The recently re-emerged mpox(monkeypox)virus that causes mpox disease is a member of genus Orthopoxvirus and has unprecedentedly spread worldwide.Numerous studies have contributed to our understanding of its evolution...The recently re-emerged mpox(monkeypox)virus that causes mpox disease is a member of genus Orthopoxvirus and has unprecedentedly spread worldwide.Numerous studies have contributed to our understanding of its evolution,pathophysiology,and clinical manifestations.The current outbreak of the mpox virus depicts its novel route of transmission as a new variant.However,the exact reason for its transition from an epidemic to a pandemic remains unclear.Furthermore,other poxviruses such as vaccinia virus,variola virus,and cowpox virus,also belong to the same genus,Orthopoxvirus.In the present review,our objective was to summarize the evidence on evolution,pathophysiology,and clinical manifestations of mpox virus and its related poxviruses.The present review would aid in a better understanding of the current circulating mpox virus and its differences from other poxviruses.In addition,the shared genetic factors contributing to virulence in these Orthopoxvirus highlight their evolutionary connections and genetic similarities.While they exhibit differences in virulence,studying these genetic relationships is crucial for understanding their biology,pathogenicity,and the development of effective vaccines and antiviral therapeutics to curb mpox disease.展开更多
Mitigating preterm encephalopathy continues to be one of the greatest challenges in perinatal medicine.Preterm encephalopathy is associated with high mortality,serious morbidity,and significant socio-economic impacts ...Mitigating preterm encephalopathy continues to be one of the greatest challenges in perinatal medicine.Preterm encephalopathy is associated with high mortality,serious morbidity,and significant socio-economic impacts on the individuals,their families,and public health sectors and welfare systems that last a lifetime.The cost of disability associated with preterm brain injury continues to rise.Prevention of this injury,and disability,would significantly reduce this socioeconomic burden.展开更多
Course based ideological and political education (CIPE) is an important way to improve the quality of ideological and political work and talent cultivation. This study explores for the first time the implementation of...Course based ideological and political education (CIPE) is an important way to improve the quality of ideological and political work and talent cultivation. This study explores for the first time the implementation of ideological and political education in the teaching of pathophysiology courses, and also analyzes the evaluation of student psychological status and the importance of mental health education in the implementation of IPE courses. A survey was conducted on 211 students at Yangtze University to understand their motivation and behavior towards learning ideological, political, and pathophysiological courses. In addition, a questionnaire survey was used to explore the relationship between pathophysiology and ideological and political courses, as well as the importance of their satisfaction with the implementation of ideological and political courses in pathophysiology and mental health education. The research results indicate that factors such as educational background and gender differences affect the learning of CIPE. Graduate students are more interested in ideological and political courses, while female students find it difficult to study pathophysiology;In addition, the results of one-way ANOVA indicate that the implementation effect of IPE in pathophysiology courses depends on the level of interest in IPE and pathophysiology courses, the level of consideration for the importance of professional courses, the professional gains after studying pathophysiology, and the level of understanding of the relationship between IPE and CIPE. 81.04% of students believe that in the CIPE process, telling stories by teachers themselves is the most popular way of communication and education. This reflects the importance of mental health education from the perspective of CIPE. In addition, this study also indicates that PBL and flipped classroom teaching models are popular teaching models in CIPE. This study is beneficial for promoting the improvement and implementation of CIPE and mental health education in higher education curricula, thus providing valuable insights for educational decision-makers.展开更多
Slow inward currents are known as neuronal excitatory currents mediated by glutamate release and activation of neuronal extra synaptic N-met hyl-D-aspartate receptors with the contribution of astrocytes.These events a...Slow inward currents are known as neuronal excitatory currents mediated by glutamate release and activation of neuronal extra synaptic N-met hyl-D-aspartate receptors with the contribution of astrocytes.These events are significantly slower than the excitatory postsynaptic currents.Parameters of slow inward currents are determined by seve ral factors including the mechanisms of astrocytic activation and glutamate release,as well as the diffusion pathways from the release site towards the extra synaptic recepto rs.Astrocytes are stimulated by neuronal network activity,which in turn excite neurons,forming an astrocyte-neuron feedback loop.Mostly as a consequence of brain edema,astrocytic swelling can also induce slow inward currents under pathological conditions.There is a growing body of evidence on the roles of slow inward currents on a single neuron or local network level.These events often occur in synchro ny on neurons located in the same astrocytic domain.Besides synchronization of neuronal excitability,slow inward currents also set synaptic strength via eliciting timing-dependent synaptic plasticity.In addition,slow inward currents are also subject to non-synaptic plasticity triggered by long-la sting stimulation of the excitatory inputs.Of note,there might be important regionspecific differences in the roles and actions triggering slow inward currents.In greater networks,the pathophysiological roles of slow inward currents can be better understood than physiological ones.Slow inward currents are identified in the pathophysiological background of autism,as slow inward currents drive early hypersynchrony of the neural networks.Slow inward currents are significant contributors to paroxysmal depolarizational shifts/interictal spikes.These events are related to epilepsy,but also found in Alzheimer's disease,Parkinson's disease,and stroke,leading to the decline of cognitive functions.Events with features overlapping with slow inward currents(excitatory,N-methyl-Daspartate-receptor mediated currents with astrocytic contribution) as ischemic currents and spreading depolarization also have a well-known pathophysiological role in worsening consequences of stroke,traumatic brain injury,or epilepsy.One might assume that slow inward currents occurring with low frequency under physiological conditions might contribute to synaptic plasticity and memory formation.However,to state this,more experimental evidence from greater neuronal networks or the level of the individual is needed.In this review,I aimed to summarize findings on slow inward currents and to speculate on the potential functions of it.展开更多
Autism spectrum disorders are a group of neurodevelopmental disorders involving more than 1100 genes,including Ctnnd2 as a candidate gene.Ctnnd2knockout mice,serving as an animal model of autis m,have been demonstrate...Autism spectrum disorders are a group of neurodevelopmental disorders involving more than 1100 genes,including Ctnnd2 as a candidate gene.Ctnnd2knockout mice,serving as an animal model of autis m,have been demonstrated to exhibit decreased density of dendritic spines.The role of melatonin,as a neuro hormone capable of effectively alleviating social interaction deficits and regulating the development of dendritic spines,in Ctnnd2 deletion-induced nerve injury remains unclea r.In the present study,we discove red that the deletion of exon 2 of the Ctnnd2 gene was linked to social interaction deficits,spine loss,impaired inhibitory neurons,and suppressed phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt) signal pathway in the prefrontal cortex.Our findings demonstrated that the long-term oral administration of melatonin for 28 days effectively alleviated the aforementioned abnormalities in Ctnnd2 gene-knockout mice.Furthermore,the administration of melatonin in the prefro ntal cortex was found to improve synaptic function and activate the PI3K/Akt signal pathway in this region.The pharmacological blockade of the PI3K/Akt signal pathway with a PI3K/Akt inhibitor,wo rtmannin,and melatonin receptor antagonists,luzindole and 4-phenyl-2-propionamidotetralin,prevented the melatonin-induced enhancement of GABAergic synaptic function.These findings suggest that melatonin treatment can ameliorate GABAe rgic synaptic function by activating the PI3K/Akt signal pathway,which may contribute to the improvement of dendritic spine abnormalities in autism spectrum disorders.展开更多
