Advanced microsystems in traumatic brain injury research:Traumatic brain injury(TBI)results from a mechanical insult to the brain,leading to neuronal and axonal damage and subsequently causing a secondary injury.Withi...Advanced microsystems in traumatic brain injury research:Traumatic brain injury(TBI)results from a mechanical insult to the brain,leading to neuronal and axonal damage and subsequently causing a secondary injury.Within minutes of TBI,a neuroinflammatory response is triggered,driven by intricate molecular and cellular inflammatory processes.展开更多
The sleep-wake cycle stands as an integrative process essential for sustaining optimal brain function and,either directly or indirectly,overall body health,encompassing metabolic and cardiovascular well-being.Given th...The sleep-wake cycle stands as an integrative process essential for sustaining optimal brain function and,either directly or indirectly,overall body health,encompassing metabolic and cardiovascular well-being.Given the heightened metabolic activity of the brain,there exists a considerable demand for nutrients in comparison to other organs.Among these,the branched-chain amino acids,comprising leucine,isoleucine,and valine,display distinctive significance,from their contribution to protein structure to their involvement in overall metabolism,especially in cerebral processes.Among the first amino acids that are released into circulation post-food intake,branched-chain amino acids assume a pivotal role in the regulation of protein synthesis,modulating insulin secretion and the amino acid sensing pathway of target of rapamycin.Branched-chain amino acids are key players in influencing the brain's uptake of monoamine precursors,competing for a shared transporter.Beyond their involvement in protein synthesis,these amino acids contribute to the metabolic cycles ofγ-aminobutyric acid and glutamate,as well as energy metabolism.Notably,they impact GABAergic neurons and the excitation/inhibition balance.The rhythmicity of branchedchain amino acids in plasma concentrations,observed over a 24-hour cycle and conserved in rodent models,is under circadian clock control.The mechanisms underlying those rhythms and the physiological consequences of their disruption are not fully understood.Disturbed sleep,obesity,diabetes,and cardiovascular diseases can elevate branched-chain amino acid concentrations or modify their oscillatory dynamics.The mechanisms driving these effects are currently the focal point of ongoing research efforts,since normalizing branched-chain amino acid levels has the ability to alleviate the severity of these pathologies.In this context,the Drosophila model,though underutilized,holds promise in shedding new light on these mechanisms.Initial findings indicate its potential to introduce novel concepts,particularly in elucidating the intricate connections between the circadian clock,sleep/wake,and metabolism.Consequently,the use and transport of branched-chain amino acids emerge as critical components and orchestrators in the web of interactions across multiple organs throughout the sleep/wake cycle.They could represent one of the so far elusive mechanisms connecting sleep patterns to metabolic and cardiovascular health,paving the way for potential therapeutic interventions.展开更多
Over the centuries,the regeneration field has been puzzled by the dual response of the central nervous system(CNS-brain,spinal cord,cranial nervesⅠandⅡ)and the peripheral nervous system(PNS that refers to all the ne...Over the centuries,the regeneration field has been puzzled by the dual response of the central nervous system(CNS-brain,spinal cord,cranial nervesⅠandⅡ)and the peripheral nervous system(PNS that refers to all the nerves that innervate muscles,skin,organs,bones among others).Even Ramon y Cajal had noticed that an injury to the PNS often leads to axon regrowth,in contrast to the CNS.展开更多
The second messengers 3',5'-cyclic adenosine monophosphate(cAMP)and 3',5'-cyclic guanosine monophosphate(cGMP)modulate molecular pathways that are involved in a large variety of cellular processes.In t...The second messengers 3',5'-cyclic adenosine monophosphate(cAMP)and 3',5'-cyclic guanosine monophosphate(cGMP)modulate molecular pathways that are involved in a large variety of cellular processes.In the brain,these processes include neurogenesis,neuronal differentiation,activation and function of microglia,and synaptic plasticity,finally resulting in memory formation.展开更多
After brain damage,regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals,suggesting a close link between these processes.However,the mechanisms by which these processes interact...After brain damage,regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals,suggesting a close link between these processes.However,the mechanisms by which these processes interact are not well understood.In this work,we aimed to study the correlation between angiogenesis and neurogenesis after a telencephalic stab wound injury.To this end,we used zebrafish as a relevant model of neuroplasticity and brain repair mechanisms.First,using the Tg(fli1:EGFP×mpeg1.1:mCherry)zebrafish line,which enables visualization of blood vessels and microglia respectively,we analyzed regenerative angiogenesis from 1 to 21 days post-lesion.In parallel,we monitored brain cell proliferation in neurogenic niches localized in the ventricular zone by using immunohistochemistry.We found that after brain damage,the blood vessel area and width as well as expression of the fli1 transgene and vascular endothelial growth factor(vegfaa and vegfbb)were increased.At the same time,neural stem cell proliferation was also increased,peaking between 3 and 5 days post-lesion in a manner similar to angiogenesis,along with the recruitment of microglia.Then,through pharmacological manipulation by injecting an anti-angiogenic drug(Tivozanib)or Vegf at the lesion site,we demonstrated that blocking or activating Vegf signaling modulated both angiogenic and neurogenic processes,as well as microglial recruitment.Finally,we showed that inhibition of microglia by clodronate-containing liposome injection or dexamethasone treatment impairs regenerative neurogenesis,as previously described,as well as injury-induced angiogenesis.In conclusion,we have described regenerative angiogenesis in zebrafish for the first time and have highlighted the role of inflammation in this process.In addition,we have shown that both angiogenesis and neurogenesis are involved in brain repair and that microglia and inflammation-dependent mechanisms activated by Vegf signaling are important contributors to these processes.This study paves the way for a better understanding of the effect of Vegf on microglia and for studies aimed at promoting angiogenesis to improve brain plasticity after brain injury.展开更多
