Repression of oxidative stress/reactive metabolite regulated gene expression is associated with conversion of carbamazepine into a hepatotoxicant in LPS and DSS rat models

Idiosyncratic hepatotoxicity accounts for many drug failures in the clinic and is a leading cause for black-boxed and withdrawn drugs. This toxicity has proven difficult to predict preclinically, but correlates with oxidative stress/reactive metabolites (OS/RM). As noted previously for antiepileptic compounds, many drugs causing idiosyncratic adverse drug effects are detected by OS/RM gene expression responses in the rat. In the present study, two immune activation models, low dose lipopolysaccharide (1 mg/kg IV) and 5% dextran sulphate sodium (DSS) in drinking water, were examined to determine if either would convert the non-toxic idiosyncratic toxicant carbamazepine (225 mg/kg) into a rat hepatotoxicant at 24 hours. Using the low dose LPS model, about 1/3 of the carbamazepine-treated rats either showed robust ALT and AST elevations with histopathological evidence of hepatotoxicity, or died. Rats in this LPS/carbamazepine group were subdivided based on ALT values into non-responders, responders or robust responders. Whereas most carbamazepine-induced mRNAs were repressed by LPS across all rats in this group, the OS/ RM genes aflatoxin aldehyde reductase (Afar) and glutathione transferase Ya (Gstya) were repressed only in the robust responder subgroup;it is unclear whether repression of these genes contributes to or results from hepatotoxicity. The OS/RM gene microsomal epoxide hydrolase (mEphx) showed repression across all rats. NAD(P)H: menadione oxidoreductase (Nmor) is an OS/RM-responsive gene that is also induced by LPS, confounding interpretation of its changes. After pretreatment with 5% DSS at 24 hours or for 5 days, using a protocol that reportedly produces increased endotoxin absorption, carbamazepine was not converted to a hepatototoxicant in any rats. Instead, DSS produced a pronounced (2- to 6-fold) and selective potentiation of carbamazepine induction of OS/RM-responsive mRNAs. The lack of repressive effects of DSS on these mRNAs or in converting carbamazepine to a hepatotoxicant was not due to desensitization of endotoxin responses since LPS was at least as effective when administered to DSS-pretreated rats. OS/RM gene repression may contribute to development of hepatotoxicity of carbamazepine in immune activation models.

Impacts of PI3K/protein kinase B pathway activation in reactive astrocytes: from detrimental effects to protective functions

Astrocytes are the most abundant type of glial cell in the central nervous system.Upon injury and inflammation,astrocytes become reactive and undergo morphological and functional changes.Depending on their phenotypic classification as A1 or A2,reactive astrocytes contribute to both neurotoxic and neuroprotective responses,respectively.However,this binary classification does not fully capture the diversity of astrocyte responses observed across different diseases and injuries.Transcriptomic analysis has revealed that reactive astrocytes have a complex landscape of gene expression profiles,which emphasizes the heterogeneous nature of their reactivity.Astrocytes actively participate in regulating central nervous system inflammation by interacting with microglia and other cell types,releasing cytokines,and influencing the immune response.The phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway is a central player in astrocyte reactivity and impacts various aspects of astrocyte behavior,as evidenced by in silico,in vitro,and in vivo results.In astrocytes,inflammatory cues trigger a cascade of molecular events,where nuclear factor-κB serves as a central mediator of the pro-inflammatory responses.Here,we review the heterogeneity of reactive astrocytes and the molecular mechanisms underlying their activation.We highlight the involvement of various signaling pathways that regulate astrocyte reactivity,including the PI3K/AKT/mammalian target of rapamycin(mTOR),αvβ3 integrin/PI3K/AKT/connexin 43,and Notch/PI3K/AKT pathways.While targeting the inactivation of the PI3K/AKT cellular signaling pathway to control reactive astrocytes and prevent central nervous system damage,evidence suggests that activating this pathway could also yield beneficial outcomes.This dual function of the PI3K/AKT pathway underscores its complexity in astrocyte reactivity and brain function modulation.The review emphasizes the importance of employing astrocyte-exclusive models to understand their functions accurately and these models are essential for clarifying astrocyte behavior.The findings should then be validated using in vivo models to ensure real-life relevance.The review also highlights the significance of PI3K/AKT pathway modulation in preventing central nervous system damage,although further studies are required to fully comprehend its role due to varying factors such as different cell types,astrocyte responses to inflammation,and disease contexts.Specific strategies are clearly necessary to address these variables effectively.