We previously showed that hydrogen sulfide(H2S)has a neuroprotective effect in the context of hypoxic ischemic brain injury in neonatal mice.However,the precise mechanism underlying the role of H2S in this situation r...We previously showed that hydrogen sulfide(H2S)has a neuroprotective effect in the context of hypoxic ischemic brain injury in neonatal mice.However,the precise mechanism underlying the role of H2S in this situation remains unclear.In this study,we used a neonatal mouse model of hypoxic ischemic brain injury and a lipopolysaccharide-stimulated BV2 cell model and found that treatment with L-cysteine,a H2S precursor,attenuated the cerebral infarction and cerebral atrophy induced by hypoxia and ischemia and increased the expression of miR-9-5p and cystathionineβsynthase(a major H2S synthetase in the brain)in the prefrontal cortex.We also found that an miR-9-5p inhibitor blocked the expression of cystathionineβsynthase in the prefrontal cortex in mice with brain injury caused by hypoxia and ischemia.Furthermore,miR-9-5p overexpression increased cystathionine-β-synthase and H2S expression in the injured prefrontal cortex of mice with hypoxic ischemic brain injury.L-cysteine decreased the expression of CXCL11,an miR-9-5p target gene,in the prefrontal cortex of the mouse model and in lipopolysaccharide-stimulated BV-2 cells and increased the levels of proinflammatory cytokines BNIP3,FSTL1,SOCS2 and SOCS5,while treatment with an miR-9-5p inhibitor reversed these changes.These findings suggest that H2S can reduce neuroinflammation in a neonatal mouse model of hypoxic ischemic brain injury through regulating the miR-9-5p/CXCL11 axis and restoringβ-synthase expression,thereby playing a role in reducing neuroinflammation in hypoxic ischemic brain injury.展开更多
Brain tissue requires high amounts of copper(Cu)for its key physiological processes,such as energy production,neurotransmitter synthesis,maturation of neuropeptides,myelination,synaptic plasticity,and radical scavengi...Brain tissue requires high amounts of copper(Cu)for its key physiological processes,such as energy production,neurotransmitter synthesis,maturation of neuropeptides,myelination,synaptic plasticity,and radical scavenging.The requirements for Cu in the brain vary depending on specific brain regions,cell types,organism age,and nutritional status.Cu imbalances cause or contribute to several life-threatening neurologic disorders including Menkes disease,Wilson disease,Alzheimer’s disease,Parkinson’s disease,and others.Despite the well-established role of Cu homeostasis in brain development and function,the mechanisms that govern Cu delivery to the brain are not well defined.This review summarizes available information on Cu transfer through the brain barriers and discusses issues that require further research.展开更多
Parkinson's disease is characterized by the selective degeneration of dopamine neurons in the nigrostriatal pathway and dopamine deficiency in the striatum.The precise reasons behind the specific degeneration of t...Parkinson's disease is characterized by the selective degeneration of dopamine neurons in the nigrostriatal pathway and dopamine deficiency in the striatum.The precise reasons behind the specific degeneration of these dopamine neurons remain largely elusive.Genetic investigations have identified over 20 causative PARK genes and 90 genomic risk loci associated with both familial and sporadic Parkinson's disease.Notably,several of these genes are linked to the synaptic vesicle recycling process,particularly the clathrinmediated endocytosis pathway.This suggests that impaired synaptic vesicle recycling might represent an early feature of Parkinson's disease,followed by axonal degeneration and the eventual loss of dopamine cell bodies in the midbrain via a"dying back"mechanism.Recently,several new animal and cellular models with Parkinson's disease-linked mutations affecting the endocytic pathway have been created and extensively characterized.These models faithfully recapitulate certain Parkinson's disease-like features at the animal,circuit,and cellular levels,and exhibit defects in synaptic membrane trafficking,further supporting the findings from human genetics and clinical studies.In this review,we will first summarize the cellular and molecular findings from the models of two Parkinson's disease-linked clathrin uncoating proteins:auxilin(DNAJC6/PARK19)and synaptojanin 1(SYNJ1/PARK20).The mouse models carrying these two PARK gene mutations phenocopy each other with specific dopamine terminal pathology and display a potent synergistic effect.Subsequently,we will delve into the involvement of several clathrin-mediated endocytosis-related proteins(GAK,endophilin A1,SAC2/INPP5 F,synaptotagmin-11),identified as Parkinson's disease risk factors through genome-wide association studies,in Parkinson's disease pathogenesis.We will also explore the direct or indirect roles of some common Parkinson's disease-linked proteins(alpha-synuclein(PARK1/4),Parkin(PARK2),and LRRK2(PARK8))in synaptic endocytic trafficking.Additionally,we will discuss the emerging novel functions of these endocytic proteins in downstream membrane traffic pathways,particularly autophagy.Given that synaptic dysfunction is considered as an early event in Parkinson's disease,a deeper understanding of the cellular mechanisms underlying synaptic vesicle endocytic trafficking may unveil novel to rgets for early diagnosis and the development of interventional therapies for Parkinson's disease.Future research should aim to elucidate why generalized synaptic endocytic dysfunction leads to the selective degeneration of nigrostriatal dopamine neurons in Parkinson's disease.展开更多
Tissue regeneration maintains homeostasis and preserves the functional features of each tissue.However,not all tissues show a strong repairing capacity.This is the case of the central nervous system.It is now well est...Tissue regeneration maintains homeostasis and preserves the functional features of each tissue.However,not all tissues show a strong repairing capacity.This is the case of the central nervous system.It is now well established that the generation of new functional neurons from stem cells in the adult brain occurs in specific regions of the brain of different species such as rodents,birds,primates,and humans(Eriksson et al.,1998).展开更多
De novo mutations in genes encoding K^(+)channels are implicated in many severe neurodevelopmental disorders.Specifically,mutations in KCNA2,encoding the Shaker-type voltage-gated K^(+)channel Kv1.2,and KCNJ2,encoding...De novo mutations in genes encoding K^(+)channels are implicated in many severe neurodevelopmental disorders.Specifically,mutations in KCNA2,encoding the Shaker-type voltage-gated K^(+)channel Kv1.2,and KCNJ2,encoding the inwardly rectifying K^(+)channel Kir2.1,associate with focal and generalized epilepsies,brain atrophy,autism,ataxia and hereditary spastic paraplegia(Syrbe et al.,2015;Masnada et al.,2017;Cheng et al.,2021).展开更多
Gene therapies,despite of being a relatively new therapeutic approach,have a potential to become an important alternative to current treatment strategies in glaucoma.Since glaucoma is not considered a single gene dise...Gene therapies,despite of being a relatively new therapeutic approach,have a potential to become an important alternative to current treatment strategies in glaucoma.Since glaucoma is not considered a single gene disease,the identified goals of gene therapy would be rather to provide neuroprotection of retinal ganglion cells,especially,in intraocular-pressure-independent manner.The most commonly reported type of vector for gene delivery in glaucoma studies is adeno-associated virus serotype 2 that has a high tro pism to retinal ganglion cells,res ulting in long-term expression and low immunogenic profile.The gene thera py studies recruit inducible and genetic animal models of optic neuropathy,like DBA/2J mice model of high-tension glaucoma and the optic nerve crush-model.Reported gene therapy-based neuroprotection of retinal ganglion cells is targeting specific genes translating to growth factors(i.e.,brain derived neurotrophic factor,and its receptor TrkB),regulation of apoptosis and neurodegeneration(i.e.,Bcl-xl,Xiap,FAS system,nicotinamide mononucleotide adenylyl transferase 2,Digit3 and Sarm1),immunomodulation(i.e.,Crry,C3 complement),modulation of neuroinflammation(i.e.,e rythropoietin),reduction of excitotoxicity(i.e.,Com KIlα)and transcription regulation(i.e.,Max,Nrf2).On the other hand,some of gene therapy studies focus on lowering intra ocular pressure,by impacting genes involved in both,decreasing aqueous humor production(i.e.,aquaporin 1),and increasing outflow facility(i.e.,COX2,prostaglandin F2a receptor,RhoA/RhoA kinase signaling pathway,MMP1,Myocilin).The goal of this review is to summarize the current stateof-art and the direction of development of gene therapy strategies for glaucomatous neuropathy.展开更多
