expected, in vitro experiments showed that CuO2 nanodots possessed excellent bactericidal properties against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and even methicillin-resistant Staphylococcus aureus (MRSA). CuO2 nanodots induced the high expression of hypoxia-inducible factor (HIF-1α) and vascular endothelial growth factor (VEGF) in human umbilical vein endothelial cells (HUVECs), subsequently promoting the cell migration and tube formation for angiogenesis. In particular, CuO2 nanodots exhibited good dispersibility and sprayable behavior in water. In vivo experiments demonstrated that the spayed CuO2 nanodots in the wound area could effectively combat MRSA, reduce inflammation, promote angiogenesis, and consequently accelerate wound healing. Moreover, the sprayed CuO2 nanodots in the wound sites caused negligible system toxicity. This study provides proof-of-principle evidence for applying the sprayed CuO2 nanodots for infected diabetic ulcer treatment.

Background: The combination of photothermal therapy (PTT) and chemotherapy has proven to be a promising strategy for cancer treatment. Various nanomaterials have shown great potential in combination therapy, including gold, graphene oxide, iron oxide, and other nanoparticles. However, their undefinable toxicity in vivo greatly slowed down their development for clinical applications. Objective: The present work aimed to develop a multifunctional nanoparticle for chemo-photothermal therapy composed of acknowledged biocompatible materials. Methods: A novel biocompatible nanoparticle (HIT-NPs) was self-assembled through the intrinsic interaction between D-α-tocopherol Succinate (TOS), human serum albumin (HSA) and indocyanine green (ICG). Doxorubicin (DOX) was then loaded due to the ion pairing between DOX and TOS. The feasibility of combined chemo-photothermal therapy induced by DOX-loaded HIT-NPs was carefully evaluated. Results: In vitro, HIT-NPs showed no cytotoxicity on human normal liver cells (HL-7702 cells) but obvious killing effects on murine breast cancer cells (4T1 cells). The combined chemo-photothermal therapeutic effect on 4T1 cells was successfully obtained. DOX-loaded HIT-NPs could effectively accumulate in 4T1 subcutaneous tumors after intravenous injection, and the tumor temperature rapidly increased under laser exposure, indicating the feasibility of PTT in vivo. Conclusion: The self-assembled HIT-NPs could provide a promising platform for combined chemo- photothermal cancer therapy with full biocompatibility.

The output power of the hydro-turbine is a key component in precisely modeling the stability characteristics of a hydro-turbine governing system (HTGS), especially in working conditions that is far away the optimum operating condition. In this study, first, we formulate the energy losses of HTGS's components to present the hydro-turbine's output power and utilize it to establish a novel mathematical model of HTGS. Second, we perform global sensitivity analysis to extract sensitive parameters of the conversion efficiency, optimize the values of model parameters based sensitive results, and verify HTGS model to be effective in different working conditions by experimental data. Third, the distribution characteristics of energy losses are investigated with the increasing guide vane, and the corresponding stability regions are presented to predict the characteristics of transient stability trend. The obtained results could contribute to the optimization analysis and control of HTGS in working conditions that is far away the optimum operating condition.

AIMS Diabetes mellitus (DM) is one of the most common metabolic diseases worldwide characterized by insulin resistance and pancreatic β-cell dysfunction. In the previous study, endoplasmic reticulum (ER) stress could increase the C/EBP homologous protein (CHOP) expression through inhibiting C/EBβ transcriptional activity. However, the role of CHOP and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in pancreatic β-cell dysfunction remains unknown. The aim of the study was to investigate the effect of CHOP and PGC-1α in pancreatic β-cell dysfunction and the potential mechanisms underlying its actions. METHODS We established the pancreatic β-cell dysfunction model to identify the biological features and functions of CHOP. Apoptosis was detected using Western blot analysis and real-time polymerase chain reaction (RT-PCR). RESULTS Our results showed that high glucose (HG) increases CHOP and inhibits PGC-1α expression and ameliorates apoptosis in pancreatic β cells. Silenced CHOP elevates the PGC-1α expression and ameliorates HG-induced apoptosis in pancreatic β cells. Furthermore, upregulation of the PGC-1α alleviates HG-induced apoptosis in pancreatic β cells. We also expounded that HG-activated phosphorylation of nuclear factor-κB through increasing PGC-1α expression. CONCLUSION We verified the function and mechanism of CHOP and provide evidence that CHOP and PGC-1α may serve as potential candidates for the clinical treatment of DM.

