Repurposing DNase I and alginate lyase to degrade the biofilm matrix of dual-species biofilms of Staphylococcus aureus and Pseudomonas aeruginosa grown in artificial sputum medium: In-vitro assessment of their activity in combination with broad-spectrum antibiotics.

BACKGROUND: Biofilm-associated pulmonary infections pose therapeutic challenges in cystic fibrosis patients, especially when involving multiple bacterial species. Enzymatic degradation of the biofilm matrix may offer a potential solution to enhance antibiotic efficacy. This study investigated the repurposing of DNase I, commonly used for its mucolytic activity in cystic fibrosis, to target extracellular DNA within biofilms, as well as potential synergies with alginate lyase and broad-spectrum antibiotics in dual-species biofilms of Pseudomonas aeruginosa and Staphylococcus aureus. METHODS: Dual-species biofilms were grown in artificial sputum medium using S. aureus and P. aeruginosa isolated by pairs from the same patients and exposed to various combinations of enzymes, meropenem, or tobramycin. Activity was assessed by measuring biofilm biomass and viable counts. Matrix degradation and decrease in bacterial load were visualized using confocal microscopy. Biofilm viscoelasticity was estimated by rheology. RESULTS: Nearly complete destruction of the biofilms was achieved only if combining the enzymatic cocktail with the two antibiotics, and if using supratherapeutic levels of DNase I and high concentrations of alginate lyase. Biofilms containing non-pigmented mucoid P. aeruginosa required higher antibiotic concentrations, despite low viscoelasticity. In contrast, for biofilms with pigmented mucoid P. aeruginosa, a correlation was observed between the efficacy of different treatments and the reduction they caused in elasticity and viscosity of the biofilm. CONCLUSIONS: In this complex, highly drug-tolerant biofilm model, enzymes prove useful adjuvants to enhance antibiotic activity. However, the necessity for high enzyme concentrations emphasizes the need for thorough concentration-response evaluations and safety assessments before considering clinical applications.

ASTRAGALOSIDE â £ MODULATES GUT MACROPHAGES M1/M2 POLARIZATION BY RESHAPING GUT MICROBIOTA AND SHORT CHAIN FATTY ACIDS IN SEPSIS.

ABSTRACT: M1 macrophage-mediated inflammation is critical in sepsis. We previously found the protective role of astragaloside intravenous (AS-IV) in sepsis-associated gut impairment, whose specific mechanism remains unknown. Gut microbiota modulates gut homeostatic balance to avoid excessive inflammation. Here, we aimed to investigate effects of AS-IV on gut macrophages polarization and potential roles of gut microbiota and short chain fatty acids (SCFAs) in septic gut damage. Mice were pretreated by AS-IV gavage for 7 days before cecal ligation and puncture. M1 polarization of gut lamina propria macrophages (LpMs) was promoted by cecal ligation and puncture, accompanied by abnormal cytokines release and intestinal barrier dysfunction. NLRP3 inflammasome was activated in M1 LpMs. 16S rRNA sequencing demonstrated gut microbiota imbalance. The levels of acetate, propionate, and butyrate in fecal samples decreased. Notably, AS-IV reversed LpMs M1/M2 polarization, lightened gut inflammation and barrier injury, reduced NLRP3 inflammasome expression in LpMs, restored the diversity of gut microbiome, and increased butyrate levels. Similarly, these benefits were mimicked by fecal microbiota transplantation or exogenous butyrate supplementation. In Caco-2 and THP-1 cocultured model, LPS and interferon γ caused THP-1 M1 polarization, Caco-2 barrier impairment, abnormal cytokines release, and high NLRP3 inflammasome expression in THP-1 cells, all of which were mitigated by butyrate administration. However, these protective effects of butyrate were abrogated by NLRP3 gene overexpression in THP-1. In conclusion, AS-IV can ameliorate sepsis-induced gut inflammation and barrier dysfunction by modulating M1/M2 polarization of gut macrophages, whose underlying mechanism may be restoring gut microbiome and SCFA to restrain NLRP3 inflammasome activation.

