Olfactory receptors are crucial for detecting odors and play a vital role in our sense of smell,influencing behaviors from food choices to emotional memories.These receptors also contribute to our perception of flavor...Olfactory receptors are crucial for detecting odors and play a vital role in our sense of smell,influencing behaviors from food choices to emotional memories.These receptors also contribute to our perception of flavor and have potential applications in medical diagnostics and environmental monitoring.The ability of the olfactory system to regenerate its sensory neurons provides a unique model to study neural regeneration,a phenomenon largely absent in the central nervous system.Insights gained from how olfactory neurons continuously replace themselves and reestablish functional connections can provide strategies to promote similar regenerative processes in the central nervous system,where damage often results in permanent deficits.Understanding the molecular and cellular mechanisms underpinning olfactory neuron regeneration could pave the way for developing therapeutic approaches to treat spinal co rd injuries and neurodegenerative diseases like Alzheimer's disease.Olfa ctory receptors are found in almost any cell of eve ry orga n/tissue of the mammalian body.This ectopic expression provides insights into the chemical structures that can activate olfactory receptors.In addition to odors,olfactory receptors in ectopic expression may respond to endogenous compounds and molecules produced by mucosal colonizing microbiota.The analysis of the function of olfactory receptors in ectopic expression provides valuable information on the signaling pathway engaged upon receptor activation and the receptor's role in proliferation and cell differentiation mechanisms.This review explo res the ectopic expression of olfa ctory receptors and the role they may play in neural regeneration within the central nervous system,with particular attention to compounds that can activate these receptors to initiate regenerative processes.Evidence suggests that olfactory receptors could serve as potential therapeutic targets for enhancing neural repair and recovery following central nervous system injuries.展开更多
“Last scene of all that ends this strange,eventful history,is second childishness and mere oblivion.I am sans teeth,sans eyes,sans taste,sans everything.”William Shakespeare‘As You Like It'Act 2,Sc.7,l.139Aging...“Last scene of all that ends this strange,eventful history,is second childishness and mere oblivion.I am sans teeth,sans eyes,sans taste,sans everything.”William Shakespeare‘As You Like It'Act 2,Sc.7,l.139Aging of the human brain is characterized by a progressive decline of its functional capacity;this decline however varies widely,and cognitive longevity differs substantially between individuals.展开更多
Autophagy is a cellular degradation and recycling system,indispensable for cellular and organ development,homeostasis,and function.This cellular process is evolutionarily highly conserved to quality control of many pr...Autophagy is a cellular degradation and recycling system,indispensable for cellular and organ development,homeostasis,and function.This cellular process is evolutionarily highly conserved to quality control of many proteins and dysfunctional organelles,which finally recycle components as amino acids.This process is effective during normal physiology as part of anabolism and plays an additional important role during starvation(Dikic and Elazar,2018).Different types of autophagy have been chara cterized based on their dynamic,mechanism of action,target substrates,and protein markers.Some of them are macroautophagy(hereafter called"autophagy"),microa utophagy,and chape rone-media ted autophagy(Fleming et al.,2022).展开更多
Metabolism is a fundamental process by which biochemicals are broken down to produce energy(catabolism) or used to build macromolecules(anabolism). Metabolism has received renewed attention as a mechanism that generat...Metabolism is a fundamental process by which biochemicals are broken down to produce energy(catabolism) or used to build macromolecules(anabolism). Metabolism has received renewed attention as a mechanism that generates molecules that modulate multiple cellular responses. This was first identified in cancer cells as the Warburg effect, but it is also present in immunocompetent cells. Studies have revealed a bidirectional influence of cellular metabolism and immune cell function, highlighting the significance of metabolic reprogramming in immune cell activation and effector functions. Metabolic processes such as glycolysis, oxidative phosphorylation, and fatty acid oxidation have been shown to undergo dynamic changes during immune cell response, facilitating the energetic and biosynthetic demands. This review aims to provide a better understanding of the metabolic reprogramming that occurs in different immune cells upon activation, with a special focus on central nervous system disorders. Understanding the metabolic changes of the immune response not only provides insights into the fundamental mechanisms that regulate immune cell function but also opens new approaches for therapeutic strategies aimed at manipulating the immune system.展开更多
The intricacies of Alzheimer’s disease pathogenesis are being increasingly illuminated by the exploration of epigenetic mechanisms,particularly DNA methylation.This review comprehensively surveys recent human-centere...The intricacies of Alzheimer’s disease pathogenesis are being increasingly illuminated by the exploration of epigenetic mechanisms,particularly DNA methylation.This review comprehensively surveys recent human-centered studies that investigate whole genome DNA methylation in Alzheimer’s disease neuropathology.The examination of various brain regions reveals distinctive DNA methylation patterns that associate with the Braak stage and Alzheimer’s disease progression.The entorhinal cortex emerges as a focal point due to its early histological alterations and subsequent impact on downstream regions like the hippocampus.Notably,ANK1 hypermethylation,a protein implicated in neurofibrillary tangle formation,was recurrently identified in the entorhinal cortex.Further,the middle temporal gyrus and prefrontal cortex were shown to exhibit significant hypermethylation of genes like HOXA3,RHBDF2,and MCF2L,potentially influencing neuroinflammatory processes.The complex role of BIN1 in late-onset Alzheimer’s disease is underscored by its association with altered methylation patterns.Despite the disparities across studies,these findings highlight the intricate interplay between epigenetic modifications and Alzheimer’s disease pathology.Future research efforts should address methodological variations,incorporate diverse cohorts,and consider environmental factors to unravel the nuanced epigenetic landscape underlying Alzheimer’s disease progression.展开更多
Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress.Likewise,microRNAs are inv...Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress.Likewise,microRNAs are involved in many biological processes and diseases playing a key role in pathogenesis,especially in multifactorial diseases such as Alzheimer’s disease.Therefore,our aim has been to provide partial insights into the interconnection between G9a,microRNAs,oxidative stress,and neuroinflammation.To better understand the biology of G9a,we compared the global microRNA expression between senescence-accelerated mouse-prone 8(SAMP8)control mice and SAMP8 treated with G9a inhibitor UNC0642.We found a downregulation of miR-128 after a G9a inhibition treatment,which interestingly binds to the 3′untranslated region(3′-UTR)of peroxisome-proliferator activator receptor γ(PPARG)mRNA.Accordingly,Pparg gene expression levels were higher in the SAMP8 group treated with G9a inhibitor than in the SAMP8 control group.We also observed modulation of oxidative stress responses might be mainly driven Pparg after G9a inhibitor.To confirm these antioxidant effects,we treated primary neuron cell cultures with hydrogen peroxide as an oxidative insult.In this setting,treatment with G9a inhibitor increases both cell survival and antioxidant enzymes.Moreover,up-regulation of PPARγby G9a inhibitor could also increase the expression of genes involved in DNA damage responses and apoptosis.In addition,we also described that the PPARγ/AMPK axis partially explains the regulation of autophagy markers expression.Finally,PPARγ/GADD45αpotentially contributes to enhancing synaptic plasticity and neurogenesis after G9a inhibition.Altogether,we propose that pharmacological inhibition of G9a leads to a neuroprotective effect that could be due,at least in part,by the modulation of PPARγ-dependent pathways by miR-128.展开更多
Dysfunction in circadian rhythms is a common occurrence in patients with Alzheimer’s disease.A predominant function of the retina is circadian synchronization,carrying information to the brain through the retinohypot...Dysfunction in circadian rhythms is a common occurrence in patients with Alzheimer’s disease.A predominant function of the retina is circadian synchronization,carrying information to the brain through the retinohypothalamic tract,which projects to the suprachiasmatic nucleus.Notably,Alzheimer’s disease hallmarks,including amyloid-β,are present in the retinas of Alzheimer’s disease patients,followed/associated by structural and functional disturbances.However,the mechanistic link between circadian dysfunction and the pathological changes affecting the retina in Alzheimer’s disease is not fully understood,although some studies point to the possibility that retinal dysfunction could be considered an early pathological process that directly modulates the circadian rhythm.展开更多
Modern neuroscience began from all reaching and fierce conflict between“neuronismo and reticulismo”——between neuronal and reticular theories of the organization of the nervous system;the conflict culminated in Dec...Modern neuroscience began from all reaching and fierce conflict between“neuronismo and reticulismo”——between neuronal and reticular theories of the organization of the nervous system;the conflict culminated in December of 1906 in Stockholm where Santiago Ramon y Cajal(the proponent of the neuronal doctrine)and Camillo Golgi(who advocated the syncytial reticular organization of neural networks)delivered their Noble prize lectures(Verkhratsky,2009).展开更多
Memory deficit,which is often associated with aging and many psychiatric,neurological,and neurodegenerative diseases,has been a challenging issue for treatment.Up till now,all potential drug candidates have failed to ...Memory deficit,which is often associated with aging and many psychiatric,neurological,and neurodegenerative diseases,has been a challenging issue for treatment.Up till now,all potential drug candidates have failed to produce satisfa ctory effects.Therefore,in the search for a solution,we found that a treatment with the gene corresponding to the RGS14414protein in visual area V2,a brain area connected with brain circuits of the ventral stream and the medial temporal lobe,which is crucial for object recognition memory(ORM),can induce enhancement of ORM.In this study,we demonstrated that the same treatment with RGS14414in visual area V2,which is relatively unaffected in neurodegenerative diseases such as Alzheimer s disease,produced longlasting enhancement of ORM in young animals and prevent ORM deficits in rodent models of aging and Alzheimer’s disease.Furthermore,we found that the prevention of memory deficits was mediated through the upregulation of neuronal arbo rization and spine density,as well as an increase in brain-derived neurotrophic factor(BDNF).A knockdown of BDNF gene in RGS14414-treated aging rats and Alzheimer s disease model mice caused complete loss in the upregulation of neuronal structural plasticity and in the prevention of ORM deficits.These findings suggest that BDNF-mediated neuronal structural plasticity in area V2 is crucial in the prevention of memory deficits in RGS14414-treated rodent models of aging and Alzheimer’s disease.Therefore,our findings of RGS14414gene-mediated activation of neuronal circuits in visual area V2 have therapeutic relevance in the treatment of memory deficits.展开更多
This letter praises a recent article in the World Journal of Clinical Cases(Roles of biochemistry data,lifestyle,and inflammation in identifying abnormal renal function in old Chinese),examining factors affecting abno...This letter praises a recent article in the World Journal of Clinical Cases(Roles of biochemistry data,lifestyle,and inflammation in identifying abnormal renal function in old Chinese),examining factors affecting abnormal renal function in elderly Chinese using advanced machine learning.It highlights the importance of uric acid,age,hemoglobin,body mass index,sport hours,and systolic blood pressure.The study's holistic approach,integrating lifestyle and inflammation,offers a nuanced understanding of chronic kidney disease risk factors.The letter suggests exploring mechanistic pathways of hyperuricemia,the link between anemia and renal function,and the connection between body mass index and estimated glomerular filtration rate.It advocates investigating physical activity's impact on renal health and the independent effects of blood pressure.The study significantly contributes to chronic kidney disease understanding,proposing avenues for further exploration and interventions.Commendations are extended to the authors and the journal.展开更多