Cancer is a serious threat to human health. Graphene oxide (GO) is a good carrier for cancer treatment due to its large surface area and high drug loading, while it's unstable under physiological conditions with a high tendency to be uptaken by macrophages in the body. This paper constructs a red blood cell (RBC) membrane modified GO nanocarrier system for cancer chemotherapy. After the modification of RBC, the stability and hemolysis performance of GO were greatly improved, which is beneficial to the biological application. Moreover, DOX-loaded RBC-GO still able to maintain good stability with a pH-dependent DOX release profile. RBC-GO can be uptaken by MCF-7 cells and DOX-loaded RBC-GO nanocomposites have strong concentration-dependent cytotoxicity. More importantly, in vivo study showed that RBC-GO can accumulate at the tumor site in a large quantity, and among all the experimental groups, RBC-GO-DOX had the best anti-tumor effect after tail vein injection in mice and the lowest systemic toxicity. Experiments have proved that RBC-GO can be used as a drug carrier to achieve targeted drug delivery.

Multifunctional dual-core@shell (Fe

Multi-component combination therapy of cancer is currently a hot spot in the field of cancer treatment research. In this study, a WS2 nanosheet was selected as the substrate material and modified with a cell-like membrane biomimetic liposome (WS2-lipid). The lipid-modified WS2 nanomaterials were successfully prepared with good stability and biocompatibility. Its good photothermal characteristics and high drug loading amount were utilized to achieve a comprehensive chemo and photothermal therapeutic effect. The results showed that the lipid coating strongly enhanced the stability of the WS2 nanosheets before and after DOX loading and the WS2-lipid had a good photothermal performance and drug loading amount. According to the cellular results, WS2-lipid was able to be taken up by MCF-7 cells. Both photothermo-therapy and chemotherapy had a concentration dependent cytotoxicity on MCF-7 cells, and the combined application of both methods had an improved cytotoxicity. In addition, in vivo photothermal experiments indicated that lipid modification could promote intratumoral accumulation of the material. Thus, WS2-lipid can be used as a good nano-platform for phototherapy and chemotherapy combination therapy and has good application prospects in cancer therapy.

