ROLE OF Na^+-Ca^(2+) EXCHANGE SYSTEM IN THE PATHOGENESIS OF MYOCARDIAL ISCHEMIA-REPERFUSION DAMAGE

Results from a systematic experiment on isolated perfused rat heart and isolated myc-cytes of adult rat showed that the mechanism of calcium influx during myocardial ischemia-reperfusion is due to the development of intracellular sodium overload during ischemic pe-riod, on reperfusion, the high intracellular Na^+ content activated the reverse direction ofNa^+-Ca^(2+) exchange over myocardial sarcolemma (SL), thus a large quantity of extracellularCa^(2+) fluxed over the SL to the intracellular space, forming a condition of intracellular Ca^(2+)overload, which leads to irreversible damage of the myocardium.

Impact of Zika virus non-structural protein mutations on hippocampal damage

The Zika virus(ZIKV),a member of the Flaviviridae family,attracted worldwide attention for its connection to severe neurological effects,notably microcephaly in newborns,first reported during the 2015 epidemic in Brazil.Yet,its impact goes beyond fetal and neonatal abnormalities,also affecting the central nervous system(CNS)in both children and adults,leading to enduring cognitive and behavioral impairments.

Inhibition of the cGAS–STING pathway:contributing to the treatment of cerebral ischemia-reperfusion injury

The cGAS–STING pathway plays an important role in ischemia-reperfusion injury in the heart,liver,brain,and kidney,but its role and mechanisms in cerebral ischemia-reperfusion injury have not been systematically reviewed.Here,we outline the components of the cGAS–STING pathway and then analyze its role in autophagy,ferroptosis,cellular pyroptosis,disequilibrium of calcium homeostasis,inflammatory responses,disruption of the blood–brain barrier,microglia transformation,and complement system activation following cerebral ischemia-reperfusion injury.We further analyze the value of cGAS–STING pathway inhibitors in the treatment of cerebral ischemia-reperfusion injury and conclude that the pathway can regulate cerebral ischemia-reperfusion injury through multiple mechanisms.Inhibition of the cGAS–STING pathway may be helpful in the treatment of cerebral ischemia-reperfusion injury.

Effects of penehyclidine hydrochloride in small intestinal damage caused by limb ischemia-reperfusion

AIM:To investigate the protective effect of penehyclidine hydrochloride post-conditioning in the damage to the barrier function of the small intestinal mucosa caused by limb ischemia-reperfusion(LIR) injury. METHODS:Male Wistar rats were randomly divided into three groups(36 rats each) :the sham-operation group(group S) ,lower limb ischemia-reperfusion group(group LIR) ,and penehyclidine hydrochloride postconditioning group(group PHC) .Each group was divided into subgroups(n=6 in each group) according to ischemic-reperfusion time,i.e.immediately 0 h(T1) ,1 h(T2) ,3 h(T3) ,6 h(T4) ,12 h(T5) ,and 24 h(T6) .Bilateral hind-limb ischemia was induced by rubber band application proximal to the level of the greater trochanter for 3 h.In group PHC,0.15 mg/kg of penehyclidine hydrochloride was injected into the tail vein immediately after 3 h of bilateral hind-limb ischemia.The designated rats were sacrificed at different time-points of reperfusion;diamine oxidase(DAO) ,superoxide dismutase(SOD) activity,myeloperoxidase(MPO) of small intestinal tissue,plasma endotoxin,DAO,tumor necrosis factor-α(TNF-α) ,and interleukin(IL) -10 in serum were detected in the rats. RESULTS:The pathological changes in the small intestine were observed under light microscope.The levels of MPO,endotoxin,serum DAO,and IL-10 at T1-T6,and TNF-αlevel at T1-T4 increased in groups LIR and PHC(P<0.05) compared with those in group S,but tissue DAO and SOD activity at T1-T6 decreased(P<0.05) .In group PHC,the tissue DAO and SOD activity at T2-T6,and IL-10 at T2-T5 increased to higher levels than those in group LIR(P<0.05) ;however,the levels of MPO,endotoxin,and DAO in the blood at T2-T6,and TNF-αat T2 and T4 decreased(P<0.05) . CONCLUSION:Penehyclidine hydrochloride post-conditioning may reduce the permeability of the small intestines after LIR.Its protection mechanisms may be related to inhibiting oxygen free radicals and inflammatory cytokines for organ damage.