Alzheimer’s disease(AD)is a major age-related form of dementia with a number of cases exponentially growing,causing enormous social and economic impact on individuals and society.Neuropathological hallmarks of AD,evi...Alzheimer’s disease(AD)is a major age-related form of dementia with a number of cases exponentially growing,causing enormous social and economic impact on individuals and society.Neuropathological hallmarks of AD,evident in postmortem AD brains,include a massive loss of the grey matter in the neocortex,extracellular deposition of amyloid-β(Aβ)in the form of senile plaques and cerebrovascular amyloid angiopathy,and intra-neuronal accumulation of neurofibrillary tangles,formed by hyper-phosphorylated tau protein.展开更多
Saffron has many pharmacological properties in addition to being a frequently used food seasoning.Crocin and picrocrocin which accumulate in saffron stigma,are responsible for these pharmacological properties.These na...Saffron has many pharmacological properties in addition to being a frequently used food seasoning.Crocin and picrocrocin which accumulate in saffron stigma,are responsible for these pharmacological properties.These natural products have health-promoting effects for the prevention and treatment of numerous diseases,including age-related cognitive and memory disfunction.Currently,crocin and picrocrocin are obtained from saffron,considered as the spice with the highest price in the market.To develop an efficient and low-cost approach to producing these compounds with high bioactivity,biosynthetic genes isolated from saffron can be exploited in the metabolic engineering of heterologous hosts and the production of crocins in productive crop plants.Recently,we engineered tomato fruit producing crocins(Tomafran).In this study,we demonstrated that crocin-rich extract,encapsulated in chitosan or in exosomes may function as a neuroprotective strategy.Crocins contained in the Tomafran extracts and much lower doses in chitosan nanoparticles or exosomes were enough to rescue the neuroblastoma cell line SH-SY5Y after damage caused by okadaic acid.Our results confirm the neuroprotective effect of Tomafran and its exosomes that may be useful for the delay or prevention of neurodegenerative disorders such as Alzheimer’s disease.展开更多
In recent years,the number of known disease genes has exponentially grown due to the widespread adoption of cost-effective massive parallel sequencing.To identify new disease variants,especially in monogenic disorders...In recent years,the number of known disease genes has exponentially grown due to the widespread adoption of cost-effective massive parallel sequencing.To identify new disease variants,especially in monogenic disorders,a frequency-based filtering approach has proved very useful(Dopazo et al.,2016).展开更多
Parkinson’s disease is a neurodegenerative condition characterized by motor impairments caused by the selective loss of dopaminergic neurons in the substantia nigra.Levodopa is an effective and well-tolerated dopamin...Parkinson’s disease is a neurodegenerative condition characterized by motor impairments caused by the selective loss of dopaminergic neurons in the substantia nigra.Levodopa is an effective and well-tolerated dopamine replacement agent.However,levodopa provides only symptomatic improvements,without affecting the underlying pathology,and is associated with side effects after long-term use.Cell-based replacement is a promising strategy that offers the possibility to replace lost neurons in Parkinson’s disease treatment.Clinical studies of transplantation of human fetal ventral mesencephalic tissue have provided evidence that the grafted dopaminergic neurons can reinnervate the striatum,release dopamine,integrate into the host neural circuits,and improve motor functions.One of the limiting factors for cell therapy in Parkinson’s disease is the low survival rate of grafted dopaminergic cells.Different factors could cause cell death of dopaminergic neurons after grafting such as mechanical trauma,growth factor deprivation,hypoxia,and neuroinflammation.Neurotrophic factors play an essential role in the survival of grafted cells.However,direct,timely,and controllable delivery of neurotrophic factors into the brain faces important limitations.Different types of cells secrete neurotrophic factors constitutively and co-transplantation of these cells with dopaminergic neurons represents a feasible strategy to increase neuronal survival.In this review,we provide a general overview of the pioneering studies on cell transplantation developed in patients and animal models of Parkinson’s disease,with a focus on neurotrophic factor-secreting cells,with a particular interest in mesenchymal stromal cells;that co-implanted with dopaminergic neurons would serve as a strategy to increase cell survival and improve graft outcomes.展开更多
Neurodegeneration affects a large number of cell types including neurons,astrocytes or oligodendrocytes,and neural stem cells.Neural stem cells can generate new neuronal populations through proliferation,migration,and...Neurodegeneration affects a large number of cell types including neurons,astrocytes or oligodendrocytes,and neural stem cells.Neural stem cells can generate new neuronal populations through proliferation,migration,and differentiation.This neurogenic potential may be a relevant factor to fight neurodegeneration and aging.In the last years,we can find growing evidence suggesting that melatonin may be a potential modulator of adult hippocampal neurogenesis.The lack of therapeutic strategies targeting neurogenesis led researchers to explore new molecules.Numerous preclinical studies with melatonin observed how melatonin can modulate and enhance molecular and signaling pathways involved in neurogenesis.We made a special focus on the connection between these modulation mechanisms and their implication in neurodegeneration,to summarize the current knowledge and highlight the therapeutic potential of melatonin.展开更多
