Polyethylene glycol fusion repair of severed rat sciatic nerves reestablishes axonal continuity and reorganizes sensory terminal fields in the spinal cord

Peripheral nerve injuries result in the rapid degeneration of distal nerve segments and immediate loss of motor and sensory functions;behavioral recovery is typically poor.We used a plasmalemmal fusogen,polyethylene glycol(PEG),to immediately fuse closely apposed open ends of severed proximal and distal axons in rat sciatic nerves.We have previously reported that sciatic nerve axons repaired by PEG-fusion do not undergo Wallerian degeneration,and PEG-fused animals exhibit rapid(within 2–6 weeks)and extensive locomotor recovery.Furthermore,our previous report showed that PEG-fusion of severed sciatic motor axons was non-specific,i.e.,spinal motoneurons in PEG-fused animals were found to project to appropriate as well as inappropriate target muscles.In this study,we examined the consequences of PEG-fusion for sensory axons of the sciatic nerve.Young adult male and female rats(Sprague–Dawley)received either a unilateral single cut or ablation injury to the sciatic nerve and subsequent repair with or without(Negative Control)the application of PEG.Compound action potentials recorded immediately after PEG-fusion repair confirmed conduction across the injury site.The success of PEG-fusion was confirmed through Sciatic Functional Index testing with PEG-fused animals showing improvement in locomotor function beginning at 35 days postoperatively.At 2–42 days postoperatively,we anterogradely labeled sensory afferents from the dorsal aspect of the hindpaw following bilateral intradermal injection of wheat germ agglutinin conjugated horseradish peroxidase.PEG-fusion repair reestablished axonal continuity.Compared to unoperated animals,labeled sensory afferents ipsilateral to the injury in PEG-fused animals were found in the appropriate area of the dorsal horn,as well as inappropriate mediolateral and rostrocaudal areas.Unexpectedly,despite having intact peripheral nerves,similar reorganizations of labeled sensory afferents were also observed contralateral to the injury and repair.This central reorganization may contribute to the improved behavioral recovery seen after PEG-fusion repair,supporting the use of this novel repair methodology over currently available treatments.

Clinicopathological differences between patients with schistosomal appendicitis and non schistosomal appendicitis:A retrospectively study of past ten years

BACKGROUND Chronic schistosomiasis causes multiple organ and multiple system diseases,especially the digestive system.Schistosome eggs are mainly deposited in the stomach,liver and colorectal,but a few eggs are deposited in the appendix and cause disease.At present,there are few studies on schistosomal appendicitis.AIM To explore the differences in epidemiological,clinical and pathological characteristics between schistosomal appendicitis and non-schistosomal appendicitis over the past decade in order to assess the impact of schistosomiasis on appendicitis.METHODS The differences of general data,clinical data and laboratory examination data of patients with appendicitis from October 2013 to October 2023 were retrospectively analyzed.All patients were divided into two groups for analysis.There were 136 patients in schistosomal appendicitis group and 5418 patients in non-schistosomal appendicitis group.RESULTS Schistosomal appendicitis accounted for 2.45%of all patients with appendicitis,and the annual proportion in the past decade was 2.2%,2.9%,1.8%,1.9%,3.4%,3.1%,1.9%,1.6%,3%,2.6%,respectively.The prevalence of schistosomal appendicitis was middle-aged and elderly males,with an average age of 61.73±15.335 years.The main population of non-schistosomal appendicitis was middle-aged men,with an average age of 35.8±24.013 years(P<0.001).The distribution of pathological types of appendicitis was different between the two groups(P<0.001).The incidence of acute suppurative appendicitis in non-schistosomal appendicitis was higher than that in schistosomal appendicitis[odds ratio(OR)=0.504;95%confidence interval(CI):0.349-0.728;P<0.001].The proportion of acute attack of chronic appendicitis in schistosomal appendicitis was higher than that in non-schistosomal appendicitis(OR=2.614;95%CI:1.815-3.763;P<0.001).The proportion of schistosomal appendicitis patients complicated with colorectal cancer was higher than that of nonschistosomal appendicitis patients(OR=5.087;95%CI:1.427-18.132;P=0.012).There was no difference in clinical symptoms between the two groups.In the laboratory examination,there was a significant difference in white blood cells between schistosomal appendicitis and non-schistosomal appendicitis.The level of white blood cells in schistosomal appendicitis group was slightly higher than the upper limit of the normal range.Other statistically significant indicators were in the normal range.CONCLUSION Schistosomal appendicitis is a severe condition that is often associated with intestinal malignancies,potentially leading to a poor prognosis.Schistosomal appendicitis is more likely to be misdiagnosed and missed diagnosed in clinical work because of its nonspecific clinical manifestations and laboratory examination.It is crucial to differentiate schistosomal appendicitis in middle-aged and elderly male patients presenting with appendicitis,and to ensure early detection and treatment.