Multiple sclerosis(MS)is the most common chronic disease of the central nervous system(CNS)in young adults and represents the first cause of severe handicap,originally non-traumatic(Oh et al.,2018).MS is chara cterize...Multiple sclerosis(MS)is the most common chronic disease of the central nervous system(CNS)in young adults and represents the first cause of severe handicap,originally non-traumatic(Oh et al.,2018).MS is chara cterized by the infiltration of auto reactive lymphocytes specific to myelin through the blood-brain barrier,which results in the appearance of inflammatory demyelinating lesions caused by the death of the central nervous system myelinating cells,oligodendrocytes(Oh et al.,2018).There is a prevalence sexual with a ratio of three times more affected women than men.展开更多
Mitochondria and mitochondria-associated endoplasmic reticulum membrane in neurodegenerative diseases:Mitochondria generate most of the chemical energy needed to power the biochemical reactions of cells,and thus are o...Mitochondria and mitochondria-associated endoplasmic reticulum membrane in neurodegenerative diseases:Mitochondria generate most of the chemical energy needed to power the biochemical reactions of cells,and thus are often referred to as the"powerhouse"of the cell.Nevertheless,this organelle is also involved in a pleth,ora of different cellular functions such as calcium(Ca^(2+))homeostasis,apoptosis,oxidative stress,and several metabolic pathways including oxidative phosphorylation,tricarboxylic acid cycle,andβ-oxidation of fatty acids.展开更多
The mature central nervous system(CNS,composed of the brain,spinal cord,olfactory and optic nerves)is unable to regenerate spontaneously after an insult,both in the cases of neurodegenerative diseases(for example Alzh...The mature central nervous system(CNS,composed of the brain,spinal cord,olfactory and optic nerves)is unable to regenerate spontaneously after an insult,both in the cases of neurodegenerative diseases(for example Alzheimer's or Parkinson's disease)or traumatic injuries(such as spinal cord lesions).In the last 20 years,the field has made significant progress in unlocking axon regrowth.展开更多
Metabolic dysfunction-associated steatotic liver disease(MASLD)is a highly prevalent liver pathology in need of novel pharmacological treatments to complement lifestyle-based interventions.Nuclear receptor agonists ha...Metabolic dysfunction-associated steatotic liver disease(MASLD)is a highly prevalent liver pathology in need of novel pharmacological treatments to complement lifestyle-based interventions.Nuclear receptor agonists have been under scrutiny as potential pharmacological targets and as of today,resmetirom,a thyroid hormone receptor b agonist,is the only approved agent.The dual PPARαandδagonist elafibranor has also undergone extensive clinical testing,which reached the phase III clinical trial but failed to demonstrate a beneficial effect on MASLD.As alcohol-associated liver disease and MASLD can be interconnected,whether elafibranor might be affective against liver disease caused by alcohol consumption is worth investigating.Writing recently in the World Journal of Gastroenterology,Koizumi et al reported using a mouse model of alcoholassociated liver disease and found that hepatic steatosis,liver fibrosis,and hepatocyte apoptosis were alleviated by administration of elafibranor.Although preclinical in nature,these data support the potential beneficial action of elafibranor in alcohol-induced MASLD,warranting the testing of this molecule in patients with steatotic liver disease caused by alcohol consumption.展开更多
In 1993,the World Bank released a global report on the efficacy of health promotion,introducing the disability-adjusted life years(DALY)as a novel indicator.The DALY,a composite metric incorporating temporal and quali...In 1993,the World Bank released a global report on the efficacy of health promotion,introducing the disability-adjusted life years(DALY)as a novel indicator.The DALY,a composite metric incorporating temporal and qualitative data,is grounded in preferences regarding disability status.This review delineates the algorithm used to calculate the value of the proposed DALY synthetic indicator and elucidates key methodological challenges associated with its application.In contrast to the quality-adjusted life years approach,derived from multi-attribute utility theory,the DALY stands as an independent synthetic indicator that adopts the assumptions of the Time Trade Off utility technique to define Disability Weights.Claiming to rely on no mathematical or economic theory,DALY users appear to have exempted themselves from verifying whether this indicator meets the classical properties required of all indicators,notably content validity,reliability,specificity,and sensitivity.The DALY concept emerged primarily to facilitate comparisons of the health impacts of various diseases globally within the framework of the Global Burden of Disease initiative,leading to numerous publications in international literature.Despite widespread adoption,the DALY synthetic indicator has prompted significant methodological concerns since its inception,manifesting in inconsistent and non-reproducible results.Given the substantial diffusion of the DALY indicator and its critical role in health impact assessments,a reassessment is warranted.This reconsideration is imperative for enhancing the robustness and reliability of public health decisionmaking processes.展开更多
N-methyl-D-aspartate receptors(NMDARs)play crucial roles in neuronal plasticity and brain function by sensing key neurotransmitters,such as glutamate and glycine.In a tour-de-force,Zhang et al.[1]provide the first ima...N-methyl-D-aspartate receptors(NMDARs)play crucial roles in neuronal plasticity and brain function by sensing key neurotransmitters,such as glutamate and glycine.In a tour-de-force,Zhang et al.[1]provide the first images of native NMDARs directly extracted from rat brains,revealing key aspects of NMDAR assembly and diversity.展开更多
