Over a century ago,the first clinical and neuropathological insights into major neurodegenerative diseases began to emerge:the description of Alzheimer’s disease(AD)by Alois Alzheimer in 1906,frontotemporal dementia ...Over a century ago,the first clinical and neuropathological insights into major neurodegenerative diseases began to emerge:the description of Alzheimer’s disease(AD)by Alois Alzheimer in 1906,frontotemporal dementia by Arnold Pick in the same years,and Lewy bodies by Friedrich Lewy in 1912.These foundational studies laid the groundwork for the classification of what we now recognize as distinct neurodegenerative entities(Allali,2024).展开更多
BCL2-associated anthanogene 3 facilitates the clearance of tau protein aggregates:BCL2-associated anthanogene 3(BAG3)is a ubiquitously expressed and highly conserved multi-functional co-chaperone protein involved in m...BCL2-associated anthanogene 3 facilitates the clearance of tau protein aggregates:BCL2-associated anthanogene 3(BAG3)is a ubiquitously expressed and highly conserved multi-functional co-chaperone protein involved in many biological processes that supports cellular homeostasis,including the inhibition of apoptosis by preventing mitochondrial BAX localization(Lin et al.,2022)and the promotion of the degradation of hyperphosphorylated tau aggregates by its interactions with SQSTM1(p62)(Hamano and Mutoh,2022).展开更多
Calcium (Ca^(2+)) is a key intracellular messenger involved in a variety of cellular functions.Intracellular Ca^(2+)dysregulation drives neuron cell death in multiple degenerative diseases and traumatic conditions.Ret...Calcium (Ca^(2+)) is a key intracellular messenger involved in a variety of cellular functions.Intracellular Ca^(2+)dysregulation drives neuron cell death in multiple degenerative diseases and traumatic conditions.Retinal ganglion cell(RGC) degeneration occurs in blinding diseases such as glaucoma and other optic neuropathies.展开更多
Moringa oleifera(MO)is traditionally used to mitigate inflammatory-mediated disorders;however,the influence of ecotypic variation on its anti-inflammatory activity remains poorly understood.In this study,we compared t...Moringa oleifera(MO)is traditionally used to mitigate inflammatory-mediated disorders;however,the influence of ecotypic variation on its anti-inflammatory activity remains poorly understood.In this study,we compared the phytochemical composition and anti-inflammatory activity of ethanolic extracts obtained from fresh and dried leaves of four MO ecotypes(India,Paraguay,Mozambique,and Pakistan),all grown under the same outdoor conditions,as well as two commercial powders(Just Moringa and WISSA),using LPS-stimulated RAW 264.7 macrophages.Extracts from fresh leaves were 19-43%more cytotoxic than those from dried leaves,depending on the ecotype,likely due to higher cyanogenic glycoside content.Extracts from the India and Paraguay ecotypes,characterized by high levels of quercetin derivatives and caffeic acids,as well as Just Moringa,enriched in kaempferol derivatives,significantly inhibited LPS-induced nitric oxide(NO)production(p<0.05).Just Moringa and Paraguay extracts also reduced iNOS gene expression(p<0.05 and p<0.01,respectively),whereas only the Paraguay extract decreased iNOS protein levels(p<0.05).In contrast,quercetin-3-O-glucoside and rutin showed significant effects only at concentrations approximately 100-fold higher than those present in the extracts,indicating that the phytocomplex displays greater bioactivity than individual compounds.Overall,these results demonstrate that ecotypic variation strongly affects the polyphenolic composition and anti-inflammatory properties of MO leaves,highlighting the importance of reporting both origin and phytochemical composition in MO-based products.展开更多
The adult subventricular zone of the lateral ventricles and the subgranular zone in the hippocampal dentate gyrus(DG)are the two brain regions where neurogenesis occurs throughout life in the adult mammalian brain(Min...The adult subventricular zone of the lateral ventricles and the subgranular zone in the hippocampal dentate gyrus(DG)are the two brain regions where neurogenesis occurs throughout life in the adult mammalian brain(Ming and Song,2011).Adult quiescent hippocampal neural stem cells(NSCs)are bona fide stem cells and,when activated,give rise to newborn granule neurons in the adult brain,which play vital roles in learning,memory,mood,and affective cognition(Bonaguidi et al.,2011;Ming and Song,2011).展开更多
Spinal cord injury necessitates effective rehabilitation strategies, with exercise therapies showing promise in promoting recovery. This study investigated the impact of rehabilitation exercise on functional recovery ...Spinal cord injury necessitates effective rehabilitation strategies, with exercise therapies showing promise in promoting recovery. This study investigated the impact of rehabilitation exercise on functional recovery and morphological changes following thoracic contusive spinal cord injury. After a 7-day recovery period after spinal cord injury, mice were assigned to either a trained group(10 weeks of voluntary running wheel or forced treadmill exercise) or an untrained group. Bi-weekly assessments revealed that the exercise-trained group, particularly the voluntary wheel exercise subgroup, displayed significantly improved locomotor recovery, more plasticity of dopaminergic and serotonin modulation compared with the untrained group. Additionally, exercise interventions led to gait pattern restoration and enhanced transcranial magnetic motor-evoked potentials. Despite consistent injury areas across groups, exercise training promoted terminal innervation of descending axons. In summary, voluntary wheel exercise shows promise for enhancing outcomes after thoracic contusive spinal cord injury, emphasizing the role of exercise modality in promoting recovery and morphological changes in spinal cord injuries. Our findings will influence future strategies for rehabilitation exercises, restoring functional movement after spinal cord injury.展开更多
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 g...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.展开更多
Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease.Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease.Exercise stimulates adult hippocampal neurogenesis in rode...Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease.Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease.Exercise stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer’s disease.However,the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer’s disease are poorly understood.Recently,regulator of G protein signaling 6(RGS6)was identified as the mediator of voluntary running-induced adult hippocampal neurogenesis in mice.Here,we generated novel RGS6fl/fl;APP_(SWE) mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running-induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer’s disease mouse model.We found that voluntary running in APP_(SWE) mice restored their hippocampal cognitive impairments to that of control mice.This cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells,which also abolished running-mediated increases in adult hippocampal neurogenesis.Adult hippocampal neurogenesis was reduced in sedentary APP_(SWE) mice versus control mice,with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor cells.RGS6 was expressed in neurons within the dentate gyrus of patients with Alzheimer’s disease with significant loss of these RGS6-expressing neurons.Thus,RGS6 mediated voluntary running-induced rescue of impaired cognition and adult hippocampal neurogenesis in APP_(SWE) mice,identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer’s disease.展开更多
The involvement of the excitatory amino acids glutamate and aspartate in ce rebral ischemia and excitotoxicity is well-documented.Nevertheless,the role of non-excitatory amino acids in brain damage following a stroke ...The involvement of the excitatory amino acids glutamate and aspartate in ce rebral ischemia and excitotoxicity is well-documented.Nevertheless,the role of non-excitatory amino acids in brain damage following a stroke or brain trauma remains largely understudied.The release of amino acids by necrotic cells in the ischemic core may contribute to the expansion of the penumbra.Our findings indicated that the reversible loss of field excitato ry postsynaptic potentials caused by transient hypoxia became irreversible when exposed to a mixture of just four non-excitatory amino acids(L-alanine,glycine,L-glutamine,and L-serine)at their plasma concentrations.These amino acids induce swelling in the somas of neurons and astrocytes during hypoxia,along with permanent dendritic damage mediated by N-methyl-D-aspartate receptors.Blocking N-methyl-D-aspartate receptors prevented neuronal damage in the presence of these amino acids during hypoxia.It is likely that astroglial swelling caused by the accumulation of these amino acids via the alanine-serine-cysteine transporter 2 exchanger and system N transporters activates volume-regulated anion channels,leading to the release of excitotoxins and subsequent neuronal damage through N-methyl-D-aspartate receptor activation.Thus,previously unrecognized mechanisms involving non-excitatory amino acids may contribute to the progression and expansion of brain injury in neurological emergencies such as stroke and traumatic brain injury.Understanding these pathways co uld highlight new therapeutic targets to mitigate brain injury.展开更多
Depressive disorder is a chronic,recurring,and potentially life-endangering neuropsychiatric disease.According to a report by the World Health Organization,the global population suffering from depression is experienci...Depressive disorder is a chronic,recurring,and potentially life-endangering neuropsychiatric disease.According to a report by the World Health Organization,the global population suffering from depression is experiencing a significant annual increase.Despite its prevalence and considerable impact on people,little is known about its pathogenesis.One major reason is the scarcity of reliable animal models due to the absence of consensus on the pathology and etiology of depression.Furthermore,the neural circuit mechanism of depression induced by various factors is particularly complex.Considering the variability in depressive behavior patterns and neurobiological mechanisms among different animal models of depression,a comparison between the neural circuits of depression induced by various factors is essential for its treatment.In this review,we mainly summarize the most widely used behavioral animal models and neural circuits under different triggers of depression,aiming to provide a theoretical basis for depression prevention.展开更多
Successful polyethylene glycol fusion(PEG-fusion)of severed axons following peripheral nerve injuries for PEG-fused axons has been reported to:(1)rapidly restore electrophysiological continuity;(2)prevent distal Walle...Successful polyethylene glycol fusion(PEG-fusion)of severed axons following peripheral nerve injuries for PEG-fused axons has been reported to:(1)rapidly restore electrophysiological continuity;(2)prevent distal Wallerian Degeneration and maintain their myelin sheaths;(3)promote primarily motor,voluntary behavioral recoveries as assessed by the Sciatic Functional Index;and,(4)rapidly produce correct and incorrect connections in many possible combinations that produce rapid and extensive recovery of functional peripheral nervous system/central nervous system connections and reflex(e.g.,toe twitch)or voluntary behaviors.The preceding companion paper describes sensory terminal field reo rganization following PEG-fusion repair of sciatic nerve transections or ablations;howeve r,sensory behavioral recovery has not been explicitly explored following PEG-fusion repair.In the current study,we confirmed the success of PEG-fusion surgeries according to criteria(1-3)above and more extensively investigated whether PEG-fusion enhanced mechanical nociceptive recovery following sciatic transection in male and female outbred Sprague-Dawley and inbred Lewis rats.Mechanical nociceptive responses were assessed by measuring withdrawal thresholds using von Frey filaments on the dorsal and midplantar regions of the hindpaws.Dorsal von Frey filament tests were a more reliable method than plantar von Frey filament tests to assess mechanical nociceptive sensitivity following sciatic nerve transections.Baseline withdrawal thresholds of the sciatic-mediated lateral dorsal region differed significantly across strain but not sex.Withdrawal thresholds did not change significantly from baseline in chronic Unoperated and Sham-operated rats.Following sciatic transection,all rats exhibited severe hyposensitivity to stimuli at the lateral dorsal region of the hindpaw ipsilateral to the injury.However,PEG-fused rats exhibited significantly earlier return to baseline withdrawal thresholds than Negative Control rats.Furthermore,PEG-fused rats with significantly improved Sciatic Functional Index scores at or after 4 weeks postoperatively exhibited yet-earlier von Frey filament recove ry compared with those without Sciatic Functional Index recovery,suggesting a correlation between successful PEG-fusion and both motor-dominant and sensory-dominant behavioral recoveries.This correlation was independent of the sex or strain of the rat.Furthermore,our data showed that the acceleration of von Frey filament sensory recovery to baseline was solely due to the PEG-fused sciatic nerve and not saphenous nerve collateral outgrowths.No chronic hypersensitivity developed in any rat up to 12 weeks.All these data suggest that PEG-fusion repair of transection peripheral nerve injuries co uld have important clinical benefits.展开更多