Evaluation of right heart function changes in patients with pulmonary hypertension via two-dimensional speckle tracking imaging: a retrospective study.

Objective: To realize the changes in pulmonary hypertension (PH) patients' right ventricular function.Methods: A total number of 74 patients with PH were included, and the parameters of standard echocardiographic were measured as well as the strain of peak longitudinal of each segment during the systole of the right ventricle to calculate the global longitudinal strain (LS) during systole of the right ventricular free wall.Results: ① As pulmonary arterial pressure increased, the right ventricular area gradually increased, and the case group showed the decreased right ventricular fractional area change (RVFAC), tricuspid annular plane systolic excursion (TAPSE), and tricuspid annular peak systolic velocity (S') (p < 0.05). They, RVFAC, and TAPSE depicted significant differences that were statistical (p < 0.05) from the other groups. ② With increasing pulmonary arterial pressure, the right ventricular free wall's LS gradually reduced (p < 0.05).Conclusion: ① LS right ventricular free wall is useful in detecting changes in right ventricular systolic function early on with greater sensitivity than RVFAC, TAPSE, and S'. In addition, increased right ventricular pressure loading can result in a subsequent impairment of right ventricular myocardial mechanics. ② As right ventricular pressure loading increases, right ventricular strain decreases. ③ In mild PH, the right ventricular free wall's. LS is more sensitive than standard measures in spotting early alterations in myocardial mechanics.

Quantitative evaluation of renal tissue changes in patients with liver cirrhosis by shear wave elastography.

PURPOSE: Hepatocirrhotic nephropathy progresses rapidly and has a poor prognosis, and early detection of renal changes in patients with cirrhosis is particularly important for its prevention and treatment. The objective of this study was to evaluate the value of shear wave elastography (SWE) in the early diagnosis of hepatocirrhotic nephropathy. METHODS: 206 hepatic cirrhosis patients with normal conventional renal function were enrolled and divided into Child-Pugh grade A (Group A), Child-Pugh grade B (Group B), and Child-Pugh grade C (Group C) according to the Child-Pugh grading method. Meanwhile, 60 healthy volunteers matched in age and sex were selected as the control group. The maximum Young's modulus (Emax), average Young's modulus (Emean), and minimum Young's modulus (Emin) of the left renal parenchyma were measured by SWE in all subjects. The Emax, Emean, and Emin values of the left renal parenchyma were compared between the cirrhosis and control groups. RESULTS: The Emax, Emean, and Emin values of left renal parenchyma in cirrhosis group were higher than those in control group (p = 0.00, 0.00, 0.00). The Emax, Emean, and Emin values of left renal parenchyma in cirrhosis group B and group C were higher than those in control group (p = 0.00, 0.00, 0.00; p = 0.00, 0.00, 0.00), but these values in cirrhosis group A were not significantly different from control group(p = 0.48, 0.52, 0.92). Comparison of the Emax, Emean, and Emin values in left renal parenchyma of three cirrhosis groups, the values of Group B and Group C were higher than those of Group A (p = 0.00, 0.00, 0.00; p = 0.00, 0.00, 0.00), and there was no significant difference between Group B and Group C (p = 0.71, 0.18, 0.39). CONCLUSION: SWE can detect renal tissue damage in patients with liver cirrhosis earlier than changes identified during routine laboratory examination by quantitatively measuring the elastic parameters of renal parenchyma and may become a new method for early diagnosis of hepatorenal syndrome.

Tough, Recyclable, and Degradable Elastomers for Potential Biomedical Applications.