Haijun Shen,1 Qianqian Gao,1 Qi Ye,1 Shiyun Yang,1 Yuqian Wu,1 Qin Huang,1 Xiaona Wang,2 Zhenhua Sun3 1Department of Preventive Medicine and Public Health Laboratory Science, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, China; 2Department of Internal Medicine of Jiangsu University Hospital Workers, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, China; 3Department of Thyroid and Breast Surgery, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, China Background and purpose: Nanoparticle-loaded hydrogels – localized drug delivery devices containing a combination of therapeutic nanoparticles and implantable hydrogel – have been recipients of increased focus and interest for cancer treatment. However, it is difficult for the released nanoparticles to penetrate deeply into tumors because of the dense collagen network in the tumor extracellular matrix, which greatly limits their antitumor effect. We hypothesized that the implantation of a hydrogel loaded with both nanoparticles and losartan (Los) might enhance penetration because Los has been proven to effectively reduce collagen levels in various tumors. Herein, we developed a nanoparticle/Los-loaded hydrogel system and evaluated the intratumoral distribution and anticancer effect after peritumoral implantation of nanoparticles. Methods: Fluorescent polystyrene nanoparticles (FPNPs, size ~100 nm) and Los were simultaneously encapsulated in a polyethylene glycol (PEG) hydrogel to form the FPNP/Los-loaded hydrogel. After peritumoral implantation in 4T1 tumor-bearing mice for 2 weeks, intratumoral distributions of FPNPs and collagen level were determined. Based on the results, liposomal doxorubicin (Doxil, ~100 nm) was subsequently substituted for FPNPs in the hydrogel. The cellular uptake and cytotoxicity of the Doxil/Los-loaded hydrogel were studied, and the in vivo antitumor efficacy after peritumoral implantation was evaluated. Results: Compared with a standard FPNP-loaded hydrogel, the FPNP/Los-loaded hydrogel resulted in enhanced penetration and reduced collagen levels after implantation. Thereafter, the potential of a Doxil/Los-loaded hydrogel for cancer treatment was studied. Doxorubicin was released from the hydrogel and induced effective cytotoxicity against 4T1 cells. The Doxil/Los-loaded hydrogel showed synergistic antitumor effects in 4T1 tumor-bearing mice and was more effective at tumor inhibition than the Doxil-loaded hydrogel. Conclusion: This study provides a proof of principle that the implantation of nanoparticles/Los-loaded hydrogel can increase the intratumoral distribution and antitumor efficacy of nanoparticles, owing to collagen depletion by Los. Future studies may build on this strategy for enhanced tumor penetration of nanoparticles. Keywords: localized drug delivery, tumor penetration, tumor extracellular matrix, collagen, matrix metalloproteinase, breast cancer

Haijun Shen,1 Fang Li,1 Dongxia Wang,1 Zhihan Yang,1 Chunfang Yao,1 Yang Ye,1 Xiaona Wang2 1Department of Preventive Medicine and Public Health Laboratory Science, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, China; 2Department of Internal Medicine of Jiangsu University Hospital Workers, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, China Background and object: Polyelectrolyte microcapsule is a promising candidate for multifunctional drug delivery system. However, the lack of reports about animal experiments have greatly slowed down their development for drug delivery. We engineered biodegradable chitosan–alginate polyelectrolyte multilayer capsule filled with bovine serum albumin gel (BSA-gel-capsule). Herein, we demonstrated their applicability for local chemotherapy, a means of treating local or regional malignancies by direct administration of anti-tumor agents to tumor sites. Method: Doxorubicin (DOX) was loaded in BSA-gel-capsules and DOX-resistant cell line (MCF-7/ADR cells) was employed for antitumor studies in vitro. The cytotoxicity, cellular uptake and distribution of DOX from BSA-gel-capsules were studied. Afterwards, MCF-7/ADR xenografts tumor model was established in nude mice. The in vivo antitumor efficacy of DOX-loaded BSA-gel-capsules by intratumor injection was then evaluated. Result: Compared with free DOX, more effective cytotoxicity against MCF-7/ADR cells after treatment with DOX-loaded BSA-gel-capsules was revealed, demonstrating the positive reversal effect on drug-resistance. Thereafter, the more cellular uptake and nucleus distribution of DOX from BSA-gel-capsules in MCF-7/ADR cells provided convincing explanation for the reversal effect. DOX-loaded BSA-gel-capsules displayed remarkably more antitumor efficacy than free DOX in MCF-7/ADR cell-xenografted mice. Finally, the high DOX accumulation and prolonged retention in tumor site after local administration of DOX-loaded BSA-gel-capsules was demonstrated, displaying the unique advantages of BSA-gel-capsules for local chemotherapy. Conclusion: These findings indicate that DOX-loaded BSA-gel-capsules should be considered a potential candidate for the treatment of drug-resistant breast cancer. This paper provides a feasibility for the local chemotherapy of polyelectrolyte microcapsules, which will be a big step towards their application as drug delivery vehicles. Keywords: polyelectrolyte capsule, bovine serum albumin, layer-by-layer, pH-responsive, intratumor injection, multidrug resistance

The heat conduction and its dependence on fullerene coalescence in carbon nanopeapods (CNPs) have been investigated by equilibrium molecular dynamics simulations. The effects of fullerene coalescen...