PrPSc,a misfolded,aggregation-prone isoform of the cellular prion protein(PrPC),is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals.PrPSccan adopt different patho...PrPSc,a misfolded,aggregation-prone isoform of the cellular prion protein(PrPC),is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals.PrPSccan adopt different pathogenic conformations(prion strains),which can be resistant to potential drugs,or acquire drug resistance,posing challenges for the development of effective therapies.Since PrPCis the obligate precursor of any prion strain and serves as the mediator of prion neurotoxicity,it represents an attractive therapeutic target fo r prion diseases.In this minireview,we briefly outline the approaches to target PrPCand discuss our recent identification of Zn(Ⅱ)-Bn PyP,a PrPC-targeting porphyrin with an unprecedented bimodal mechanism of action.We argue that in-depth understanding of the molecular mechanism by which Zn(Ⅱ)-Bn PyP targets PrPCmay lead toward the development of a new class of dual mechanism anti-prion compounds.展开更多
Astrocytes,the main population of glial cells in the central nervous system(CNS),exert essential tasks for the control of brain tissue homeostasis,supporting neuron and other glial cell activity from the developmental...Astrocytes,the main population of glial cells in the central nervous system(CNS),exert essential tasks for the control of brain tissue homeostasis,supporting neuron and other glial cell activity from the developmental stage to adult life.To maintain the optimal functionality of the brain,astroglial cells are particularly committed to reacting to every change in tissue homeostatic conditions,from mild modifications of the physiological environment,a process called astrocyte activation,to the more severe alterations occurring in pathological situations causing astrocyte reactivity or reactive astrogliosis(Escartin et al.,2021).During these reactive states,astrocytes mount an active,progressive response encompassing morphological,molecular,and interactional remodeling,leading to the acquisition of new functions and the loss of others,whose intensity,duration,and reversibility are dependent on the nature of the stimulus and regulated in a context-specific manner.展开更多
1Early history In1963the Howard Florey Laboratories were first established as a component of the Department of Physiology at the University of Melbourne.The laboratories quickly expanded under the founding directorshi...1Early history In1963the Howard Florey Laboratories were first established as a component of the Department of Physiology at the University of Melbourne.The laboratories quickly expanded under the founding directorship of Dr.Derek Denton and the funds were obtained with the philanthropic assistance of Sir Ian Potter and Mr.Ken Myer to create a new building on the south-west corner University site.This enabled the building to be opened in August1963.The Nobel laureate,Sir Howard Florey,well-known discoverer of the technique to mass-produce penicillin was pleased to lend his name to the new initiative,and was present at its opening with the Prime Minister,Sir Robert Menzies,and other dignitaries.展开更多
Schizophrenia is a multifaceted neurodevelopmental disorder characterized by hallucinations,delusions,cognitive deficits,and emotional dysregulation.The prefrontal cortex(PFC),essential for executive functions,working...Schizophrenia is a multifaceted neurodevelopmental disorder characterized by hallucinations,delusions,cognitive deficits,and emotional dysregulation.The prefrontal cortex(PFC),essential for executive functions,working memory,and emotional regulation,is notably impaired in this condition.This review consolidates current insights into the role of PFC dysfunction in schizophrenia,with a focus on its implications for therapeutic strategies.The neuroanatomical and neurobiological foundations of PFC dysfunction are explored,emphasizing structural abnormalities,functional dysconnectivity,and microcircuit disruptions that contribute to cognitive deficits and impaired decision-making.Clinical implications are discussed,particularly the correlation between PFC dysfunction and the severity and progression of schizophrenia symptoms.Additionally,pharmacological and non-pharmacological approaches aimed at modulating PFC activity are reviewed as potential therapeutic options.In conclusion,a deeper understanding of PFC dysfunction is pivotal for developing targeted treatments,and ongoing research offers promising avenues for enhancing outcomes for individuals affected by this debilitating disorder.展开更多
Background: Neurodevelopmental abnormalities in experimental fetal alcohol spectrum disorder (FASD) are associated with impaired signaling through complex pathways that mediate neuronal survival, growth, migration, en...Background: Neurodevelopmental abnormalities in experimental fetal alcohol spectrum disorder (FASD) are associated with impaired signaling through complex pathways that mediate neuronal survival, growth, migration, energy metabolism, and plasticity. Gestational dietary soy prevents alcohol-related impairments in placentation and FASD-associated fetal anomalies. Objective: This study was designed to determine if gestational dietary soy would be sufficient to normalize cognitive function in young adolescent offspring after chronic in utero exposure to alcohol. In addition, efforts were made to characterize the mechanisms of FASD prevention by maternal dietary soy. Methods: Pregnant Long Evans rats were fed isocaloric liquid diets containing 0% or 26% caloric ethanol with casein or soy isolate as the protein source from gestation day 6 through delivery/postnatal day 0 (P0). From P24 - P28, the offspring were subjected to Morris water maze (MWM) testing, and on P35, they were sacrificed to harvest temporal lobes for histopathologic and molecular studies. Results: The in-utero ethanol-exposed offspring exhibited significant performance impairments on the MWM test, and they had a significantly reduced mean brain weight with neuronal loss in the CA1 hippocampal region and evidence of white matter myelin loss. Gestational dietary soy nearly normalized MWM performance and preserved brain weight, hippocampal CA1 architecture, and white matter myelin staining in alcohol-exposed offspring. Mechanistically, the main positive effects of soy included increased temporal lobe expression of HES-1 and HIF-1α, reflecting enhanced Notch signaling, and broadly increased expression of GnRH network molecules, including Erb1, Gper1, GnRH, GnRH-R, KiSS, and KiSS-R, irrespective of gestational ethanol exposure. Conclusions: Dietary soy intervention early in pregnancy may reduce FASD-associated cognitive deficits. The findings suggest that targeting Notch and GnRH-related networks may help reduce long-term disability with FASD. Additional mechanistic and experimental research is needed to determine if longer-duration, postnatal dietary soy could prevent the adverse neurobehavioral effects of FASD.展开更多