Gain-of-function mutations in fibroblast growth factor receptor(FGFR) genes lead to chondrodysplasia and craniosynostoses. FGFR signaling has a key role in the formation and repair of the craniofacial skeleton. Here, ...Gain-of-function mutations in fibroblast growth factor receptor(FGFR) genes lead to chondrodysplasia and craniosynostoses. FGFR signaling has a key role in the formation and repair of the craniofacial skeleton. Here, we analyzed the impact of Fgfr2- and Fgfr3- activating mutations on mandibular bone formation and endochondral bone repair after non-stabilized mandibular fractures in mouse models of Crouzon syndrome(Crz) and hypochondroplasia(Hch).展开更多
Neurodevelopmental and neurodegenerative illnesses constitute a global health issue and a foremost economic burden since they are a large cause of incapacity and death worldwide.Altogether,the burden of neurological d...Neurodevelopmental and neurodegenerative illnesses constitute a global health issue and a foremost economic burden since they are a large cause of incapacity and death worldwide.Altogether,the burden of neurological disorders has increased considerably over the past 30 years because of population aging.Overall,neurological diseases significantly impair cognitive and motor functions and their incidence will increase as societies age and the world's population continues to grow.Autism spectrum disorder,motor neuron disease,encephalopathy,epilepsy,stroke,ataxia,Alzheimer's disease,amyotrophic lateral sclerosis,Huntington's disease,and Parkinson's disease represent a non-exhaustive list of neurological illnesses.These affections are due to perturbations in cellular homeostasis leading to the progressive injury and death of neurons in the nervous system.Among the common features of neurological handicaps,we find protein aggregation,oxidative stress,neuroinflammation,and mitochondrial impairment in the target tissues,e.g.,the brain,cerebellum,and spinal cord.The high energy requirements of neurons and their inability to produce sufficient adenosine triphosphate by glycolysis,are responsible for their dependence on functional mitochondria for their integrity.Reactive oxygen species,produced along with the respiration process within mitochondria,can lead to oxidative stress,which compromises neuronal survival.Besides having an essential role in energy production and oxidative stress,mitochondria are indispensable for an array of cellular processes,such as amino acid metabolism,iron-sulfur cluster biosynthesis,calcium homeostasis,intrinsic programmed cell death(apoptosis),and intraorganellar signaling.Despite the progress made in the last decades in the understanding of a growing number of genetic and molecular causes of central nervous diseases,therapies that are effective to diminish or halt neuronal dysfunction/death are rare.Given the genetic complexity responsible for neurological disorders,the development of neuroprotective strategies seeking to preserve mitochondrial homeostasis is a realistic challenge to lastingly diminish the harmful evolution of these pathologies and so to recover quality of life.A promising candidate is the neuroglobin,a globin superfamily member of 151 amino acids,which is found at high levels in the brain,the eye,and the cerebellum.The protein,which localizes to mitochondria,is involved in electron transfer,oxygen storage and defence against oxidative stress;hence,possessing neuroprotective properties.This review surveys up-to-date knowledge and emphasizes on existing investigations regarding neuroglobin physiological functions,which remain since its discovery in 2000 under intense debate and the possibility of using neuroglobin either by gene therapy or its direct delivery into the brain to treat neurological disorders.展开更多
Human-derived tumor models are essential for preclinical development of new anti-cancer drug entities.Generating animal models bearing tumors of human origin,such as patient-derived or cell line-derived xenograft tumo...Human-derived tumor models are essential for preclinical development of new anti-cancer drug entities.Generating animal models bearing tumors of human origin,such as patient-derived or cell line-derived xenograft tumors,is dependent on immuno-deficient strains.Tumor-bearing immunodeficient mice are susceptible to develop-ing unwanted disorders primarily irrelevant to the tumor nature;and if get involved with such disorders,reliability of the study results will be undermined,inevitably con-founding the research in general.Therefore,a rigorous health surveillance and clinical monitoring system,along with the establishment of a strictly controlled barrier facility to maintain a pathogen-free state,are mandatory.Even if all pathogen control and biosafety measures are followed,there are various noninfectious disorders capable of causing tissue and multiorgan damage in immunodeficient animals.Therefore,the re-searchers should be aware of sentinel signs to carefully monitor and impartially report them.This review discusses clinical signs of common unwanted disorders in experi-mental immunodeficient mice,and how to examine and report them.展开更多