Elastomers have many industrial, medical and commercial applications, however, their huge demand raises an important question of how to dispose of the out-of-service elastomers. Ideal elastomers that are concurrently tough, recyclable, and degradable are in urgent need, but their preparation remains a rigorous challenge. Herein, a polycaprolactone (PCL) based polyurethane elastomer is designed and prepared to meet this demand. Owing to the presence of dynamic coordination bond and the occurrence of strain-induced crystallization, the obtained elastomer exhibits a high toughness of ≈372 MJ m-3 and an unprecedented fracture energy of ≈646 kJ m-2 , which is much higher than natural rubber (≈50 MJ m-3 for toughness and ≈10 kJ m-2 for fracture energy). In addition, the elastomer can be recycled at least three times using solvent without losing its mechanical properties and can be degraded by lipase in ≈2 months. Finally, biological experiments demonstrate that the elastomer possesses good biocompatibility and can facilitate wound healing in mice when used as sutures. It is believed that the obtained elastomer meets the requirements for next-generation elastomers and is expected to be used in emerging fields such as biomedicine, flexible electronics, robotics and beyond.

Highly Strong and Damage-Resistant Natural Rubber Membrane via Self-Assembly and Construction of Double Network.

Natural rubber latex (NRL) is commonly employed to manufacture medical protective appliances. However, the characteristics of weakness and fragility of NRL membranes limit their further application. To achieve excellent strength and damage-resistance of the rubber membrane, this work reported a facile core-shell structure construction strategy via self-assembly with modified sodium lignosulfonate (MSLS) and NRL to create a tough membrane. The double network can be formed after introducing polyamide epichlorohydrin resin (PAE) into the NRL membrane. Specifically, the first robust MSLS-PAE network can break in advance to dissipate applied energy, thereby achieving high fracture energy and tensile strength of ~111.51 kJ m-2 and ~37 MPa, respectively, which overtakes numerous soft materials. This work facilitates more studies on latex/lignin-based products with high performance and good stability for the functional application of biopolymer.

Rational Design of Photothermal and Anti-Bacterial Foam With Macroporous Structure for Efficient Desalination of Water.

With the environmental deterioration and the rise in demand for sustainability, the lack of freshwater resources has emerged as a global concern. To address this issue, the desalination of water using solar evaporation is centered on as a promising approach. In this study, we designed a light and photothermal liquefied-chitin-based polyurethane foam to achieve efficient water evaporation benefiting from their powerful solar spectral absorption, low thermal conductivity, quick transportation of water, hierarchically porous structures, and anti-biofouling natures. Moreover, because of the introduction of nano-silver, the newly developed foam exhibits considerable antibacterial ability and improved photothermal performance. Notably, the low thermal conductivity of the foam can reduce the loss of absorbed solar heat, whereas its large porous structure provides a smooth water transport channel. More importantly, with the assistance of heat, polyacrylamide hydrogels adhering along with the pores rapidly absorb and desorb water molecules, promoting the evaporation of water and improving solar energy conversion efficiency. Ultimately, under irradiation by one sunlight, the proposed material demonstrated a water evaporation rate and solar photothermal conversion efficiency of 2.44 kg m-2 h-1 and 153.2%, respectively.

A comparative study of bacterial diversity based on effects of three different shade shed types in the rhizosphere of Panax quiquefolium L.

BACKGROUND: Shading is an important factor affecting the cultivation of American ginseng, as it influences crop quality and yield. Rhizosphere microorganisms are also crucial for normal plant growth and development. However, whether different shade types significantly change American ginseng rhizosphere microorganisms is unknown. METHODS: This study evaluated the rhizosphere soils of American ginseng under traditional, high flag and high arch shade sheds. High-throughput 16S rRNA gene sequencing determined the change of rhizosphere bacterial communities. RESULTS: The microbial diversity in rhizosphere soils of American ginseng significantly changed under different shading conditions. The bacteria diversity was more abundant in the high arch shade than flat and traditional shades. Different bacterial genera, including Bradyrhizobium, Rhizobium, Sphingomonas, Streptomyces and Nitrospira, showed significantly different abundances. Different shading conditions changed the microbial metabolic function in the American ginseng rhizosphere soils. The three types of shade sheds had specific enriched functional groups. The abundance of ATP-binding cassette (ABC) transporters consistently increased in the bacterial microbiota. These results help understand the influence of shading systems on the rhizosphere microecology of American ginseng, and contribute to the American ginseng cultivation.

SE-COTR: A Novel Fruit Segmentation Model for Green Apples Application in Complex Orchard.

