The metabolite lactate (L-lactate) can be generated and released by diverse brain cells,including neurons,astrocytes,and oligodendrocytes (Kann,2023;Rae et al.,2024).Lactate production usually requires the degradation...The metabolite lactate (L-lactate) can be generated and released by diverse brain cells,including neurons,astrocytes,and oligodendrocytes (Kann,2023;Rae et al.,2024).Lactate production usually requires the degradation of glucose (D-glucose)-and glycogen in astrocytes-to pyruvate by glycolysis and subsequent conversion of pyruvate to lactate by the enzyme lactate dehydrogenase(Figure 1A;Dienel,2019;Rae et al.,2024).展开更多
BACKGROUND Single-nucleotide polymorphisms(SNPs)of the serotonin type 3 receptor subunit(HTR3)genes have been associated with psychosomatic symptoms,but it is not clear whether these associations exist in irritable bo...BACKGROUND Single-nucleotide polymorphisms(SNPs)of the serotonin type 3 receptor subunit(HTR3)genes have been associated with psychosomatic symptoms,but it is not clear whether these associations exist in irritable bowel syndrome(IBS).AIM To assess the association of HTR3 polymorphisms with depressive,anxiety,and somatization symptoms in individuals with IBS.METHODS In this retrospective study,623 participants with IBS were recruited from five specialty centers in Germany,Sweden,the United States,the United Kingdom,and Ireland.Depressive,anxiety,and somatization symptoms and sociodemographic characteristics were collected.Four functional SNPs—HTR3A c.-42C>T,HTR3B c.386A>C,HTR3C c.489C>A,and HTR3E c.*76G>A—were genotyped and analyzed using the dominant and recessive models.We also performed separate analyses for sex and IBS subtypes.SNP scores were calculated as the number of minor alleles of the SNPs above.The impact of HTR3C c.489C>A was tested by radioligand-binding and calcium influx assays.RESULTS Depressive and anxiety symptoms significantly worsened with increasing numbers of minor HTR3C c.489C>A alleles in the dominant model(F_(depressive)=7.475,P_(depressive)=0.006;F_(anxiety)=6.535,P_(anxiety)=0.011).A higher SNP score(range 0-6)was linked to a worsened depressive symptoms score(F=7.710,P-linear trend=0.006)in IBS.The potential relevance of the HTR3C SNP was corroborated,showing changes in the expression level of 5-HT3AC variant receptors.CONCLUSION We have provided the first evidence that HTR3C c.489C>A is involved in depressive and anxiety symptoms in individuals with IBS.The SNP score indicated that an increasing number of minor alleles is linked to the worsening of depressive symptoms in IBS.展开更多
Oxidative stress has long been implicated as a driving force in neurodegenerative disease,with studies of human brain tissue and animal models revealing its important role.Parkinson’s disease(PD),in particular,highli...Oxidative stress has long been implicated as a driving force in neurodegenerative disease,with studies of human brain tissue and animal models revealing its important role.Parkinson’s disease(PD),in particular,highlights the selective vulnerability of neurons to the insults of reactive oxygen species.The motor symptoms of PD are caused by degeneration of dopamine neurons in the substantia nigra.These neurons experience increased oxidative stress due in part to highly active mitochondria that support their high bioenergetic demand and the generation of reactive oxygen species by dopamine metabolism(Watanabe et al.,2024).展开更多
Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical d...Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development. Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites. Aging, preexisting liver disease, enzyme induction or inhibition, genetic variances, local 02 supply and, above all, the intrinsic molecular properties of the drug may affect this process. Necrotic death follows antioxidant consumption and oxidation of intracellular proteins, which determine increased permeability of mitochondrial membranes, loss of potential, decreased ATP synthesis, inhibition of Ca^2＋-dependent ATPase, reduced capability to sequester Ca^2＋ within mitochondria, and membrane bleb formation. Conversely, activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis. Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage. Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis, in which different HLA genotypes might play a major role. This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage. Future perspectives including new frontiers for research are discussed.展开更多
Neuroimaging of cerebral glucose metabolism and blood flow is ideally suited to assay widely-distributed brain circuits as a result of local molecular events and behavioral modulation in the central nervous system. Wi...Neuroimaging of cerebral glucose metabolism and blood flow is ideally suited to assay widely-distributed brain circuits as a result of local molecular events and behavioral modulation in the central nervous system. With the progress in novel analytical methodology, this endeavor has succeeded in unraveling the mechanisms underlying a wide spectrum of neurodegenerative diseases. In particular, statistical brain mapping studies have made significant strides in describing the pathophysiology of Parkinson＇s disease （PD） and related disorders by providing signature biomarkers to determine the systemic abnormalities in brain function and evaluate disease progression, therapeutic responses, and clinical correlates in patients. In this article, we review the relevant clinical applications in patients in relation to healthy volunteers with a focus on the generation of unique spatial covariance patterns associated with the motor and cognitive symptoms underlying PD. These characteristic biomarkers can be potentially used not only to improve patient recruitment but also to predict outcomes in clinical trials.展开更多