Medicinal plants,as a good therapeutic strategy,can be used to treat a wide spectrum of diseases.Coriandrum sativum(C.sativum)is a plant from Apiaceae family.Numerous reports indicate that C.sativum has positive effec...Medicinal plants,as a good therapeutic strategy,can be used to treat a wide spectrum of diseases.Coriandrum sativum(C.sativum)is a plant from Apiaceae family.Numerous reports indicate that C.sativum has positive effects on anxiety,seizure,learning and memory ability,as well as pain.This annual plant can also treat colitis,increase appetite,reduce blood pressure,and attenuate myocardial damage.Additionally,it improves liver and kidney function and diabetes mellitus and inhibits osteoclast activity.These beneficial effects of C.sativum mainly are attributed to its antioxidant and anti-inflammatory properties.The present paper reviews the impacts of C.sativum on different body systems.Information was extracted by searching the Web of Science,PubMed,Scopus,and Google Scholar from January 2010 until the end of February 2024.展开更多
We have previously shown the neuroprotective and pro-neurogenic activity of microneurotrophin BNN-20 in the substantia nigra of the“weaver”mouse,a model of progressive nigrostriatal degeneration.Here,we extended our...We have previously shown the neuroprotective and pro-neurogenic activity of microneurotrophin BNN-20 in the substantia nigra of the“weaver”mouse,a model of progressive nigrostriatal degeneration.Here,we extended our investigation in two clinically-relevant ways.First,we assessed the effects of BNN-20 on human induced pluripotent stem cell-derived neural progenitor cells and neurons derived from healthy and parkinsonian donors.Second,we assessed if BNN-20 can boost the outcome of mouse neural progenitor cell intranigral transplantations in weaver mice,at late stages of degeneration.We found that BNN-20 has limited direct effects on cultured human induced pluripotent stem cell-derived neural progenitor cells,marginally enhancing their differentiation towards neurons and partially reversing the pathological phenotype of dopaminergic neurons generated from parkinsonian donors.In agreement,we found no effects of BNN-20 on the mouse neural progenitor cells grafted in the substantia nigra of weaver mice.However,the graft strongly induced an endogenous neurogenic response throughout the midbrain,which was significantly enhanced by the administration of microneurotrophin BNN-20.Our results provide straightforward evidence of the existence of an endogenous midbrain neurogenic system that can be specifically strengthened by BNN-20.Interestingly,the lack of major similar activity on cultured human induced pluripotent stem cell-derived neural progenitors and their progeny reveals the in vivo specificity of the aforementioned pro-neurogenic effect.展开更多
Memory loss and dementia are major public health concerns with a substantial economic burden.Oxidative stress has been shown to play a crucial role in the pathophysiology of hippocampal damage-induced memory impairmen...Memory loss and dementia are major public health concerns with a substantial economic burden.Oxidative stress has been shown to play a crucial role in the pathophysiology of hippocampal damage-induced memory impairment.To investigate whether the antioxidant and anti-inflammatory compound vanillyla cetone(zingerone) can protect against hippocampal damage and memory loss induced by cadmium chloride(CdCl_(2)) administration in rats,we explo red the potential involvement of the nuclear factor erythroid 2-related factor 2(Nrf2) signaling pathway,which is known to modulate oxidative stress and inflammation.Sixty healt hy male Wistar rats were divided into five groups:vehicle-treated(control),vanillylacetone,CdCl_(2),vanillylacetone+ CdCl_(2),vanillylacetone+ CdCl_(2)+ brusatol(a selective pharmacological N rf2inhibitor) groups.Vanillylacetone effectively attenuated CdCl_(2)-induced damage in the dental gyrus of the hippocampus and improved the memory function assessed by the Morris Water Maze test.Additionally,vanillylacetone markedly decreased the hippocampal tissue levels of inflammatory biomarkers(interleukin-6,tumor necrosis factor-α,intracellular cell adhesive molecules) and apoptosis biomarkers(Bax and cleaved caspase-3).The control and CdCl_(2)-treated groups treated with va nillylacetone showed reduced generation of reactive oxygen species,decreased malondialdehyde levels,and increased superoxide dismutase and glutathione activities,along with significant elevation of nuclear Nrf2 mRNA and protein expression in hippocampal tissue.All the protective effects of vanillylacetone we re substantially blocked by the co-administration of brusatol(a selective N rf2 inhibitor).Va nillylacetone mitigated hippocampal damage and memory loss induced by CdCl_(2),at least in part, by activating the nuclear transcription factor Nrf2.Additionally,vanillylacetone exerted its potent antioxidant and antiinflammatory actions.展开更多
Our previous studies have reported that activation of the NLRP3(NOD-,LRR-and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with ...Our previous studies have reported that activation of the NLRP3(NOD-,LRR-and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with neuroinflammation and brain damage.Mesenchymal stem cell-derived extracellular vesicles(MSC-EVs)have been shown to restore the neuroinflammatory response,along with myelin and synaptic structural alterations in the prefrontal cortex,and alleviate cognitive and memory dysfunctions induced by binge-like ethanol treatment in adolescent mice.Considering the therapeutic role of the molecules contained in mesenchymal stem cell-derived extracellular vesicles,the present study analyzed whether the administration of mesenchymal stem cell-derived extracellular vesicles isolated from adipose tissue,which inhibited the activation of the NLRP3 inflammasome,was capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge drinking.We demonstrated that the administration of mesenchymal stem cell-derived extracellular vesicles ameliorated the activation of the hippocampal NLRP3 inflammasome complex and other NLRs inflammasomes(e.g.,pyrin domain-containing 1,caspase recruitment domain-containing 4,and absent in melanoma 2,as well as the alterations in inflammatory genes(interleukin-1β,interleukin-18,inducible nitric oxide synthase,nuclear factor-kappa B,monocyte chemoattractant protein-1,and C–X3–C motif chemokine ligand 1)and miRNAs(miR-21a-5p,miR-146a-5p,and miR-141-5p)induced by binge-like ethanol treatment in adolescent mice.Bioinformatic analysis further revealed the involvement of miR-21a-5p and miR-146a-5p with inflammatory target genes and NOD-like receptor signaling pathways.Taken together,these findings provide novel evidence of the therapeutic potential of MSC-derived EVs to ameliorate the hippocampal neuroinflammatory response associated with NLRP3 inflammasome activation induced by binge drinking in adolescence.展开更多
Lung cancer has the highest mortality rate among all cancers,in part because it readily metastasizes.The tumor microenvironment,comprising blood vessels,fibroblasts,immune cells,and macrophages[including tumor-associa...Lung cancer has the highest mortality rate among all cancers,in part because it readily metastasizes.The tumor microenvironment,comprising blood vessels,fibroblasts,immune cells,and macrophages[including tumor-associated macrophages(TAMs)],is closely related to cancer cell growth,migration,and invasion.TAMs secrete several cytokines,including interleukin(IL)-1β,which participate in cancer migration and invasion.p21-activated kinase 1(PAK1),an important signaling molecule,induces cell migration and invasion in several carcinomas.Tonicityresponsive enhancer-binding protein(TonEBP)is also known to participate in cancer cell growth,migration,and invasion.However,the mechanisms by which it increases lung cancer migration remain unclear.Therefore,in this study,we aimed to elucidate the mechanisms by which IL-1βand TonEBP affect lung cancer cell migration and invasion.We found that A549 cocultured-MΦ-secreted IL-1βinduced A549 cell migration and invasion via the PAK1 pathway.TonEBP deficiency reduced A549 cell migration and invasion and increased responsiveness to IL-1β–induced migration and invasion.PAK1 phosphorylation,which was promoted by IL-1β,was reduced when TonEBP was depleted.These results suggest that TonEBP plays an important role in IL-1βinduction and invasiveness of A549 cells via the PAK1 pathway.These findings could be valuable in identifying potential targets for lung cancer treatment.展开更多