Taxifolin attenuates ischemia-reperfusion induced oxidative ovarian damage in rats

Objective:To investigate preventive effects of taxifolin on ischemia-reperfusion induced oxidative ovarian damage in rats.Methods:A total of 18 female Wistar albino rats were randomly and equally divided into three groups:the sham group,the ovarian ischemia reperfusion group,and the 50 mg/kg taxifolin+ovarian ischemia reperfusion group.The ovarian ischemia reperfusion and taxifolin+ovarian ischemia reperfusion groups were exposed to ischemia for 2 h and then followed by two-hour reperfusion protocol.Biochemical and histopathologic examinations were performed on the extracted ovaries.Results:Levels of malondialdehyde and cyclooxygenase-2 were increased,while reduced-glutathione and cyclooxygenase-1 were decreased in the ovarian ischemia reperfusion group.However,these values were reversed in the taxifolin+ovarian ischemia reperfusion group.Similarly,the number of primordial and developing follicules decreased in the ovarian ischemia reperfusion group,while they were within normal range in the taxifolin+ovarian ischemia reperfusion group.Conclusions:Ischemia followed by reperfusion leads to oxidative stress-related ovarian injury,and taxifolin may be useful for protecting ovarian tissue from such injury.

Influence of edaravone on growth arrest and DNA damage-inducible protein 34 expression following focal cerebral ischemia-reperfusion in rats

Objective:To investigate the influence of edaravone on the expression of growth arrest and DNA damage-inducible protein 34(GADD34).Methods:A total of 108 healthy male Sprague-Dawlcy rats were randomly divided into sham operation group,model group and edaravone.group(36 cases for each group).Transient focal cerebral ischemia was induced by middle cerebral artery occlusion for 2 h followed by reperfusion in Sprague-Dawlev rats.Then.GAOD34 expression was measured with immunohistochemistry at different time-points after reperfusion in the peri-infarct regions of all rats.Results:The GADD34 expression was detected in the peri-infaret regions of rats 1 h after reperfusion,which reached its peak 24 h after reperfusion.And edaravone could significantly down-regulate the GAOD34 expression.Conclusions:Edaravon could down-regulate GADD34 expression,which suggests that edaravone may exert an important function in inhibiting endoplasmic reticulum stress reaction by scavenging free radicals in the upper stream.

Methylene blue attenuates white matter damage after focal cerebral ischemia-reperfusion in rats

Methylene blue(MB)was reported to have neuronal protective effect after brain ischermia.In this study,we aimed to investigate the effect of MB on white matter in rats after focal cerebral ischemia-reperfusion(MCAO/R)injury.MCAO/R model was set and 54 male SD rats were randomly divided into 3 groups:control(sham surgery group),middle cerebral artery occlusion and reperfusion(MCAO),MCAO treated with MB of 10 mg/kg(MB)by intraperitoneal injection 1.5 h after surgery.We observed the neurological deficits in different groups using foot fault test 24 h after MCAO.We measured the infarction volume using TTC staining and showed the morphological changes of neurons and myelin using Nissl and black gold staining.