Heterogeneity of mature oligodendrocytes in the central nervous system

Mature oligodendrocytes form myelin sheaths that are crucial for the insulation of axons and efficient signal transmission in the central nervous system.Recent evidence has challenged the classical view of the functionally static mature oligodendrocyte and revealed a gamut of dynamic functions such as the ability to modulate neuronal circuitry and provide metabolic support to axons.Despite the recognition of potential heterogeneity in mature oligodendrocyte function,a comprehensive summary of mature oligodendrocyte diversity is lacking.We delve into early 20th-century studies by Robertson and Río-Hortega that laid the foundation for the modern identification of regional and morphological heterogeneity in mature oligodendrocytes.Indeed,recent morphologic and functional studies call into question the long-assumed homogeneity of mature oligodendrocyte function through the identification of distinct subtypes with varying myelination preferences.Furthermore,modern molecular investigations,employing techniques such as single cell/nucleus RNA sequencing,consistently unveil at least six mature oligodendrocyte subpopulations in the human central nervous system that are highly transcriptomically diverse and vary with central nervous system region.Age and disease related mature oligodendrocyte variation denotes the impact of pathological conditions such as multiple sclerosis,Alzheimer's disease,and psychiatric disorders.Nevertheless,caution is warranted when subclassifying mature oligodendrocytes because of the simplification needed to make conclusions about cell identity from temporally confined investigations.Future studies leveraging advanced techniques like spatial transcriptomics and single-cell proteomics promise a more nuanced understanding of mature oligodendrocyte heterogeneity.Such research avenues that precisely evaluate mature oligodendrocyte heterogeneity with care to understand the mitigating influence of species,sex,central nervous system region,age,and disease,hold promise for the development of therapeutic interventions targeting varied central nervous system pathology.

Understanding the link between type 2 diabetes mellitus and Parkinson's disease:role of brain insulin resistance

Type 2 diabetes mellitus and Parkinson's disease are chronic diseases linked to a growing pandemic that affects older adults and causes significant socio-economic burden.Epidemiological data supporting a close relationship between these two aging-related diseases have resulted in the investigation of shared pathophysiological molecular mechanisms.Impaired insulin signaling in the brain has gained increasing attention during the last decade and has been suggested to contribute to the development of Parkinson's disease through the dysregulation of several pathological processes.The contribution of type 2 diabetes mellitus and insulin resistance in neurodegeneration in Parkinson's disease,with emphasis on brain insulin resistance,is extensively discussed in this article and new therapeutic strategies targeting this pathological link are presented and reviewed.

A Synergistic Multi-Attribute Decision-Making Method for Educational Institutions Evaluation Using Similarity Measures of Possibility Pythagorean Fuzzy Hypersoft Sets

Due to the numerous variables to take into account as well as the inherent ambiguity and uncertainty,evaluating educational institutions can be difficult.The concept of a possibility Pythagorean fuzzy hypersoft set(pPyFHSS)is more flexible in this regard than other theoretical fuzzy set-like models,even though some attempts have been made in the literature to address such uncertainties.This study investigates the elementary notions of pPyFHSS including its set-theoretic operations union,intersection,complement,OR-and AND-operations.Some results related to these operations are also modified for pPyFHSS.Additionally,the similarity measures between pPyFHSSs are formulated with the assistance of numerical examples and results.Lastly,an intelligent decision-assisted mechanism is developed with the proposal of a robust algorithm based on similarity measures for solving multi-attribute decision-making(MADM)problems.A case study that helps the decision-makers assess the best educational institution is discussed to validate the suggested system.The algorithmic results are compared with the most pertinent model to evaluate the adaptability of pPyFHSS,as it generalizes the classical possibility fuzzy set-like theoretical models.Similarly,while considering significant evaluating factors,the flexibility of pPyFHSS is observed through structural comparison.