Gender disparities are evident across different types of digestive system cancers,which are typically characterized by a lower incidence and mortality rate in females compared to males.This finding suggests a potentia...Gender disparities are evident across different types of digestive system cancers,which are typically characterized by a lower incidence and mortality rate in females compared to males.This finding suggests a potential protective role of female steroid hormones,particularly estrogen,in the development of these cancers.Estrogen is a well-known sex hormone that not only regulates the reproductive system but also exerts diverse effects on non-reproductive organs mediated through interactions with estrogen receptors(ERs),including the classic(ERαand ERβ)and non-traditional ERs[G protein-coupled estrogen receptor(GPER)].Recent advances have contributed to our comprehension of the mechanisms underlying ERs in digestive system cancers.In this comprehensive review we summarize the current understanding of the intricate roles played by estrogen and ERs in the major types of digestive system cancers,including hepatocellular,pancreatic,esophageal,gastric,and colorectal carcinoma.Furthermore,we discuss the potential molecular mechanisms underlying ERα,ERβ,and GPER effects,and propose perspectives on innovative therapies and preventive measures targeting the pathways regulated by estrogen and ERs.The roles of estrogen and ERs in digestive system cancers are complicated and depend on the cell type and tissue involved.Additionally,deciphering the intricate roles of estrogen,ERs,and the associated signaling pathways may guide the discovery of novel and tailored therapeutic and preventive strategies for digestive system cancers,eventually improving the care and clinical outcomes for the substantial number of individuals worldwide affected by these malignancies.展开更多
The globus pallidus plays a pivotal role in the basal ganglia circuit. Parkinson's disease is characterized by degeneration of dopamine-producing cells in the substantia nigra, which leads to dopamine deficiency i...The globus pallidus plays a pivotal role in the basal ganglia circuit. Parkinson's disease is characterized by degeneration of dopamine-producing cells in the substantia nigra, which leads to dopamine deficiency in the brain that subsequently manifests as various motor and non-motor symptoms. This review aims to summarize the involvement of the globus pallidus in both motor and non-motor manifestations of Parkinson's disease. The firing activities of parvalbumin neurons in the medial globus pallidus, including both the firing rate and pattern, exhibit strong correlations with the bradykinesia and rigidity associated with Parkinson's disease. Increased beta oscillations, which are highly correlated with bradykinesia and rigidity, are regulated by the lateral globus pallidus. Furthermore,bradykinesia and rigidity are strongly linked to the loss of dopaminergic projections within the cortical-basal ganglia-thalamocortical loop. Resting tremors are attributed to the transmission of pathological signals from the basal ganglia through the motor cortex to the cerebellum-ventral intermediate nucleus circuit. The cortico–striato–pallidal loop is responsible for mediating pallidi-associated sleep disorders. Medication and deep brain stimulation are the primary therapeutic strategies addressing the globus pallidus in Parkinson's disease. Medication is the primary treatment for motor symptoms in the early stages of Parkinson's disease, while deep brain stimulation has been clinically proven to be effective in alleviating symptoms in patients with advanced Parkinson's disease,particularly for the movement disorders caused by levodopa. Deep brain stimulation targeting the globus pallidus internus can improve motor function in patients with tremordominant and non-tremor-dominant Parkinson's disease, while deep brain stimulation targeting the globus pallidus externus can alter the temporal pattern of neural activity throughout the basal ganglia–thalamus network. Therefore, the composition of the globus pallidus neurons, the neurotransmitters that act on them, their electrical activity,and the neural circuits they form can guide the search for new multi-target drugs to treat Parkinson's disease in clinical practice. Examining the potential intra-nuclear and neural circuit mechanisms of deep brain stimulation associated with the globus pallidus can facilitate the management of both motor and non-motor symptoms while minimizing the side effects caused by deep brain stimulation.展开更多
Our previous study found that rat bone marrow–derived neural crest cells(acting as Schwann cell progenitors)have the potential to promote long-distance nerve repair.Cell-based therapy can enhance peripheral nerve rep...Our previous study found that rat bone marrow–derived neural crest cells(acting as Schwann cell progenitors)have the potential to promote long-distance nerve repair.Cell-based therapy can enhance peripheral nerve repair and regeneration through paracrine bioactive factors and intercellular communication.Nevertheless,the complex contributions of various types of soluble cytokines and extracellular vesicle cargos to the secretome remain unclear.To investigate the role of the secretome and extracellular vesicles in repairing damaged peripheral nerves,we collected conditioned culture medium from hypoxia-pretreated neural crest cells,and found that it significantly promoted the repair of sensory neurons damaged by oxygen-glucose deprivation.The mRNA expression of trophic factors was highly expressed in hypoxia-pretreated neural crest cells.We performed RNA sequencing and bioinformatics analysis and found that miR-21-5p was enriched in hypoxia-pretreated extracellular vesicles of neural crest cells.Subsequently,to further clarify the role of hypoxia-pretreated neural crest cell extracellular vesicles rich in miR-21-5p in axonal growth and regeneration of sensory neurons,we used a microfluidic axonal dissociation model of sensory neurons in vitro,and found that hypoxia-pretreated neural crest cell extracellular vesicles promoted axonal growth and regeneration of sensory neurons,which was greatly dependent on loaded miR-21-5p.Finally,we constructed a miR-21-5p-loaded neural conduit to repair the sciatic nerve defect in rats and found that the motor and sensory functions of injured rat hind limb,as well as muscle tissue morphology of the hind limbs,were obviously restored.These findings suggest that hypoxia-pretreated neural crest extracellular vesicles are natural nanoparticles rich in miRNA-21-5p.miRNA-21-5p is one of the main contributors to promoting nerve regeneration by the neural crest cell secretome.This helps to explain the mechanism of action of the secretome and extracellular vesicles of neural crest cells in repairing damaged peripheral nerves,and also promotes the application of miR-21-5p in tissue engineering regeneration medicine.展开更多
In this editorial,we comment on an article by Liao et al published in the current issue of the World Journal of Diabetes.We focus on the clinical significance of tibial transverse transport(TTT)as an effective treatme...In this editorial,we comment on an article by Liao et al published in the current issue of the World Journal of Diabetes.We focus on the clinical significance of tibial transverse transport(TTT)as an effective treatment for patients with diabetic foot ulcers(DFU).TTT has been associated with tissue regeneration,improved blood circulation,reduced amputation rates,and increased expression of early angiogenic factors.Mechanistically,TTT can influence macrophage polarization and growth factor upregulation.Despite this potential,the limitations and conflicting results of existing studies justify the need for further research into its optimal application and development.These clinical implications highlight the efficacy of TTT in recalcitrant DFU and provide lasting stimuli for tissue re-generation,and blood vessel and bone marrow improvement.Immunomodu-lation via systemic responses contributes to its therapeutic potential.Future studies should investigate the underlying molecular mechanisms to enhance our understanding and the efficacy of TTT.This manuscript emphasizes the potential of TTT in limb preservation and diabetic wound healing and suggests avenues for preventive measures against limb amputation in diabetes and peripheral artery disease.Here,we highlight the clinical significance of the TTT and its importance in healing DFU to promote the use of this technique in tissue regeneration.展开更多
文摘The recently re-emerged mpox(monkeypox)virus that causes mpox disease is a member of genus Orthopoxvirus and has unprecedentedly spread worldwide.Numerous studies have contributed to our understanding of its evolution,pathophysiology,and clinical manifestations.The current outbreak of the mpox virus depicts its novel route of transmission as a new variant.However,the exact reason for its transition from an epidemic to a pandemic remains unclear.Furthermore,other poxviruses such as vaccinia virus,variola virus,and cowpox virus,also belong to the same genus,Orthopoxvirus.In the present review,our objective was to summarize the evidence on evolution,pathophysiology,and clinical manifestations of mpox virus and its related poxviruses.The present review would aid in a better understanding of the current circulating mpox virus and its differences from other poxviruses.In addition,the shared genetic factors contributing to virulence in these Orthopoxvirus highlight their evolutionary connections and genetic similarities.While they exhibit differences in virulence,studying these genetic relationships is crucial for understanding their biology,pathogenicity,and the development of effective vaccines and antiviral therapeutics to curb mpox disease.