In the last decade,attention has become greater to the relationship between neurodegeneration and abnormal insulin signaling in the central nervous system,as insulin in the brain is implicated in neuronal survival,pla...In the last decade,attention has become greater to the relationship between neurodegeneration and abnormal insulin signaling in the central nervous system,as insulin in the brain is implicated in neuronal survival,plasticity,oxidative stress and neuroinflammation.Diabetes mellitus and Parkinson’s disease are both aging-associated diseases that are turning into epidemics worldwide.Diabetes mellitus and insulin resistance not only increase the possibility of developing Parkinson’s disease but can also determine the prognosis and progression of Parkinsonian symptoms.Today,there are no available curative or disease modifying treatments for Parkinson’s disease,but the role of insulin and antidiabetic medications in neurodegeneration opens a door to treatment repurposing to fight against Parkinson’s disease,both in diabetic and nondiabetic Parkinsonian patients.Furthermore,it is essential to comprehend how a frequent and treatable disease such as diabetes can influence the progression of neurodegeneration in a challenging disease such as Parkinson’s disease.Here,we review the present evidence on the connection between Parkinson’s disease and diabetes and the consequential implications of the existing antidiabetic molecules in the severity and development of Parkinsonism,with a particular focus on glucagon-like peptide-1 receptor agonists.展开更多
Peripheral nerve injuries caused by accidents may lead to paralysis,sensory disturbances,anaesthesia,and lack of autonomic functions.Functional recovery after disconnection of the motoneuronal soma from target tissue ...Peripheral nerve injuries caused by accidents may lead to paralysis,sensory disturbances,anaesthesia,and lack of autonomic functions.Functional recovery after disconnection of the motoneuronal soma from target tissue with proximal rupture of axons is determined by several factors:motoneuronal soma viability,proper axonal sprouting across inhibitory zones and elongation toward specific muscle,effective synapse contact rebuilding,and prevention of muscle atrophy.Therapies,such as adjuvant drugs with pleiotropic effects,that promote functional recovery after peripheral nerve injury are needed.Toward this aim,we designed a drug discovery workflow based on a network-centric molecular vision using unbiased proteomic data and neural artificial computational tools.Our focus is on boosting intrinsic capabilities of neurons for neuroprotection;this is in contrast to the common approach based on suppression of a pathobiological pathway known to be associated with disease condition.Using our workflow,we discovered neuroheal,a combination of two repurposed drugs that promotes motoneuronal soma neuroprotection,is anti-inflammatory,enhances axonal regeneration after axotomy,and reduces muscle atrophy.This drug discovery workflow has thus yielded a therapy that is close to its clinical application.展开更多
Acetylation is a post-translational modification that is regulated by two antagonistic enzymes,histone acetyltransferases(HATs)and histone deacetylases(HDACs).HATs transfer the acetyl group from acetyl-CoA to lysine r...Acetylation is a post-translational modification that is regulated by two antagonistic enzymes,histone acetyltransferases(HATs)and histone deacetylases(HDACs).HATs transfer the acetyl group from acetyl-CoA to lysine residues of proteins while HDACs remove it(Yakhine-Diop et al.,2018b).The impairment of HAT or HDAC activity elicits changes in the protein acetylation status which disturb several cellular processes,among others,gene expression,autophagy etc.,leading finally to cell death.Both enzymes are associated with Parkinson’s disease(PD)pathogenesis.In dopaminergic cells,neurotoxins provoke apoptotic cell death by increasing histone acetylation levels.While paraquat(Song et al.,2011)and rotenone(Feng et al.,2015)reduce HDAC activity,dieldrin(Song et al.,2010)enhances HAT activity.However in vivo,paraquat-induced upregulation ofα-synuclein triggers histone hypoacetylation.展开更多
Chemotherapy-induced peripheral neuropathy is a very frequent neurological complication in cancer. Oxaliplatin（OXA） is a platinum analogue used as a first-line agent in the treatment of colorectal cancer. OXA induce...Chemotherapy-induced peripheral neuropathy is a very frequent neurological complication in cancer. Oxaliplatin（OXA） is a platinum analogue used as a first-line agent in the treatment of colorectal cancer. OXA induced peripheral neuropathy（OIN） is the main toxicity both during and after the completion of chemotherapy that presents as two distinct syndromes： acute and chronic neuropathy. None of the neuroprotective agents previously tested had prevented or limited the acute and/or chronic OIN. MR309（previously developed as E-52862） is a novel selective sigma-1 receptor（S1R） antagonist with preclinical analgesic activity in OXA-induced neuropathic pain in animal models. This review analyzes the results of the recently published phase Ⅱ, randomized, double-blind, placebo-controlled clinical trial including 124 patients with colorectal cancer（CRC） treated with MR309. This study shows encouraging findings in the setting of neuroprotection against OIN with an acceptable safety profile. The study demonstrated MR309 usefulness in decreasing acute OIN, by reducing cold hypersensitivity experienced by patients, and pointed to the amelioration of chronic OIN by lowering the proportion of patients who developed severe chronic OIN. In addition, we provide a summary and discussion on the pathways that can be modulated by the S1R to explain the observed clinical benefits in the OIN.展开更多
Alzheimer’s disease(AD)is a progressive neurodegenerative disease that was histopathologically characterized in the brain by the presence of extracellular senile plaques made of amyloid β peptides and intracellular ...Alzheimer’s disease(AD)is a progressive neurodegenerative disease that was histopathologically characterized in the brain by the presence of extracellular senile plaques made of amyloid β peptides and intracellular neurofibrillary tangles composed of hyperphosphorylated Tau protein.Over the years,AD has been classified in two subgroups:early onset or familial AD and late onset or sporadic AD.On the one hand,familial AD has been described to be the result of genetic mutations that cause,in some cases,for the overproduction of amyloid β.On the other,the cause of late onset or sporadic AD is still unclear even though several hypotheses have been proposed to explain the process of severe and progressive memory and cognitive loss.In the present review,some of the current hypotheses that try to explain the origin of late onset or sporadic AD have been summarized.Also,their potential implication in the development of new drugs for the presymptomatic treatment of late onset or sporadic AD has been considered.展开更多