Current treatments for glioblastoma face challenges such as the blood-brain barrier and lack of targeted therapy,compounded by the aggressive nature,high invasiveness,and heterogeneity of the disease.Exosomes,a subtyp...Current treatments for glioblastoma face challenges such as the blood-brain barrier and lack of targeted therapy,compounded by the aggressive nature,high invasiveness,and heterogeneity of the disease.Exosomes,a subtype of extracellular vesicles are emerging as promising nanocarrier drug delivery systems to address these limitations.Exosomes released by all cell types can be easily obtained and modified as delivery vehicles or therapeutic agents.A systematic review was conducted to evaluate various methods for exosome isolation,characterization,engineering or modification,drug loading and delivery efficiency,including exosome biodistribution and treatment efficacy.A search of four databases for in vitro and in vivo studies(2000–,2023)identified 6165 records,of which 23 articles were found eligible and included for analyses.Most studies applied ultracentrifugation(UC)for exosomes isolation.Cancer cell lines being the most frequently used source of exosomes,followed by stem cells.The incubation approach was predominantly utilized to modify exosomes for drug loading.In vivo analysis showed that exosome biodistribution was primarily concentrated in the brain region,peaking in the first 6 h and remained moderately high.Compared to native exosomes and untreated control groups,utilizing modified native exosomes(cargo loaded)for treating glioblastoma disease models led to more pronounced suppression of tumor growth and proliferation,enhanced stimulation of immune response and apoptosis,effective restoration of drug chemosensitivity,increased anti-tumor effect and prolonged survival rates.Modified exosomes whether through incubation,sonication,transfection,freeze-thawing or their combination,improve targeted delivery and therapeutic efficacy against glioblastoma.展开更多
Rapid and sensitive detection of targeted biomarkers in trace samples is of great significance for early in vitro diagnosis of diseases.Microfluidic technology has competitive advantages in this field due to its low c...Rapid and sensitive detection of targeted biomarkers in trace samples is of great significance for early in vitro diagnosis of diseases.Microfluidic technology has competitive advantages in this field due to its low cost,high efficiency,and high portability;however,the analysis of results tends to rely on bulky and sophisticated instruments,and this limits its applications.In this work,we developed a Raspberry Pi camera-based biomarker detection device based on microfluidic technology and digital image colorimetry.For highly sensitive biomarker detection on microfluidic chips,we propose a three-step signal-amplification colorimetric detection strategy consisting of:(1)the release of Ag^(+)ions from silver nanoparticles,(2)Ag^(+)-inhibited urea hydrolysis colorimetry,and(3)microscopic lens magnification.For efficient evaluation of results,we employed an RGB image-processing system to quantitatively analyze color images captured by the Raspberry Pi camera.Further,we tested the functionality of the device with procalcitonin(PCT)in phosphate-buffered saline,plasma,and serum to simulate clinical situations.We determined the limit of detection as 1 ng/ml,and a good linear relationship was established between PCT concentration and color intensity within the detection range 1–10 ng/ml.Importantly,only a relatively short detection time(40 min)was required in all three environments.The results demonstrate the great potential of this device for biomarker detection and facilitating biomedical research.展开更多
The presence of the blood–brain barrier limits the drug concentration in the brain,while low concentrations of antibiotics make it difficult to kill infecting bacteria and tends to induce drug resistance,making the c...The presence of the blood–brain barrier limits the drug concentration in the brain,while low concentrations of antibiotics make it difficult to kill infecting bacteria and tends to induce drug resistance,making the clinical treatment of bacterial meningitis challenging.Herein,a nose-to-brain delivery strategy of small-sized nanozyme has been fabricated for combating bacterial meningitis,to overcome the low drug concentration and drug resistance.This strategy was achieved by a proteinsupported Au nanozyme(ANZ).With a particle size of less than 10 nm,it possesses both glucose oxidase-like and peroxidase-like activities and can generate large amounts of reactive oxygen species through a cascade effect without the addition of external H_(2)O_(2).Benefiting from the cascade catalytic amplification effect generated by its dual enzymelike activities,ANZ shows significant broad-spectrum antibacterial activity without inducing bacterial resistance in vitro.Notably,small-sized ANZ exhibits higher brain entry efficiency and greater accumulation after intranasal administration compared to oral or intravenous administration.In a mouse model of bacterial meningitis,the mice treated with ANZ had lower bacterial loads in the brain and higher survival and clinical behavior scores compared to the classical antibiotic ceftriaxone.Additionally,the meningitis mice exhibited undamaged cognitive and behavioral abilities,indicating the excellent biocompatibility of ANZ.The above results demonstrate that nose-to-brain delivery of ANZ exhibits high intracerebral accumulation,strong antibacterial efficacy and does not lead to bacterial resistance.It holds broad prospects for the treatment of bacterial meningitis.展开更多
Alzheimer's disease (AD) is the most common form of dementia,affecting millions worldwide.It is cha racterized by progressive cognitive decline and changes in behavior and personality,attributed to neuropathologic...Alzheimer's disease (AD) is the most common form of dementia,affecting millions worldwide.It is cha racterized by progressive cognitive decline and changes in behavior and personality,attributed to neuropathological changes,such as amyloid-beta (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein.展开更多
文摘Over a century ago,the first clinical and neuropathological insights into major neurodegenerative diseases began to emerge:the description of Alzheimer’s disease(AD)by Alois Alzheimer in 1906,frontotemporal dementia by Arnold Pick in the same years,and Lewy bodies by Friedrich Lewy in 1912.These foundational studies laid the groundwork for the classification of what we now recognize as distinct neurodegenerative entities(Allali,2024).