基金This work was supported by Health Research Council of New Zealand(grants 17/601 and 22/559)the Auckland Medical Research Foundation,the Lottery Health Grants Board of New Zealand,the C.J.Martin Postdoctoral Fellowship and project grant from the National Health and Medical Research Council of Australia(APP1090890 and APP1164954)the Victorian Government’s Operational Infrastructure Support Program(to RG).
文摘Mitigating preterm encephalopathy continues to be one of the greatest challenges in perinatal medicine.Preterm encephalopathy is associated with high mortality,serious morbidity,and significant socio-economic impacts on the individuals,their families,and public health sectors and welfare systems that last a lifetime.The cost of disability associated with preterm brain injury continues to rise.Prevention of this injury,and disability,would significantly reduce this socioeconomic burden.
文摘Course based ideological and political education (CIPE) is an important way to improve the quality of ideological and political work and talent cultivation. This study explores for the first time the implementation of ideological and political education in the teaching of pathophysiology courses, and also analyzes the evaluation of student psychological status and the importance of mental health education in the implementation of IPE courses. A survey was conducted on 211 students at Yangtze University to understand their motivation and behavior towards learning ideological, political, and pathophysiological courses. In addition, a questionnaire survey was used to explore the relationship between pathophysiology and ideological and political courses, as well as the importance of their satisfaction with the implementation of ideological and political courses in pathophysiology and mental health education. The research results indicate that factors such as educational background and gender differences affect the learning of CIPE. Graduate students are more interested in ideological and political courses, while female students find it difficult to study pathophysiology;In addition, the results of one-way ANOVA indicate that the implementation effect of IPE in pathophysiology courses depends on the level of interest in IPE and pathophysiology courses, the level of consideration for the importance of professional courses, the professional gains after studying pathophysiology, and the level of understanding of the relationship between IPE and CIPE. 81.04% of students believe that in the CIPE process, telling stories by teachers themselves is the most popular way of communication and education. This reflects the importance of mental health education from the perspective of CIPE. In addition, this study also indicates that PBL and flipped classroom teaching models are popular teaching models in CIPE. This study is beneficial for promoting the improvement and implementation of CIPE and mental health education in higher education curricula, thus providing valuable insights for educational decision-makers.
基金funded by the National Research Developm ent and Innovation Office (NKFIH-K1468 73) (to BP)。
文摘Slow inward currents are known as neuronal excitatory currents mediated by glutamate release and activation of neuronal extra synaptic N-met hyl-D-aspartate receptors with the contribution of astrocytes.These events are significantly slower than the excitatory postsynaptic currents.Parameters of slow inward currents are determined by seve ral factors including the mechanisms of astrocytic activation and glutamate release,as well as the diffusion pathways from the release site towards the extra synaptic recepto rs.Astrocytes are stimulated by neuronal network activity,which in turn excite neurons,forming an astrocyte-neuron feedback loop.Mostly as a consequence of brain edema,astrocytic swelling can also induce slow inward currents under pathological conditions.There is a growing body of evidence on the roles of slow inward currents on a single neuron or local network level.These events often occur in synchro ny on neurons located in the same astrocytic domain.Besides synchronization of neuronal excitability,slow inward currents also set synaptic strength via eliciting timing-dependent synaptic plasticity.In addition,slow inward currents are also subject to non-synaptic plasticity triggered by long-la sting stimulation of the excitatory inputs.Of note,there might be important regionspecific differences in the roles and actions triggering slow inward currents.In greater networks,the pathophysiological roles of slow inward currents can be better understood than physiological ones.Slow inward currents are identified in the pathophysiological background of autism,as slow inward currents drive early hypersynchrony of the neural networks.Slow inward currents are significant contributors to paroxysmal depolarizational shifts/interictal spikes.These events are related to epilepsy,but also found in Alzheimer's disease,Parkinson's disease,and stroke,leading to the decline of cognitive functions.Events with features overlapping with slow inward currents(excitatory,N-methyl-Daspartate-receptor mediated currents with astrocytic contribution) as ischemic currents and spreading depolarization also have a well-known pathophysiological role in worsening consequences of stroke,traumatic brain injury,or epilepsy.One might assume that slow inward currents occurring with low frequency under physiological conditions might contribute to synaptic plasticity and memory formation.However,to state this,more experimental evidence from greater neuronal networks or the level of the individual is needed.In this review,I aimed to summarize findings on slow inward currents and to speculate on the potential functions of it.
基金supported by the Chongqing Science and Technology CommitteeNatural Science Foundation of Chongqing,No.cstc2021jcyj-msxmX0065 (to YL)。
文摘Autism spectrum disorders are a group of neurodevelopmental disorders involving more than 1100 genes,including Ctnnd2 as a candidate gene.Ctnnd2knockout mice,serving as an animal model of autis m,have been demonstrated to exhibit decreased density of dendritic spines.The role of melatonin,as a neuro hormone capable of effectively alleviating social interaction deficits and regulating the development of dendritic spines,in Ctnnd2 deletion-induced nerve injury remains unclea r.In the present study,we discove red that the deletion of exon 2 of the Ctnnd2 gene was linked to social interaction deficits,spine loss,impaired inhibitory neurons,and suppressed phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt) signal pathway in the prefrontal cortex.Our findings demonstrated that the long-term oral administration of melatonin for 28 days effectively alleviated the aforementioned abnormalities in Ctnnd2 gene-knockout mice.Furthermore,the administration of melatonin in the prefro ntal cortex was found to improve synaptic function and activate the PI3K/Akt signal pathway in this region.The pharmacological blockade of the PI3K/Akt signal pathway with a PI3K/Akt inhibitor,wo rtmannin,and melatonin receptor antagonists,luzindole and 4-phenyl-2-propionamidotetralin,prevented the melatonin-induced enhancement of GABAergic synaptic function.These findings suggest that melatonin treatment can ameliorate GABAe rgic synaptic function by activating the PI3K/Akt signal pathway,which may contribute to the improvement of dendritic spine abnormalities in autism spectrum disorders.
基金supported by the National Natural Science Foundation of China,Nos.82271327(to ZW),82072535(to ZW),81873768(to ZW),and 82001253(to TL).