Liposomes as versatile agents for the management of traumatic and nontraumatic central nervous system disorders:drug stability,targeting efficiency,and safety

Various nanoparticle-based drug delivery systems for the treatment of neurological disorders have been widely studied.However,their inability to cross the blood–brain barrier hampers the clinical translation of these therapeutic strategies.Liposomes are nanoparticles composed of lipid bilayers,which can effectively encapsulate drugs and improve drug delivery across the blood–brain barrier and into brain tissue through their targeting and permeability.Therefore,they can potentially treat traumatic and nontraumatic central nervous system diseases.In this review,we outlined the common properties and preparation methods of liposomes,including thin-film hydration,reverse-phase evaporation,solvent injection techniques,detergent removal methods,and microfluidics techniques.Afterwards,we comprehensively discussed the current applications of liposomes in central nervous system diseases,such as Alzheimer's disease,Parkinson's disease,Huntington's disease,amyotrophic lateral sclerosis,traumatic brain injury,spinal cord injury,and brain tumors.Most studies related to liposomes are still in the laboratory stage and have not yet entered clinical trials.Additionally,their application as drug delivery systems in clinical practice faces challenges such as drug stability,targeting efficiency,and safety.Therefore,we proposed development strategies related to liposomes to further promote their development in neurological disease research.

Solid Waste Management:A MADM Approach Using Fuzzy Parameterized Possibility Single-Valued Neutrosophic Hypersoft Expert Settings

The dramatic rise in the number of people living in cities has made many environmental and social problems worse.The search for a productive method for disposing of solid waste is the most notable of these problems.Many scholars have referred to it as a fuzzy multi-attribute or multi-criteria decision-making problem using various fuzzy set-like approaches because of the inclusion of criteria and anticipated ambiguity.The goal of the current study is to use an innovative methodology to address the expected uncertainties in the problem of solid waste site selection.The characteristics(or sub-attributes)that decision-makers select and the degree of approximation they accept for various options can both be indicators of these uncertainties.To tackle these problems,a novel mathematical structure known as the fuzzy parameterized possibility single valued neutrosophic hypersoft expert set(ρˆ-set),which is initially described,is integrated with a modified version of Sanchez’s method.Following this,an intelligent algorithm is suggested.The steps of the suggested algorithm are explained with an example that explains itself.The compatibility of solid waste management sites and systems is discussed,and rankings are established along with detailed justifications for their viability.This study’s strengths lie in its application of fuzzy parameterization and possibility grading to effectively handle the uncertainties embodied in the parameters’nature and alternative approximations,respectively.It uses specific mathematical formulations to compute the fuzzy parameterized degrees and possibility grades that are missing from the prior literature.It is simpler for the decisionmakers to look at each option separately because the decision is uncertain.Comparing the computed results,it is discovered that they are consistent and dependable because of their preferred properties.

Overexpression of low-density lipoprotein receptor prevents neurotoxic polarization of astrocytes via inhibiting NLRP3 inflammasome activation in experimental ischemic stroke

Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit NLR family pyrin domain containing protein 3(NLRP3)inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease.However,little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke.To address this issue in the present study,we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models.First,we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis.We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation.Second,we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus.Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype.Finally,we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin,an NLRP3 agonist,restored the neurotoxic astrocyte phenotype.These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.

Targeting capabilities of engineered extracellular vesicles for the treatment of neurological diseases

Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases.Owing to their therapeutic properties and ability to cross the blood–brain barrier,extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions,including ischemic stroke,traumatic brain injury,neurodegenerative diseases,glioma,and psychosis.However,the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body.To address these limitations,multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles,thereby enabling the delivery of therapeutic contents to specific tissues or cells.Therefore,this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles,exploring their applications in treating traumatic brain injury,ischemic stroke,Parkinson's disease,Alzheimer's disease,amyotrophic lateral sclerosis,glioma,and psychosis.Additionally,we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases.This review offers new insights for developing highly targeted therapies in this field.