Dichloroacetonitrile (DCAN), an emerging nitrogenous disinfection by-product, is more genotoxic and cytotoxic than the currently regulated carbonaceous disinfection by-products such as haloacetic acids. Few mechanistic studies have been conducted on the hepatic and renal toxicities of DCAN. This study examined the clinical biochemical, hematological, histopathological, oxidative, and mitochondrial functional alterations to evaluate the systematic toxicity after subacute oral exposure of 11 or 44 mg/kg/day in rats for 28 days. Body and spleen weights were lower, and organ-to-body weight ratios of the liver and kidney were higher in rats administered 44-mg/kg DCAN than in controls. The activities of serum alanine aminotransferase and alkaline phosphatase, and concentrations of blood serum urea nitrogen and retinol-binding protein were increased in rats administered 44-mg/kg DCAN compared with those of controls, thereby indicating hepatic and renal damage in this group. This was confirmed by histopathological alterations, including hepatic sinus dilation, extensive hemorrhage, vacuolar degeneration in the liver and glomerulus hemorrhage, and renal tubular swelling, in DCAN-exposed rats. Exposure to 44-mg/kg DCAN induced hepatic oxidative damage shown by the significant increase in malonaldehyde levels, a poisonous product of lipid peroxidation. Exposure to 44-mg/kg DCAN significantly increased hepatic glutathione content and mitochondrial bioenergy as noted by the elevation of mitochondrial membrane potential and cytochrome c oxidase activity, which might be attributed to compensatory pathophysiologic responses to DCAN-induced hepatic mitochondrial damage.

The major obstacles opposed to doxorubicin (Dox) based chemotherapy are the induction of drug resistance, together with non-specific toxicities for healthy cells. In this study, we prepared a peptide-Dox conjugate aimed at offering Dox molecules a tumor-specific functionality and improving the therapeutic effects of Dox against resistant tumor cells. A slightly acidic pH-sensitive peptide (SAPSP) with high selectivity for cancer cells was attached to Dox to obtain SAPSP-Dox prodrug. The structures and properties of this prodrug were characterized, confirming several merits, including desirable pH-sensitive property, good serum stability and favorable release behavior. Cellular uptake studies demonstrated that SAPSP-Dox was preferably accumulated in cancer cells (Dox-sensitive MCF-7 and Dox-resistant MCF-7/ADR), followed by displaying 26-fold less toxic toward noncancerous MCF-10A cells than free Dox do. The conjugated peptides enabled Dox to escape the efflux effect of P-glycoprotein mediated pump via endocytotic pathway, giving rise to remarkable cytotoxicity and apoptotic effect on MCF-7/ADR cells. Moreover, the superior inhibition efficacy of SAPSP-Dox in vivo was more evident in the both drug-sensitive and drug-resistant xenograft tumor animal models, which enabled Dox to primarily accumulated in tumor. The conjugates also demonstrated a longer half-life in plasma and a lower side effect, for example, reduced cardiac toxicity. Evidence of this study suggests that SAPSP-Dox has the potential to be a potent prodrug for treating drug resistant cancers.

© 2018 Elsevier Ltd Conversion efficiency and unit vibration are two important indexes in evaluating the stability of hydraulic generating systems (HGSs). Most of related studies have been carried out in the deterministic theory framework. As running times of HGS increased, understanding uncertainties and limitations of model parameters are important for accurate modeling and stability evaluation. In this study, first, we establish an integrated model of a HGS by proposing unbalanced hydraulic forces based on the Kutta-Zhoukowski assumption. Second, global sensitivity and parametric interactions for conversion efficiency and unit vibration are investigated based on this model. Finally, the novel unified model is verified with two conventional models. This integrated and accurate mathematical model is a major advance in the diagnosis and prediction of failures in hydropower operation.