Reactive oxygen species and oxidative stress in acute pancreatitis:Pathogenesis and new therapeutic interventions

Acute pancreatitis(AP)is a common acute gastrointestinal disorder affecting approximately 20%of patients with systemic inflammatory responses that may cause pancreatic and peripancreatic fat necrosis.This condition often progresses to multiple organ failure,significantly increasing morbidity and mortality.Oxidative stress,characterized by an imbalance between the body’s reactive oxygen species(ROS)and antioxidants,activates the inflammatory signaling pathways.Although the pathogenesis of AP is not fully understood,ROS are increasingly recognized as critical in the disease's progression and development.Modulating the oxidative stress pathway has shown efficacy in mitigating the progression of AP.Despite numerous basic studies examining this pathway,comprehensive reviews of recent research remain sparse.This systematic review offers an in-depth examination of the critical role of oxidative stress in the pathogenesis and progression of AP and evaluates the therapeutic potential of antioxidant interventions in its management.

Effects of Nitric Oxide on the Germination of Wheat Seeds and Its Reactive Oxygen Species Metabolisms Under Osmotic Stress

Effects of sodium nitroprusside (SNP), a nitric oxide (NO) donor, on the germination and metabolism of reactive oxygen species were surveyed in wheat (Triticum aestivum L.) seeds. Germination of wheat seeds and even the elongation of radicle and plumule were dramatically promoted by SNP treatments during the germination under osmotic stress. Meanwhile, activities of amylase and EP were enhanced, thus leading to the degradation of storage reserve in seeds. After osmotic stress was removed, higher viability of wheat seeds was also maintained. In addition, the activities of CAT, APX and the content of proline were increased by SNP treatment simultaneously, but activities of LOX were inhibited, and both of which were beneficial for improving the antioxidant capacity during the germination of wheat seeds under osmotic stress. It was also shown that the increase of the activity of amylase induced by SNP in embryoless half-seeds of wheat in the beginning period of germination (6 h) might be indirectly related to GA(3).

Formation behaviors of rod-like reactive shaped charge penetrator and their effects on damage capability

Formation behaviors of rod-like reactive shaped charge penetrator(RRSCP)and their effects on damage capability are investigated by experiments and numerical simulations.The pulsed X-ray technology and a spaced aluminum/steel plate with the thicknesses of 5 mm/100 mm are used.Three types of sphericalsegment aluminum-polytetrafluoroethylene-copper(Al-PTFE-Cu)reactive liners with Cu contents of 0%,46.6%,and 66%are fabricated and tested.The experimental results show that the reactive liners can form excellent rod-shaped penetrators with tail skirts under the shaped charge effect,but the tail skirts disappear over time.Moreover,rupturing damage to the aluminum plate and penetration to the steel plate are caused by the RRSCP impact.From simulation analysis,the RRSCP is formed by a mechanically and chemically coupled response with the reactive liner activated by shock in its outer walls and bottom and then backward overturning,forming a leading reactive penetrator and a following chemical energy cluster.The unique formation structure determines the damage modes of the aluminum plate and the steel plate.Further analysis indicates that the formation behaviors and damage capability of Al-PTFE-Cu RRSCP strongly depend on Cu content.With increasing Cu content,the velocity,activation extent,and reaction extent of Al-PTFE-Cu RRSCP decrease,which contribute to elongation and alleviate the negative effects of chemical reactions on elongation,significantly increasing the length-diameter ratio and thus enhancing the capability of steel plate penetration.However,the lower activation extent and energetic density will weaken the RRSCP's capability of causing rupturing damage to the aluminum plate.

软件定义网络Reactive交换模式IP转发效率研究

现代计算机网络技术发展迅速,SDN具有转发与控制分离、应用灵活多变、适应性强等特点,已逐渐被IT厂商和电信运营商所接纳并采用,但SDN作为一种发展中的技术很多方面还有待完善。本文首先将IP层相关协议的通信过程进行了分析,然后针对SDN的Reactive交换机模式将这些协议的通信效率与以太网进行了对比。实验与分析表明,在地址解析、连通性测试和数据传输等基本网络行为中,SDN的Reactive交换模式效率并不占据优势,需要进一步优化。

Monomeric C-reactive protein:a link between chronic inflammation and neurodegeneration?