Background:Scientific evidence to guide clinicians on the use of different antiseizure drugs in combination therapy is either very limited or lacking.In this study,the impact of lacosamide and perampanel alone and in ...Background:Scientific evidence to guide clinicians on the use of different antiseizure drugs in combination therapy is either very limited or lacking.In this study,the impact of lacosamide and perampanel alone and in combination was tested in corneal kindling model in mice,which is a cost-effective mechanism for screening of antiseizure drugs.Methods:The impact of lacosamide(5 mg/kg)and perampanel(0.125 mg/kg)alone and their combination was tested in corneal kindling process(3-mA current for 3 s applied twice daily for consecutive 12 days)in male BALB/c mice.Post-kindling,mice were subjected to a battery of behavioral tests assessing anxiety,memory,and depression-like behaviors.Brain tissues were then harvested for analysis of oxidative stress biomarkers.Results:Our results showed that the combination therapy of lacosamide and perampanel was more effective in reducing seizure progression than monotherapy of these drugs.Animals treated with combination therapy showed significant behavioral improvements,as reduced anxiety and depression were noticed,and their cognitive abilities were notably better compared to animals of all other groups.Moreover,biochemical assays of isolated brains from combination-treated group revealed lesser amount of oxidative stress.In addition,outcomes of dual regime were comparable to the phenytoin in seizure control but showed superior benefits in mitigation of kindling-prompted behavioral dysfunction and oxidative stress.Conclusions:This study suggests that the lacosamide and perampanel combination therapy worked noticeably better in halting the corneal kindling process in mice and improved the epilepsy-associated psychiatric disorders that might be due to antioxidant effects of both drugs.展开更多
Gallstone pancreatitis is the leading cause of acute pancreatitis,accounting for more than 40%of cases.Etiological treatment is a critical issue in acute biliary pancreatitis as it helps reduce the risk of recurrence....Gallstone pancreatitis is the leading cause of acute pancreatitis,accounting for more than 40%of cases.Etiological treatment is a critical issue in acute biliary pancreatitis as it helps reduce the risk of recurrence.Patients who have ex-perienced a complicated form of biliary disease are at high risk for recurrent episodes,and the severity of these new episodes can be unpredictable.In recent years,the role and timing of cholecystectomy and endoscopic retrograde cholan-giopancreatography(ERCP),which are the main therapeutic interventions in the etiological treatment,have been considerably clarified.This review aims to detail the different aspects of the etiological treatment of acute biliary pancreatitis.Currently,it is established that cholecystectomy should be performed early during the initial hospitalization in cases of non-severe acute pancreatitis.However,the optimal timing of this procedure in severe acute pancreatitis remains a subject of debate.Emergency ERCP is no longer indicated for acute biliary pancreatitis,except in cases of associated acute cholangitis.ERCP can be useful for the management of persistent bile duct stones.Finally,the role of interval sphincterotomy in frail or elderly patients or to reduce the risk of re-currence in those awaiting cholecystectomy in cases of severe acute pancreatitis remains to be fully established.展开更多
Background:Besides seizures,a myriad of overlapping neuropsychiatric and cognitive comorbidities occur in patients with epilepsy,which further debilitates their quality of life.This study provides an in-depth characte...Background:Besides seizures,a myriad of overlapping neuropsychiatric and cognitive comorbidities occur in patients with epilepsy,which further debilitates their quality of life.This study provides an in-depth characterization of the impact of brivaracetam and rufinamide individually and in combination at 10 and 20 mg/kg doses,respec-tively,on corneal kindling-induced generalized seizures and behavioral alterations.Furthermore,observed convulsive frequency and behavioral changes were corre-lated to post-kindling-induced changes in the activity of markers of oxidative stress.Methods:Adult C57BL/6 mice were kindled via twice-daily transcorneal 50-Hz elec-trical stimulations(3 mA)for 3 s for 12 days until animals reached a fully kindled state.After the kindling procedure,animals were tested using a set of behavioral tests,and neurochemical alterations were assessed.Results:Corneal-kindled animals exhibited intense generalized convulsions,altered behavioral phenotypes typified by positive symptoms(hyperlocomotion),negative symptoms(anxiety and anhedonia),and deficits in semantic and working memory.BRV 10+RFM 20 dual regime increased convulsive threshold and propensity toward the start of stage 4–5 seizures and improved phenotypical deficits,that is,anxiety,depression,and memory impairments.Moreover,this combination therapy mitigated kindling-induced redox impairments as evidenced by reduced malondialdehyde and acetylcholinesterase levels and increased glutathione antioxidant activity in the brain of animals subjected to repetitive brain insult.Conclusion:Based on our outcomes,this dual therapy provides supporting evidence in alleviating epilepsy-induced neurobehavioral comorbidities and changes in redox homeostasis.展开更多
To the editor:The superior semicircular canal dehiscence was first described by Minor et all in 1998 as a condition in which the superior semicircular canal lacks a bony covering and has gained constantly increasing i...To the editor:The superior semicircular canal dehiscence was first described by Minor et all in 1998 as a condition in which the superior semicircular canal lacks a bony covering and has gained constantly increasing interest since its discovery.2 The symptoms are varied but specific what is known as Minor syndrome or‘third mobile window’syndrome,'as patients may experience autophony with abnormally loud sounds like footsteps,chewing,breathing,eye movement,echoing voice,distortion of environmental sounds and pulsatile tinnitus.展开更多
基金FEDER Prostem Research Project,No.1510614(Wallonia DG06)the F.R.S.-FNRS Epiforce Project,No.T.0092.21+4 种基金the F.R.S.-FNRS Cell Squeezer Project,No.J.0061.23the F.R.S.-FNRS Optopattern Project,No.U.NO26.22the Interreg MAT(T)ISSE Project,which is financially supported by Interreg France-Wallonie-Vlaanderen(Fonds Européen de Développement Régional,FEDER-ERDF)Programme Wallon d’Investissement Région Wallone pour les instruments d’imagerie(INSTIMAG UMONS#1910169)support from the European Research Council(ERC)under the European Union’s Horizon 2020 research and innovation programme(AdG grant agreement no.834317,Fueling Transport,PI Frédéric Saudou)。
文摘Advanced microsystems in traumatic brain injury research:Traumatic brain injury(TBI)results from a mechanical insult to the brain,leading to neuronal and axonal damage and subsequently causing a secondary injury.Within minutes of TBI,a neuroinflammatory response is triggered,driven by intricate molecular and cellular inflammatory processes.
