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We developed a voltage-sensitive artificial transmembrane channel by mimicking the dipolar structure of natural alamethicin channel. The artificial channel featured a zwitterionic structure and could undergo voltage-driven flipping in the lipid bilayers. Importantly, this flipping of the channel could lead to their directional alignment in the bilayers and rectifying behavior for ion transport.

A series of glycoside-peptide conjugates were prepared by engineering at the N-terminus of the natural peptide gramicidin A. The conjugate containing galactose moiety formed a unimolecular transmembrane channel and mediated ion transport to induce apoptosis of cancer cells. More importantly, it exhibited liver cancer cell-targeting behavior due to the galactose-asialoglycoprotein receptor recognition.

Chronic atrophic gastritis (CAG) is one of the most common digestive system diseases worldwide which defined by WHO as initial step of cancer. Gastrodia elata Blume (GEB) is a traditional herbal with multiple pharmacological activities which was widely used in Asian countries. This study aims to explore the preventive and therapeutical effects of Gastrodia elata Blume on auto-immune induced CAG in rats. Tissues of stomachs were collected and submitted to 1H NMR-based metabolomics analysis and histopathological inspection. The biochemical indexes of MDA, SOD, GSH, NO and XOD were measured. Gastrodia elata Blume could apparently ameliorate the damaged gastric glands and the biochemical parameters, enhance gastric acid secretion, and significantly relieve the inflammation of the stomach. Orthogonal signal correction-partial least squares-discriminant analysis (OSC-PLS-DA) of NMR profiles and correlation network analysis revealed that Gastrodia elata Blume could effectively treat CAG via regulating energy and purine metabolisms, and by anti-oxidation and anti-inflammation effects.

Isoniazid (INH) is a well-known therapeutic and preventive agent against tuberculosis. However, high rates of side effects with various symptoms concerning hepatotoxicity and neurotoxicity have been reported, hindering its wide and safe application in clinic. In this investigation, rats were intoxicated with INH by gavage at doses of 200 and 400 mg/kg for 7 consecutive days to develop a rat model of acute INH-induced toxicity, which was investigated by a 1H NMR-based metabolomics complemented with clinical assays, histopathological inspection and western blotting. INH decreased the weights of dosed rats and induced seizure and hepatic steatosis dose-dependently. Orthogonal signal correction partial least-squares discriminant analysis (OSC-PLS-DA) of the NMR profiles of rat livers, brains and serum revealed that INH dose-dependently induced oxidative stress, disorders of excitatory and inhibitory amino acid neurotransmitters, and disturbances of energy metabolism and osmotic balance, which could help clarify the mechanisms of INH-induced hepatotoxicity and neurotoxicity. This integrated metabolomics approach showcased its ability to characterize the global metabolic status of organism, providing a powerful and feasible tool to probe drug induced toxicity or side effects.

Background Sepsis and continuous renal replacement therapy (CRRT) are both responsible for the alterations of the pharmacokinetics of antibiotics. For patients with sepsis receiving CRRT, the serum concentrations of meropenem in the early phase ( 48 h). This current trial aimed to investigate whether administration of a loading dose of meropenem results in a more likely achievement of the pharmacokinetic (PK)/pharmacodynamics (PD) target (100% fT > 4 × MIC) and better therapeutic results in the patients with sepsis receiving CRRT. Methods This is a single-blinded, single-center, randomized, controlled, two-arm, and parallel-group trial. This trial will be carried out in Guangzhou First People’s Hospital, School of Medicine, South China University of Technology Guangdong, China. Adult patients (age ≥ 18 years) with critical sepsis or sepsis-related shock receiving CRRT will be included in the study. The subjects will be assigned to the control group and the intervention group (LD group) randomly at a 1:1 ratio, the estimated sample size should be 120 subjects in each group. In the LD group, the patient will receive a loading dose of 1.5-g meropenem resolved in 30-ml saline which is given via central line for 30 min. Afterward, 0.75-g meropenem will be given immediately for 30 min every 8 h. In the control group, the patient will receive 0.75-g meropenem for 30 min every 8 h. The primary objective is the probabilities of PK/PD target (100% fT > 4 × MIC) achieved in the septic patients who receive CRRT in the first 48 h. Secondary objectives include clinical cure rate, bacterial clearance rate, sepsis-related mortality and all-cause mortality, the total dose of meropenem, duration of meropenem treatment, duration of CRRT, Sequential Organ Failure Assessment (SOFA), C-reactive protein levels, procalcitonin levels, white blood cell count, and safety. Discussion This trial will assess for the first time whether administration of a loading dose of meropenem results in a more likely achievement of the PK/PD target and better therapeutic results in the patients with sepsis receiving CRRT. Since CRRT is an important therapeutic strategy for sepsis patients with hemodynamic instability, the results from this trial may help to provide evidence-based therapy for septic patients receiving CRRT. Trial registration Chinese Clinical Trials Registry, ChiCTR2000032865. Registered on 13 May 2020, http://www.chictr.org.cn/showproj.aspx?proj=53616.