Because of the unstructured characteristics of natural orchards, the efficient detection and segmentation applications of green fruits remain an essential challenge for intelligent agriculture. Therefore, an innovative fruit segmentation method based on deep learning, termed SE-COTR (segmentation based on coordinate transformer), is proposed to achieve accurate and real-time segmentation of green apples. The lightweight network MobileNetV2 is used as the backbone, combined with the constructed coordinate attention-based coordinate transformer module to enhance the focus on effective features. In addition, joint pyramid upsampling module is optimized for integrating multiscale features, making the model suitable for the detection and segmentation of target fruits with different sizes. Finally, in combination with the outputs of the function heads, the dynamic convolution operation is applied to predict the instance mask. In complex orchard environment with variable conditions, SE-COTR achieves a mean average precision of 61.6% with low complexity for green apple fruit segmentation at severe occlusion and different fruit scales. Especially, the segmentation accuracy for small target fruits reaches 43.3%, which is obviously better than other advanced segmentation models and realizes good recognition results. The proposed method effectively solves the problem of low accuracy and overly complex fruit segmentation models with the same color as the background and can be built in portable mobile devices to undertake accurate and efficient agricultural works in complex orchard.

Protocatechuic aldehyde from Salvia miltiorrhiza exhibits an anti-inflammatory effect through inhibiting MAPK signalling pathway.

BACKGROUND: The aerial parts of Salvia miltiorrhiza, which was considered to be the waste part and discarded during the root harvest, is rich in protocatechuic aldehyde (PAI). This study investigated the health-promoting effects of extracts and PAI from the aerial parts of Salvia miltiorrhiza, including its anti-inflammatory effects and the underlying mechanisms of action in vitro and in vivo. METHOD: Purification of the sample paste of Salvia miltiorrhiza was accomplished using HPLC analysis. TheMTT (Methylthiazolyldiphenyl-tetrazolium bromide) assay was employed to determine the cell viability. The production of inflammatory factors was detected by ELISA assays. The histopathological analysis was used to analyse the lungs and livers of mice treated with PAI. Western blot was performed to reveal the mechanism of PAI in anti-inflammatory. RESULTS: The extracts and PAI from the aerial parts of Salvia miltiorrhiza inhibited TNF-α, IL-6 production and promoted the production of IL-10 in vivo in mice and in vitro in the macrophage cell line RAW264.7. NF-κB and MAPKs kinase phosphorylation were also suppressed by PAI in vivo and in vitro, indicating that PAI exhibited an anti-inflammatory effect. CONCLUSION: These findings suggest that the aerial parts of Salvia miltiorrhiza extract may serve as potential protective agents for inflammatory.

Functionalized starch as a novel eco-friendly vulcanization accelerator enhancing mechanical properties of natural rubber.

A novel eco-friendly vulcanization accelerator, starch supported sodium isobutyl xanthate (SSX) has been synthesized firstly. The modification of starch using sodium isobutyl xanthate (SIBX) has improved the thermal stability significantly, and the vulcanization process of natural rubber (NR) could be accelerated by SSX at 145 ℃ accordingly. More importantly, SSX can be dispersed into NR matrix uniformly along with the strong interfacial interaction between SSX and NR, as evidenced by the constrained rubber chains around SSX surface. In addition, mechanical properties of the obtained NR have been enhanced remarkably, showing a 22.4 % increase in tensile strength when compared with traditional vulcanization accelerator. Laying on the fact that a novel vulcanization accelerator has been fabricated successfully using SIBX functionalized starch, new strategies for the preparation of green vulcanization accelerators and the functional application of biopolymers can be provided.

Spatiotemporal distribution, sources and ecological risks of perfluorinated compounds (PFCs) in the Guanlan River from the rapidly urbanizing areas of Shenzhen, China.