基金supported by a grant from the French Society of Sleep Research and Medicine(to LS)The China Scholarship Council(to HL)The CNRS,INSERM,Claude Bernard University Lyon1(to LS)。
文摘The sleep-wake cycle stands as an integrative process essential for sustaining optimal brain function and,either directly or indirectly,overall body health,encompassing metabolic and cardiovascular well-being.Given the heightened metabolic activity of the brain,there exists a considerable demand for nutrients in comparison to other organs.Among these,the branched-chain amino acids,comprising leucine,isoleucine,and valine,display distinctive significance,from their contribution to protein structure to their involvement in overall metabolism,especially in cerebral processes.Among the first amino acids that are released into circulation post-food intake,branched-chain amino acids assume a pivotal role in the regulation of protein synthesis,modulating insulin secretion and the amino acid sensing pathway of target of rapamycin.Branched-chain amino acids are key players in influencing the brain's uptake of monoamine precursors,competing for a shared transporter.Beyond their involvement in protein synthesis,these amino acids contribute to the metabolic cycles ofγ-aminobutyric acid and glutamate,as well as energy metabolism.Notably,they impact GABAergic neurons and the excitation/inhibition balance.The rhythmicity of branchedchain amino acids in plasma concentrations,observed over a 24-hour cycle and conserved in rodent models,is under circadian clock control.The mechanisms underlying those rhythms and the physiological consequences of their disruption are not fully understood.Disturbed sleep,obesity,diabetes,and cardiovascular diseases can elevate branched-chain amino acid concentrations or modify their oscillatory dynamics.The mechanisms driving these effects are currently the focal point of ongoing research efforts,since normalizing branched-chain amino acid levels has the ability to alleviate the severity of these pathologies.In this context,the Drosophila model,though underutilized,holds promise in shedding new light on these mechanisms.Initial findings indicate its potential to introduce novel concepts,particularly in elucidating the intricate connections between the circadian clock,sleep/wake,and metabolism.Consequently,the use and transport of branched-chain amino acids emerge as critical components and orchestrators in the web of interactions across multiple organs throughout the sleep/wake cycle.They could represent one of the so far elusive mechanisms connecting sleep patterns to metabolic and cardiovascular health,paving the way for potential therapeutic interventions.
基金supported by ANR(ANR-21-CE16-0008-01)ANR(ANR-21-CE16-0008-02 and ANR-23-CE52-0007)+2 种基金UNADEV(A22018CS)UNADEV(A22020CS)(to SB)ERC(ERC-St17-759089)(to HN)。
文摘Over the centuries,the regeneration field has been puzzled by the dual response of the central nervous system(CNS-brain,spinal cord,cranial nervesⅠandⅡ)and the peripheral nervous system(PNS that refers to all the nerves that innervate muscles,skin,organs,bones among others).Even Ramon y Cajal had noticed that an injury to the PNS often leads to axon regrowth,in contrast to the CNS.
文摘The second messengers 3',5'-cyclic adenosine monophosphate(cAMP)and 3',5'-cyclic guanosine monophosphate(cGMP)modulate molecular pathways that are involved in a large variety of cellular processes.In the brain,these processes include neurogenesis,neuronal differentiation,activation and function of microglia,and synaptic plasticity,finally resulting in memory formation.
基金supported by European Regional Development Funds RE0022527 ZEBRATOX(EU-Région Réunion-French State national counterpart,to Nicolas Diotel and Jean-Loup Bascands).