Owing to the promising applications of C-dots in biomedical engineering, concerns about their safety have drawn increasing attention recently. In this study, mice were intraperitoneally injected at different C-dot concentrations (0, 6.0, 12.0 and 24.0 mg kg-1) once every 2 days for 30 days. A 1H NMR-based metabolic approach supplemented with biochemical analysis and histopathology was used for the first time to explore the toxicity of C-dots in vivo. Histopathological inspection revealed that C-dots did not induce any obvious impairment in tissues. Biochemical assays showed no significant alterations of most measured biochemical parameters in tissues and serum, except for a slight reduction of the albumin level in serum as well as AChE activity in the liver and kidneys. Orthogonal signal correction-partial least squares-discriminant analysis (OSC-PLS-DA) of NMR profiles supplemented with correlation network analysis and SUS-plots disclosed that C-dots not only triggered the immune system but also disturbed the function of cell membranes as well as the normal liver clearance, indicating that the 1H NMR based metabolomics approach provided deep insights into the toxicity of C-dots in vivo and gained an advantage over traditional toxicological means, and should be helpful for the understanding of its toxic mechanism.

Datura metel L. (D. metel) is one well-known folk medical herb with wide application and also the most abused plants all over the world, mainly for spiritual or religious purpose, over-dosing of which often produces poisonous effects. In this study, mice were orally administered with the extract of D. metel once a day at doses for 10 mg/kg and 40 mg/kg for consecutive 4 days, 1H NMR based metabolomics approach aided with histopathological inspection and biochemical assays were used for the first time to study the psychoactive and toxic effects of D. metel. Histopathological inspection revealed obvious hypertrophy of hepatocytes, karyolysis and karyorrhexis in livers as well as distinct nerve cell edema, chromatolysis and lower nuclear density in brains. The increased tissue level of methane dicarboxylic aldehyde (MDA) and superoxide dismutase (SOD), decreased tissue level of glutathione (GSH) along with increased serum level of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) suggested brain and liver injury induced by D. metel. Orthogonal signal correction-partial least squares-discriminant analysis (OSC-PLS-DA) of NMR profiles supplemented with correlation network analysis revealed significant altered metabolites and related pathway that contributed to oxidative stress, energy metabolism disturbances, neurotransmitter imbalance and amino acid metabolism disorders.

Tungsten carbide (WC) reinforced Fe-matrix surface composites were prepared by in-situ synthesis between tungsten plate and graphite in grey cast iron. The microstructure, fracture toughness, and fracture of the WC layer were investigated by scanning electron microscope (SEM), X-ray diffraction (XRD) and the Vickers indentation technique, respectively. The results revealed that heat treated at 1125°C for 135min in argon atmosphere the main phase was WC with a bit of α-Fe. The fracture toughness (KIC) of the WC layer calculated using the Niihara’s equation, was 5.21 MPa·m1/2. Fractographic observations revealed that cracks propagated along the grain boundary under 2 kg loads. Moreover, both the WC particles and the interface between the WC layer and the matrix had a strong bonding strength.

The vanadium carbide (V8C7) coating was fabricated by in situ reaction which used gray cast iron and vanadium plate as raw materials providing carbon and vanadium sources, respectively. The microstructure, phases, and adhesion strength of V8C7 coating were investigated by scanning electron microscope (SEM), X-ray diffraction (XRD) and a single scratch test. The XRD results showed that the coating consisted of V8C7 and α-Fe, with the peaks of (222), (400), (440), (622) and (444) of V8C7 phase were confirmed. Moreover, the average diameter (D) of the V8C7 particles in the range of 432~582nm was calculated on the basis of the Scherrer and Halder-Wagner equations. The critical load of interface between V8C7 and substrate was 98.3 N, which implied that the interface of V8C7 coating /substrate had excellent adhesion strength.