Pre-diabetic insulin resistance is associated with sub-clinical inflammation and concomitant increase in systemic C-reactive protein(CRP)levels.Type 2 diabetes mellitus(T2DM)patients register even higher chronic levels of inflammation,with excess circulating CRP originating from both typical hepatic synthesis,and also visceral white adipose tissue.

N-acetylcysteine attenuates reactive-oxygen-speciesmediated endoplasmic reticulum stress during liver ischemia-reperfusion injury

AIM: To investigate the effects of N-acetylcysteine (NAC) on endoplasmic reticulum (ER) stress and tissue injury during liver ischemia reperfusion injury (IRI).

Effects of Water Stress on Reactive Oxygen Species Generation and Protection System in Rice During Grain-Filling Stage

Rice is one of the main staple food crops in the world, but it may suffer serious water stress during growth period. Water stress during grain filling results in decreased grain yeild, but its mechanism generating and scavenging the active oxygen is unclear under continuance of the water stress. The experiment was carried out in growth chamber to investigate the effects of water stress on the production of superoxide free radical （O2）, hydrogen peroxide （H202）, malondialdehyde （MDA）, reduced glutathione （GSH）, ascorbic acid （AsA）, and antioxidative enzyme activities in three rice hybrids with differing drought resistant under both normal and drought conditions during grain-filling stage. The results showed that water stress aggravated the membrane lipid peroxidation in rice leaves, which was more severe in less drought resistant hybrids than that in more tolerant ones. Also O2＇ and H2O2 accumulated more rapidly in less drought resistant hybrids than that in more tolerant ones. During water stress, decreases of GSH, AsA, chlorophyll, and relative water contents in more drought resistant hybrids were obvious less than those in less tolerant ones. Activities of superoxide dismutase （SOD）, catalase （CAT） and peroxidase （POD） in/eaves increased obviously in 0-14 d after heading and subsequently decreased rapidly, and those in more drought resistant hybrids were more than those in less tolerant ones. The results showed that changes of O2, H2O2, MDA, GSH, and AsA contents and antioxidative enzyme activities correlated significantly to drought resistance of rice hybrids, and more drought resistant hybrids possessed high ant oxidation capacity.

Enhanced structural damage behavior of liquid-filled tank by reactive material projectile impact

A series of ballistic experiments were performed to investigate the damage behavior of high velocity reactive material projectiles(RMPs) impacting liquid-filled tanks,and the corresponding hydrodynamic ram(HRAM) was studied in detail.PTFE/Al/W RMPs with steel-like and aluminum-like densities were prepared by a pressing/sintering process.The projectiles impacted a liquid-filled steel tank with front aluminum panel at approximately 1250 m/s.The corresponding cavity evolution characteristics and HRAM pressure were recorded by high-speed camera and pressure acquisition system,and further compared to those of steel and aluminum projectiles.Significantly different from the conical cavity formed by the inert metal projectile,the cavity formed by the RMP appeared as an ellipsoid with a conical front.The RMPs were demonstrated to enhance the radial growth velocity of cavity,the global HRAM pressure amplitude and the front panel damage,indicating the enhanced HRAM and structural damage behavior.Furthermore,combining the impact-induced fragmentation and deflagration characteristics,the cavity evolution of RMPs under the combined effect of kinetic energy impact and chemical energy release was analyzed.The mechanism of enhanced HRAM pressure induced by the RMPs was further revealed based on the theoretical model of the initial impact wave and the impulse analysis.Finally,the linear correlation between the deformation-thickness ratio and the non-dimensional impulse for the front panel was obtained and analyzed.It was determined that the enhanced near-field impulse induced by the RMPs was the dominant reason for the enhanced structural damage behavior.