Correlation between myocardial ischemia-reperfusion-induced monophasic action potential amplitude change and myocardial damage

Objective:To study the correlation between myocardial ischemia-reperfusion-induced monophasic action potential amplitude (MAPA) change and myocardial damage.Methods:New Zealand rabbits were selected as experimental animals and randomly divided into control group and ischemia-reperfusion group (I/R group), myocardial ischemia-reperfusion injury models were established, then the heart was separated and the MAPA of myocardial intima layer, media layer and outer layer were determined in Langendorff perfusion system;serum samples and myocardial tissue were collected to determine the contents of myocardial injury molecules.Results: MAPA levels of myocardial intima layer, media layer and outer layer of I/R group were significantly lower than those of control group;CK-MB, cTnI, cTnT and MDA contents in serum as well as Bax, Caspase-3 and Caspase-9 mRNA expression in myocardial tissue of I/R group were significantly higher than those of control group and negatively correlated with MAPA levels of myocardial intima layer, media layer and outer layer while SOD, GSH-Px and HO-1 contents in serum as well as Bcl-2 and Bcl-xL mRNA expression in myocardial tissue were significantly lower than those of control group and positively correlated with MAPA levels of myocardial intima layer, media layer and outer layer.Conclusion:Myocardial ischemia - reperfusion can induce the decrease of MAPA and is closely related to myocardial oxidative stress injury and apoptosis.

Modulation of p75 neurotrophin receptor mitigates brain damage following ischemic stroke in mice

Stroke is a significant leading cause of death and disability in the United States(Tsao et al.,2022).Approximately 87% of strokes fall into the ischemic category,mainly caused by arterial blockage(Jayaraj et al.,2019).Although the only FDA-approved effective medication is tissue plasminogen activator(tPA),it should be administrated within 4.5 hours of ischemic stroke.Furthermore,tPA has been an integral part of managing acute ischemic stro ke.

HSP110 aggravates ischemia-reperfusion injury after liver transplantation by promoting NF-κB pathway

Background:Ischemia-reperfusion injury(IRI)poses a significant challenge to liver transplantation(LT).The underlying mechanism primarily involves overactivation of the immune system.Heat shock protein 110(HSP110)functions as a molecular chaperone that helps stabilize protein structures.Methods:An IRI model was established by performing LT on Sprague-Dawley rats,and HSP110 was silenced using siRNA.Hematoxylin-eosin staining,TUNEL,immunohistochemistry,ELISA and liver enzyme analysis were performed to assess IRI following LT.Western blotting and quantitative reverse transcription-polymerase chain reaction were conducted to investigate the pertinent molecular changes.Results:Our findings revealed a significant increase in the expression of HSP110 at both the mRNA and protein levels in the rat liver following LT(P<0.05).However,when rats were injected with siRNAHSP110,IRI subsequent to LT was notably reduced(P<0.05).Additionally,the levels of liver enzymes and inflammatory chemokines in rat serum were significantly reduced(P<0.05).Silencing HSP110 with siRNA resulted in a marked decrease in M1-type polarization of Kupffer cells in the liver and downregulated the NF-κB pathway in the liver(P<0.05).Conclusions:HSP110 in the liver promotes IRI after LT in rats by activating the NF-κB pathway and inducing M1-type polarization of Kupffer cells.Targeting HSP110 to prevent IRI after LT may represent a promising new approach for the treatment of LT-associated IRI.

A review of reservoir damage during hydraulic fracturing of deep and ultra-deep reservoirs