基金supported by the award W81XWH1910309 (to HF) from the Department of Defensethe award R01-AG075092-01 (to HF)+2 种基金the award RF1AG063521 from the National Institute of Aging at the National Institutes of Healththe Neurological Research Institute Seed grant (to HF) from The Ohio State Universitythe Summer Undergraduate Research Fellowship (to NS) from The Ohio State University Chronic Brain Injury Discovery Theme
文摘BCL2-associated anthanogene 3 facilitates the clearance of tau protein aggregates:BCL2-associated anthanogene 3(BAG3)is a ubiquitously expressed and highly conserved multi-functional co-chaperone protein involved in many biological processes that supports cellular homeostasis,including the inhibition of apoptosis by preventing mitochondrial BAX localization(Lin et al.,2022)and the promotion of the degradation of hyperphosphorylated tau aggregates by its interactions with SQSTM1(p62)(Hamano and Mutoh,2022).
文摘Calcium (Ca^(2+)) is a key intracellular messenger involved in a variety of cellular functions.Intracellular Ca^(2+)dysregulation drives neuron cell death in multiple degenerative diseases and traumatic conditions.Retinal ganglion cell(RGC) degeneration occurs in blinding diseases such as glaucoma and other optic neuropathies.
文摘Moringa oleifera(MO)is traditionally used to mitigate inflammatory-mediated disorders;however,the influence of ecotypic variation on its anti-inflammatory activity remains poorly understood.In this study,we compared the phytochemical composition and anti-inflammatory activity of ethanolic extracts obtained from fresh and dried leaves of four MO ecotypes(India,Paraguay,Mozambique,and Pakistan),all grown under the same outdoor conditions,as well as two commercial powders(Just Moringa and WISSA),using LPS-stimulated RAW 264.7 macrophages.Extracts from fresh leaves were 19-43%more cytotoxic than those from dried leaves,depending on the ecotype,likely due to higher cyanogenic glycoside content.Extracts from the India and Paraguay ecotypes,characterized by high levels of quercetin derivatives and caffeic acids,as well as Just Moringa,enriched in kaempferol derivatives,significantly inhibited LPS-induced nitric oxide(NO)production(p<0.05).Just Moringa and Paraguay extracts also reduced iNOS gene expression(p<0.05 and p<0.01,respectively),whereas only the Paraguay extract decreased iNOS protein levels(p<0.05).In contrast,quercetin-3-O-glucoside and rutin showed significant effects only at concentrations approximately 100-fold higher than those present in the extracts,indicating that the phytocomplex displays greater bioactivity than individual compounds.Overall,these results demonstrate that ecotypic variation strongly affects the polyphenolic composition and anti-inflammatory properties of MO leaves,highlighting the importance of reporting both origin and phytochemical composition in MO-based products.
基金supported by National Institutes of Health(R35NS137480,R35NS116843,and RF1AG079557)by Dr.Miriam and Sheldon G.Adelson Medical Research Foundation.
文摘The adult subventricular zone of the lateral ventricles and the subgranular zone in the hippocampal dentate gyrus(DG)are the two brain regions where neurogenesis occurs throughout life in the adult mammalian brain(Ming and Song,2011).Adult quiescent hippocampal neural stem cells(NSCs)are bona fide stem cells and,when activated,give rise to newborn granule neurons in the adult brain,which play vital roles in learning,memory,mood,and affective cognition(Bonaguidi et al.,2011;Ming and Song,2011).
基金supported by the NIH (R01NS103481, R01NS111776, and R01NS131489)Indiana Department of Health (ISDH58180)(all to WW)。
文摘Spinal cord injury necessitates effective rehabilitation strategies, with exercise therapies showing promise in promoting recovery. This study investigated the impact of rehabilitation exercise on functional recovery and morphological changes following thoracic contusive spinal cord injury. After a 7-day recovery period after spinal cord injury, mice were assigned to either a trained group(10 weeks of voluntary running wheel or forced treadmill exercise) or an untrained group. Bi-weekly assessments revealed that the exercise-trained group, particularly the voluntary wheel exercise subgroup, displayed significantly improved locomotor recovery, more plasticity of dopaminergic and serotonin modulation compared with the untrained group. Additionally, exercise interventions led to gait pattern restoration and enhanced transcranial magnetic motor-evoked potentials. Despite consistent injury areas across groups, exercise training promoted terminal innervation of descending axons. In summary, voluntary wheel exercise shows promise for enhancing outcomes after thoracic contusive spinal cord injury, emphasizing the role of exercise modality in promoting recovery and morphological changes in spinal cord injuries. Our findings will influence future strategies for rehabilitation exercises, restoring functional movement after spinal cord injury.
基金supported by the Department of Defense AFIRMⅢW81XWH-20-2-0029 grant subcontractLone Star Paralysis gift,UT POC19-1774-13 grant+1 种基金Neuraptive Therapeutics Inc.26-7724-56 grantNational Institutes of Health R01-NS128086(all to GDB)。
文摘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.
基金supported by the National Institutes of Health,Nos.AA025919,AA025919-03S1,and AA025919-05S1(all to RAF).
文摘Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease.Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease.Exercise stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer’s disease.However,the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer’s disease are poorly understood.Recently,regulator of G protein signaling 6(RGS6)was identified as the mediator of voluntary running-induced adult hippocampal neurogenesis in mice.Here,we generated novel RGS6fl/fl;APP_(SWE) mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running-induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer’s disease mouse model.We found that voluntary running in APP_(SWE) mice restored their hippocampal cognitive impairments to that of control mice.This cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells,which also abolished running-mediated increases in adult hippocampal neurogenesis.Adult hippocampal neurogenesis was reduced in sedentary APP_(SWE) mice versus control mice,with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor cells.RGS6 was expressed in neurons within the dentate gyrus of patients with Alzheimer’s disease with significant loss of these RGS6-expressing neurons.Thus,RGS6 mediated voluntary running-induced rescue of impaired cognition and adult hippocampal neurogenesis in APP_(SWE) mice,identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer’s disease.