文摘Olfactory receptors are crucial for detecting odors and play a vital role in our sense of smell,influencing behaviors from food choices to emotional memories.These receptors also contribute to our perception of flavor and have potential applications in medical diagnostics and environmental monitoring.The ability of the olfactory system to regenerate its sensory neurons provides a unique model to study neural regeneration,a phenomenon largely absent in the central nervous system.Insights gained from how olfactory neurons continuously replace themselves and reestablish functional connections can provide strategies to promote similar regenerative processes in the central nervous system,where damage often results in permanent deficits.Understanding the molecular and cellular mechanisms underpinning olfactory neuron regeneration could pave the way for developing therapeutic approaches to treat spinal co rd injuries and neurodegenerative diseases like Alzheimer's disease.Olfa ctory receptors are found in almost any cell of eve ry orga n/tissue of the mammalian body.This ectopic expression provides insights into the chemical structures that can activate olfactory receptors.In addition to odors,olfactory receptors in ectopic expression may respond to endogenous compounds and molecules produced by mucosal colonizing microbiota.The analysis of the function of olfactory receptors in ectopic expression provides valuable information on the signaling pathway engaged upon receptor activation and the receptor's role in proliferation and cell differentiation mechanisms.This review explo res the ectopic expression of olfa ctory receptors and the role they may play in neural regeneration within the central nervous system,with particular attention to compounds that can activate these receptors to initiate regenerative processes.Evidence suggests that olfactory receptors could serve as potential therapeutic targets for enhancing neural repair and recovery following central nervous system injuries.
文摘“Last scene of all that ends this strange,eventful history,is second childishness and mere oblivion.I am sans teeth,sans eyes,sans taste,sans everything.”William Shakespeare‘As You Like It'Act 2,Sc.7,l.139Aging of the human brain is characterized by a progressive decline of its functional capacity;this decline however varies widely,and cognitive longevity differs substantially between individuals.
基金supported by Grants from Spanish FEDER/Science and Innovation Ministry I+D+i-RETOS-PID2021-124801NB-100Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas(CIBERN ED+1 种基金an initiative of the ISCIII)[PI2016/01]the Fundocion Ramon Areces and Banco Santander to the CBMSO(to FW)。
文摘Autophagy is a cellular degradation and recycling system,indispensable for cellular and organ development,homeostasis,and function.This cellular process is evolutionarily highly conserved to quality control of many proteins and dysfunctional organelles,which finally recycle components as amino acids.This process is effective during normal physiology as part of anabolism and plays an additional important role during starvation(Dikic and Elazar,2018).Different types of autophagy have been chara cterized based on their dynamic,mechanism of action,target substrates,and protein markers.Some of them are macroautophagy(hereafter called"autophagy"),microa utophagy,and chape rone-media ted autophagy(Fleming et al.,2022).
基金supported by NIH Grant Al-15614 (to CAD)the Ministerio de Ciencia e Innovacion (PID2020-120267BRI00AEI/10.13039/501100011033)(to RLV)。
文摘Metabolism is a fundamental process by which biochemicals are broken down to produce energy(catabolism) or used to build macromolecules(anabolism). Metabolism has received renewed attention as a mechanism that generates molecules that modulate multiple cellular responses. This was first identified in cancer cells as the Warburg effect, but it is also present in immunocompetent cells. Studies have revealed a bidirectional influence of cellular metabolism and immune cell function, highlighting the significance of metabolic reprogramming in immune cell activation and effector functions. Metabolic processes such as glycolysis, oxidative phosphorylation, and fatty acid oxidation have been shown to undergo dynamic changes during immune cell response, facilitating the energetic and biosynthetic demands. This review aims to provide a better understanding of the metabolic reprogramming that occurs in different immune cells upon activation, with a special focus on central nervous system disorders. Understanding the metabolic changes of the immune response not only provides insights into the fundamental mechanisms that regulate immune cell function but also opens new approaches for therapeutic strategies aimed at manipulating the immune system.
文摘The intricacies of Alzheimer’s disease pathogenesis are being increasingly illuminated by the exploration of epigenetic mechanisms,particularly DNA methylation.This review comprehensively surveys recent human-centered studies that investigate whole genome DNA methylation in Alzheimer’s disease neuropathology.The examination of various brain regions reveals distinctive DNA methylation patterns that associate with the Braak stage and Alzheimer’s disease progression.The entorhinal cortex emerges as a focal point due to its early histological alterations and subsequent impact on downstream regions like the hippocampus.Notably,ANK1 hypermethylation,a protein implicated in neurofibrillary tangle formation,was recurrently identified in the entorhinal cortex.Further,the middle temporal gyrus and prefrontal cortex were shown to exhibit significant hypermethylation of genes like HOXA3,RHBDF2,and MCF2L,potentially influencing neuroinflammatory processes.The complex role of BIN1 in late-onset Alzheimer’s disease is underscored by its association with altered methylation patterns.Despite the disparities across studies,these findings highlight the intricate interplay between epigenetic modifications and Alzheimer’s disease pathology.Future research efforts should address methodological variations,incorporate diverse cohorts,and consider environmental factors to unravel the nuanced epigenetic landscape underlying Alzheimer’s disease progression.