Deep and ultra-deep reservoirs have gradually become the primary focus of hydrocarbon exploration as a result of a series of significant discoveries in deep hydrocarbon exploration worldwide.These reservoirs present unique challenges due to their deep burial depth(4500-8882 m),low matrix permeability,complex crustal stress conditions,high temperature and pressure(HTHP,150-200℃,105-155 MPa),coupled with high salinity of formation water.Consequently,the costs associated with their exploitation and development are exceptionally high.In deep and ultra-deep reservoirs,hydraulic fracturing is commonly used to achieve high and stable production.During hydraulic fracturing,a substantial volume of fluid is injected into the reservoir.However,statistical analysis reveals that the flowback rate is typically less than 30%,leaving the majority of the fluid trapped within the reservoir.Therefore,hydraulic fracturing in deep reservoirs not only enhances the reservoir permeability by creating artificial fractures but also damages reservoirs due to the fracturing fluids involved.The challenging“three-high”environment of a deep reservoir,characterized by high temperature,high pressure,and high salinity,exacerbates conventional forms of damage,including water sensitivity,retention of fracturing fluids,rock creep,and proppant breakage.In addition,specific damage mechanisms come into play,such as fracturing fluid decomposition at elevated temperatures and proppant diagenetic reactions at HTHP conditions.Presently,the foremost concern in deep oil and gas development lies in effectively assessing the damage inflicted on these reservoirs by hydraulic fracturing,comprehending the underlying mechanisms,and selecting appropriate solutions.It's noteworthy that the majority of existing studies on reservoir damage primarily focus on conventional reservoirs,with limited attention given to deep reservoirs and a lack of systematic summaries.In light of this,our approach entails initially summarizing the current knowledge pertaining to the types of fracturing fluids employed in deep and ultra-deep reservoirs.Subsequently,we delve into a systematic examination of the damage processes and mechanisms caused by fracturing fluids within the context of hydraulic fracturing in deep reservoirs,taking into account the unique reservoir characteristics of high temperature,high pressure,and high in-situ stress.In addition,we provide an overview of research progress related to high-temperature deep reservoir fracturing fluid and the damage of aqueous fracturing fluids to rock matrix,both artificial and natural fractures,and sand-packed fractures.We conclude by offering a summary of current research advancements and future directions,which hold significant potential for facilitating the efficient development of deep oil and gas reservoirs while effectively mitigating reservoir damage.

Rockburst criterion and evaluation method for potential rockburst pit depth considering excavation damage effect

Excavation-induced disturbances in deep tunnels will lead to deterioration of rock properties and formation of excavation damaged zone(EDZ).This excavation damage effect may affect the potential rockburst pit depth.Taking two diversion tunnels of Jinping II hydropower station for example,the relationship between rockburst pit depth and excavation damage effect is first surveyed.The results indicate that the rockburst pit depth in tunnels with severe damage to rock masses is relatively large.Subsequently,the excavation-induced damage effect is characterized by disturbance factor D based on the Hoek-Brown criterion and wave velocity method.It is found that the EDZ could be further divided into a high-damage zone(HDZ)with D=1 and weak-damage zone(WDZ),and D decays from one to zero linearly.For this,a quantitative evaluation method for potential rockburst pit depth is established by presenting a three-element rockburst criterion considering rock strength,geostress and disturbance factor.The evaluation results obtained by this method match well with actual observations.In addition,the weakening of rock mass strength promotes the formation and expansion of potential rockburst pits.The potential rockburst pit depth is positively correlated with HDZ and WDZ depths,and the HDZ depth has a significant contribution to the potential rockburst pit depth.

A creep model for ultra-deep salt rock considering thermal-mechanical damage under triaxial stress conditions

To investigate the specific creep behavior of ultra-deep buried salt during oil and gas exploitation,a set of triaxial creep experiments was conducted at elevated temperatures with constant axial pressure and unloading confining pressure conditions.Experimental results show that the salt sample deforms more significantly with the increase of applied temperature and deviatoric loading.The accelerated creep phase is not occurring until the applied temperature reaches 130℃,and higher temperature is beneficial to the occurrence of accelerated creep.To describe the specific creep behavior,a novel three-dimensional(3D)creep constitutive model is developed that incorporates the thermal and mechanical variables into mechanical elements.Subsequently,the standard particle swarm optimization(SPSO)method is adopted to fit the experimental data,and the sensibility of key model parameters is analyzed to further illustrate the model function.As a result,the model can accurately predict the creep behavior of salt under the coupled thermo-mechanical effect in deep-buried condition.Based on the research results,the creep mechanical behavior of wellbore shrinkage is predicted in deep drilling projects crossing salt layer,which has practical implications for deep rock mechanics problems.

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.