基金supported by MICIU(grant number PID2021-128133NB-100/AEI/FEDER10.13039/501100011033 to JMHG)by the National Institutes of Health(grant number R01 NS083858 to SAK)+1 种基金the Intramural Grants Program IGPP00057(to SAK)VIC enjoys a FPU contract from the Comunidad de Madrid(PIPF-2022/SAL-GL-25948)。
文摘The involvement of the excitatory amino acids glutamate and aspartate in ce rebral ischemia and excitotoxicity is well-documented.Nevertheless,the role of non-excitatory amino acids in brain damage following a stroke or brain trauma remains largely understudied.The release of amino acids by necrotic cells in the ischemic core may contribute to the expansion of the penumbra.Our findings indicated that the reversible loss of field excitato ry postsynaptic potentials caused by transient hypoxia became irreversible when exposed to a mixture of just four non-excitatory amino acids(L-alanine,glycine,L-glutamine,and L-serine)at their plasma concentrations.These amino acids induce swelling in the somas of neurons and astrocytes during hypoxia,along with permanent dendritic damage mediated by N-methyl-D-aspartate receptors.Blocking N-methyl-D-aspartate receptors prevented neuronal damage in the presence of these amino acids during hypoxia.It is likely that astroglial swelling caused by the accumulation of these amino acids via the alanine-serine-cysteine transporter 2 exchanger and system N transporters activates volume-regulated anion channels,leading to the release of excitotoxins and subsequent neuronal damage through N-methyl-D-aspartate receptor activation.Thus,previously unrecognized mechanisms involving non-excitatory amino acids may contribute to the progression and expansion of brain injury in neurological emergencies such as stroke and traumatic brain injury.Understanding these pathways co uld highlight new therapeutic targets to mitigate brain injury.
基金supported by the Brain&Behavior Research Foundation(30233).
文摘Depressive disorder is a chronic,recurring,and potentially life-endangering neuropsychiatric disease.According to a report by the World Health Organization,the global population suffering from depression is experiencing a significant annual increase.Despite its prevalence and considerable impact on people,little is known about its pathogenesis.One major reason is the scarcity of reliable animal models due to the absence of consensus on the pathology and etiology of depression.Furthermore,the neural circuit mechanism of depression induced by various factors is particularly complex.Considering the variability in depressive behavior patterns and neurobiological mechanisms among different animal models of depression,a comparison between the neural circuits of depression induced by various factors is essential for its treatment.In this review,we mainly summarize the most widely used behavioral animal models and neural circuits under different triggers of depression,aiming to provide a theoretical basis for depression prevention.
基金supported by DOD AFIRMⅢW81XWH-20-2-0029 subcontract,UT POC19-1774-13Neuraptive Therapeutics Inc.26-7724-56+1 种基金NIH R01-NS128086 grantsLone Star Paralysis gift(to GDB)。
文摘Successful polyethylene glycol fusion(PEG-fusion)of severed axons following peripheral nerve injuries for PEG-fused axons has been reported to:(1)rapidly restore electrophysiological continuity;(2)prevent distal Wallerian Degeneration and maintain their myelin sheaths;(3)promote primarily motor,voluntary behavioral recoveries as assessed by the Sciatic Functional Index;and,(4)rapidly produce correct and incorrect connections in many possible combinations that produce rapid and extensive recovery of functional peripheral nervous system/central nervous system connections and reflex(e.g.,toe twitch)or voluntary behaviors.The preceding companion paper describes sensory terminal field reo rganization following PEG-fusion repair of sciatic nerve transections or ablations;howeve r,sensory behavioral recovery has not been explicitly explored following PEG-fusion repair.In the current study,we confirmed the success of PEG-fusion surgeries according to criteria(1-3)above and more extensively investigated whether PEG-fusion enhanced mechanical nociceptive recovery following sciatic transection in male and female outbred Sprague-Dawley and inbred Lewis rats.Mechanical nociceptive responses were assessed by measuring withdrawal thresholds using von Frey filaments on the dorsal and midplantar regions of the hindpaws.Dorsal von Frey filament tests were a more reliable method than plantar von Frey filament tests to assess mechanical nociceptive sensitivity following sciatic nerve transections.Baseline withdrawal thresholds of the sciatic-mediated lateral dorsal region differed significantly across strain but not sex.Withdrawal thresholds did not change significantly from baseline in chronic Unoperated and Sham-operated rats.Following sciatic transection,all rats exhibited severe hyposensitivity to stimuli at the lateral dorsal region of the hindpaw ipsilateral to the injury.However,PEG-fused rats exhibited significantly earlier return to baseline withdrawal thresholds than Negative Control rats.Furthermore,PEG-fused rats with significantly improved Sciatic Functional Index scores at or after 4 weeks postoperatively exhibited yet-earlier von Frey filament recove ry compared with those without Sciatic Functional Index recovery,suggesting a correlation between successful PEG-fusion and both motor-dominant and sensory-dominant behavioral recoveries.This correlation was independent of the sex or strain of the rat.Furthermore,our data showed that the acceleration of von Frey filament sensory recovery to baseline was solely due to the PEG-fused sciatic nerve and not saphenous nerve collateral outgrowths.No chronic hypersensitivity developed in any rat up to 12 weeks.All these data suggest that PEG-fusion repair of transection peripheral nerve injuries co uld have important clinical benefits.