基金supported by the Ministerio de Economía,Industria y Competitividad(Agencia Estatal de Investigación,AEI,to CGF and MP)Fondo Europeo de Desarrollo Regional(MINECO-FEDER)(PID2022-139016OA-I00,PDC2022-133441-I00,to CGF and MP),Generalitat de Catalunya(2021 SGR 00357+3 种基金to CGF and MP)co-financed by Secretaria d’Universitats i Recerca del Departament d’Empresai Coneixement de la Generalitat de Catalunya 2021(Llavor 00086,to CGF)the recipient of an Alzheimer’s Association Research Fellowship(AARF-21-848511)the Agència de Gestiód’Ajuts Universitaris i de Recerca(AGAUR)for her FI-SDUR fellowship(2021FISDU 00182).
文摘Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress.Likewise,microRNAs are involved in many biological processes and diseases playing a key role in pathogenesis,especially in multifactorial diseases such as Alzheimer’s disease.Therefore,our aim has been to provide partial insights into the interconnection between G9a,microRNAs,oxidative stress,and neuroinflammation.To better understand the biology of G9a,we compared the global microRNA expression between senescence-accelerated mouse-prone 8(SAMP8)control mice and SAMP8 treated with G9a inhibitor UNC0642.We found a downregulation of miR-128 after a G9a inhibition treatment,which interestingly binds to the 3′untranslated region(3′-UTR)of peroxisome-proliferator activator receptor γ(PPARG)mRNA.Accordingly,Pparg gene expression levels were higher in the SAMP8 group treated with G9a inhibitor than in the SAMP8 control group.We also observed modulation of oxidative stress responses might be mainly driven Pparg after G9a inhibitor.To confirm these antioxidant effects,we treated primary neuron cell cultures with hydrogen peroxide as an oxidative insult.In this setting,treatment with G9a inhibitor increases both cell survival and antioxidant enzymes.Moreover,up-regulation of PPARγby G9a inhibitor could also increase the expression of genes involved in DNA damage responses and apoptosis.In addition,we also described that the PPARγ/AMPK axis partially explains the regulation of autophagy markers expression.Finally,PPARγ/GADD45αpotentially contributes to enhancing synaptic plasticity and neurogenesis after G9a inhibition.Altogether,we propose that pharmacological inhibition of G9a leads to a neuroprotective effect that could be due,at least in part,by the modulation of PPARγ-dependent pathways by miR-128.
文摘Dysfunction in circadian rhythms is a common occurrence in patients with Alzheimer’s disease.A predominant function of the retina is circadian synchronization,carrying information to the brain through the retinohypothalamic tract,which projects to the suprachiasmatic nucleus.Notably,Alzheimer’s disease hallmarks,including amyloid-β,are present in the retinas of Alzheimer’s disease patients,followed/associated by structural and functional disturbances.However,the mechanistic link between circadian dysfunction and the pathological changes affecting the retina in Alzheimer’s disease is not fully understood,although some studies point to the possibility that retinal dysfunction could be considered an early pathological process that directly modulates the circadian rhythm.
基金sponsored by a grant from the National Institute of Neurological Disorders and Stroke:RO1NS116059(to MZ)。
文摘Modern neuroscience began from all reaching and fierce conflict between“neuronismo and reticulismo”——between neuronal and reticular theories of the organization of the nervous system;the conflict culminated in December of 1906 in Stockholm where Santiago Ramon y Cajal(the proponent of the neuronal doctrine)and Camillo Golgi(who advocated the syncytial reticular organization of neural networks)delivered their Noble prize lectures(Verkhratsky,2009).
基金supported by grants from the Ministerio de Economia y Competitividad(BFU2013-43458-R)Junta de Andalucia(P12-CTS-1694 and Proyexcel-00422)to ZUK。
文摘Memory deficit,which is often associated with aging and many psychiatric,neurological,and neurodegenerative diseases,has been a challenging issue for treatment.Up till now,all potential drug candidates have failed to produce satisfa ctory effects.Therefore,in the search for a solution,we found that a treatment with the gene corresponding to the RGS14414protein in visual area V2,a brain area connected with brain circuits of the ventral stream and the medial temporal lobe,which is crucial for object recognition memory(ORM),can induce enhancement of ORM.In this study,we demonstrated that the same treatment with RGS14414in visual area V2,which is relatively unaffected in neurodegenerative diseases such as Alzheimer s disease,produced longlasting enhancement of ORM in young animals and prevent ORM deficits in rodent models of aging and Alzheimer’s disease.Furthermore,we found that the prevention of memory deficits was mediated through the upregulation of neuronal arbo rization and spine density,as well as an increase in brain-derived neurotrophic factor(BDNF).A knockdown of BDNF gene in RGS14414-treated aging rats and Alzheimer s disease model mice caused complete loss in the upregulation of neuronal structural plasticity and in the prevention of ORM deficits.These findings suggest that BDNF-mediated neuronal structural plasticity in area V2 is crucial in the prevention of memory deficits in RGS14414-treated rodent models of aging and Alzheimer’s disease.Therefore,our findings of RGS14414gene-mediated activation of neuronal circuits in visual area V2 have therapeutic relevance in the treatment of memory deficits.