Micro-macro evolution of mechanical behaviors of thermally damaged rock:A state-of-the-art review

The influence of thermal damage on macroscopic and microscopic characteristics of different rocks has received much attention in the field of rock engineering.When the rocks are subjected to thermal treatment,the change of macroscopic characteristics and evolution of micro-structure would be induced,ultimately resulting in different degrees of thermal damage in rocks.To better understand the thermal damage mechanism of different rocks and its effect on the rock performance,this study reviews a large number of test results of rock specimens experiencing heating and cooling treatment in the laboratory.Firstly,the variations of macroscopic behaviors,including physical parameters,mechanical parameters,thermal conductivity and permeability,are examined.The variations of mechanical parameters with thermal treatment variables(i.e.temperature or the number of thermal cycles)are divided into four types.Secondly,several measuring methods for microstructure,such as polarizing microscopy,fluorescent method,scanning electron microscopy(SEM),X-ray computerized tomography(CT),acoustic emission(AE)and ultrasonic technique,are introduced.Furthermore,the effect of thermal damage on the mechanical parameters of rocks in response to different thermal treatments,involving temperature magnitude,cooling method and thermal cycle,are discussed.Finally,the limitations and prospects for the research of rock thermal damage are proposed.

A methodology for damage evaluation of underground tunnels subjected to static loading using numerical modeling

We have proposed a methodology to assess the robustness of underground tunnels against potential failure.This involves developing vulnerability functions for various qualities of rock mass and static loading intensities.To account for these variations,we utilized a Monte Carlo Simulation(MCS)technique coupled with the finite difference code FLAC^(3D),to conduct two thousand seven hundred numerical simulations of a horseshoe tunnel located within a rock mass with different geological strength index system(GSIs)and subjected to different states of static loading.To quantify the severity of damage within the rock mass,we selected one stress-based(brittle shear ratio(BSR))and one strain-based failure criterion(plastic damage index(PDI)).Based on these criteria,we then developed fragility curves.Additionally,we used mathematical approximation techniques to produce vulnerability functions that relate the probabilities of various damage states to loading intensities for different quality classes of blocky rock mass.The results indicated that the fragility curves we obtained could accurately depict the evolution of the inner and outer shell damage around the tunnel.Therefore,we have provided engineers with a tool that can predict levels of damages associated with different failure mechanisms based on variations in rock mass quality and in situ stress state.Our method is a numerically developed,multi-variate approach that can aid engineers in making informed decisions about the robustness of underground tunnels.

Damage evolution of rock-encased-backfill structure under stepwise cyclic triaxial loading

Rock-encased-backfill(RB)structures are common in underground mining,for example in the cut-andfill and stoping methods.To understand the effects of cyclic excavation and blasting activities on the damage of these RB structures,a series of triaxial stepwise-increasing-amplitude cyclic loading experiments was conducted with cylindrical RB specimens(rock on outside,backfill on inside)with different volume fractions of rock(VF=0.48,0.61,0.73,and 0.84),confining pressures(0,6,9,and 12 MPa),and cyclic loading rates(200,300,400,and 500 N/s).The damage evolution and meso-crack formation during the cyclic tests were analyzed with results from stress-strain hysteresis loops,acoustic emission events,and post-failure X-ray 3D fracture morphology.The results showed significant differences between cyclic and monotonic loadings of RB specimens,particularly with regard to the generation of shear microcracks,the development of stress memory and strain hardening,and the contact forces and associated friction that develops along the rock-backfill interface.One important finding is that as a function of the number of cycles,the elastic strain increases linearly and the dissipated energy increases exponentially.Also,compared with monotonic loading,the cyclic strain hardening characteristics are more sensitive to rising confining pressures during the initial compaction stage.Another finding is that compared with monotonic loading,more shear microcracks are generated during every reloading stage,but these microcracks tend to be dispersed and lessen the likelihood of large shear fracture formation.The transition from elastic to plastic behavior varies depending on the parameters of each test(confinement,volume fraction,and cyclic rate),and an interesting finding was that the transformation to plastic behavior is significantly lower under the conditions of 0.73 rock volume fraction,400 N/s cyclic loading rate,and 9 MPa confinement.All the findings have important practical implications on the ability of backfill to support underground excavations.