基金supported by Telethon Italy award GGP15225(to RC and GM)Italian Ministry of Health award RF-2016-02362950(to RC and CZ)+1 种基金the CJD Foundation USA(to RC)the Associazione Italiana Encefalopatie da Prioni(AIEnP)(to RC).
文摘PrPSc,a misfolded,aggregation-prone isoform of the cellular prion protein(PrPC),is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals.PrPSccan adopt different pathogenic conformations(prion strains),which can be resistant to potential drugs,or acquire drug resistance,posing challenges for the development of effective therapies.Since PrPCis the obligate precursor of any prion strain and serves as the mediator of prion neurotoxicity,it represents an attractive therapeutic target fo r prion diseases.In this minireview,we briefly outline the approaches to target PrPCand discuss our recent identification of Zn(Ⅱ)-Bn PyP,a PrPC-targeting porphyrin with an unprecedented bimodal mechanism of action.We argue that in-depth understanding of the molecular mechanism by which Zn(Ⅱ)-Bn PyP targets PrPCmay lead toward the development of a new class of dual mechanism anti-prion compounds.
基金supported by funds from the Italian Ministry of Health,Ricerca Finalizzata,(Grant N.GR-2013-02355882 and GR-2021-12373946 to AL)5x1000 Project of the Istituto Superiore di Sanità(Project code:ISS5x1000_21-949432e8c9be to AL)the European Union–NextGeneration EU through the Italian Ministry of University and Research under PNRR-M4C2-I1.3 Project PE_00000019“HEAL ITALIA”to EA(CUP I83C22001830006)。
文摘Astrocytes,the main population of glial cells in the central nervous system(CNS),exert essential tasks for the control of brain tissue homeostasis,supporting neuron and other glial cell activity from the developmental stage to adult life.To maintain the optimal functionality of the brain,astroglial cells are particularly committed to reacting to every change in tissue homeostatic conditions,from mild modifications of the physiological environment,a process called astrocyte activation,to the more severe alterations occurring in pathological situations causing astrocyte reactivity or reactive astrogliosis(Escartin et al.,2021).During these reactive states,astrocytes mount an active,progressive response encompassing morphological,molecular,and interactional remodeling,leading to the acquisition of new functions and the loss of others,whose intensity,duration,and reversibility are dependent on the nature of the stimulus and regulated in a context-specific manner.
文摘1Early history In1963the Howard Florey Laboratories were first established as a component of the Department of Physiology at the University of Melbourne.The laboratories quickly expanded under the founding directorship of Dr.Derek Denton and the funds were obtained with the philanthropic assistance of Sir Ian Potter and Mr.Ken Myer to create a new building on the south-west corner University site.This enabled the building to be opened in August1963.The Nobel laureate,Sir Howard Florey,well-known discoverer of the technique to mass-produce penicillin was pleased to lend his name to the new initiative,and was present at its opening with the Prime Minister,Sir Robert Menzies,and other dignitaries.
文摘Schizophrenia is a multifaceted neurodevelopmental disorder characterized by hallucinations,delusions,cognitive deficits,and emotional dysregulation.The prefrontal cortex(PFC),essential for executive functions,working memory,and emotional regulation,is notably impaired in this condition.This review consolidates current insights into the role of PFC dysfunction in schizophrenia,with a focus on its implications for therapeutic strategies.The neuroanatomical and neurobiological foundations of PFC dysfunction are explored,emphasizing structural abnormalities,functional dysconnectivity,and microcircuit disruptions that contribute to cognitive deficits and impaired decision-making.Clinical implications are discussed,particularly the correlation between PFC dysfunction and the severity and progression of schizophrenia symptoms.Additionally,pharmacological and non-pharmacological approaches aimed at modulating PFC activity are reviewed as potential therapeutic options.In conclusion,a deeper understanding of PFC dysfunction is pivotal for developing targeted treatments,and ongoing research offers promising avenues for enhancing outcomes for individuals affected by this debilitating disorder.
文摘Background: Neurodevelopmental abnormalities in experimental fetal alcohol spectrum disorder (FASD) are associated with impaired signaling through complex pathways that mediate neuronal survival, growth, migration, energy metabolism, and plasticity. Gestational dietary soy prevents alcohol-related impairments in placentation and FASD-associated fetal anomalies. Objective: This study was designed to determine if gestational dietary soy would be sufficient to normalize cognitive function in young adolescent offspring after chronic in utero exposure to alcohol. In addition, efforts were made to characterize the mechanisms of FASD prevention by maternal dietary soy. Methods: Pregnant Long Evans rats were fed isocaloric liquid diets containing 0% or 26% caloric ethanol with casein or soy isolate as the protein source from gestation day 6 through delivery/postnatal day 0 (P0). From P24 - P28, the offspring were subjected to Morris water maze (MWM) testing, and on P35, they were sacrificed to harvest temporal lobes for histopathologic and molecular studies. Results: The in-utero ethanol-exposed offspring exhibited significant performance impairments on the MWM test, and they had a significantly reduced mean brain weight with neuronal loss in the CA1 hippocampal region and evidence of white matter myelin loss. Gestational dietary soy nearly normalized MWM performance and preserved brain weight, hippocampal CA1 architecture, and white matter myelin staining in alcohol-exposed offspring. Mechanistically, the main positive effects of soy included increased temporal lobe expression of HES-1 and HIF-1α, reflecting enhanced Notch signaling, and broadly increased expression of GnRH network molecules, including Erb1, Gper1, GnRH, GnRH-R, KiSS, and KiSS-R, irrespective of gestational ethanol exposure. Conclusions: Dietary soy intervention early in pregnancy may reduce FASD-associated cognitive deficits. The findings suggest that targeting Notch and GnRH-related networks may help reduce long-term disability with FASD. Additional mechanistic and experimental research is needed to determine if longer-duration, postnatal dietary soy could prevent the adverse neurobehavioral effects of FASD.