Reactive transport modeling constraints on the complex genesis of a lacustrine dolomite reservoir:A case from the Eocene Qaidam Basin,China

Reactive transport modeling(RTM)is an emerging method used to address geological issues in diagenesis research.However,the extrapolation of RTM results to practical reservoir prediction is not sufficiently understood.This paper presents a case study of the Eocene Qaidam Basin that combines RTM results with petrological and mineralogical evidence.The results show that the Eocene Xiaganchaigou Formation is characterized by mixed siliciclastic-carbonate-evaporite sedimentation in a semiclosed saline lacustrine environment.Periodic evaporation and salinization processes during the syngeneticpenecontemporaneous stage gave rise to the replacive genesis of dolomites and the cyclic enrichment of dolomite in the middle-upper parts of the meter-scale depositional sequences.The successive change in mineral paragenesis from terrigenous clastics to carbonates to evaporites was reconstructed using RTM simulations.Parametric uncertainty analyses further suggest that the evaporation intensity(brine salinity)and particle size of sediments(reactive surface area)were important rate-determining factors in the dolomitization,as shown by the relatively higher reaction rates under conditions of higher brine salinity and fine-grained sediments.Combining the simulation results with measured mineralogical and reservoir physical property data indicates that the preservation of original intergranular pores and the generation of porosity via replacive dolomitization were the major formation mechanisms of the distinctive lacustrine dolomite reservoirs(widespread submicron intercrystalline micropores)in the Eocene Qaidam Basin.The results confirm that RTM can be effectively used in geological studies,can provide a better general understanding of the dolomitizing fluid-rock interactions,and can shed light on the spatiotemporal evolution of mineralogy and porosity during dolomitization and the formation of lacustrine dolomite reservoirs.

Production of reactive oxygen species by freezing stress and the protective roles of antioxidant enzymes in plants

As one of the most severe environmental stresses, freezing stress can determine native flora in nature and severely reduce crop production. Many mechanisms have been proposed to explain the damage induced by freezing-thawing cycle, and oxidative stress caused by uncontrollable production of harmful reactive oxygen species (ROS) are partially contributed to causing the injury. Plants in temperate regions have evolved a unique but effective metabolism of protecting themselves called cold acclimation. Cold-acclimating plants undergo a complex but orchestrated metabolic process to increase cold hardness triggered by exposure to low temperature and shortened photoperiod and achieve the maximum freezing tolerance by a concerted regulation and expression of a number of cold responsive genes. A complicated enzymatic system have been evolved in plants to scavenge the ROS to protect themselves from oxidative stress, therefore, cold-acclimating plants are expected to increase the de novo synthesis of the genes of antioxidant genes. Indeed, many antioxidant genes increase the expression levels in response to low temperature. Furthermore, the higher expression of many antioxidant enzymes are positively correlated to inducing higher tolerance levels against freezing. All the information summarized here can be applied for developing crop and horticultural plants to have more freezing tolerance for higher production with better quality. There have been extensive studies on the activities of antioxidant enzymes and the gene regulation, however, more researches will be required in near future to elucidate the most effective antioxidant enzymes to induce highest freezing tolerance in a crop plant in a transformation process or a breeding program.

All-trans retinoic acid increases ARPE-19 cell apoptosis via activation of reactive oxygen species and endoplasmic reticulum stress pathways

AIM:To explore the apoptosis of ARPE-19 cells after the treatment with different doses of all-trans-retinoic acid(ATRA).METHODS:ARPE-19 cells were used in the in-vitro experiment.Flow cytometry assay was employed to evaluate the level of reactive oxygen species(ROS)and apoptosis.The effects of ATRA(concentrations from 2.5 to 20μmol/L)on the expression of endoplasmic reticulum stress(ERS)markers in vitro were evaluated by Western blot and realtime quantitative polymerase chain reaction(qRT-PCR)assays.The contribution of ROS and ERS-induced apoptosis in vitro was determined by using N-acetyl-L-cysteine(NAC)and Salubrinal,an antagonist of NAC and ERS,respectively.RESULTS:Flow cytometry showed that ATRA significantly increased ARPE-19 cell apoptosis and ROS levels in each group(F=86.39,P<0.001;F=116.839.P<0.001).Western blot and qRT-PCR revealed that levels of CHOP and BIP were elevated in a concentration-dependent pattern after the cells were incubated with ATRA(2.5-20μmol/L).The upregulation of VEGF-A and CHOP induced by ATRA could be inhibited by NAC(antioxidant)and Salubrinal(ERS inhibitor)in vitro.CONCLUSION:ATRA induces the apoptosis of ARPE-19 cells via activated ROS and ERS signaling pathways.