The dopamine D1-D2 receptor agonist, R-apomorphine, has been shown to be neuroprotective in different models of Parkinson’s disease. Different mechanisms of action for this effect have been proposed, but not verified...The dopamine D1-D2 receptor agonist, R-apomorphine, has been shown to be neuroprotective in different models of Parkinson’s disease. Different mechanisms of action for this effect have been proposed, but not verified in the striatal 6-hydroxydopamine rat model. In this study, the expression of a set of genes involved in 1) signaling, 2) growth and differentiation, 3) neuronal regeneration and survival, 4) apoptosis and 5) inflammation in the striatum was measured after a subchronic R-apomorphine treatment (10 mg/kg/day, subcutaneously, during 11 days) in the striatal 6-hydroxydopamine rat model. The expression of 84 genes was analysed by using the rat neurotrophins and receptors RT2 ProfilerTM PCR array. The neuroprotective effects of R-apomorphine in the striatal 6-hydroxydopamine model were confirmed by neurochemical and behavioural analysis. The expression data suggest the observed neuroprotection involved the alteration of the gene and the protein expression levels of the anti-inflammatory corticotropin releasing hormone receptor (CRHR) 1 and the pro-inflammatory CRHR2 receptor confirming its potential anti-inflammatory action.展开更多
AIM: To investigate a possible association between losartan and sirtuin 1(SIRT1) in reduced-size orthotopic liver transplantation(ROLT) in rats.METHODS: Livers of male Sprague-Dawley rats(200-250 g) were preserved in ...AIM: To investigate a possible association between losartan and sirtuin 1(SIRT1) in reduced-size orthotopic liver transplantation(ROLT) in rats.METHODS: Livers of male Sprague-Dawley rats(200-250 g) were preserved in University of Wisconsin preservation solution for 1 h at 4 ℃ prior to ROLT.In an additional group,an antagonist of angiotensin Ⅱ type 1 receptor(AT1R),losartan,was orally administered(5 mg/kg) 24 h and 1 h before the surgical procedure to both the donors and the recipients.Transaminase(as an indicator of liver injury),SIRT1 activity,and nicotinamide adenine dinucleotide(NAD+,a co-factor necessary for SIRT1 activity) levels were determined by biochemical methods.Protein expression of SIRT1,acetylated Fox O1(ac-Fox O1),NAMPT(the precursor of NAD+),heat shock proteins(HSP70,HO-1) expression,endoplasmic reticulum stress(GRP78,IRE1 a,p-e IF2) and apoptosis(caspase 12 and caspase 3) parameters were determined by Western blot.Possible alterations in protein expression of mitogen activated protein kinases(MAPK),such as p-p38 and p-ERK,were also evaluated.Furthermore,the SIRT3 protein expression and m RNA levels were examined.RESULTS: The present study demonstrated that losartan administration led to diminished liver injury when compared to ROLT group,as evidenced by the significant decreases in alanine aminotransferase(358.3 ± 133.44 vs 206 ± 33.61,P < 0.05) and aspartate aminotransferase levels(893.57 ± 397.69 vs 500.85 ± 118.07,P < 0.05).The lessened hepatic injury in case of losartan was associated with enhanced SIRT1 protein expression and activity(5.27 ± 0.32 vs 6.08 ± 0.30,P < 0.05).This was concomitant with increased levels of NAD+(0.87 ± 0.22 vs 1.195 ± 0.144,P < 0.05) the co-factor necessary for SIRT1 activity,as well as with decreases in ac-Fox O1 expression.Losartan treatment also provoked significant attenuation of endoplasmic reticulum stress parameters(GRP78,IRE1 a,p-e IF2) which was consistent with reduced levels of both caspase 12 and caspase 3.Furthermore,losartan administration stimulated HSP70 protein expression and attenuated HO-1 expression.However,no changes were observed in protein or m RNA expression of SIRT3.Finally,the protein expression pattern of p-ERK and p-p38 were not altered upon losartan administration.CONCLUSION: The present study reports that losartan induces SIRT1 expression and activity,and that it reduces hepatic injury in a ROLT model.展开更多
Background:BioCen-128 is a new active pharmaceutical ingredient composed of a specific bovine thymic fraction of a polypeptide nature.Positive results of similar thymus extracts have been shown to be effective in dela...Background:BioCen-128 is a new active pharmaceutical ingredient composed of a specific bovine thymic fraction of a polypeptide nature.Positive results of similar thymus extracts have been shown to be effective in delaying the processes associated with aging,immunosenescence and Alzheimer’s disease(AD),where the inflammation plays an important role.Because of the anti-i nflammatory potential of BioCen-128,the aim of this study was to evaluate the granuloma model induced by a cotton wool implantation and the model induced by intracerebroventricular(ICV)administration of streptozotocin(STZ).Method:The experiment was carried out using male OF-1mice weighing 20±2 g.Results:Mice administered BioCen-128 in via the IP route at 5,10 and 20 mg/kg of corporal weigh showed a decrease in the wet and dry weights of the granuloma,providing evidence of a systemic anti-i nflammatory effect.In the ICV model of STZ,the administration of BioCen-128 improved cognitive function.Conclusion:These responses suggested an anti-neuroinflammatory effect explainable by the action of thymosinβ4 and thymosin alfa proteins.The results suggested that BioCen-128 could be used in the prevention and treatment of some diseases,for example AD,where neuroinflammation is one of the biological events that take place.展开更多