The mechanical properties and failure process of single-walled carbon nanotube (SWCNT) under combined electric field and tensile loading are investigated using the semi-empirical quantum mechanical method. The local and global structural deformation and variation of mechanical properties of SWCNT under different directions and intensity of external electric field are discussed systematically. It is shown that the electric field induced deformation in the radial and axial directions of the SWCNT are strongly dependent on the direction of electric field. The analysis of mechanical properties shows that the structure stiffness, tensile strength and failure strain of the SWCNT all decrease with the increase of the field intensity, which is particularly evident under the longitudinal electric field. The Young's modulus of SWCNTs vary with the tube diameter and are affected by the electric field. The increase of the length of the tubes intensifies the charge concentration at the tube ends under the elec...

NASA’s Human Exploration and Operation Mission Directorate is developing a reusable hybrid transportation architecture in which both chemical and solar-electric propulsion systems are used to deliver crew and cargo to the Martian sphere of influence. By combining chemical and solar-electric propulsions into a single spacecraft and applying each where it is the most effective, the hybrid architecture enables a series of Mars trajectories that are more fuel efficient than an all chemical propulsion architecture without significant increase to trip time. Solving the complex problem of low-thrust trajectory optimization coupled with the vehicle sizing requires development of an integrated trajectory analysis frame- work. Previous studies have utilized a more segmented optimization framework due to the limitation of the tools available. A new integrated optimization framework was recently developed to address the deficiencies of the previous methods that enables higher fidelity analysis to be performed and increases the efficiency of large design space explorations.

Hexavalent chromium [Cr(VI)] is a common human carcinogen associated with lung cancer and other pulmonary diseases as exposure to excessive Cr(VI) induces malignant transformation in human lung epithelial cells. The mechanism underlying its carcinogenicity is unclear in terms of how it facilitates metastases. Cr(VI) compounds are reported to briefly promote cell migration in a concentration-dependent manner and oncogene liver kinase B1 (LKB1) was reduced in Cr(VI)-transformed cells. Overexpression of LKB1 in Beas-2B-Cr [Cr(VI) malignantly transformed Beas-2B cells] suppressed cell migration and invasion and inactivated FAK, Src, MMP-2, GSK3β, β-catenin, and HEF1, which contribute to cell migration and invasion. Silencing LKB1 with siRNA promoted migration and invasion, and activated these downstream proteins. Long-term exposure to Cr(VI) enhanced the migration and invasiveness of Beas-2B cells and reduced the expression of LKB1, while activating these proteins as mentioned above. Data suggest that LKB1 may regulate downstream proteins such as FAK, Src, MMP-2, GSK3β, β-catenin, and HEF1, and affect the migration and invasiveness of Beas-2B-Cr cells.

BACKGROUND This research focused on the impacts of different dibutyl phthalate (DBP)/dioctyl phthalate (DOP) weight ratios on the surface morphology and the properties of poly (vinylidene fluoride) (PVDF) thermally induced phase separation (TIPS) microfiltration hollow fiber membranes. The phase diagrams of PVDF/DBP/DOP systems were determined and the optimum weight ratio DBP/DOP in the liquid–liquid region of the binary phase diagram was chosen to form a membrane with interconnected sponge-like structure. Optimum processing temperature was determined based on analysis of the phase diagrams and industrial applications. In addition, the morphology and properties of the membranes were characterized as well as the performance of the membrane modules. RESULTS Suitable processing temperature range for the PVDF TIPS process was from 430 to 493 K. A PVDF concentration of 35 wt% and weight ratio DBP/DOP of 1/2 provided the most appropriate membrane for industrial application. CONCLUSIONS The optimum processing temperature range for the PVDF TIPS process was determined. The weight ratio DBP/DOP in PVDF/DBP/DOP systems played an important role in preparing PVDF TIPS microfiltration hollow fibers with superior properties giving membranes suitable for industrial application. © 2015 Society of Chemical Industry