Overexpression of PbrGA2ox1 enhances pear drought tolerance through the regulation of GA_(3)-inhibited reactive oxygen species detoxification and abscisic acid signaling

Drought stress is a devastating natural disaster driven by the continuing intensification of global warming,which seriously threatens the productivity and quality of several horticultural crops,including pear.Gibberellins(GAs)play crucial roles in plant growth,development,and responses to drought stress.Previous studies have shown significant reductions of GA levels in plants under drought stress;however,our understanding of the intrinsic regulation mechanisms of GA-mediated drought stress in pear remains very limited.Here,we show that drought stress can impair the accumulation of bioactive GAs(BGAs),and subsequently identified PbrGA2ox1 as a chloroplast-localized GA deactivation gene.This gene was significantly induced by drought stress and abscisic acid(ABA)treatment,but was suppressed by GA_(3)treatment.PbrGA2ox1-overexpressing transgenic tobacco plants(Nicotiana benthamiana)exhibited enhanced tolerance to dehydration and drought stresses,whereas knock-down of PbrGA2ox1 in pear(Pyrus betulaefolia)by virus-induced gene silencing led to elevated drought sensitivity.Transgenic plants were hypersensitive to ABA,and had a lower BGAs content,enhanced reactive oxygen species(ROS)scavenging ability,and augmented ABA accumulation and signaling under drought stress compared to wild-type plants.However,the opposite effects were observed with PbrGA2ox1 silencing in pear.Moreover,exogenous GA_(3)treatment aggravated the ROS toxic effect and restrained ABA synthesis and signaling,resulting in the compromised drought tolerance of pear.In summary,our results shed light on the mechanism by which BGAs are eliminated in pear leaves under drought stress,providing further insights into the mechanism regulating the effects of GA on the drought tolerance of plants.

The ZmHSF08-ZmUGT92A1 module regulates heat tolerance by altering reactive oxygen species levels in maize

GTs(Glycosyltransferases)are important in plant growth and abiotic stresses.However,its role in maize heat response is far from clear.Here,we describe the constitutively expressed UDP-glycosyltransferase ZmUGT92A1,which has a highly conserved PSPG box and is localized in chloroplasts,is induced under heat stress.Functional disruption of ZmUGT92A1 leads to heat sensitivity and reactive oxygen species accumulation in maize.Metabolomics analysis revealed that ZmUGT92A1 affected multiple metabolic pathways and altered the metabolic homeostasis of flavonoids under heat stress.In vitro assay showed ZmUGT92A1 exhibits glycosyltransferase activity on flavonoids and hormones.Additionally,we identified a rapidly heat-induced transcription factor,ZmHSF08,which can directly bind and repress the promoter region of ZmUGT92A1.The ZmHSF08 overexpression line exhibits heat sensitivity and reactive oxygen species accumulation.These findings reveal that the ZmHSF08-ZmUGT92A1 module plays a role in heat tolerance in maize and provide candidate strategies for the development of heat-tolerant varieties.

Brain region-specific roles of brain-derived neurotrophic factor in social stress-induced depressive-like behavior

Brain-derived neurotrophic factor is a key factor in stress adaptation and avoidance of a social stress behavioral response.Recent studies have shown that brain-derived neurotrophic factor expression in stressed mice is brain region–specific,particularly involving the corticolimbic system,including the ventral tegmental area,nucleus accumbens,prefrontal cortex,amygdala,and hippocampus.Determining how brain-derived neurotrophic factor participates in stress processing in different brain regions will deepen our understanding of social stress psychopathology.In this review,we discuss the expression and regulation of brain-derived neurotrophic factor in stress-sensitive brain regions closely related to the pathophysiology of depression.We focused on associated molecular pathways and neural circuits,with special attention to the brain-derived neurotrophic factor–tropomyosin receptor kinase B signaling pathway and the ventral tegmental area–nucleus accumbens dopamine circuit.We determined that stress-induced alterations in brain-derived neurotrophic factor levels are likely related to the nature,severity,and duration of stress,especially in the above-mentioned brain regions of the corticolimbic system.Therefore,BDNF might be a biological indicator regulating stress-related processes in various brain regions.