To determine whether reduced striatal D2 receptor binding reported in patients with idiopathic torsion dystonia is associated with the genotype, the authors used PET and [11C]- raclopride to assess non- manifesting ca...To determine whether reduced striatal D2 receptor binding reported in patients with idiopathic torsion dystonia is associated with the genotype, the authors used PET and [11C]- raclopride to assess non- manifesting carriers of the DYT1 mutation. D2 receptor binding was reduced by approximately 15% in caudate and putamen (p < 0.005). These results suggest that striatal D2 binding reductions are a trait feature of the DYT1 genotype.展开更多
Background:Multiple sclerosis(MS)is a complex chronic inflammatory and degenerative disorder of the central nervous system.Accelerated brain volume loss,or also termed atrophy,is currently emerging as a popular imagin...Background:Multiple sclerosis(MS)is a complex chronic inflammatory and degenerative disorder of the central nervous system.Accelerated brain volume loss,or also termed atrophy,is currently emerging as a popular imaging marker of neurodegeneration in affected patients,but,unfortunately,can only be reliably interpreted at the time when irreversible tissue damage likely has already occurred.Timing of treatment decisions based on brain atrophy may therefore be viewed as suboptimal.Main body:This Narrative Review focuses on alternative techniques with the potential of detecting neurodegenerative events in the brain of subjects with MS prior to the atrophic stage.First,metabolic and molecular imaging provide the opportunity to identify early subcellular changes associated with energy dysfunction,which is an assumed core mechanism of axonal degeneration in MS.Second,cerebral hypoperfusion has been observed throughout the entire clinical spectrum of the disorder but it remains an open question whether this serves as an alternative marker of reduced metabolic activity,or exists as an independent contributing process,mediated by endothelin-1 hyperexpression.Third,both metabolic and perfusion alterations may lead to repercussions at the level of network performance and structural connectivity,respectively assessable by functional and diffusion tensor imaging.Fourth and finally,elevated body fluid levels of neurofilaments are gaining interest as a biochemical mirror of axonal damage in a wide range of neurological conditions,with early rises in patients with MS appearing to be predictive of future brain atrophy.Conclusions:Recent findings from the fields of advanced neuroradiology and neurochemistry provide the promising prospect of demonstrating degenerative brain pathology in patients with MS before atrophy has installed.Although the overall level of evidence on the presented topic is still preliminary,this Review may pave the way for further longitudinal and multimodal studies exploring the relationships between the abovementioned measures,possibly leading to novel insights in early disease mechanisms and therapeutic intervention strategies.展开更多
Dear Editor,Afferent synapses of cochlear inner hair cells(IHCs)employ a unique molecular machinery(see extended background in Supplementary Materials).Otoferlin is a key player in this machinery and its defects cause...Dear Editor,Afferent synapses of cochlear inner hair cells(IHCs)employ a unique molecular machinery(see extended background in Supplementary Materials).Otoferlin is a key player in this machinery and its defects cause human auditory synaptopathy(Moser and Starr,2016).Otoferlin,a tail-anchored(Vogl et al.,2016)multi-C_(2)-domain protein(Fig.1Ai)specific to hair cells(Roux et al.,2006),is a member of the ferlin protein family involved in membrane trafficking and repair that are of major disease relevance(Pangršičet al.,2012),also see Supplementary Materials.Otoferlin is distributed broadly within IHCs(Fig.2Ai-Aiii;Pangrsic et al.,2010;Roux et al.,2006).展开更多
Endogenous electric fields （EFs） have been detected at wounds and damaged tissues. The potential roles of EFs in tissue repair and regeneration have been an intriguing topic for centuries. Recent researches have pro...Endogenous electric fields （EFs） have been detected at wounds and damaged tissues. The potential roles of EFs in tissue repair and regeneration have been an intriguing topic for centuries. Recent researches have provided significant insights into how naturally occurring EFs may participate in the control of tissue repair and regeneration. Applied EFs equivalent to the size of fields measured in vivo direct cell migration, cell proliferation and nerve sprouting at wounds. More remarkably, physiological EFs are a guidance cue that directs cell migration which overrides other well accepted directional signals including initial injury stimulation, wound void, contact inhibition release, population pressure and chemotaxis. EFs activate many intracellular signaling pathways in a directional manner. Modulation of endogenous wound EFs affects epithelial cell migration, cell proliferation, and nerve growth at cornea wounds in vivo. Electric stimulation is being tested clinically for the treatments of bone fracture, wound healing and spinal cord injury. EFs thus may represent a novel type of signaling paradigm in tissue repair and regeneration. Combination of the electric stimulation and other well understood biochemical regulatory mechanisms may offer powerful and effective therapies for tissue repair and regeneration. This review introduces experimental evidence for the existence of endogenous EFs and discusses their roles in tissue repair and regeneration.展开更多