文摘We previously showed that hydrogen sulfide(H2S)has a neuroprotective effect in the context of hypoxic ischemic brain injury in neonatal mice.However,the precise mechanism underlying the role of H2S in this situation remains unclear.In this study,we used a neonatal mouse model of hypoxic ischemic brain injury and a lipopolysaccharide-stimulated BV2 cell model and found that treatment with L-cysteine,a H2S precursor,attenuated the cerebral infarction and cerebral atrophy induced by hypoxia and ischemia and increased the expression of miR-9-5p and cystathionineβsynthase(a major H2S synthetase in the brain)in the prefrontal cortex.We also found that an miR-9-5p inhibitor blocked the expression of cystathionineβsynthase in the prefrontal cortex in mice with brain injury caused by hypoxia and ischemia.Furthermore,miR-9-5p overexpression increased cystathionine-β-synthase and H2S expression in the injured prefrontal cortex of mice with hypoxic ischemic brain injury.L-cysteine decreased the expression of CXCL11,an miR-9-5p target gene,in the prefrontal cortex of the mouse model and in lipopolysaccharide-stimulated BV-2 cells and increased the levels of proinflammatory cytokines BNIP3,FSTL1,SOCS2 and SOCS5,while treatment with an miR-9-5p inhibitor reversed these changes.These findings suggest that H2S can reduce neuroinflammation in a neonatal mouse model of hypoxic ischemic brain injury through regulating the miR-9-5p/CXCL11 axis and restoringβ-synthase expression,thereby playing a role in reducing neuroinflammation in hypoxic ischemic brain injury.
基金supported by the National Institute of Health grant R01 GM101502(to SL).
文摘Brain tissue requires high amounts of copper(Cu)for its key physiological processes,such as energy production,neurotransmitter synthesis,maturation of neuropeptides,myelination,synaptic plasticity,and radical scavenging.The requirements for Cu in the brain vary depending on specific brain regions,cell types,organism age,and nutritional status.Cu imbalances cause or contribute to several life-threatening neurologic disorders including Menkes disease,Wilson disease,Alzheimer’s disease,Parkinson’s disease,and others.Despite the well-established role of Cu homeostasis in brain development and function,the mechanisms that govern Cu delivery to the brain are not well defined.This review summarizes available information on Cu transfer through the brain barriers and discusses issues that require further research.
文摘Parkinson's disease is characterized by the selective degeneration of dopamine neurons in the nigrostriatal pathway and dopamine deficiency in the striatum.The precise reasons behind the specific degeneration of these dopamine neurons remain largely elusive.Genetic investigations have identified over 20 causative PARK genes and 90 genomic risk loci associated with both familial and sporadic Parkinson's disease.Notably,several of these genes are linked to the synaptic vesicle recycling process,particularly the clathrinmediated endocytosis pathway.This suggests that impaired synaptic vesicle recycling might represent an early feature of Parkinson's disease,followed by axonal degeneration and the eventual loss of dopamine cell bodies in the midbrain via a"dying back"mechanism.Recently,several new animal and cellular models with Parkinson's disease-linked mutations affecting the endocytic pathway have been created and extensively characterized.These models faithfully recapitulate certain Parkinson's disease-like features at the animal,circuit,and cellular levels,and exhibit defects in synaptic membrane trafficking,further supporting the findings from human genetics and clinical studies.In this review,we will first summarize the cellular and molecular findings from the models of two Parkinson's disease-linked clathrin uncoating proteins:auxilin(DNAJC6/PARK19)and synaptojanin 1(SYNJ1/PARK20).The mouse models carrying these two PARK gene mutations phenocopy each other with specific dopamine terminal pathology and display a potent synergistic effect.Subsequently,we will delve into the involvement of several clathrin-mediated endocytosis-related proteins(GAK,endophilin A1,SAC2/INPP5 F,synaptotagmin-11),identified as Parkinson's disease risk factors through genome-wide association studies,in Parkinson's disease pathogenesis.We will also explore the direct or indirect roles of some common Parkinson's disease-linked proteins(alpha-synuclein(PARK1/4),Parkin(PARK2),and LRRK2(PARK8))in synaptic endocytic trafficking.Additionally,we will discuss the emerging novel functions of these endocytic proteins in downstream membrane traffic pathways,particularly autophagy.Given that synaptic dysfunction is considered as an early event in Parkinson's disease,a deeper understanding of the cellular mechanisms underlying synaptic vesicle endocytic trafficking may unveil novel to rgets for early diagnosis and the development of interventional therapies for Parkinson's disease.Future research should aim to elucidate why generalized synaptic endocytic dysfunction leads to the selective degeneration of nigrostriatal dopamine neurons in Parkinson's disease.
基金supported by the Spanish Ministerio de Ciencio,Innovoción y Universidades(grant number RTI-2018-099908-B-C21 and RTI-2018-099908-B-C22 granted to CC)by the Consejería de Economia,Conocimiento,Empresas y Universidades(grant number FEDERUCA18-106647 granted to CC)by the Consejería de Salud y Familias 80%co-financed by EDRFITI regional funds(ITI-Cadiz-0042-2019 to CC)。
文摘Tissue regeneration maintains homeostasis and preserves the functional features of each tissue.However,not all tissues show a strong repairing capacity.This is the case of the central nervous system.It is now well established that the generation of new functional neurons from stem cells in the adult brain occurs in specific regions of the brain of different species such as rodents,birds,primates,and humans(Eriksson et al.,1998).
基金supported by the German Research Foundation DFG grant GA 654/13-2 to OG。
文摘De novo mutations in genes encoding K^(+)channels are implicated in many severe neurodevelopmental disorders.Specifically,mutations in KCNA2,encoding the Shaker-type voltage-gated K^(+)channel Kv1.2,and KCNJ2,encoding the inwardly rectifying K^(+)channel Kir2.1,associate with focal and generalized epilepsies,brain atrophy,autism,ataxia and hereditary spastic paraplegia(Syrbe et al.,2015;Masnada et al.,2017;Cheng et al.,2021).
基金supported by Medical University of Silesia research grants,No.PCN-1-129/N/2/O(to AS)。
文摘Gene therapies,despite of being a relatively new therapeutic approach,have a potential to become an important alternative to current treatment strategies in glaucoma.Since glaucoma is not considered a single gene disease,the identified goals of gene therapy would be rather to provide neuroprotection of retinal ganglion cells,especially,in intraocular-pressure-independent manner.The most commonly reported type of vector for gene delivery in glaucoma studies is adeno-associated virus serotype 2 that has a high tro pism to retinal ganglion cells,res ulting in long-term expression and low immunogenic profile.The gene thera py studies recruit inducible and genetic animal models of optic neuropathy,like DBA/2J mice model of high-tension glaucoma and the optic nerve crush-model.Reported gene therapy-based neuroprotection of retinal ganglion cells is targeting specific genes translating to growth factors(i.e.,brain derived neurotrophic factor,and its receptor TrkB),regulation of apoptosis and neurodegeneration(i.e.,Bcl-xl,Xiap,FAS system,nicotinamide mononucleotide adenylyl transferase 2,Digit3 and Sarm1),immunomodulation(i.e.,Crry,C3 complement),modulation of neuroinflammation(i.e.,e rythropoietin),reduction of excitotoxicity(i.e.,Com KIlα)and transcription regulation(i.e.,Max,Nrf2).On the other hand,some of gene therapy studies focus on lowering intra ocular pressure,by impacting genes involved in both,decreasing aqueous humor production(i.e.,aquaporin 1),and increasing outflow facility(i.e.,COX2,prostaglandin F2a receptor,RhoA/RhoA kinase signaling pathway,MMP1,Myocilin).The goal of this review is to summarize the current stateof-art and the direction of development of gene therapy strategies for glaucomatous neuropathy.
文摘Medicinal plants,as a good therapeutic strategy,can be used to treat a wide spectrum of diseases.Coriandrum sativum(C.sativum)is a plant from Apiaceae family.Numerous reports indicate that C.sativum has positive effects on anxiety,seizure,learning and memory ability,as well as pain.This annual plant can also treat colitis,increase appetite,reduce blood pressure,and attenuate myocardial damage.Additionally,it improves liver and kidney function and diabetes mellitus and inhibits osteoclast activity.These beneficial effects of C.sativum mainly are attributed to its antioxidant and anti-inflammatory properties.The present paper reviews the impacts of C.sativum on different body systems.Information was extracted by searching the Web of Science,PubMed,Scopus,and Google Scholar from January 2010 until the end of February 2024.