This study aims to reduce the sensitivity of the unscented Kalman filter (UKF) estimates with respect to uncertain model parameters, leading to a more robust UKF. The standard minimum-variance cost index is augmented to include a penalty on the sensitivities of the state estimates about parameter uncertainties in the form of a weighted norm. A new filter gain is thus obtained, and the desensitised UKF (DUKF) provides better estimation of the true states than the standard UKF with an imperfect plant model. Numerical examples are shown to demonstrate the efficacy of the DUKF.

Diabetes mellitus has potential to alter the toxicity of hazardous chemicals. Dichloroacetonitrile (DCAN) is one of high-risk nitrogenous disinfection by-products. This study evaluated the neurotoxicity of DCAN (11, 44 and 88mg/kg) in normoglycaemic and streptozotocin (STZ)-induced diabetic rats via orally for 28days. STZ diabetes prolonged the median survival time and total lethal time after DCAN (88mg/kg) exposure when compared with that observed in normoglycaemic rats. DCAN altered motor activity and induced anxiety behaviour in normoglycaemic rats; but it did not exaggerate behavioural changes in STZ diabetic rats. DCAN -induced brain oxidative damage by compensatory increase glutathione content and decrease malonaldehyde levels; but it did not induce oxidative damage in diabetic rats. STZ diabetes slowed down the pathological pace of DCAN-induced brain mitochondrial dysfunction by decreasing reactive oxygen species and increasing cytochrome C oxidase activity. In conclusion, the present study indicated that STZ diabetic rats are resistant to DCAN-induced neurotoxicity at the dosage and with the dosage schedule in 28-day subacute toxicity test.

The dispersion of longitudinal and transverse waves in (n,0)–(2n,0) intramolecular junctions (IMJs) are investigated using an atomistic finite element method (FEM). The transient responses of IMJs with different connection types subjected to harmonic incident wave were modelled using three-dimensional elastic beams of carbon bonds and point masses. The linkage between the force-field constants of molecular mechanics and input parameters of beam and mass elements was established through the molecular structural mechanics approach. The wave dispersion simulated by FEM shows good agreement with that of the non-local elastic model in a wide frequency range up to the terahertz region. It is shown that both the microstructure of conical part (connection part) and the coupling of longitudinal vibration and transverse vibration brought by the conicity play important roles in the dispersion of longitudinal and transverse wave in a single-walled IMJ. The amplitude decay of longitudinal wave depended on the distance...

The rigorous QM/MM-PB/SA is employed to screen for strong Akt binders from a set of apigenin analogues and, consequently, four compounds, namely apigenin, quercetin, gallocatechin and myricetin, are suggested to have high binding potency to Akt active site, which are further solidified by a kinase assay.Display Omitted The QM/MM-PB/SA is compared with empirical scoring functions and free energy analysis.The QM/MM-PB/SA is used to score the binding affinity of apigenin analogues to Akt.Kinase assay is performed to solidify the results arising from theoretical analysis.Four apigenin analogues are found to exhibit Akt inhibitory activity at nanomolar level. Identification of small-molecule compounds that can bind specifically and stably to protein targets of biological interest is a challenge task in structure-based drug design. Traditionally, several fast approaches such as empirical scoring functions and free energy analysis have been widely used to fulfill for this purpose. In the current study, we raised the rigorous quantum mechanics/molecular mechanics in combination with semi-empirical Poisson-Boltzmann/surface area (QM/MM-PB/SA) as an efficient strategy to characterize the intermolecular interaction between Akt kinase and its small-molecule ligands, although this hybrid approach is computationally expensive as compared to those empirical methods. In a round of experimental activity reproduction test based on a set of known Akt-inhibitor complexes, QM/MM-PB/SA has been shown to perform much better than two widely used scoring functions as well as the sophisticated MM-PB/SA analysis with or without improvement by molecular dynamics (MD) simulations. Next, the QM/MM-PB/SA was employed to screen for strong Akt binders from an apigenin analogue set. Consequently, four compounds, namely apigenin, quercetin, gallocatechin and myricetin, were suggested to have high binding potency to Akt active site. A further kinase assay was conducted to determine the inhibitory activity of the four promising candidates against Akt kinase, resulting in IC50 values of 38.4, 67.5, 157.1 and 25.5nM, respectively.