Optical microscopy is an indispensable tool in biomedical sciences,but its reach in deep tissues is limited due to aberrations and scattering.This problem can be overcome by wavefront-shaping techniques,albeit at limi...Optical microscopy is an indispensable tool in biomedical sciences,but its reach in deep tissues is limited due to aberrations and scattering.This problem can be overcome by wavefront-shaping techniques,albeit at limited fields of view(FOVs).Inspired by astronomical imaging,conjugate wavefront shaping can lead to an increased field of view in microscopy,but this correction is limited to a set depth and cannot be dynamically adapted.Here,we present a conjugate wavefront-shaping scheme based on focus scanning holographic aberration probing(F-SHARP).We combine it with a compact implementation that can be readily adapted to a variety of commercial and home-built two-photon microscopes.We demonstrate the power of the method by imaging with high resolution over extended FOV(>80μm)deeper than 400μm inside a mouse brain through a thinned skull.展开更多
The aggregation of Amyloid-β(Aβ)peptides is associated with neurodegeneration in Alzheimer's disease(AD).We previously identified novel naphtalene derivatives,including the lead compound Amylovis-201,able to for...The aggregation of Amyloid-β(Aβ)peptides is associated with neurodegeneration in Alzheimer's disease(AD).We previously identified novel naphtalene derivatives,including the lead compound Amylovis-201,able to form thermodynamically stable complexes with Aβspecies,peptides and fibrils.As the drug showed a chemical scaffold coherent for an effective interaction with theσ_(1) receptor chaperone and asσ_(1) agonists are currently developed as potent neuroprotectants in AD,we investigated the pharmacological action of Amylovis-201 on theσ_(1) receptor.We report that Amylovis-201 is a potentσ_(1) agonist by several in silico,in vitro and in vivo assays and that its anti-amnesic and neuroprotective effects involve a pharmacological action atσ_(1) receptors.Furthermore,we show for the first time that classicalσ_(1) receptor agonist(PRE-084),and antagonist(NE-100)are able to interact and disaggregate Aβ_(25-35) fibrils.Interestingly,Amylovis-201 was the only compound inhibiting Aβ_(25-35) aggregates formation.Our results therefore highlight a dual action of Amylovis-201 as anti-aggregating agent andσ_(1) receptor agonist that could be highly effective in long-term treatment against neurodegeneration in AD.展开更多
A recent study by Chen et al.published in Nature reported the presence of activated T cells in the brains of transgenic mice with frontotemporal dementia(FTD)-like Tau protein pathology and in postmortem Alzheimer’s ...A recent study by Chen et al.published in Nature reported the presence of activated T cells in the brains of transgenic mice with frontotemporal dementia(FTD)-like Tau protein pathology and in postmortem Alzheimer’s disease(AD)brains.1 The infiltration of T cells correlated with the degree of Tau pathology and microglia activation,and appeared to promote neurotoxicity.The progressive aggregation of amyloid-β in extracellular amyloid plaques and of Tau in neurofibrillary tangles are the two main protein pathological hallmarks of AD.They are accompanied by synaptic loss,neuroinflammation,and neuronal death,and com-promise the blood-brain barrier,allowing immune cells to infiltrate the brain parenchyma and interact with glial cells and neurons;all of these factors contribute to disease progression.2 Activated T cells can be found in postmortem brains of different neurological disorders,in AD,particularly in areas with neuronal loss and Tau pathology,i.e.,the hippocampus and limbic structures.展开更多
The use of unconstrained lower limb exoskeletons has become a promising approach to assist individuals with gait impairments.The Honda Walking Assist(HWA)is a hip-assistive exoskeleton functioning as a gait trainer an...The use of unconstrained lower limb exoskeletons has become a promising approach to assist individuals with gait impairments.The Honda Walking Assist(HWA)is a hip-assistive exoskeleton functioning as a gait trainer and has been shown to improve several gait related outcomes after training.Studies investigating its immediate effects on spatiotemporal gait parameters other than walking speed in stroke survivors are lacking.The aim of this study was to investigate immediate differences in spatiotemporal gait parameters of stroke survivors between normal overground walking,walking with an unpowered,non-assisting HWA and walking with an optimally assisting HWA.Five ischemic stroke survivors(mean time since stroke 115±213.6 days)walked 3 times 5 m in each condition.Differences in 14 spatiotemporal gait parameters between all 3 conditions were registered and reported in a descriptive manner.With optimal assistance,4 patients walked faster(0.057–0.095 m/s)with longer strides of the paretic(0.055–0.069 m)and non-paretic(0.053–0.077 m)leg compared to normal walking.Compared to unpowered walking,all patients walked faster(0.020–0.063 m/s)in the optimal assist condition,with longer strides of the paretic(0.036–0.072 m)and non-paretic leg(0.045–0.082 m).During unpowered walking,gait velocity remained unchanged in 2 patients,increased(0.012_0.051 m/s)in 2 patients and decreased(-0.022 m/s)in 1 patient compared to normal walking.Changes in paretic stride lengths ranged from-0.066 to 0.029 m.The optimal individualized motor assistance provided by the HWA induces small,positive changes in gait parameters.This indicates that this light-weight hip-assistive exoskeleton can be of value in rehabilitation setting,where multiple training sessions with the device are possible.展开更多
文摘The metabolite lactate (L-lactate) can be generated and released by diverse brain cells,including neurons,astrocytes,and oligodendrocytes (Kann,2023;Rae et al.,2024).Lactate production usually requires the degradation of glucose (D-glucose)-and glycogen in astrocytes-to pyruvate by glycolysis and subsequent conversion of pyruvate to lactate by the enzyme lactate dehydrogenase(Figure 1A;Dienel,2019;Rae et al.,2024).