基金co-financed by Greece and the European Union(European Social Fund-ESF)through the Operational Programme《Human Resources Development,Education and Lifelong Learning 2014–2020》in the context of the project“NeuroProPar”(MIS 5047138,to IK)。
文摘We have previously shown the neuroprotective and pro-neurogenic activity of microneurotrophin BNN-20 in the substantia nigra of the“weaver”mouse,a model of progressive nigrostriatal degeneration.Here,we extended our investigation in two clinically-relevant ways.First,we assessed the effects of BNN-20 on human induced pluripotent stem cell-derived neural progenitor cells and neurons derived from healthy and parkinsonian donors.Second,we assessed if BNN-20 can boost the outcome of mouse neural progenitor cell intranigral transplantations in weaver mice,at late stages of degeneration.We found that BNN-20 has limited direct effects on cultured human induced pluripotent stem cell-derived neural progenitor cells,marginally enhancing their differentiation towards neurons and partially reversing the pathological phenotype of dopaminergic neurons generated from parkinsonian donors.In agreement,we found no effects of BNN-20 on the mouse neural progenitor cells grafted in the substantia nigra of weaver mice.However,the graft strongly induced an endogenous neurogenic response throughout the midbrain,which was significantly enhanced by the administration of microneurotrophin BNN-20.Our results provide straightforward evidence of the existence of an endogenous midbrain neurogenic system that can be specifically strengthened by BNN-20.Interestingly,the lack of major similar activity on cultured human induced pluripotent stem cell-derived neural progenitors and their progeny reveals the in vivo specificity of the aforementioned pro-neurogenic effect.
基金funded by the Research Deanship of King Khalid University,No.GRP-215-43 (to FHA)Princess Nourah bint Abdulrohman University Researchers Supporting Project,No.PNURSP2023R110 (to AFD)。
文摘Memory loss and dementia are major public health concerns with a substantial economic burden.Oxidative stress has been shown to play a crucial role in the pathophysiology of hippocampal damage-induced memory impairment.To investigate whether the antioxidant and anti-inflammatory compound vanillyla cetone(zingerone) can protect against hippocampal damage and memory loss induced by cadmium chloride(CdCl_(2)) administration in rats,we explo red the potential involvement of the nuclear factor erythroid 2-related factor 2(Nrf2) signaling pathway,which is known to modulate oxidative stress and inflammation.Sixty healt hy male Wistar rats were divided into five groups:vehicle-treated(control),vanillylacetone,CdCl_(2),vanillylacetone+ CdCl_(2),vanillylacetone+ CdCl_(2)+ brusatol(a selective pharmacological N rf2inhibitor) groups.Vanillylacetone effectively attenuated CdCl_(2)-induced damage in the dental gyrus of the hippocampus and improved the memory function assessed by the Morris Water Maze test.Additionally,vanillylacetone markedly decreased the hippocampal tissue levels of inflammatory biomarkers(interleukin-6,tumor necrosis factor-α,intracellular cell adhesive molecules) and apoptosis biomarkers(Bax and cleaved caspase-3).The control and CdCl_(2)-treated groups treated with va nillylacetone showed reduced generation of reactive oxygen species,decreased malondialdehyde levels,and increased superoxide dismutase and glutathione activities,along with significant elevation of nuclear Nrf2 mRNA and protein expression in hippocampal tissue.All the protective effects of vanillylacetone we re substantially blocked by the co-administration of brusatol(a selective N rf2 inhibitor).Va nillylacetone mitigated hippocampal damage and memory loss induced by CdCl_(2),at least in part, by activating the nuclear transcription factor Nrf2.Additionally,vanillylacetone exerted its potent antioxidant and antiinflammatory actions.
基金supported by grants from the Spanish Ministry of Health-PNSD(2019-I039 and 2023-I024)(to MP)FEDER/Ministerio de Ciencia e Innovación-Agencia Estatal de Investigación PID2021-1243590B-I100(to VMM)+2 种基金GVA(CIAICO/2021/203)(to MP)the Primary Addiction Care Research Network(RD21/0009/0005)(to MP)a predoctoral fellowship from the Generalitat Valenciana(ACIF/2021/338)(to CPC).
文摘Our previous studies have reported that activation of the NLRP3(NOD-,LRR-and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with neuroinflammation and brain damage.Mesenchymal stem cell-derived extracellular vesicles(MSC-EVs)have been shown to restore the neuroinflammatory response,along with myelin and synaptic structural alterations in the prefrontal cortex,and alleviate cognitive and memory dysfunctions induced by binge-like ethanol treatment in adolescent mice.Considering the therapeutic role of the molecules contained in mesenchymal stem cell-derived extracellular vesicles,the present study analyzed whether the administration of mesenchymal stem cell-derived extracellular vesicles isolated from adipose tissue,which inhibited the activation of the NLRP3 inflammasome,was capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge drinking.We demonstrated that the administration of mesenchymal stem cell-derived extracellular vesicles ameliorated the activation of the hippocampal NLRP3 inflammasome complex and other NLRs inflammasomes(e.g.,pyrin domain-containing 1,caspase recruitment domain-containing 4,and absent in melanoma 2,as well as the alterations in inflammatory genes(interleukin-1β,interleukin-18,inducible nitric oxide synthase,nuclear factor-kappa B,monocyte chemoattractant protein-1,and C–X3–C motif chemokine ligand 1)and miRNAs(miR-21a-5p,miR-146a-5p,and miR-141-5p)induced by binge-like ethanol treatment in adolescent mice.Bioinformatic analysis further revealed the involvement of miR-21a-5p and miR-146a-5p with inflammatory target genes and NOD-like receptor signaling pathways.Taken together,these findings provide novel evidence of the therapeutic potential of MSC-derived EVs to ameliorate the hippocampal neuroinflammatory response associated with NLRP3 inflammasome activation induced by binge drinking in adolescence.
基金the National Research Foundation of Korea(NRF)funded by the Ministry of Education(NRF-2014R1A6A1029617).
文摘Lung cancer has the highest mortality rate among all cancers,in part because it readily metastasizes.The tumor microenvironment,comprising blood vessels,fibroblasts,immune cells,and macrophages[including tumor-associated macrophages(TAMs)],is closely related to cancer cell growth,migration,and invasion.TAMs secrete several cytokines,including interleukin(IL)-1β,which participate in cancer migration and invasion.p21-activated kinase 1(PAK1),an important signaling molecule,induces cell migration and invasion in several carcinomas.Tonicityresponsive enhancer-binding protein(TonEBP)is also known to participate in cancer cell growth,migration,and invasion.However,the mechanisms by which it increases lung cancer migration remain unclear.Therefore,in this study,we aimed to elucidate the mechanisms by which IL-1βand TonEBP affect lung cancer cell migration and invasion.We found that A549 cocultured-MΦ-secreted IL-1βinduced A549 cell migration and invasion via the PAK1 pathway.TonEBP deficiency reduced A549 cell migration and invasion and increased responsiveness to IL-1β–induced migration and invasion.PAK1 phosphorylation,which was promoted by IL-1β,was reduced when TonEBP was depleted.These results suggest that TonEBP plays an important role in IL-1βinduction and invasiveness of A549 cells via the PAK1 pathway.These findings could be valuable in identifying potential targets for lung cancer treatment.