Limited studies have demonstrated the environmental concerns of perfluorinated compounds (PFCs) in the rivers flowing through the rapidly urbanizing areas. Therefore, this study aims to investigate the spatial and temporal distribution, major sources and ecological risks of PFCs in the surface water samples, collecting from the Guanlan River, Shenzhen, China. The concentrations of ∑PFCs ranged from 11.3 to 384 ng/L, with a mean value of 81.8 ng/L in the dry season, and ranged from 6.90 to 619 ng/L, with a mean value of 339 ng/L in the wet season. Short-chain PFCs such as perfluorohexane sulfonate (PFHxS) and perfluorobutane sulfonate (PFBS) were detected as the predominant compounds. Further, the spatiotemporal distribution revealed significantly higher levels of PFCs in the wet season than those in the dry season, and relatively higher levels in the tributaries than those in the mainstream. Source apportionment highlighted the industrial discharges, domestic wastewater, precipitation, and wastewater treatment plants as the major sources of PFCs. Moreover, the population density and associated urban sewage emissions observed as important indicators for PFCs uneven distribution in the area. The ecological risk assessment revealed perfluorotetradecanoic acid (PFTA, C14) posed high ecological risks to the aquatic organisms (especially for mysid) in the Guanlan River. Taken all together, this study not only unveiled the characteristics of PFCs contamination in the rapidly urbanizing catchment, but also provided the baseline data for policy makers to protect the ecological environment of the urban rivers in the rapidly growing area.

Astragaloside IV attenuates sepsis-induced intestinal barrier dysfunction via suppressing RhoA/NLRP3 inflammasome signaling.

Intestinal barrier dysfunction is a trigger for sepsis progression. NLRP3 inflammasome and RhoA contribute to sepsis and intestinal inflammation. The current study aimed to explore the effects of Astragaloside IV (AS-IV), a bioactive compound from Astragalus membranaceus, on sepsis-caused intestinal barrier dysfunction and whether NLRP3 inflammasome and RhoA are involved. Septic mice modeled by cecal ligation and puncture (CLP) operation were administered with 3 mg/kg AS-IV intravenously. AS-IV decreased mortality, cytokines release, I-FABP secretion, intestinal histological score and barrier permeability, and increased tight junction (TJ) expression in intestine in CLP model. Also, in Caco-2 cells subjected to lipopolysaccharide (LPS), 200 µg/mL AS-IV co-incubation reduced cytokines levels and enhanced in vitro gut barrier function without cytotoxicity. Subsequently, NLRP3 inflammasome and RhoA were highly activated both in intestinal tissue in vivo and in Caco-2 cells in vitro, both of which were significantly suppressed by AS-IV treatment. In addition, the benefits of AS-IV on Caco-2 monolayer barrier were largely counteracted by RhoA agonist CN03 and NLRP3 gene overexpression, respectively. Furthermore, LPS-induced NLRP3 inflammasome activation was abrogated by RhoA inhibitor C3 exoenzyme. However, NLRP3 knockdown by siRNA hardly affected RhoA activation in Caco-2 cells. These data suggest that AS-IV protects intestinal epithelium from sepsis-induced barrier dysfunction via inhibiting RhoA/NLRP3 inflammasome signal pathway.

Spatiotemporal distribution, source apportionment and ecological risk assessment of PBDEs and PAHs in the Guanlan River from rapidly urbanizing areas of Shenzhen, China.

In this study, nine congeners of polybrominated diphenyl ethers (PBDEs) and sixteen congeners of polycyclic aromatic hydrocarbons (PAHs) were measured in water samples to elucidate their spatial distribution, congener profiles, sources and ecological risks in the Guanlan River during both the dry season (DS) and the wet season (WS). The concentration of Σ9PBDE ranged from 58.40 to 186.35 ng/L with an average of 115.72 ng/L in the DS, and from 8.20 to 37.80 ng/L with an average of 22.15 ng/L in the WS. Meanwhile, the concentration of Σ16PAHs was ranged from 121.80 to 8371.70 ng/L with an average of 3271.18 ng/L in the DS and from 1.85 to 7124.25 ng/L with an average of 908.11 ng/L in the WS. The concentrations of PBDEs and PAHs in the DS were significantly higher than those in the WS, probably due to the dilution of the river during the rainy season. Moreover, the spatial distribution of pollutants revealed decreasing trend in the concentration from upstream to downstream and almost identical pattern was observed during both seasons. The source apportionment suggested that penta-BDE and to some extent octa-BDE commercial products were major sources of PBDEs in the study area. However, the sources of PAHs were mainly comprised of fossil fuels and biomass burning, followed by the petroleum products and their mixtures. The results of the ecological risk assessment indicated PBDEs contamination posed high ecological risks, while PAHs exhibited low or no ecological risks in the study area. Consistent with the environmental levels, the ecological risks of pollutants were relatively lower in the WS, compared to that in the DS. The results from this study would provide valuable baseline data and technical support for policy makers to protect the ecological environment of the Guanlan River.