基金supported by the Bridging Grant from Universiti Sains Malaysia (R501LR-RND003–0000001319–0000)funding through the Fundamental Research Grant Scheme (FRGS/1/2020/TK0/USM/02/32–6171275) awarded by the Ministry of Higher Education Malaysia
文摘Current treatments for glioblastoma face challenges such as the blood-brain barrier and lack of targeted therapy,compounded by the aggressive nature,high invasiveness,and heterogeneity of the disease.Exosomes,a subtype of extracellular vesicles are emerging as promising nanocarrier drug delivery systems to address these limitations.Exosomes released by all cell types can be easily obtained and modified as delivery vehicles or therapeutic agents.A systematic review was conducted to evaluate various methods for exosome isolation,characterization,engineering or modification,drug loading and delivery efficiency,including exosome biodistribution and treatment efficacy.A search of four databases for in vitro and in vivo studies(2000–,2023)identified 6165 records,of which 23 articles were found eligible and included for analyses.Most studies applied ultracentrifugation(UC)for exosomes isolation.Cancer cell lines being the most frequently used source of exosomes,followed by stem cells.The incubation approach was predominantly utilized to modify exosomes for drug loading.In vivo analysis showed that exosome biodistribution was primarily concentrated in the brain region,peaking in the first 6 h and remained moderately high.Compared to native exosomes and untreated control groups,utilizing modified native exosomes(cargo loaded)for treating glioblastoma disease models led to more pronounced suppression of tumor growth and proliferation,enhanced stimulation of immune response and apoptosis,effective restoration of drug chemosensitivity,increased anti-tumor effect and prolonged survival rates.Modified exosomes whether through incubation,sonication,transfection,freeze-thawing or their combination,improve targeted delivery and therapeutic efficacy against glioblastoma.
基金supported by the National Key Research and Development Program of China(Grant Nos.2023YFA0915200 and 2023YFA0915204)Outstanding Young Scientist in Shandong Province(Grant No.ZR2024YQ064)+4 种基金Shandong Province Science and Technology Small and Medium Enterprises Innovation Capacity Improvement Project(Grant No.2024TSGC008)Shandong Provincial Key Research and Development Project(Grant Nos.2020CXGC011304 and 2022CXGC020206)Taishan Scholar Foundation of Shandong Province(Grant No.tsqn202408256)the Major Innovation Project for the Science Education Industry Integration Pilot Project of Qilu University of Technology(Shandong Academy of Sciences)(Grant No.2023JBZ03)Shanghai Science and Technology Development Funds(Grant No.23J21900100).
文摘Rapid and sensitive detection of targeted biomarkers in trace samples is of great significance for early in vitro diagnosis of diseases.Microfluidic technology has competitive advantages in this field due to its low cost,high efficiency,and high portability;however,the analysis of results tends to rely on bulky and sophisticated instruments,and this limits its applications.In this work,we developed a Raspberry Pi camera-based biomarker detection device based on microfluidic technology and digital image colorimetry.For highly sensitive biomarker detection on microfluidic chips,we propose a three-step signal-amplification colorimetric detection strategy consisting of:(1)the release of Ag^(+)ions from silver nanoparticles,(2)Ag^(+)-inhibited urea hydrolysis colorimetry,and(3)microscopic lens magnification.For efficient evaluation of results,we employed an RGB image-processing system to quantitatively analyze color images captured by the Raspberry Pi camera.Further,we tested the functionality of the device with procalcitonin(PCT)in phosphate-buffered saline,plasma,and serum to simulate clinical situations.We determined the limit of detection as 1 ng/ml,and a good linear relationship was established between PCT concentration and color intensity within the detection range 1–10 ng/ml.Importantly,only a relatively short detection time(40 min)was required in all three environments.The results demonstrate the great potential of this device for biomarker detection and facilitating biomedical research.
基金financially supported by the National Natural Science Foundation of China(No.32172855)Fundamental Research Funds for the Central Universities(Nos.2632024ZD07,2632024TD02)the Open Project of Jiangsu Provincial Science and Technology Resources(Clinical Resources)Coordination Service Platform(No.TC2023B001)。
文摘The presence of the blood–brain barrier limits the drug concentration in the brain,while low concentrations of antibiotics make it difficult to kill infecting bacteria and tends to induce drug resistance,making the clinical treatment of bacterial meningitis challenging.Herein,a nose-to-brain delivery strategy of small-sized nanozyme has been fabricated for combating bacterial meningitis,to overcome the low drug concentration and drug resistance.This strategy was achieved by a proteinsupported Au nanozyme(ANZ).With a particle size of less than 10 nm,it possesses both glucose oxidase-like and peroxidase-like activities and can generate large amounts of reactive oxygen species through a cascade effect without the addition of external H_(2)O_(2).Benefiting from the cascade catalytic amplification effect generated by its dual enzymelike activities,ANZ shows significant broad-spectrum antibacterial activity without inducing bacterial resistance in vitro.Notably,small-sized ANZ exhibits higher brain entry efficiency and greater accumulation after intranasal administration compared to oral or intravenous administration.In a mouse model of bacterial meningitis,the mice treated with ANZ had lower bacterial loads in the brain and higher survival and clinical behavior scores compared to the classical antibiotic ceftriaxone.Additionally,the meningitis mice exhibited undamaged cognitive and behavioral abilities,indicating the excellent biocompatibility of ANZ.The above results demonstrate that nose-to-brain delivery of ANZ exhibits high intracerebral accumulation,strong antibacterial efficacy and does not lead to bacterial resistance.It holds broad prospects for the treatment of bacterial meningitis.
文摘Alzheimer's disease (AD) is the most common form of dementia,affecting millions worldwide.It is cha racterized by progressive cognitive decline and changes in behavior and personality,attributed to neuropathological changes,such as amyloid-beta (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein.