Transforming growth factor-beta 1 enhances discharge activity of cortical neurons

Transforming growth factor-beta 1(TGF-β1)has been extensively studied for its pleiotropic effects on central nervous system diseases.The neuroprotective or neurotoxic effects of TGF-β1 in specific brain areas may depend on the pathological process and cell types involved.Voltage-gated sodium channels(VGSCs)are essential ion channels for the generation of action potentials in neurons,and are involved in various neuroexcitation-related diseases.However,the effects of TGF-β1 on the functional properties of VGSCs and firing properties in cortical neurons remain unclear.In this study,we investigated the effects of TGF-β1 on VGSC function and firing properties in primary cortical neurons from mice.We found that TGF-β1 increased VGSC current density in a dose-and time-dependent manner,which was attributable to the upregulation of Nav1.3 expression.Increased VGSC current density and Nav1.3 expression were significantly abolished by preincubation with inhibitors of mitogen-activated protein kinase kinase(PD98059),p38 mitogen-activated protein kinase(SB203580),and Jun NH2-terminal kinase 1/2 inhibitor(SP600125).Interestingly,TGF-β1 significantly increased the firing threshold of action potentials but did not change their firing rate in cortical neurons.These findings suggest that TGF-β1 can increase Nav1.3 expression through activation of the ERK1/2-JNK-MAPK pathway,which leads to a decrease in the firing threshold of action potentials in cortical neurons under pathological conditions.Thus,this contributes to the occurrence and progression of neuroexcitatory-related diseases of the central nervous system.

Modulation of the Nogo signaling pathway to overcome amyloid-β-mediated neurite inhibition in human pluripotent stem cell-derived neurites

Neuronal cell death and the loss of connectivity are two of the primary pathological mechanisms underlying Alzheimer's disease.The accumulation of amyloid-βpeptides,a key hallmark of Alzheimer's disease,is believed to induce neuritic abnormalities,including reduced growth,extension,and abnormal growth cone morphology,all of which contribute to decreased connectivity.However,the precise cellular and molecular mechanisms governing this response remain unknown.In this study,we used an innovative approach to demonstrate the effect of amyloid-βon neurite dynamics in both two-dimensional and three-dimensional cultu re systems,in order to provide more physiologically relevant culture geometry.We utilized various methodologies,including the addition of exogenous amyloid-βpeptides to the culture medium,growth substrate coating,and the utilization of human-induced pluripotent stem cell technology,to investigate the effect of endogenous amyloid-βsecretion on neurite outgrowth,thus paving the way for potential future applications in personalized medicine.Additionally,we also explore the involvement of the Nogo signaling cascade in amyloid-β-induced neurite inhibition.We demonstrate that inhibition of downstream ROCK and RhoA components of the Nogo signaling pathway,achieved through modulation with Y-27632(a ROCK inhibitor)and Ibuprofen(a Rho A inhibitor),respectively,can restore and even enhance neuronal connectivity in the presence of amyloid-β.In summary,this study not only presents a novel culture approach that offers insights into the biological process of neurite growth and inhibition,but also proposes a specific mechanism for reduced neural connectivity in the presence of amyloid-βpeptides,along with potential intervention points to restore neurite growth.Thereby,we aim to establish a culture system that has the potential to serve as an assay for measuring preclinical,predictive outcomes of drugs and their ability to promote neurite outgrowth,both generally and in a patient-specific manner.

Chondroitinase ABC combined with Schwann cell transplantation enhances restoration of neural connection and functional recovery following acute and chronic spinal cord injury

Schwann cell transplantation is considered one of the most promising cell-based therapy to repair injured spinal cord due to its unique growth-promoting and myelin-forming properties.A the Food and Drug Administration-approved Phase I clinical trial has been conducted to evaluate the safety of transplanted human autologous Schwann cells to treat patients with spinal cord injury.A major challenge for Schwann cell transplantation is that grafted Schwann cells are confined within the lesion cavity,and they do not migrate into the host environment due to the inhibitory barrier formed by injury-induced glial scar,thus limiting axonal reentry into the host spinal cord.Here we introduce a combinatorial strategy by suppressing the inhibitory extracellular environment with injection of lentivirus-mediated transfection of chondroitinase ABC gene at the rostral and caudal borders of the lesion site and simultaneously leveraging the repair capacity of transplanted Schwann cells in adult rats following a mid-thoracic contusive spinal cord injury.We report that when the glial scar was degraded by chondroitinase ABC at the rostral and caudal lesion borders,Schwann cells migrated for considerable distances in both rostral and caudal directions.Such Schwann cell migration led to enhanced axonal regrowth,including the serotonergic and dopaminergic axons originating from supraspinal regions,and promoted recovery of locomotor and urinary bladder functions.Importantly,the Schwann cell survival and axonal regrowth persisted up to 6 months after the injury,even when treatment was delayed for 3 months to mimic chronic spinal cord injury.These findings collectively show promising evidence for a combinatorial strategy with chondroitinase ABC and Schwann cells in promoting remodeling and recovery of function following spinal cord injury.