文摘This letter praises a recent article in the World Journal of Clinical Cases(Roles of biochemistry data,lifestyle,and inflammation in identifying abnormal renal function in old Chinese),examining factors affecting abnormal renal function in elderly Chinese using advanced machine learning.It highlights the importance of uric acid,age,hemoglobin,body mass index,sport hours,and systolic blood pressure.The study's holistic approach,integrating lifestyle and inflammation,offers a nuanced understanding of chronic kidney disease risk factors.The letter suggests exploring mechanistic pathways of hyperuricemia,the link between anemia and renal function,and the connection between body mass index and estimated glomerular filtration rate.It advocates investigating physical activity's impact on renal health and the independent effects of blood pressure.The study significantly contributes to chronic kidney disease understanding,proposing avenues for further exploration and interventions.Commendations are extended to the authors and the journal.
基金the following financial support grant FAR-2019 to DL from The Universita del Piemonte Orientale。
文摘Alzheimer’s disease(AD)is a major age-related form of dementia with a number of cases exponentially growing,causing enormous social and economic impact on individuals and society.Neuropathological hallmarks of AD,evident in postmortem AD brains,include a massive loss of the grey matter in the neocortex,extracellular deposition of amyloid-β(Aβ)in the form of senile plaques and cerebrovascular amyloid angiopathy,and intra-neuronal accumulation of neurofibrillary tangles,formed by hyper-phosphorylated tau protein.
基金supported by grants BIO2016-77000-R,PIB2020-114761RB-I00 and FJC2021-046632-I(to M.E.)from the Ministerio de Ciencia e Innovación(MCIN),SBPLY/17/180501/000234,and SBPLY/21/180501/000012 from the Junta de Comunidades de Castilla-La Mancha(co-financed European Union FEDER funds)to LGG and OA.
文摘Saffron has many pharmacological properties in addition to being a frequently used food seasoning.Crocin and picrocrocin which accumulate in saffron stigma,are responsible for these pharmacological properties.These natural products have health-promoting effects for the prevention and treatment of numerous diseases,including age-related cognitive and memory disfunction.Currently,crocin and picrocrocin are obtained from saffron,considered as the spice with the highest price in the market.To develop an efficient and low-cost approach to producing these compounds with high bioactivity,biosynthetic genes isolated from saffron can be exploited in the metabolic engineering of heterologous hosts and the production of crocins in productive crop plants.Recently,we engineered tomato fruit producing crocins(Tomafran).In this study,we demonstrated that crocin-rich extract,encapsulated in chitosan or in exosomes may function as a neuroprotective strategy.Crocins contained in the Tomafran extracts and much lower doses in chitosan nanoparticles or exosomes were enough to rescue the neuroblastoma cell line SH-SY5Y after damage caused by okadaic acid.Our results confirm the neuroprotective effect of Tomafran and its exosomes that may be useful for the delay or prevention of neurodegenerative disorders such as Alzheimer’s disease.
基金funded by Instituto de Salud Carlos Ill(IsCll)and co-funded by the European Union(grants Pl16/00612 and PI20/01200 to MCS)Junta de Andalucia-Consejeria de Salud y Consumo(grant PIER-0468-2019 to MCS)+4 种基金MCS has been supported by ISCIII(JR15/00042)Junta de Andalucia-Consejeria de Salud y Consumo(B-0005-2017)JD has been supported by grants PID2020-117979RB-100 from the Spanish Ministry of Science and Innovation and IMP/00019 from the Instituto de Salud Carlos III(ISCIII)RC has been supported by Junta de Andalucia-Consejeria de Salud y Familias(RH-0052-2021)by the European Union,European Social Fund(FSE)2014-2020.
文摘In recent years,the number of known disease genes has exponentially grown due to the widespread adoption of cost-effective massive parallel sequencing.To identify new disease variants,especially in monogenic disorders,a frequency-based filtering approach has proved very useful(Dopazo et al.,2016).
基金supported by grants from Consellería de Cultura,Educación e Ordenación Universitaria,Xunta de Galicia(ED431G/05,ED431C 2018/10)European Regional Development Fund(FEDER),Instituto de Salud CarlosⅢ(RD16/011/0016,RD21/0017/0031)Secretaría de Estado de Investigación,Desarrollo e Innovación(Grant/Award,number RTI2018-098830-B-I00)(to JLLG)。
文摘Parkinson’s disease is a neurodegenerative condition characterized by motor impairments caused by the selective loss of dopaminergic neurons in the substantia nigra.Levodopa is an effective and well-tolerated dopamine replacement agent.However,levodopa provides only symptomatic improvements,without affecting the underlying pathology,and is associated with side effects after long-term use.Cell-based replacement is a promising strategy that offers the possibility to replace lost neurons in Parkinson’s disease treatment.Clinical studies of transplantation of human fetal ventral mesencephalic tissue have provided evidence that the grafted dopaminergic neurons can reinnervate the striatum,release dopamine,integrate into the host neural circuits,and improve motor functions.One of the limiting factors for cell therapy in Parkinson’s disease is the low survival rate of grafted dopaminergic cells.Different factors could cause cell death of dopaminergic neurons after grafting such as mechanical trauma,growth factor deprivation,hypoxia,and neuroinflammation.Neurotrophic factors play an essential role in the survival of grafted cells.However,direct,timely,and controllable delivery of neurotrophic factors into the brain faces important limitations.Different types of cells secrete neurotrophic factors constitutively and co-transplantation of these cells with dopaminergic neurons represents a feasible strategy to increase neuronal survival.In this review,we provide a general overview of the pioneering studies on cell transplantation developed in patients and animal models of Parkinson’s disease,with a focus on neurotrophic factor-secreting cells,with a particular interest in mesenchymal stromal cells;that co-implanted with dopaminergic neurons would serve as a strategy to increase cell survival and improve graft outcomes.