The natural product apigenin is a flavonoid derivative substituted by three hydroxyl functional groups at positions 4′, 5 and 7 [OH(4′), OH(5) and OH(7)] of the basic flavonoid skeleton, which has shown strong inhibition on the development, proliferation and invasion of tumour cells by binding specifically to Akt kinase to inactivate the Akt signalling pathway. In this study, a typical non-additivity of the three hydroxyl substituents’ contributions to Akt–apigenin binding affinity is demonstrated by combination of four empirical scoring functions, molecular dynamics simulations, molecular mechanics-Poisson–Boltzmann/surface area (MM/PBSA) analyses and hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. It is found that (i) the empirical scoring functions are incapable of properly reflecting the non-additivity feature, which, however, can be well described by the more rigorous MM/PBSA and QM/MM methods, (ii) the hydroxyl group contributions to ligand binding affinity are deviated significan...

Molecular dynamics method was used to simulate the twists of four GNRs (graphene nanoribbons), two AGNRs (armchair GNRs), and two ZGNRs (zigzag GNRs). Thermal conductivity of the length-fixing GNRs under torsion and at high temperature was calculated. It is found that the ZGNRs have better torsional rigidity than the AGNRs; under the torsional deformation of 34.2°/nm local buckling occurs in the length-fixing GNRs, and under the deformation of 22.8°/nm overall buckling occurs in the ones with free-length. In the range of investigated twist-angle and temperature, the thermal conductivity of the length-fixing GNRs decreases with the increase of torsional deformation and temperature. The wider GNRs have better anti-torsion capability and thermal conductivity.

Tersoff-potential - based molecular dynamics method is used to simulate wrinkling deformation of one graphene sheet under shear, and the obtained deformation is compared with analytical solutions of macro-membrane. Furthermore, thermal conductivity of the wrinkled graphene at different temperatures is calculated. It is found that (1) the wrinkling deformation of graphene sheet under shear is close to the analytical solutions of macro-membrane under shear, which implies that the solutions of macro-membrane are applicable to predict the wrinkling deformation of graphene sheets under shear; (2) the more serious the wrinkling of the graphene under shear is, the stronger the phonon scattering is and, therefore, the lower the thermal conductivity of the wrinkled graphene is; (3) within the temperature range of 400–700 K, the thermal conductivity of graphene sheet decreases with increase in temperature.

Multifunctional dual-core@shell (Fe3O4–NaYF4@TiO2) nanocomposite (DCSNC) loaded with doxorubicin (DOX) have been developed for synergetic sonodynamic cancer chemotherapy, where titanium dioxide (TiO2) is employed as a sonosensitizer for sonodynamic therapy (SDT) of the tumor in deep tissues, and NaYF4 is used for upconversion luminescence (UCL) imaging. After being coated with hyaluronic acid (HA), the nanocomposites exhibit a time dependent cellular uptake and an excellent nucleus targeting effect in KB and MCF-7 cells. The ultrasound of HA–DCSNCs obviously enhances the apoptosis rate of MCF-7 cells. A greater tumor inhibition rate is observed when the tumor-bearing mice are treated with combined therapy (88.36%) compared with chemotherapy (28.36%) or sonodynamic therapy (38.91%) alone, indicating the potential of sonodynamic chemotherapy for cancer treatment.