Ginkgolic acid (15:1) is a major toxic component in extracts obtained from Ginkgo biloba (EGb) that has allergic and genotoxic effects. This study is the first to explore the hepatotoxicity of ginkgolic acid (15:1) using a NMR (nuclear magnetic resonance)-based metabolomics approach in combination with biochemistry assays. Mice were orally administered two doses of ginkgolic acid (15:1), and mouse livers and serum were then collected for NMR recordings and biochemical assays. The levels of activity of alanine aminotransferase (ALT) and glutamic aspartate transaminase (AST) observed in the ginkgolic acid (15:1)-treated mice suggested that it had induced severe liver damage. An orthogonal signal correction partial least-squares discriminant analysis (OSC-PLSDA) performed to determine the metabolomic profile of mouse liver tissues indicated that many metabolic disturbances, especially oxidative stress and purine metabolism, were induced by ginkgolic acid (15:1). A correlation network analysis combined with information related to structural similarities further confirmed that purine metabolism was disturbed by ginkgolic acid (15:1). This mechanism might represent the link between the antitumour activity and the liver injury-inducing effect of ginkgolic acid (15:1). A SUS (Shared and Unique Structure) plot suggested that a two-dose treatment of ginkgolic acid (15:1) had generally the same effect on metabolic variations but that its effects were dose-dependent, revealing some of the common features of ginkgolic acid (15:1) dosing. This integrated metabolomics approach helped us to characterise ginkgolic acid (15:1)-induced liver damage in mice.

Quorum sensing (QS) is a process of bacterial communication that has been a novel target for drug discovery. Pyocyanin quantification assay confirmed that resveratrol was an effective quorum sensing inhibitor (QSI) against Pseudomonas aeruginosa PAO1. In this study, the global metabolite changes of P. aeruginosa PAO1 exposed to QSI resveratrol were investigated by 1H NMR spectroscopy. A total of 40 metabolites containing amino acids, organic acid, organic amine, and energy storage compounds were identified. The changed metabolic profile indicated that resveratrol influenced pathways including oxidative stress, protein synthesis, and energy metabolism. Oxidative stress could upregulate the expression of genes related to QS in P. aeruginosa. It suggested that resveratrol could inhibit the QS systems in P. aeruginosa PAO1 by relieving oxidative stress due to its antioxidant activity. On the other hand, resveratrol could attenuate the pathogenicity of P. aeruginosa PAO1 by disturbing the TCA cycle so that ana...

Pyrazinamide (PZA) is a well-known first line anti-tuberculosis drug used in combination with other drugs such as isoniazid and rifampicin. Unfortunately, PZA suffered from a high rate of hepatotoxicity and hyperuricemia, which has not been clearly elucidated, hindering its wide application for therapeutic purposes. The purpose of this investigation was to develop a model of rat sub-acute hepatotoxicity induced by PZA and to explore the affected metabolic pathways by a 1H NMR-based metabolomics approach complemented with histopathological analysis and clinical chemistry. Rats of both genders were administered with PZA by gavage at doses of 1.0 and 2.0 g kg−1 for 4 weeks. PZA decreased the weights of dosed rats and induced liver injury dose-dependently. The female rats were more sensitive to PZA induced damage. Orthogonal signal correction partial least-squares discriminant analysis (OSC-PLS-DA) of the NMR profiles of the rat liver and serum revealed that PZA produced a status of oxidative stress and disturbances in purine metabolism, energy metabolism and NAD+ metabolism in a gender-specific and dose-dependent manner. These findings could be helpful to clarify the mechanism of PZA-induced hepatotoxicity and hyperuricemia. This integrated metabolomics approach showcased its ability to characterize the global metabolic status of organisms, providing a powerful and feasible tool to probe drug induced toxicity or side effects.

Most genetically modified crops are engineered for herbicide tolerance, among them, glyphosate tolerant crops have the greatest share. Glyphosate is one of the most extensively used herbicides worldwide. The popularity of glyphosate stems from its low cost, low environmental impact, and effectiveness while being safe for animals. The toxicity of glyphosate to untargeted organisms was studied using goldfish (Carassius auratus) after exposure to different concentrations of glyphosate isopropylamine salt, a glyphosate based herbicide for 96 hours. Tissues of brain, kidney and liver were collected and subjected to NMR-based metabolomics analysis and histopathological inspection. Plasma was collected and the hematological parameters of glutamic-oxaloacetic transaminase (GOT), glutamate-pyruvate transaminase (GPT), lactate dehydrogenase (LDH), blood urea nitrogen (BUN) and creatinine (CRE) were quantified. Glyphosate produced an increase in the hematological parameters of BUN and CRE and dose-dependent injuries. Metabolomics analysis revealed significant perturbations in neurotransmitter equilibrium, energy metabolism and amino acid metabolism in glyphosate dosed fish, which are associated with the toxicity of glyphosate. The results highlight the vulnerability of glutaminergic neurons to glyphosate and enlighten the potential of glutamine as an early marker of glyphosate induced neurotoxicity.