文摘After brain damage,regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals,suggesting a close link between these processes.However,the mechanisms by which these processes interact are not well understood.In this work,we aimed to study the correlation between angiogenesis and neurogenesis after a telencephalic stab wound injury.To this end,we used zebrafish as a relevant model of neuroplasticity and brain repair mechanisms.First,using the Tg(fli1:EGFP×mpeg1.1:mCherry)zebrafish line,which enables visualization of blood vessels and microglia respectively,we analyzed regenerative angiogenesis from 1 to 21 days post-lesion.In parallel,we monitored brain cell proliferation in neurogenic niches localized in the ventricular zone by using immunohistochemistry.We found that after brain damage,the blood vessel area and width as well as expression of the fli1 transgene and vascular endothelial growth factor(vegfaa and vegfbb)were increased.At the same time,neural stem cell proliferation was also increased,peaking between 3 and 5 days post-lesion in a manner similar to angiogenesis,along with the recruitment of microglia.Then,through pharmacological manipulation by injecting an anti-angiogenic drug(Tivozanib)or Vegf at the lesion site,we demonstrated that blocking or activating Vegf signaling modulated both angiogenic and neurogenic processes,as well as microglial recruitment.Finally,we showed that inhibition of microglia by clodronate-containing liposome injection or dexamethasone treatment impairs regenerative neurogenesis,as previously described,as well as injury-induced angiogenesis.In conclusion,we have described regenerative angiogenesis in zebrafish for the first time and have highlighted the role of inflammation in this process.In addition,we have shown that both angiogenesis and neurogenesis are involved in brain repair and that microglia and inflammation-dependent mechanisms activated by Vegf signaling are important contributors to these processes.This study paves the way for a better understanding of the effect of Vegf on microglia and for studies aimed at promoting angiogenesis to improve brain plasticity after brain injury.
基金supported by a grant from the French Multiple Sclerosis Society(ARSEP,Grant Number:R20163LL)(to AMG)。
文摘Multiple sclerosis(MS)is the most common chronic disease of the central nervous system(CNS)in young adults and represents the first cause of severe handicap,originally non-traumatic(Oh et al.,2018).MS is chara cterized by the infiltration of auto reactive lymphocytes specific to myelin through the blood-brain barrier,which results in the appearance of inflammatory demyelinating lesions caused by the death of the central nervous system myelinating cells,oligodendrocytes(Oh et al.,2018).There is a prevalence sexual with a ratio of three times more affected women than men.
基金supported by LifeArc Philanthropic Fund(P2019-0004)LifeArc Pathfinder Award+7 种基金along with Wellcome Trust Seed Award(109626/Z/15/Z)FA PESP-UoB Strategic Collaboration FundBirmingham Fellowship(to SS)grants from Laboratoire d'Excellence Revive(Investissement d'AvenirANR-10-LABX-73)the Region lle-de-France via doctoral school Innovation Therapeutique,du Fondamentalàl'Appliqué(ED569)from Universite Paris-Saclay(to LA)Medical Research Council(MRC)Developmental Pathway Funding Scheme(DPFS)grant(MR/P007732/1)(to TB)supported by the Association Fran?aise contre les Myopathies(AFM-Téléthon)。
文摘Mitochondria and mitochondria-associated endoplasmic reticulum membrane in neurodegenerative diseases:Mitochondria generate most of the chemical energy needed to power the biochemical reactions of cells,and thus are often referred to as the"powerhouse"of the cell.Nevertheless,this organelle is also involved in a pleth,ora of different cellular functions such as calcium(Ca^(2+))homeostasis,apoptosis,oxidative stress,and several metabolic pathways including oxidative phosphorylation,tricarboxylic acid cycle,andβ-oxidation of fatty acids.
基金supported by ANR(ANR-21CE16-0008-01)ANR(ANR-21-CE16-0008-02 and ANR-23CE52-0007)+1 种基金UNADEV(A22018CS)(to HN)UNADEV(A22020CS)(to SB)。
文摘The mature central nervous system(CNS,composed of the brain,spinal cord,olfactory and optic nerves)is unable to regenerate spontaneously after an insult,both in the cases of neurodegenerative diseases(for example Alzheimer's or Parkinson's disease)or traumatic injuries(such as spinal cord lesions).In the last 20 years,the field has made significant progress in unlocking axon regrowth.
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD)is a highly prevalent liver pathology in need of novel pharmacological treatments to complement lifestyle-based interventions.Nuclear receptor agonists have been under scrutiny as potential pharmacological targets and as of today,resmetirom,a thyroid hormone receptor b agonist,is the only approved agent.The dual PPARαandδagonist elafibranor has also undergone extensive clinical testing,which reached the phase III clinical trial but failed to demonstrate a beneficial effect on MASLD.As alcohol-associated liver disease and MASLD can be interconnected,whether elafibranor might be affective against liver disease caused by alcohol consumption is worth investigating.Writing recently in the World Journal of Gastroenterology,Koizumi et al reported using a mouse model of alcoholassociated liver disease and found that hepatic steatosis,liver fibrosis,and hepatocyte apoptosis were alleviated by administration of elafibranor.Although preclinical in nature,these data support the potential beneficial action of elafibranor in alcohol-induced MASLD,warranting the testing of this molecule in patients with steatotic liver disease caused by alcohol consumption.
文摘In 1993,the World Bank released a global report on the efficacy of health promotion,introducing the disability-adjusted life years(DALY)as a novel indicator.The DALY,a composite metric incorporating temporal and qualitative data,is grounded in preferences regarding disability status.This review delineates the algorithm used to calculate the value of the proposed DALY synthetic indicator and elucidates key methodological challenges associated with its application.In contrast to the quality-adjusted life years approach,derived from multi-attribute utility theory,the DALY stands as an independent synthetic indicator that adopts the assumptions of the Time Trade Off utility technique to define Disability Weights.Claiming to rely on no mathematical or economic theory,DALY users appear to have exempted themselves from verifying whether this indicator meets the classical properties required of all indicators,notably content validity,reliability,specificity,and sensitivity.The DALY concept emerged primarily to facilitate comparisons of the health impacts of various diseases globally within the framework of the Global Burden of Disease initiative,leading to numerous publications in international literature.Despite widespread adoption,the DALY synthetic indicator has prompted significant methodological concerns since its inception,manifesting in inconsistent and non-reproducible results.Given the substantial diffusion of the DALY indicator and its critical role in health impact assessments,a reassessment is warranted.This reconsideration is imperative for enhancing the robustness and reliability of public health decisionmaking processes.