By using the molecular dynamics (MD) method, the deceleration of Cn(n = 60, 180, 240, 540) and C60@C240 fullerenes is simulated in aqueous solution. The curves of resistance–velocity and resistance–Renault (Re) number are also obtained. Further the MD results are compared with the Stokes ones of sphere, i.e., the macroscopic theoretical fluid mechanics (FM) results for low Re number. It is shown that under low Re number, the resistance of the fullerenes in aqueous solution is higher than the Stokes results by two orders of magnitude, and it can be estimated through the Stokes results multiplied by (110.38 - 1.48/Re).

The classical MD (Molecular Dynamics) method was used to simulate the tension of three kinds of C240 isomers, i.e., C240 nanotube, chain-like 4C60 fullerene polymer and peanut-like 4C60 fullerene polymer. Then, the semi-empirical PM3 method was used to calculate their electronic structures under tension. Lastly, according to the calculated results, their differences in tensile mechanical properties, as well as the change of their FMO (Frontier Molecular Orbital) energy during tension, were discussed. It is shown that: (1) the load-support capability of the C240 molecules has the order of C240 nanotube > peanut-like 4C60 polymer > linear 4C60 polymer, but their deformation-support capability has the contrary order, (2) of the C240 isomers, the C240 nanotube has the best chemical stability, and the chain-like 4C240 molecule has the worst one, and (3) the deformed C240 isomers have narrower energy-gap between their LUMO and HOMO, and higher chemical activity.

In this study, a targeting drug delivery system based on mesoporous silica nanoparticle (MSN) was successfully developed for anti-cancer drug delivery and bioimaging. Carboxyl functionalized MSN (MSN/COOH) was firstly prepared and then modified with folate as the cancer targeting moiety and a near infrared fluorescent dye as labeling segment. Folate was conjugated to MSN/COOH via functional polyethyleneglycol (PEG), constructing the vector MSN/COOH-PEG-FA. The functionalization with carboxyl caused the pore surface of the nanocarrier more negative than native MSN, which could provide attractive forces between the nanoparticles and positively charged doxorubicin hydrochloride (DOX). Meanwhile, the folate modification significantly enhanced the cellular uptake of the delivery system compared to unmodified counterparts. Furthermore, the introduction of PEG increased the water dispersibility. Besides, the modification with the near infrared fluorescent dye Cy5 made the system effective for live cell and in vivo imaging. Therefore, the Cy5-MSN/COOH-PEG-FA system could be a promising nanocarrier for simultaneous diagnosis and treatment of diseases.

Molecular dynamics simulations were performed to investigate the wrinkling deformation of one single-layer graphane (GA) sheet under shear, and the shear deformation was compared with that of the macromembrane under shear. Furthermore, the thermal conductivity of the wrinkled GA sheet at 300 K was calculated. Moreover, the differences of anti-shear capability and thermal conductance between the GA and another corresponding graphene sheet are discussed. The results show that the solutions of the macromembrane are applicable to predict the wrinkling deformation of the GA sheet under shear and that both the GA and the graphene sheet under shear have comparable anti-buckling capability, whereas the GA sheet has much lower post-buckling load-carrying capacity. By increasing the shear strain, the thermal conductivity of both the GA and the graphene sheets decreases, and under the same shear strain the graphene sheet has higher thermal conductivity than the GA sheet.

This paper develops a robust divided difference filtering approach based on the concept of Desensitized Kalman Filtering. The filters are formulated using a minimum variance cost function, augmented with a penalty function consisting of a weighted norm of the state sensitivities. Solutions are provided for first and second-order Divided Difference Filters. The resulting filters are non-minimum variance but exhibit reduced sensitivity to deviations in the assumed plant model parameters. The proposed algorithms are demonstrated using Monte Carlo simulation techniques for an induction motor state estimation problem with parameter uncertainties.