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.

Silk-based nerve guidance conduits with macroscopic holes modulate the vascularization of regenerating rat sciatic nerve

Peripheral nerve injuries induce a severe motor and sensory deficit. Since the availability of autologous nerve transplants for nerve repair is very limited, alternative treatment strategies are sought, including the use of tubular nerve guidance conduits(tNGCs). However, the use of tNGCs results in poor functional recovery and central necrosis of the regenerating tissue, which limits their application to short nerve lesion defects(typically shorter than 3 cm). Given the importance of vascularization in nerve regeneration, we hypothesized that enabling the growth of blood vessels from the surrounding tissue into the regenerating nerve within the tNGC would help eliminate necrotic processes and lead to improved regeneration. In this study, we reported the application of macroscopic holes into the tubular walls of silk-based tNGCs and compared the various features of these improved silk^(+) tNGCs with the tubes without holes(silk^(–) tNGCs) and autologous nerve transplants in an 8-mm sciatic nerve defect in rats. Using a combination of micro-computed tomography and histological analyses, we were able to prove that the use of silk^(+) tNGCs induced the growth of blood vessels from the adjacent tissue to the intraluminal neovascular formation. A significantly higher number of blood vessels in the silk^(+) group was found compared with autologous nerve transplants and silk^(–), accompanied by improved axon regeneration at the distal coaptation point compared with the silk^(–) tNGCs at 7 weeks postoperatively. In the 15-mm(critical size) sciatic nerve defect model, we again observed a distinct ingrowth of blood vessels through the tubular walls of silk^(+) tNGCs, but without improved functional recovery at 12 weeks postoperatively. Our data proves that macroporous tNGCs increase the vascular supply of regenerating nerves and facilitate improved axonal regeneration in a short-defect model but not in a critical-size defect model. This study suggests that further optimization of the macroscopic holes silk^(+) tNGC approach containing macroscopic holes might result in improved grafting technology suitable for future clinical use.

Impact of Pollutant Concentration and Particle Deposition on the Radiative Flow of Casson-Micropolar Fluid between Parallel Plates

Assessing the behaviour and concentration of waste pollutants deposited between two parallel plates is essential for effective environmental management.Determining the effectiveness of treatment methods in reducing pollution scales is made easier by analysing waste discharge concentrations.The waste discharge concentration analysis is useful for assessing how effectively wastewater treatment techniques reduce pollution levels.This study aims to explore the Casson micropolar fluid flow through two parallel plates with the influence of pollutant concentration and thermophoretic particle deposition.To explore the mass and heat transport features,thermophoretic particle deposition and thermal radiation are considered.The governing equations are transformed into ordinary differential equations with the help of suitable similarity transformations.The Runge-Kutta-Fehlberg’s fourthfifth order technique and shooting procedure are used to solve the reduced set of equations and boundary conditions.The integration of a neural network model based on the Levenberg-Marquardt algorithm serves to improve the accuracy of predictions and optimize the analysis of parameters.Graphical outcomes are displayed to analyze the characteristics of the relevant dimensionless parameters in the current problem.Results reveal that concentration upsurges as the micropolar parameter increases.The concentration reduces with an upsurge in the thermophoretic parameter.An upsurge in the external pollutant source variation and the local pollutant external source parameters enhances mass transport.The surface drag force declines for improved values of porosity and micropolar parameters.