基金results in part from collaboration and network activities promoted under the frame of the international network GENIEUR (Genes in Irritable Bowel Syndrome Research Network Europe),which has been funded by the COST program (BM1106, www.GENIEUR.eu)currently supported by the European Society of Neurogastroenterology and Motility (ESNM, www.ESNM.eu)
文摘BACKGROUND Single-nucleotide polymorphisms(SNPs)of the serotonin type 3 receptor subunit(HTR3)genes have been associated with psychosomatic symptoms,but it is not clear whether these associations exist in irritable bowel syndrome(IBS).AIM To assess the association of HTR3 polymorphisms with depressive,anxiety,and somatization symptoms in individuals with IBS.METHODS In this retrospective study,623 participants with IBS were recruited from five specialty centers in Germany,Sweden,the United States,the United Kingdom,and Ireland.Depressive,anxiety,and somatization symptoms and sociodemographic characteristics were collected.Four functional SNPs—HTR3A c.-42C>T,HTR3B c.386A>C,HTR3C c.489C>A,and HTR3E c.*76G>A—were genotyped and analyzed using the dominant and recessive models.We also performed separate analyses for sex and IBS subtypes.SNP scores were calculated as the number of minor alleles of the SNPs above.The impact of HTR3C c.489C>A was tested by radioligand-binding and calcium influx assays.RESULTS Depressive and anxiety symptoms significantly worsened with increasing numbers of minor HTR3C c.489C>A alleles in the dominant model(F_(depressive)=7.475,P_(depressive)=0.006;F_(anxiety)=6.535,P_(anxiety)=0.011).A higher SNP score(range 0-6)was linked to a worsened depressive symptoms score(F=7.710,P-linear trend=0.006)in IBS.The potential relevance of the HTR3C SNP was corroborated,showing changes in the expression level of 5-HT3AC variant receptors.CONCLUSION We have provided the first evidence that HTR3C c.489C>A is involved in depressive and anxiety symptoms in individuals with IBS.The SNP score indicated that an increasing number of minor alleles is linked to the worsening of depressive symptoms in IBS.
基金supported by OHSU Neurology Foundation Funds and NIH Grant R01NS119226 to IM.
文摘Oxidative stress has long been implicated as a driving force in neurodegenerative disease,with studies of human brain tissue and animal models revealing its important role.Parkinson’s disease(PD),in particular,highlights the selective vulnerability of neurons to the insults of reactive oxygen species.The motor symptoms of PD are caused by degeneration of dopamine neurons in the substantia nigra.These neurons experience increased oxidative stress due in part to highly active mitochondria that support their high bioenergetic demand and the generation of reactive oxygen species by dopamine metabolism(Watanabe et al.,2024).
文摘Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development. Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites. Aging, preexisting liver disease, enzyme induction or inhibition, genetic variances, local 02 supply and, above all, the intrinsic molecular properties of the drug may affect this process. Necrotic death follows antioxidant consumption and oxidation of intracellular proteins, which determine increased permeability of mitochondrial membranes, loss of potential, decreased ATP synthesis, inhibition of Ca^2＋-dependent ATPase, reduced capability to sequester Ca^2＋ within mitochondria, and membrane bleb formation. Conversely, activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis. Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage. Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis, in which different HLA genotypes might play a major role. This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage. Future perspectives including new frontiers for research are discussed.
基金supported by NIH(R01 NS 35069)the Morris K.Udall Center of Excellence for Parkinson's Disease Research (NIH P50 NS 071675) at The Feinstein Institute for Medical Research,USA
文摘Neuroimaging of cerebral glucose metabolism and blood flow is ideally suited to assay widely-distributed brain circuits as a result of local molecular events and behavioral modulation in the central nervous system. With the progress in novel analytical methodology, this endeavor has succeeded in unraveling the mechanisms underlying a wide spectrum of neurodegenerative diseases. In particular, statistical brain mapping studies have made significant strides in describing the pathophysiology of Parkinson＇s disease （PD） and related disorders by providing signature biomarkers to determine the systemic abnormalities in brain function and evaluate disease progression, therapeutic responses, and clinical correlates in patients. In this article, we review the relevant clinical applications in patients in relation to healthy volunteers with a focus on the generation of unique spatial covariance patterns associated with the motor and cognitive symptoms underlying PD. These characteristic biomarkers can be potentially used not only to improve patient recruitment but also to predict outcomes in clinical trials.