Role of α7nAChR-NMDAR in sevoflurane-induced memory deficits in the developing rat hippocampus.

Detrimental effects of volatile anaesthetics, including sevoflurane, on the structure and function of the developing brain have been reported. The internalization of N-methyl-D-aspartate receptors (NMDARs) contributes to anaesthetic neurotoxicity. Both nicotinic acetylcholine receptors (nAChRs) and NMDAR play a critical role in the development of the nervous system. Moreover, nAChR can interact with NMDAR, and previous studies have demonstrated modulation of NMDAR by nAChR. In our study, we used an α7 nicotinic acetylcholine receptor (α7nAChR) agonist and α7nAChR antagonist to explore the role of α7nAChR and NMDAR in sevoflurane-induced long-term effects on memory and dendritic spine both in vivo and in vitro. The results revealed that the activation of α7nAChR attenuated the development of sevoflurane-induced memory deficit and dendritic spine changes, which might be by regulating NR2B-containing NMDAR trafficking from the intracellular pool to the cell surface pool in the hippocampus. Moreover, we demonstrated that α7nAChR could regulate NR2B-containing NMDAR via Src-family tyrosine kinase (SFK). Thus, our current study indicates that the trafficking of NR2B-containing NMDAR is regulated by α7nAChR via SFK in neonatal rat hippocampus, which may be secondary to sevoflurane-induced cognitive deficits in the developing hippocampus.

Enhanced power generation and wastewater treatment in sustainable biochar electrodes based bioelectrochemical system.

Corn-straw biochar (BC500 and BC900) and KOH modified biochar (BAC) were used as the electrode materials of bioelectrochemical system (BES). Compared to carbon felt (CF) electrodes BES, the maximum power density of BC500, BC900 and BAC anodes BES increased by 10.7%, 56.0% and 92.0%, and that of BC500, BC900 and BAC cathodes BES increased by 3.1, 5.2 and 4.8 times, respectively. The CF electrodes BES was optimized to decolor the AO7 simulated wastewater and 97% of AO7 was quickly degraded within 2h. When using biochar anodes, the decoloration rates were enhanced. The apparent rate constant (kapp) increased from 2.93h-1 for CF anode BES to 3.58, 4.35 and 5.33h-1 for BC500, BC900 and BAC anode system, respectively. AO7 could also be effectively decolored in biochar cathode systems, which was mainly due to adsorption.

Treatability of volatile chlorinated hydrocarbon-contaminated soils of different textures along a vertical profile by mechanical soil aeration: A laboratory test.

Mechanical soil aeration is a simple, effective, and low-cost soil remediation technology that is suitable for sites contaminated with volatile chlorinated hydrocarbons (VCHs). Conventionally, this technique is used to treat the mixed soil of a site without considering the diversity and treatability of different soils within the site. A laboratory test was conducted to evaluate the effectiveness of mechanical soil aeration for remediating soils of different textures (silty, clayey, and sandy soils) along a vertical profile at an abandoned chloro-alkali chemical site in China. The collected soils were artificially contaminated with chloroform (TCM) and trichloroethylene (TCE). Mechanical soil aeration was effective for remediating VCHs (removal efficiency >98%). The volatilization process was described by an exponential kinetic function. In the early stage of treatment (0-7hr), rapid contaminant volatilization followed a pseudo-first order kinetic model. VCH concentrations decreased to low levels and showed a tailing phenomenon with very slow contaminant release after 8hr. Compared with silty and sandy soils, clayey soil has high organic-matter content, a large specific surface area, a high clay fraction, and a complex pore structure. These characteristics substantially influenced the removal process, making it less efficient, more time consuming, and consequently more expensive. Our findings provide a potential basis for optimizing soil remediation strategy in a cost-effective manner.