Clinical effects of phospholipase D2 in attenuating acute pancreatitis

BACKGROUND The objective of the current study was to elucidate the clinical mechanism through which phospholipase D2(PLD2)exerted a regulatory effect on neutrophil migra-tion,thereby alleviating the progression of acute pancreatitis.AIM To elucidate the clinical mechanism through which PLD2 exerted a regulatory effect on neutrophil migration,thereby alleviating the progression of acute pan-creatitis.METHODS The study involved 90 patients diagnosed with acute pancreatitis,admitted to our hospital between March 2020 and November 2022.A retrospective analysis was conducted,categorizing patients based on Ranson score severity into mild(n=25),moderate(n=30),and severe(n=35)groups.Relevant data was collected for each group.Western blot analysis assessed PLD2 protein expression in patient serum.Real-time reverse transcription polymerase chain reaction was used to evaluate the mRNA expression of chemokine receptors associated with neutrophil migration.Serum levels of inflammatory factors in patients were detected using enzyme-linked immunosorbent assay.Transwell migration tests were conducted to compare migration of neutrophils across groups and analyze the influence of PLD2 on neutrophil migration.RESULTS Overall data analysis did not find significant differences between patient groups(P>0.05).The expression of PLD2 protein in the severe group was lower than that in the moderate and mild groups(P<0.05).The expression level of PLD2 in the moderate group was also lower than that in the mild group(P<0.05).The severity of acute pancreatitis is negatively correlated with PLD2 expression(r=-0.75,P=0.002).The mRNA levels of C-X-C chemokine receptor type 1,C-X-C chemokine receptor type 2,C-C chemokine receptor type 2,and C-C chemokine receptor type 5 in the severe group are significantly higher than those in the moderate and mild groups(P<0.05),and the expression levels in the moderate group are also higher than those in the mild group(P<0.05).The levels of C-reactive protein,tumor necrosis factor-α,interleukin-1β,and interleukin-6 in the severe group were higher than those in the moderate and mild groups(P<0.05),and the levels in the moderate group were also higher than those in the mild group(P<0.05).The number of migrating neutrophils in the severe group was higher than that in the moderate and mild groups(P<0.05),and the moderate group was also higher than the mild group(P<0.05).In addition,the number of migrating neutrophils in the mild group combined with PLD2 inhibitor was higher than that in the mild group(P<0.05),and the number of migrating neutrophils in the moderate group combined with PLD2 inhibitor was higher than that in the moderate group(P<0.05).The number of migrating neutrophils in the severe group+PLD2 inhibitor group was significantly higher than that in the severe group(P<0.05),indicating that PLD2 inhibitors significantly stimulated neutrophil migration.CONCLUSION PLD2 exerted a crucial regulatory role in the pathological progression of acute pancreatitis.Its protein expression varied among patients based on the severity of the disease,and a negative correlation existed between PLD2 expression and disease severity.Additionally,PLD2 appeared to impede acute pancreatitis progression by limiting neutrophil migration.

Utilizing engineered extracellular vesicles as delivery vectors in the management of ischemic stroke:a special outlook on mitochondrial delivery

Ischemic stroke is a secondary cause of mortality worldwide,imposing considerable medical and economic burdens on society.Extracellular vesicles,serving as natural nanocarriers for drug delivery,exhibit excellent biocompatibility in vivo and have significant advantages in the management of ischemic stroke.However,the uncertain distribution and rapid clearance of extracellular vesicles impede their delivery efficiency.By utilizing membrane decoration or by encapsulating therapeutic cargo within extracellular vesicles,their delivery efficacy may be greatly improved.Furthermore,previous studies have indicated that microvesicles,a subset of large-sized extracellular vesicles,can transport mitochondria to neighboring cells,thereby aiding in the restoration of mitochondrial function post-ischemic stroke.Small extracellular vesicles have also demonstrated the capability to transfer mitochondrial components,such as proteins or deoxyribonucleic acid,or their sub-components,for extracellular vesicle-based ischemic stroke therapy.In this review,we undertake a comparative analysis of the isolation techniques employed for extracellular vesicles and present an overview of the current dominant extracellular vesicle modification methodologies.Given the complex facets of treating ischemic stroke,we also delineate various extracellular vesicle modification approaches which are suited to different facets of the treatment process.Moreover,given the burgeoning interest in mitochondrial delivery,we delved into the feasibility and existing research findings on the transportation of mitochondrial fractions or intact mitochondria through small extracellular vesicles and microvesicles to offer a fresh perspective on ischemic stroke therapy.