Reduction Discoloration of Reactive Dyed Cotton Waste and Chemical Recycling via Ionic Liquid

The textile industry generates large volumes of waste throughout its production process.Most of this waste is colored,therefore,discoloration is an important step toward recycling and reusing this waste.This study focused on the chemical reductive discoloration of textile waste composed of cotton dyed with reactive dye.The experimental design demonstrated the significant influence of the concentration of reducing agent and time of reaction on the degree of whiteness of the cotton fibers.The concentration of the alkaline agent was not significant in the process.The optimization of the reaction conditions lead to Berger degree of 50.5±3.5.The discolored cotton was chemically recycled through dissolution in ionic liquid 1-ethyl-3-methylimidazolium chloride and regeneration in film form in water.The microstructure of the regenerated cellulose films was evaluated by Scanning Electron Microscopy(SEM)indicating complete dissolution and uniform regeneration.The discoloration process reduced the polymerization degree and crystallinity index of the cotton fibers but retained the cellulose I structure.The dissolution and cellulose regeneration process results in transparent films with an amorphous structure.The thermal behavior,evaluated by thermogravimetric analysis,indicated that residues and regenerated film presented a main decomposition step.The maximum decomposition rate temperature of the regenerated films was approximately 40℃lower than the cotton fibers,which correlates well with the reduction in polymerization degree and amorphous structure.In general,the study demonstrated that textile cotton waste dyed with reactive dyes can be chemically discolored to form transparent and amorphous films,contributing to the development of sustainable strategies for the textile industry.

Fabrication and Properties of a New Reactive Diluent for Cationic UV Curing

The reactive diluent prepared by siloxane modified Trimethylene oxide can improve the performance of the UV curing system.Therefore,1,7-bis[(3-ethyl-3-methoxyoxacylobutane)propyl]octadecylosiloxane(BEMOPOMTS)was synthesized from diethyl carbonate,trimethylopropanes,allyl bromide,and 1,1,3,3,5,5,7,7-octadecylosiloxane as the main raw materials.BEMOPOMTS can be used as reactive diluents in the field of cationic UV curing.It has good thermal stability,and the addition of BEMOPOMTS significantly improves the tensile strength and elongation at break of epoxy resin.Compared with the pure epoxy resin,adding 20%BEMOPOMTS increased the elastic modulus by 25%to 677 MPa.

Alternative Splicing of OsCYL4 Controls Drought Resistance via Regulating Water Loss and Reactive Oxygen Species-Scavenging in Rice

A rice cyclase gene,OsCYL4b,identified as an alternative splice variant of the cyclase gene OsCYL4a,is involved in the regulation of drought stress and oxidative response.Compared with OsCYL4a,OsCYL4b lacks the second exon,which is located in the conserved motif 3,and may be a functionally important site.Our results suggested that OsCYL4b was responsive to multiple abiotic stresses,and was localized to both the cytoplasm and plasma membrane.The overexpression of OsCYL4b resulted in significantly enhanced drought and osmotic stress tolerance,reduced water loss,and increased abscisic acid(ABA)content compared with the wild type(WT).

Adaptive optimisation of explosive reactive armour for protection against kinetic energy and shaped charge threats

We evaluate an adaptive optimisation methodology,Bayesian optimisation(BO),for designing a minimum weight explosive reactive armour(ERA)for protection against a surrogate medium calibre kinetic energy(KE)long rod projectile and surrogate shaped charge(SC)warhead.We perform the optimisation using a conventional BO methodology and compare it with a conventional trial-and-error approach from a human expert.A third approach,utilising a novel human-machine teaming framework for BO is also evaluated.Data for the optimisation is generated using numerical simulations that are demonstrated to provide reasonable qualitative agreement with reference experiments.The human-machine teaming methodology is shown to identify the optimum ERA design in the fewest number of evaluations,outperforming both the stand-alone human and stand-alone BO methodologies.From a design space of almost 1800 configurations the human-machine teaming approach identifies the minimum weight ERA design in 10 samples.