Isoniazid (INH) is a well-known therapeutic and preventive agent against tuberculosis. However, high rates of side effects with various symptoms concerning hepatotoxicity and neurotoxicity have been reported, hindering its wide and safe application in clinic. In this investigation, rats were intoxicated with INH by gavage at doses of 200 and 400 mg/kg for 7 consecutive days to develop a rat model of acute INH-induced toxicity, which was investigated by a

The toxic effects of AVM were investigated using a teleost experimental model, the juvenile goldfish (Carassius auratus). Goldfish were consecutively exposed to AVM for 7 days and then the tissues of brains, kidneys and livers and plasma were collected and subjected to a NMR based metabolomics study. AVM changed the metabolomic profiles of goldfish dose-dependently and significantly changed the levels of metabolites in dosed goldfish, such as the branch-chain amino acids (BCAAs), aromatic amino acids (AAAs), betaine, taurine, lactate, etc. These metabolite changes affect energy metabolism, amino acid metabolism, nucleic acids metabolism, osmotic equilibrium as well as redox equilibrium, and are related with the toxicity of AVM. 1H NMR-based metabolomics approach promises to be an advantageous tool for the systematic and holistic view of the response of aquatic organisms to pesticides and is thus suitable for the assessment of the environmental risk of pesticides and the understanding of the underlying mechanism.

This study reported the efficacy of the metabolites of Plectosphaerella cucumerina, one phyllosphere fungus from Orychophragmus violaceus, against Pseudomonas aeruginosa quorum sensing (QS) and QS-regulated biofilms. The minimum inhibitory concentration (MIC) of the ethyl acetate (EtOAc) extract from P. cucumerina against P. aeruginosa PAO1 was 1.25 mg mL-1. At sub-MIC concentrations, P. cucumerina extract (0.25-1 mg mL-1) not only inhibited biofilm formation but also disrupted preformed biofilms of P. aeruginosa PAO1 without affecting its growth. Fluorescence and scanning electron microscope (SEM) showed architectural disruption of the biofilms when treated with P. cucumerina metabolites. Further investigation demonstrated that metabolites in P. cucumerina attenuated the QS-dependent virulence factors. LC-MS/MS spectra coupled with experimentally standard samples suggested that patulin and emodin might act as the principal components possessing anti-biofilm and antivirulence activities. This is the first report of (1) the isolation of P. cucumerina from the phyllosphere of Orychophragmus violaceus and (2) anti-biofilm, antivirulence and biofilm disruption activities of this fungus. Thus, this study provides fascinating new pathways for screening antipathogenic agents.

Glyphosate is an efficient herbicide widely used worldwide. However, its toxicity to non-targeted organisms has not been fully elucidated. In this study, the toxicity of glyphosate-based herbicide was evaluated on goldfish (Carassius auratus) after long-term exposure. Tissues of brains, kidneys and livers were collected and submitted to NMR-based metabolomics analysis and histopathological inspection. Plasma was collected and the blood biochemical indexes of AST, ALT, BUN, CRE, LDH, SOD, GSH-Px, GR and MDA were measured. Long-term glyphosate exposure caused disorders of blood biochemical indexes and renal tissue injury in goldfish. Metabolomics analysis combined with correlation network analysis uncovered significant perturbations in oxidative stress, energy metabolism, amino acids metabolism and nucleosides metabolism in glyphosate dosed fish, which provide new clues to the toxicity of glyphosate. This integrated metabolomics approach showed its applicability in discovering the toxic mechanisms of pesticides, which provided new strategy for the assessment of the environmental risk of herbicides to non-target organisms.