Inhibition of the NLRP3 inflammasome attenuates spiral ganglion neuron degeneration in aminoglycoside-induced hearing loss

Aminoglycosides are a widely used class of antibacterials renowned for their effectiveness and broad antimicrobial spectrum.However,their use leads to irreversible hearing damage by causing apoptosis of hair cells as their direct target.In addition,the hearing damage caused by aminoglycosides involves damage of spiral ganglion neurons upon exposure.To investigate the mechanisms underlying spiral ganglion neuron degeneration induced by aminoglycosides,we used a C57BL/6J mouse model treated with kanamycin.We found that the mice exhibited auditory deficits following the acute loss of outer hair cells.Spiral ganglion neurons displayed hallmarks of pyroptosis and exhibited progressive degeneration over time.Transcriptomic profiling of these neurons showed significant upregulation of genes associated with inflammation and immune response,particularly those related to the NLRP3 inflammasome.Activation of the canonical pyroptotic pathway in spiral ganglion neurons was observed,accompanied by infiltration of macrophages and the release of proinflammatory cytokines.Pharmacological intervention targeting NLRP3 using Mcc950 and genetic intervention using NLRP3 knockout ameliorated spiral ganglion neuron degeneration in the injury model.These findings suggest that NLRP3 inflammasome-mediated pyroptosis plays a role in aminoglycoside-induced spiral ganglion neuron degeneration.Inhibition of this pathway may offer a potential therapeutic strategy for treating sensorineural hearing loss by reducing spiral ganglion neuron degeneration.

Imaging characteristics of hypervascular focal nodular hyperplasialike lesions in patients with chronic alcoholic liver disease

BACKGROUND Focal nodular hyperplasia(FNH)-like lesions are hyperplastic formations in patients with micronodular cirrhosis and a history of alcohol abuse.Although pathologically similar to hepatocellular carcinoma(HCC)lesions,they are benign.As such,it is important to develop methods to distinguish between FNH-like lesions and HCC.AIM To evaluate diagnostically differential radiological findings between FNH-like lesions and HCC.METHODS We studied pathologically confirmed FNH-like lesions in 13 patients with alco-holic cirrhosis[10 men and 3 women;mean age:54.5±12.5(33-72)years]who were negative for hepatitis-B surface antigen and hepatitis-C virus antibody and underwent dynamic computed tomography(CT)and magnetic resonance imaging(MRI),including superparamagnetic iron oxide(SPIO)and/or gadoxetic acid-enhanced MRI.Seven patients also underwent angiography-assisted CT.RESULTS The evaluated lesion features included arterial enhancement pattern,washout appearance(low density compared with that of surrounding liver parenchyma),signal intensity on T1-weighted image(T1WI)and T2-weighted image(T2WI),central scar presence,chemical shift on in-and out-of-phase images,and uptake pattern on gadoxetic acid-enhanced MRI hepatobiliary phase and SPIO-enhanced MRI.Eleven patients had multiple small lesions(<1.5 cm).Radiological features of FNH-like lesions included hypervascularity despite small lesions,lack of“corona-like”enhancement in the late phase on CT during hepatic angiography(CTHA),high-intensity on T1WI,slightly high-or iso-intensity on T2WI,no signal decrease in out-of-phase images,and complete SPIO uptake or incomplete/partial uptake of gadoxetic acid.Pathologically,similar to HCC,FNH-like lesions showed many unpaired arteries and sinusoidal capillarization.CONCLUSION Overall,the present study showed that FNH-like lesions have unique radiological findings useful for differential diagnosis.Specifically,SPIO-and/or gadoxetic acid-enhanced MRI and CTHA features might facilitate differential diagnosis of FNH-like lesions and HCC.

Global Piecewise Analysis of HIV Model with Bi-Infectious Categories under Ordinary Derivative and Non-Singular Operator with Neural Network Approach

This study directs the discussion of HIV disease with a novel kind of complex dynamical generalized and piecewise operator in the sense of classical and Atangana Baleanu(AB)derivatives having arbitrary order.The HIV infection model has a susceptible class,a recovered class,along with a case of infection divided into three sub-different levels or categories and the recovered class.The total time interval is converted into two,which are further investigated for ordinary and fractional order operators of the AB derivative,respectively.The proposed model is tested separately for unique solutions and existence on bi intervals.The numerical solution of the proposed model is treated by the piece-wise numerical iterative scheme of Newtons Polynomial.The proposed method is established for piece-wise derivatives under natural order and non-singular Mittag-Leffler Law.The cross-over or bending characteristics in the dynamical system of HIV are easily examined by the aspect of this research having a memory effect for controlling the said disease.This study uses the neural network(NN)technique to obtain a better set of weights with low residual errors,and the epochs number is considered 1000.The obtained figures represent the approximate solution and absolute error which are tested with NN to train the data accurately.