基金financial support of the Institute for the promotion of Innovation by Science and Technology in Flanders(IWT)(IWT420)National Fund for Scientific Research(FWO-Vlaanderen)(G.0071.05)and of the Research Council of the Vrije Universiteit Brusselresearch grant from the IWT(IWT420).
文摘The dopamine D1-D2 receptor agonist, R-apomorphine, has been shown to be neuroprotective in different models of Parkinson’s disease. Different mechanisms of action for this effect have been proposed, but not verified in the striatal 6-hydroxydopamine rat model. In this study, the expression of a set of genes involved in 1) signaling, 2) growth and differentiation, 3) neuronal regeneration and survival, 4) apoptosis and 5) inflammation in the striatum was measured after a subchronic R-apomorphine treatment (10 mg/kg/day, subcutaneously, during 11 days) in the striatal 6-hydroxydopamine rat model. The expression of 84 genes was analysed by using the rat neurotrophins and receptors RT2 ProfilerTM PCR array. The neuroprotective effects of R-apomorphine in the striatal 6-hydroxydopamine model were confirmed by neurochemical and behavioural analysis. The expression data suggest the observed neuroprotection involved the alteration of the gene and the protein expression levels of the anti-inflammatory corticotropin releasing hormone receptor (CRHR) 1 and the pro-inflammatory CRHR2 receptor confirming its potential anti-inflammatory action.
基金Supported by Grants from Fondo de Investigaciones Sanitarias,No.FIS PI12/00519fellowship from Agència de Gestiód’Ajuts Universitaris i de Recerca,No.2012FI_B00382Generalitat de Catalunya,Barcelona,Catalonia,Spain(to Pantazi E)
文摘AIM: To investigate a possible association between losartan and sirtuin 1(SIRT1) in reduced-size orthotopic liver transplantation(ROLT) in rats.METHODS: Livers of male Sprague-Dawley rats(200-250 g) were preserved in University of Wisconsin preservation solution for 1 h at 4 ℃ prior to ROLT.In an additional group,an antagonist of angiotensin Ⅱ type 1 receptor(AT1R),losartan,was orally administered(5 mg/kg) 24 h and 1 h before the surgical procedure to both the donors and the recipients.Transaminase(as an indicator of liver injury),SIRT1 activity,and nicotinamide adenine dinucleotide(NAD+,a co-factor necessary for SIRT1 activity) levels were determined by biochemical methods.Protein expression of SIRT1,acetylated Fox O1(ac-Fox O1),NAMPT(the precursor of NAD+),heat shock proteins(HSP70,HO-1) expression,endoplasmic reticulum stress(GRP78,IRE1 a,p-e IF2) and apoptosis(caspase 12 and caspase 3) parameters were determined by Western blot.Possible alterations in protein expression of mitogen activated protein kinases(MAPK),such as p-p38 and p-ERK,were also evaluated.Furthermore,the SIRT3 protein expression and m RNA levels were examined.RESULTS: The present study demonstrated that losartan administration led to diminished liver injury when compared to ROLT group,as evidenced by the significant decreases in alanine aminotransferase(358.3 ± 133.44 vs 206 ± 33.61,P < 0.05) and aspartate aminotransferase levels(893.57 ± 397.69 vs 500.85 ± 118.07,P < 0.05).The lessened hepatic injury in case of losartan was associated with enhanced SIRT1 protein expression and activity(5.27 ± 0.32 vs 6.08 ± 0.30,P < 0.05).This was concomitant with increased levels of NAD+(0.87 ± 0.22 vs 1.195 ± 0.144,P < 0.05) the co-factor necessary for SIRT1 activity,as well as with decreases in ac-Fox O1 expression.Losartan treatment also provoked significant attenuation of endoplasmic reticulum stress parameters(GRP78,IRE1 a,p-e IF2) which was consistent with reduced levels of both caspase 12 and caspase 3.Furthermore,losartan administration stimulated HSP70 protein expression and attenuated HO-1 expression.However,no changes were observed in protein or m RNA expression of SIRT3.Finally,the protein expression pattern of p-ERK and p-p38 were not altered upon losartan administration.CONCLUSION: The present study reports that losartan induces SIRT1 expression and activity,and that it reduces hepatic injury in a ROLT model.
文摘Background:BioCen-128 is a new active pharmaceutical ingredient composed of a specific bovine thymic fraction of a polypeptide nature.Positive results of similar thymus extracts have been shown to be effective in delaying the processes associated with aging,immunosenescence and Alzheimer’s disease(AD),where the inflammation plays an important role.Because of the anti-i nflammatory potential of BioCen-128,the aim of this study was to evaluate the granuloma model induced by a cotton wool implantation and the model induced by intracerebroventricular(ICV)administration of streptozotocin(STZ).Method:The experiment was carried out using male OF-1mice weighing 20±2 g.Results:Mice administered BioCen-128 in via the IP route at 5,10 and 20 mg/kg of corporal weigh showed a decrease in the wet and dry weights of the granuloma,providing evidence of a systemic anti-i nflammatory effect.In the ICV model of STZ,the administration of BioCen-128 improved cognitive function.Conclusion:These responses suggested an anti-neuroinflammatory effect explainable by the action of thymosinβ4 and thymosin alfa proteins.The results suggested that BioCen-128 could be used in the prevention and treatment of some diseases,for example AD,where neuroinflammation is one of the biological events that take place.