文摘N-methyl-D-aspartate receptors(NMDARs)play crucial roles in neuronal plasticity and brain function by sensing key neurotransmitters,such as glutamate and glycine.In a tour-de-force,Zhang et al.[1]provide the first images of native NMDARs directly extracted from rat brains,revealing key aspects of NMDAR assembly and diversity.
基金National Research Agency under the Investments for the Future program (ANR-10-IAHU-01)Filière Nationale TeteCou for financial support。
文摘Gain-of-function mutations in fibroblast growth factor receptor(FGFR) genes lead to chondrodysplasia and craniosynostoses. FGFR signaling has a key role in the formation and repair of the craniofacial skeleton. Here, we analyzed the impact of Fgfr2- and Fgfr3- activating mutations on mandibular bone formation and endochondral bone repair after non-stabilized mandibular fractures in mouse models of Crouzon syndrome(Crz) and hypochondroplasia(Hch).
基金supported by AFM-Telethon grants N°21704 and 23264,Universite Paris Cite(Paris)the National Institute of Health and Medical Research(INSERM)+3 种基金the National Center for Scientific Research(CNRS)the French Association Connaître les Syndromes Cerebelleux(CSC)(to MCD)GV/2021/188 granted from Conselleria of Innovation,Universities,28 Science and Society digital of the Community of Valencia(Spain)(to ITC)Subprograma Atraccion de Talento-Contratos Postdoctorales de la Universitat de Valencia(to IMY).
文摘Neurodevelopmental and neurodegenerative illnesses constitute a global health issue and a foremost economic burden since they are a large cause of incapacity and death worldwide.Altogether,the burden of neurological disorders has increased considerably over the past 30 years because of population aging.Overall,neurological diseases significantly impair cognitive and motor functions and their incidence will increase as societies age and the world's population continues to grow.Autism spectrum disorder,motor neuron disease,encephalopathy,epilepsy,stroke,ataxia,Alzheimer's disease,amyotrophic lateral sclerosis,Huntington's disease,and Parkinson's disease represent a non-exhaustive list of neurological illnesses.These affections are due to perturbations in cellular homeostasis leading to the progressive injury and death of neurons in the nervous system.Among the common features of neurological handicaps,we find protein aggregation,oxidative stress,neuroinflammation,and mitochondrial impairment in the target tissues,e.g.,the brain,cerebellum,and spinal cord.The high energy requirements of neurons and their inability to produce sufficient adenosine triphosphate by glycolysis,are responsible for their dependence on functional mitochondria for their integrity.Reactive oxygen species,produced along with the respiration process within mitochondria,can lead to oxidative stress,which compromises neuronal survival.Besides having an essential role in energy production and oxidative stress,mitochondria are indispensable for an array of cellular processes,such as amino acid metabolism,iron-sulfur cluster biosynthesis,calcium homeostasis,intrinsic programmed cell death(apoptosis),and intraorganellar signaling.Despite the progress made in the last decades in the understanding of a growing number of genetic and molecular causes of central nervous diseases,therapies that are effective to diminish or halt neuronal dysfunction/death are rare.Given the genetic complexity responsible for neurological disorders,the development of neuroprotective strategies seeking to preserve mitochondrial homeostasis is a realistic challenge to lastingly diminish the harmful evolution of these pathologies and so to recover quality of life.A promising candidate is the neuroglobin,a globin superfamily member of 151 amino acids,which is found at high levels in the brain,the eye,and the cerebellum.The protein,which localizes to mitochondria,is involved in electron transfer,oxygen storage and defence against oxidative stress;hence,possessing neuroprotective properties.This review surveys up-to-date knowledge and emphasizes on existing investigations regarding neuroglobin physiological functions,which remain since its discovery in 2000 under intense debate and the possibility of using neuroglobin either by gene therapy or its direct delivery into the brain to treat neurological disorders.
文摘Human-derived tumor models are essential for preclinical development of new anti-cancer drug entities.Generating animal models bearing tumors of human origin,such as patient-derived or cell line-derived xenograft tumors,is dependent on immuno-deficient strains.Tumor-bearing immunodeficient mice are susceptible to develop-ing unwanted disorders primarily irrelevant to the tumor nature;and if get involved with such disorders,reliability of the study results will be undermined,inevitably con-founding the research in general.Therefore,a rigorous health surveillance and clinical monitoring system,along with the establishment of a strictly controlled barrier facility to maintain a pathogen-free state,are mandatory.Even if all pathogen control and biosafety measures are followed,there are various noninfectious disorders capable of causing tissue and multiorgan damage in immunodeficient animals.Therefore,the re-searchers should be aware of sentinel signs to carefully monitor and impartially report them.This review discusses clinical signs of common unwanted disorders in experi-mental immunodeficient mice,and how to examine and report them.