Most genetically modified crops are engineered for herbicide tolerance, among them, glyphosate tolerant crops have the greatest share. Glyphosate is one of the most extensively used herbicides worldwide. The popularity of glyphosate stems from its low cost, low environmental impact, and effectiveness while being safe for animals. The toxicity of glyphosate to untargeted organisms was studied using goldfish (

A kind of centrifugal casting plus in situ techniques of fabricating iron-based composite coating reinforced by tungsten carbide (WC) particles was developed. The experimental results show that the reinforcing particles were generated by reaction between dissolved tungten wires and carbon from gray cast iron molten. The composite coating mainly consists of primary WC carbides, some fine secondly WC carbides as the reinforcing phase and pearlite accompanied by negligible graphite flakes as the matrix. Compared with the unreinforced gray cast iron, the in situ synthesized WC particles can enhance the ultimate tensile strength and decrease elongation rate of the composite coating. Fracture morphology reveals that fracture mode of composite coating is brittle and ductile mixed fractures, the fracture mechanism of the composite is not only related with the introduction of reinforcement but also with the reduction of graphite flakes in the matrix

A mathematical model is established based on a modified Reynolds equation in polar coordinates, and solved by the multi-grid method to demonstrate the performance of micro-texturing mechanical seal surface. Sample cases of cylinder-shaped, square-shaped and diamond-shaped micro-asperity are studied to show the performance of micro-texturing mechanical seals. The results show that geometry has a vital influence on the friction coefficient and leakage. Diamond-shaped micro-texturing asperities have better performance than the others. And the performance is sensitive to the area density than the micro-texturing depth. The numerical approach can be a useful engineering tool, analyzing and optimizing the performance of micro-texturing mechanical face seals.

In order to predict the geometry character of laser surface micro-texturing, the finite element analyzing software ANSYS is used to simulate temperature field and crater on the laser ablation. The influence and change regulation of laser intensity, laser pulse number and pulse duration in laser surface texturing are analyzed in detail. The simulation results conclude the best laser intensity in laser-pulse and materials interactions on certain conditions, and the best pulse duration in nanosecond laser micromachining. This research establishes the foundation for laser machining regular non-smooth surface in a rapid and effective way.

Numerical simulation of 3-D inner flow between Up-stream Pumping Mechanical Face Seals (UPMFS) faces was initially done by CFD software, which made the flow visualization come true. Simulation results directly discover the action of hydrodynamic lubrication, and by comparison with that of Conventional Mechanic Face Seals (CMFS), the advantage over bigger bearing capability, less friction and much less leakage are explained clearly. Otherwise there are also some different ideas and results from precedent analysis and computational research results: dynamic and static pressure profiles can be obtained respectively instead of the analytic total pressure distribution only, pressure distribution is nonlinear, while always be solved as linear, lower pressure is observed at the area of inner diameter caused by the grooves, but its possible cavitations effects to the performance of UPMFS still need further study.

Currently only the bearing was usually taken as the studing object in the optimization of crankshaft bearing. However, there is the corresponding relationship between the main dimensions (the diameter and width of journal) of the crankshaft bearing and crankshaft in an internal combustion engine, and there is the interaction between the crankshaft bearing and crankshaft in operation. In this paper, the crankshaft-bearing system of a four-cylinder engine was taken as the studing object, and an integrated optimization design of crankshaft bearing based on the multi-object was carried out. The total average frictional power loss of crankshaft bearings and the crankshaft mass were chosen as the objective functions, and the algorithms of the Particle Swarm Optimization (PSO) with the idea of decreasing inertia weight based on exponential curve strategy and the simulated annealing (SA) were used in the intelligent optimization. The results of comparing the two algorithms with the ones of original design show that, 26.2% and 25.8% reduction in total average frictional power loss of crankshaft beatings and 5.3% reduction of the crankshaft mass were presented by the optimization design, which are more reasonable than the original design. By comparison, the PSO algorithm has higher precision than the SA algorithm, but the calculation time of the SA algorithm is less than that of the PSO algorithm.

A review of literature about the effect of various Reynolds numbers, being based on kinematic viscosity and sliding velocities each other, on improvement of sliding elements tribological performance is shown. This is accomplished by the computational fluid dynamic approach where the momentum and continuity equations are solved separately, one of low Reynolds number (LRN) turbulence models-Abid index and SIMPLE algorithm in theory of Control Volume Method are adopted, and the rheology is assumed to be Newtonian. For different Re of micro-flow fields that those motionless surfaces with micro artificial grooves, the load supporting capacity of oil-film are compared in the form of the net total force, the ratio of net viscous force and net pressure force of micro-flow field, and the mean friction coefficient of upper surface are presented. The results are summarized in the form of maps. It was found that these parameters show diverse variation with the change of Reynolds number based on sliding velocity (Re_u) and kinematic viscosity (Re_ηk).