Modeling time-dependent mechanical behavior of hard rock considering excavation-induced damage and complex 3D stress states

To investigate the long-term stability of deep rocks,a three-dimensional(3D)time-dependent model that accounts for excavation-induced damage and complex stress state is developed.This model comprises three main components:a 3D viscoplastic isotropic constitutive relation that considers excavation damage and complex stress state,a quantitative relationship between critical irreversible deformation and complex stress state,and evolution characteristics of strength parameters.The proposed model is implemented in a self-developed numerical code,i.e.CASRock.The reliability of the model is validated through experiments.It is indicated that the time-dependent fracturing potential index(xTFPI)at a given time during the attenuation creep stage shows a negative correlation with the extent of excavationinduced damage.The time-dependent fracturing process of rock demonstrates a distinct interval effect of the intermediate principal stress,thereby highlighting the 3D stress-dependent characteristic of the model.Finally,the influence of excavation-induced damage and intermediate principal stress on the time-dependent fracturing characteristics of the surrounding rocks around the tunnel is discussed.

Comparison of displacement damage effects on the dark signal in CMOS image sensors induced by CSNS back-n and XAPR neutrons

This study investigates the effects of displacement damage on the dark signal of a pinned photodiode CMOS image sensor(CIS)following irradiation with back-streaming white neutrons from white neutron sources at the China spallation neutron source(CSNS)and Xi'an pulsed reactor(XAPR).The mean dark signal,dark signal non-uniformity(DSNU),dark signal distribution,and hot pixels of the CIS were compared between the CSNS back-n and XAPR neutron irradiations.The nonionizing energy loss and energy distribution of primary knock-on atoms in silicon,induced by neutrons,were calculated using the open-source package Geant4.An analysis combining experimental and simulation results showed a noticeable proportionality between the increase in the mean dark signal and the displacement damage dose(DDD).Additionally,neutron energies influence DSNU,dark signal distribution,and hot pixels.High neutron energies at the same DDD level may lead to pronounced dark signal non-uniformity and elevated hot pixel values.

Polydatin ameliorates hepatic ischemia-reperfusion injury by modulating macrophage polarization

Background:Polydatin,a glucoside of resveratrol,has shown protective effects against various diseases.However,little is known about its effect on hepatic ischemia-reperfusion(I/R)injury.This study aimed to elucidate whether polydatin protects liver against I/R-induced injury and to explore the underlying mechanism.Methods:After gavage feeding polydatin once daily for a week,mice underwent a partial hepatic I/R procedure.Serum alanine aminotransferase(ALT)/aspartate aminotransferase(AST),hematoxylin-eosin(H&E)and TdT-mediated dUTP nick-end labeling(TUNEL)staining were used to evaluate liver injury.The severity related to the inflammatory response and reactive oxygen species(ROS)production was also investigated.Furthermore,immunofluorescence and Western blotting were used to detect macrophage polarization and the NF-κB signaling pathway in macrophages.Results:Compared with the I/R group,polydatin pretreatment significantly attenuated I/R-induced liver damage and apoptosis.The oxidative stress marker(dihydroethidium fluorescence,malondialdehyde,superoxide dismutase and glutathione peroxidase)and I/R related inflammatory cytokines(interleukin1β,interleukin-10 and tumor necrosis factor-α)were significantly suppressed after polydatin treatment.In addition,the result of immunofluorescence indicated that polydatin reduced the polarization of macrophages toward M1 macrophages both in vivo and in vitro.Western blotting showed that polydatin inhibited the pro-inflammatory function of RAW264.7 via down-regulating the NF-κB signaling pathway.Conclusions:Polydatin protects the liver from I/R injury by remodeling macrophage polarization via NFκB signaling.