基金The authors extended their appreciation to Distinguished Scientist Fellowship program at King Saud University,Riyadh,Saudi Arabia,for funding this work through research supporting project number(RSP2024R131).
文摘Background:Scientific evidence to guide clinicians on the use of different antiseizure drugs in combination therapy is either very limited or lacking.In this study,the impact of lacosamide and perampanel alone and in combination was tested in corneal kindling model in mice,which is a cost-effective mechanism for screening of antiseizure drugs.Methods:The impact of lacosamide(5 mg/kg)and perampanel(0.125 mg/kg)alone and their combination was tested in corneal kindling process(3-mA current for 3 s applied twice daily for consecutive 12 days)in male BALB/c mice.Post-kindling,mice were subjected to a battery of behavioral tests assessing anxiety,memory,and depression-like behaviors.Brain tissues were then harvested for analysis of oxidative stress biomarkers.Results:Our results showed that the combination therapy of lacosamide and perampanel was more effective in reducing seizure progression than monotherapy of these drugs.Animals treated with combination therapy showed significant behavioral improvements,as reduced anxiety and depression were noticed,and their cognitive abilities were notably better compared to animals of all other groups.Moreover,biochemical assays of isolated brains from combination-treated group revealed lesser amount of oxidative stress.In addition,outcomes of dual regime were comparable to the phenytoin in seizure control but showed superior benefits in mitigation of kindling-prompted behavioral dysfunction and oxidative stress.Conclusions:This study suggests that the lacosamide and perampanel combination therapy worked noticeably better in halting the corneal kindling process in mice and improved the epilepsy-associated psychiatric disorders that might be due to antioxidant effects of both drugs.
文摘Gallstone pancreatitis is the leading cause of acute pancreatitis,accounting for more than 40%of cases.Etiological treatment is a critical issue in acute biliary pancreatitis as it helps reduce the risk of recurrence.Patients who have ex-perienced a complicated form of biliary disease are at high risk for recurrent episodes,and the severity of these new episodes can be unpredictable.In recent years,the role and timing of cholecystectomy and endoscopic retrograde cholan-giopancreatography(ERCP),which are the main therapeutic interventions in the etiological treatment,have been considerably clarified.This review aims to detail the different aspects of the etiological treatment of acute biliary pancreatitis.Currently,it is established that cholecystectomy should be performed early during the initial hospitalization in cases of non-severe acute pancreatitis.However,the optimal timing of this procedure in severe acute pancreatitis remains a subject of debate.Emergency ERCP is no longer indicated for acute biliary pancreatitis,except in cases of associated acute cholangitis.ERCP can be useful for the management of persistent bile duct stones.Finally,the role of interval sphincterotomy in frail or elderly patients or to reduce the risk of re-currence in those awaiting cholecystectomy in cases of severe acute pancreatitis remains to be fully established.
基金The authors extend their appreciation to the Distinguished Scientist Fellowship program at King Saud University,Riyadh,Saudi Arabia,for funding this work through Research Supporting Project Number RSP2024R131.
文摘Background:Besides seizures,a myriad of overlapping neuropsychiatric and cognitive comorbidities occur in patients with epilepsy,which further debilitates their quality of life.This study provides an in-depth characterization of the impact of brivaracetam and rufinamide individually and in combination at 10 and 20 mg/kg doses,respec-tively,on corneal kindling-induced generalized seizures and behavioral alterations.Furthermore,observed convulsive frequency and behavioral changes were corre-lated to post-kindling-induced changes in the activity of markers of oxidative stress.Methods:Adult C57BL/6 mice were kindled via twice-daily transcorneal 50-Hz elec-trical stimulations(3 mA)for 3 s for 12 days until animals reached a fully kindled state.After the kindling procedure,animals were tested using a set of behavioral tests,and neurochemical alterations were assessed.Results:Corneal-kindled animals exhibited intense generalized convulsions,altered behavioral phenotypes typified by positive symptoms(hyperlocomotion),negative symptoms(anxiety and anhedonia),and deficits in semantic and working memory.BRV 10+RFM 20 dual regime increased convulsive threshold and propensity toward the start of stage 4–5 seizures and improved phenotypical deficits,that is,anxiety,depression,and memory impairments.Moreover,this combination therapy mitigated kindling-induced redox impairments as evidenced by reduced malondialdehyde and acetylcholinesterase levels and increased glutathione antioxidant activity in the brain of animals subjected to repetitive brain insult.Conclusion:Based on our outcomes,this dual therapy provides supporting evidence in alleviating epilepsy-induced neurobehavioral comorbidities and changes in redox homeostasis.
文摘To the editor:The superior semicircular canal dehiscence was first described by Minor et all in 1998 as a condition in which the superior semicircular canal lacks a bony covering and has gained constantly increasing interest since its discovery.2 The symptoms are varied but specific what is known as Minor syndrome or‘third mobile window’syndrome,'as patients may experience autophony with abnormally loud sounds like footsteps,chewing,breathing,eye movement,echoing voice,distortion of environmental sounds and pulsatile tinnitus.