文摘To determine whether reduced striatal D2 receptor binding reported in patients with idiopathic torsion dystonia is associated with the genotype, the authors used PET and [11C]- raclopride to assess non- manifesting carriers of the DYT1 mutation. D2 receptor binding was reduced by approximately 15% in caudate and putamen (p < 0.005). These results suggest that striatal D2 binding reductions are a trait feature of the DYT1 genotype.
文摘Background:Multiple sclerosis(MS)is a complex chronic inflammatory and degenerative disorder of the central nervous system.Accelerated brain volume loss,or also termed atrophy,is currently emerging as a popular imaging marker of neurodegeneration in affected patients,but,unfortunately,can only be reliably interpreted at the time when irreversible tissue damage likely has already occurred.Timing of treatment decisions based on brain atrophy may therefore be viewed as suboptimal.Main body:This Narrative Review focuses on alternative techniques with the potential of detecting neurodegenerative events in the brain of subjects with MS prior to the atrophic stage.First,metabolic and molecular imaging provide the opportunity to identify early subcellular changes associated with energy dysfunction,which is an assumed core mechanism of axonal degeneration in MS.Second,cerebral hypoperfusion has been observed throughout the entire clinical spectrum of the disorder but it remains an open question whether this serves as an alternative marker of reduced metabolic activity,or exists as an independent contributing process,mediated by endothelin-1 hyperexpression.Third,both metabolic and perfusion alterations may lead to repercussions at the level of network performance and structural connectivity,respectively assessable by functional and diffusion tensor imaging.Fourth and finally,elevated body fluid levels of neurofilaments are gaining interest as a biochemical mirror of axonal damage in a wide range of neurological conditions,with early rises in patients with MS appearing to be predictive of future brain atrophy.Conclusions:Recent findings from the fields of advanced neuroradiology and neurochemistry provide the promising prospect of demonstrating degenerative brain pathology in patients with MS before atrophy has installed.Although the overall level of evidence on the presented topic is still preliminary,this Review may pave the way for further longitudinal and multimodal studies exploring the relationships between the abovementioned measures,possibly leading to novel insights in early disease mechanisms and therapeutic intervention strategies.
基金supported by the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation),under Germany’s Excellence Strategy—EXC 2067/1-390729940(to T.M.,N.B.and J.P.),via the Collaborative Research Center 889(to N.S.,C.W.,J.P.,N.B.and T.M.),via DFG VO 2138/7‐1(to B.V.),and via the Leibniz Program(to T.M.)supported by Fondation Pour l’Audition(FPA RD-2020-10)to T.M.Fundação de AmparoàPesquisa do Estado de São Paulo(CEPID 2013/08028-1)to R.C.M.N..
文摘Dear Editor,Afferent synapses of cochlear inner hair cells(IHCs)employ a unique molecular machinery(see extended background in Supplementary Materials).Otoferlin is a key player in this machinery and its defects cause human auditory synaptopathy(Moser and Starr,2016).Otoferlin,a tail-anchored(Vogl et al.,2016)multi-C_(2)-domain protein(Fig.1Ai)specific to hair cells(Roux et al.,2006),is a member of the ferlin protein family involved in membrane trafficking and repair that are of major disease relevance(Pangršičet al.,2012),also see Supplementary Materials.Otoferlin is distributed broadly within IHCs(Fig.2Ai-Aiii;Pangrsic et al.,2010;Roux et al.,2006).
基金This research was supported by the National Natural Science Foundation of China （No. 30871269）.Acknowledgement We are very grateful to Mr. Vu Tran （Dermatology, University of California Davis, USA） for his critical reading of this manuscript.
文摘Endogenous electric fields （EFs） have been detected at wounds and damaged tissues. The potential roles of EFs in tissue repair and regeneration have been an intriguing topic for centuries. Recent researches have provided significant insights into how naturally occurring EFs may participate in the control of tissue repair and regeneration. Applied EFs equivalent to the size of fields measured in vivo direct cell migration, cell proliferation and nerve sprouting at wounds. More remarkably, physiological EFs are a guidance cue that directs cell migration which overrides other well accepted directional signals including initial injury stimulation, wound void, contact inhibition release, population pressure and chemotaxis. EFs activate many intracellular signaling pathways in a directional manner. Modulation of endogenous wound EFs affects epithelial cell migration, cell proliferation, and nerve growth at cornea wounds in vivo. Electric stimulation is being tested clinically for the treatments of bone fracture, wound healing and spinal cord injury. EFs thus may represent a novel type of signaling paradigm in tissue repair and regeneration. Combination of the electric stimulation and other well understood biochemical regulatory mechanisms may offer powerful and effective therapies for tissue repair and regeneration. This review introduces experimental evidence for the existence of endogenous EFs and discusses their roles in tissue repair and regeneration.