基金supported by grants from the Project of Scientific and Technologic Bureau of Guangzhou City(Grant No.202201010165)the Key Project of Scientific and Technologic Bureau of Guangzhou City(Grant No.202201020335).
文摘Gender disparities are evident across different types of digestive system cancers,which are typically characterized by a lower incidence and mortality rate in females compared to males.This finding suggests a potential protective role of female steroid hormones,particularly estrogen,in the development of these cancers.Estrogen is a well-known sex hormone that not only regulates the reproductive system but also exerts diverse effects on non-reproductive organs mediated through interactions with estrogen receptors(ERs),including the classic(ERαand ERβ)and non-traditional ERs[G protein-coupled estrogen receptor(GPER)].Recent advances have contributed to our comprehension of the mechanisms underlying ERs in digestive system cancers.In this comprehensive review we summarize the current understanding of the intricate roles played by estrogen and ERs in the major types of digestive system cancers,including hepatocellular,pancreatic,esophageal,gastric,and colorectal carcinoma.Furthermore,we discuss the potential molecular mechanisms underlying ERα,ERβ,and GPER effects,and propose perspectives on innovative therapies and preventive measures targeting the pathways regulated by estrogen and ERs.The roles of estrogen and ERs in digestive system cancers are complicated and depend on the cell type and tissue involved.Additionally,deciphering the intricate roles of estrogen,ERs,and the associated signaling pathways may guide the discovery of novel and tailored therapeutic and preventive strategies for digestive system cancers,eventually improving the care and clinical outcomes for the substantial number of individuals worldwide affected by these malignancies.
基金supported by the National Natural Science Foundation of China,No.31771143 (to QZ)Shanghai Municipal Science and Technology Major Project,ZJ Lab+1 种基金Shanghai Center for Brain Science and Brain-Inspired Technology,No.2018SHZDZX01 (to LC)Shanghai Zhou Liangfu Medical Development Foundation “Brain Science and Brain Diseases Youth Innovation Program”(to ZQ)。
文摘The globus pallidus plays a pivotal role in the basal ganglia circuit. Parkinson's disease is characterized by degeneration of dopamine-producing cells in the substantia nigra, which leads to dopamine deficiency in the brain that subsequently manifests as various motor and non-motor symptoms. This review aims to summarize the involvement of the globus pallidus in both motor and non-motor manifestations of Parkinson's disease. The firing activities of parvalbumin neurons in the medial globus pallidus, including both the firing rate and pattern, exhibit strong correlations with the bradykinesia and rigidity associated with Parkinson's disease. Increased beta oscillations, which are highly correlated with bradykinesia and rigidity, are regulated by the lateral globus pallidus. Furthermore,bradykinesia and rigidity are strongly linked to the loss of dopaminergic projections within the cortical-basal ganglia-thalamocortical loop. Resting tremors are attributed to the transmission of pathological signals from the basal ganglia through the motor cortex to the cerebellum-ventral intermediate nucleus circuit. The cortico–striato–pallidal loop is responsible for mediating pallidi-associated sleep disorders. Medication and deep brain stimulation are the primary therapeutic strategies addressing the globus pallidus in Parkinson's disease. Medication is the primary treatment for motor symptoms in the early stages of Parkinson's disease, while deep brain stimulation has been clinically proven to be effective in alleviating symptoms in patients with advanced Parkinson's disease,particularly for the movement disorders caused by levodopa. Deep brain stimulation targeting the globus pallidus internus can improve motor function in patients with tremordominant and non-tremor-dominant Parkinson's disease, while deep brain stimulation targeting the globus pallidus externus can alter the temporal pattern of neural activity throughout the basal ganglia–thalamus network. Therefore, the composition of the globus pallidus neurons, the neurotransmitters that act on them, their electrical activity,and the neural circuits they form can guide the search for new multi-target drugs to treat Parkinson's disease in clinical practice. Examining the potential intra-nuclear and neural circuit mechanisms of deep brain stimulation associated with the globus pallidus can facilitate the management of both motor and non-motor symptoms while minimizing the side effects caused by deep brain stimulation.
基金supported by the National Natural Science Foundation of China,No.31870977(to HYS)the National Key Technologies Research and Development Program of China,No.2017YFA0104700(to FD)+2 种基金2022 Jiangsu Funding Program for Excellent Postdoctoral Talent(to MC)Priority Academic Program Development of Jiangsu Higher Education Institutions[PAPD]the Major Project of Basic Science(Natural Science)Research in Higher Education Institutions of Jiangsu Province,No.22KJA180001(to QRH)。
文摘Our previous study found that rat bone marrow–derived neural crest cells(acting as Schwann cell progenitors)have the potential to promote long-distance nerve repair.Cell-based therapy can enhance peripheral nerve repair and regeneration through paracrine bioactive factors and intercellular communication.Nevertheless,the complex contributions of various types of soluble cytokines and extracellular vesicle cargos to the secretome remain unclear.To investigate the role of the secretome and extracellular vesicles in repairing damaged peripheral nerves,we collected conditioned culture medium from hypoxia-pretreated neural crest cells,and found that it significantly promoted the repair of sensory neurons damaged by oxygen-glucose deprivation.The mRNA expression of trophic factors was highly expressed in hypoxia-pretreated neural crest cells.We performed RNA sequencing and bioinformatics analysis and found that miR-21-5p was enriched in hypoxia-pretreated extracellular vesicles of neural crest cells.Subsequently,to further clarify the role of hypoxia-pretreated neural crest cell extracellular vesicles rich in miR-21-5p in axonal growth and regeneration of sensory neurons,we used a microfluidic axonal dissociation model of sensory neurons in vitro,and found that hypoxia-pretreated neural crest cell extracellular vesicles promoted axonal growth and regeneration of sensory neurons,which was greatly dependent on loaded miR-21-5p.Finally,we constructed a miR-21-5p-loaded neural conduit to repair the sciatic nerve defect in rats and found that the motor and sensory functions of injured rat hind limb,as well as muscle tissue morphology of the hind limbs,were obviously restored.These findings suggest that hypoxia-pretreated neural crest extracellular vesicles are natural nanoparticles rich in miRNA-21-5p.miRNA-21-5p is one of the main contributors to promoting nerve regeneration by the neural crest cell secretome.This helps to explain the mechanism of action of the secretome and extracellular vesicles of neural crest cells in repairing damaged peripheral nerves,and also promotes the application of miR-21-5p in tissue engineering regeneration medicine.
基金Supported by Grants of the Korea Research Foundation,an NRF Grant Funded by the Korea Government,No.NRF-2023R1A2C3003717.
文摘In this editorial,we comment on an article by Liao et al published in the current issue of the World Journal of Diabetes.We focus on the clinical significance of tibial transverse transport(TTT)as an effective treatment for patients with diabetic foot ulcers(DFU).TTT has been associated with tissue regeneration,improved blood circulation,reduced amputation rates,and increased expression of early angiogenic factors.Mechanistically,TTT can influence macrophage polarization and growth factor upregulation.Despite this potential,the limitations and conflicting results of existing studies justify the need for further research into its optimal application and development.These clinical implications highlight the efficacy of TTT in recalcitrant DFU and provide lasting stimuli for tissue re-generation,and blood vessel and bone marrow improvement.Immunomodu-lation via systemic responses contributes to its therapeutic potential.Future studies should investigate the underlying molecular mechanisms to enhance our understanding and the efficacy of TTT.This manuscript emphasizes the potential of TTT in limb preservation and diabetic wound healing and suggests avenues for preventive measures against limb amputation in diabetes and peripheral artery disease.Here,we highlight the clinical significance of the TTT and its importance in healing DFU to promote the use of this technique in tissue regeneration.