Intraperitoneal gardiquimod protects against hepatotoxicity through inhibition of oxidative stress and inflammation in mice with sepsis.

Many reports recapitulate the contribution of reactive oxygen species (ROS) over-accumulation to the organ damage; it is of significance to strictly target ROS production. In this study, we evaluated the potential role of TLR7 agonist gardiquimod (GDQ) in oxidative stress (OS) in liver injury induced by sepsis. Here, we observed that intraperitoneal pretreatment with GDQ dramatically elevated the septic survival rate and effectively attenuated the septic liver injury. Interestingly, the increased ROS and inflammatory factor IL-6 levels were reversed after GDQ intervention. Subsequently, Western blot was employed to determine the definite mechanism. As expected, it was showed that the upregulation of c-Jun N-terminal kinase (JNK)/c-Jun pathway in liver of septic animals was considerably suppressed by GDQ pre-exposure. Our current result highlight that pre-administration of GDQ ameliorated sepsis induced hepatotoxicity and reduced the generation of IL-6 and OS responses, which was associated with downregulation of JNK/c-Jun pathway. Our strategies might be ultimately beneficial in mitigating liver injury symptom.

Prevention of Remifentanil Induced Postoperative Hyperalgesia by Dexmedetomidine via Regulating the Trafficking and Function of Spinal NMDA Receptors as well as PKC and CaMKII Level In Vivo and In Vitro.

Remifentanil-induced secondary hyperalgesia has been demonstrated in both animal experiments and clinical trials. Enhancement of N-methyl-D-aspartate (NMDA) receptor trafficking as well as protein kinase C (PKC) and calmodulin-dependent protein kinase II (CaMKII) have been reported to be involved in the induction and maintenance of central sensitization. In the current study, it was demonstrated that dexmedetomidine could prevent remifentanil-induced hyperalgesia (RIH) via regulating spinal NMDAR-PKC-Ca2+/ CaMKII pathway in vivo and in vitro. We firstly investigated the effect of dexmedetomidine, a highly selective α2-adrenergic receptor agonist, on mechanical and thermal hyperalgesia using a rat model of RIH. NMDA receptor subunits (NR1, NR2A and NR2B) expression and membrane trafficking as well as PKC and CaMKII expression in spinal cord L4-L5 segments were measured by Western blot analysis. The expression of NMDA receptor subunits (NR1, NR2A and NR2B) were also detected by immunohistochemistry. Further more, the effect of dexmedetomidine on NMDA receptor current amplitude and frequency in spinal cord slices were investigated by whole-cell patch-clamp recording. We found that remifentail infusion at 1.2 µg.kg-1.min-1 for 90 min caused mechanical and thermal hyperalgesia, up-regulated NMDA receptor subunits NR1 and NR2B expression in both membrane fraction and total lysate as well as increased PKC and CaMKII expression in spinal cord dorsal horn. Subcutaneously injection of dexmedetomidine at the dose of 50 µg/kg at 30 min before plantar incision significantly attenuated remifentanil-induced mechanical and thermal hyperalgesia from 2 h to 48 h after infusion, and this was associated with reversal of up-regulated NR1 and NR2B subunits in both membrane fraction and total lysate as well as increased PKC and CaMKII expression in spinal cord dorsal horn. Furthermore, remifentanil incubation increased amplitude and frequency of NMDA receptor-induced current in dorsal horn neurons, which was dose-dependently attenuated by dexmedetomidine. These results suggest that dexmedetomidine can significantly ameliorate RIH via modulating the expression, membrane trafficking and function of NMDA receptors as well as PKC and CaMKII level in spinal dorsal horn, which present useful insights into the mechanistic action of dexmedetomidine as a potential anti-hyperalgesic agents for treating RIH.