基金funding by the German Science Foundation DFG(projects 326649520 and 327654276/SFB 1315)the Human Frontiers Science Programme+1 种基金a Starting Grant by the European Research Council(ERC-2016-StG-714560)the Alfried Krupp Prize for Young University Teachers,awarded by the Alfried Krupp von Bohlen und Halbach-Stiftung.
文摘Optical microscopy is an indispensable tool in biomedical sciences,but its reach in deep tissues is limited due to aberrations and scattering.This problem can be overcome by wavefront-shaping techniques,albeit at limited fields of view(FOVs).Inspired by astronomical imaging,conjugate wavefront shaping can lead to an increased field of view in microscopy,but this correction is limited to a set depth and cannot be dynamically adapted.Here,we present a conjugate wavefront-shaping scheme based on focus scanning holographic aberration probing(F-SHARP).We combine it with a compact implementation that can be readily adapted to a variety of commercial and home-built two-photon microscopes.We demonstrate the power of the method by imaging with high resolution over extended FOV(>80μm)deeper than 400μm inside a mouse brain through a thinned skull.
基金supported by a PHC Carlos J.Finlay program from Campus France(project 47069SA)to TM and CRT.
文摘The aggregation of Amyloid-β(Aβ)peptides is associated with neurodegeneration in Alzheimer's disease(AD).We previously identified novel naphtalene derivatives,including the lead compound Amylovis-201,able to form thermodynamically stable complexes with Aβspecies,peptides and fibrils.As the drug showed a chemical scaffold coherent for an effective interaction with theσ_(1) receptor chaperone and asσ_(1) agonists are currently developed as potent neuroprotectants in AD,we investigated the pharmacological action of Amylovis-201 on theσ_(1) receptor.We report that Amylovis-201 is a potentσ_(1) agonist by several in silico,in vitro and in vivo assays and that its anti-amnesic and neuroprotective effects involve a pharmacological action atσ_(1) receptors.Furthermore,we show for the first time that classicalσ_(1) receptor agonist(PRE-084),and antagonist(NE-100)are able to interact and disaggregate Aβ_(25-35) fibrils.Interestingly,Amylovis-201 was the only compound inhibiting Aβ_(25-35) aggregates formation.Our results therefore highlight a dual action of Amylovis-201 as anti-aggregating agent andσ_(1) receptor agonist that could be highly effective in long-term treatment against neurodegeneration in AD.
基金This work was funded by the DZNE in the Helmholtz Society and the Einstein Foundation Berlin.
文摘A recent study by Chen et al.published in Nature reported the presence of activated T cells in the brains of transgenic mice with frontotemporal dementia(FTD)-like Tau protein pathology and in postmortem Alzheimer’s disease(AD)brains.1 The infiltration of T cells correlated with the degree of Tau pathology and microglia activation,and appeared to promote neurotoxicity.The progressive aggregation of amyloid-β in extracellular amyloid plaques and of Tau in neurofibrillary tangles are the two main protein pathological hallmarks of AD.They are accompanied by synaptic loss,neuroinflammation,and neuronal death,and com-promise the blood-brain barrier,allowing immune cells to infiltrate the brain parenchyma and interact with glial cells and neurons;all of these factors contribute to disease progression.2 Activated T cells can be found in postmortem brains of different neurological disorders,in AD,particularly in areas with neuronal loss and Tau pathology,i.e.,the hippocampus and limbic structures.
基金the Research Foundation Flanders(Fonds Wetenschappelijk Onderzoek,FWO)E.De Keersmaecker is funded by the FWO,award n°1S58421 N.M.Firouzi is funded by the FWO,award n°11G9622 N.
文摘The use of unconstrained lower limb exoskeletons has become a promising approach to assist individuals with gait impairments.The Honda Walking Assist(HWA)is a hip-assistive exoskeleton functioning as a gait trainer and has been shown to improve several gait related outcomes after training.Studies investigating its immediate effects on spatiotemporal gait parameters other than walking speed in stroke survivors are lacking.The aim of this study was to investigate immediate differences in spatiotemporal gait parameters of stroke survivors between normal overground walking,walking with an unpowered,non-assisting HWA and walking with an optimally assisting HWA.Five ischemic stroke survivors(mean time since stroke 115±213.6 days)walked 3 times 5 m in each condition.Differences in 14 spatiotemporal gait parameters between all 3 conditions were registered and reported in a descriptive manner.With optimal assistance,4 patients walked faster(0.057–0.095 m/s)with longer strides of the paretic(0.055–0.069 m)and non-paretic(0.053–0.077 m)leg compared to normal walking.Compared to unpowered walking,all patients walked faster(0.020–0.063 m/s)in the optimal assist condition,with longer strides of the paretic(0.036–0.072 m)and non-paretic leg(0.045–0.082 m).During unpowered walking,gait velocity remained unchanged in 2 patients,increased(0.012_0.051 m/s)in 2 patients and decreased(-0.022 m/s)in 1 patient compared to normal walking.Changes in paretic stride lengths ranged from-0.066 to 0.029 m.The optimal individualized motor assistance provided by the HWA induces small,positive changes in gait parameters.This indicates that this light-weight hip-assistive exoskeleton can be of value in rehabilitation setting,where multiple training sessions with the device are possible.