文摘Neurodegeneration affects a large number of cell types including neurons,astrocytes or oligodendrocytes,and neural stem cells.Neural stem cells can generate new neuronal populations through proliferation,migration,and differentiation.This neurogenic potential may be a relevant factor to fight neurodegeneration and aging.In the last years,we can find growing evidence suggesting that melatonin may be a potential modulator of adult hippocampal neurogenesis.The lack of therapeutic strategies targeting neurogenesis led researchers to explore new molecules.Numerous preclinical studies with melatonin observed how melatonin can modulate and enhance molecular and signaling pathways involved in neurogenesis.We made a special focus on the connection between these modulation mechanisms and their implication in neurodegeneration,to summarize the current knowledge and highlight the therapeutic potential of melatonin.
基金supported by the Spanish Ministry of Health(PI17/00828 and Ciberned)Galician Government(XUGA,ED431C 2018/10,ED431G/05)FEDER(Regional European Development Fund),all to AIRP.
文摘In the last decade,attention has become greater to the relationship between neurodegeneration and abnormal insulin signaling in the central nervous system,as insulin in the brain is implicated in neuronal survival,plasticity,oxidative stress and neuroinflammation.Diabetes mellitus and Parkinson’s disease are both aging-associated diseases that are turning into epidemics worldwide.Diabetes mellitus and insulin resistance not only increase the possibility of developing Parkinson’s disease but can also determine the prognosis and progression of Parkinsonian symptoms.Today,there are no available curative or disease modifying treatments for Parkinson’s disease,but the role of insulin and antidiabetic medications in neurodegeneration opens a door to treatment repurposing to fight against Parkinson’s disease,both in diabetic and nondiabetic Parkinsonian patients.Furthermore,it is essential to comprehend how a frequent and treatable disease such as diabetes can influence the progression of neurodegeneration in a challenging disease such as Parkinson’s disease.Here,we review the present evidence on the connection between Parkinson’s disease and diabetes and the consequential implications of the existing antidiabetic molecules in the severity and development of Parkinsonism,with a particular focus on glucagon-like peptide-1 receptor agonists.
基金mainly supported by the Ministerio de Economíay Competitividad of Spain(#SAF 2014-59701)(to CC)
文摘Peripheral nerve injuries caused by accidents may lead to paralysis,sensory disturbances,anaesthesia,and lack of autonomic functions.Functional recovery after disconnection of the motoneuronal soma from target tissue with proximal rupture of axons is determined by several factors:motoneuronal soma viability,proper axonal sprouting across inhibitory zones and elongation toward specific muscle,effective synapse contact rebuilding,and prevention of muscle atrophy.Therapies,such as adjuvant drugs with pleiotropic effects,that promote functional recovery after peripheral nerve injury are needed.Toward this aim,we designed a drug discovery workflow based on a network-centric molecular vision using unbiased proteomic data and neural artificial computational tools.Our focus is on boosting intrinsic capabilities of neurons for neuroprotection;this is in contrast to the common approach based on suppression of a pathobiological pathway known to be associated with disease condition.Using our workflow,we discovered neuroheal,a combination of two repurposed drugs that promotes motoneuronal soma neuroprotection,is anti-inflammatory,enhances axonal regeneration after axotomy,and reduces muscle atrophy.This drug discovery workflow has thus yielded a therapy that is close to its clinical application.
文摘Acetylation is a post-translational modification that is regulated by two antagonistic enzymes,histone acetyltransferases(HATs)and histone deacetylases(HDACs).HATs transfer the acetyl group from acetyl-CoA to lysine residues of proteins while HDACs remove it(Yakhine-Diop et al.,2018b).The impairment of HAT or HDAC activity elicits changes in the protein acetylation status which disturb several cellular processes,among others,gene expression,autophagy etc.,leading finally to cell death.Both enzymes are associated with Parkinson’s disease(PD)pathogenesis.In dopaminergic cells,neurotoxins provoke apoptotic cell death by increasing histone acetylation levels.While paraquat(Song et al.,2011)and rotenone(Feng et al.,2015)reduce HDAC activity,dieldrin(Song et al.,2010)enhances HAT activity.However in vivo,paraquat-induced upregulation ofα-synuclein triggers histone hypoacetylation.
文摘Chemotherapy-induced peripheral neuropathy is a very frequent neurological complication in cancer. Oxaliplatin（OXA） is a platinum analogue used as a first-line agent in the treatment of colorectal cancer. OXA induced peripheral neuropathy（OIN） is the main toxicity both during and after the completion of chemotherapy that presents as two distinct syndromes： acute and chronic neuropathy. None of the neuroprotective agents previously tested had prevented or limited the acute and/or chronic OIN. MR309（previously developed as E-52862） is a novel selective sigma-1 receptor（S1R） antagonist with preclinical analgesic activity in OXA-induced neuropathic pain in animal models. This review analyzes the results of the recently published phase Ⅱ, randomized, double-blind, placebo-controlled clinical trial including 124 patients with colorectal cancer（CRC） treated with MR309. This study shows encouraging findings in the setting of neuroprotection against OIN with an acceptable safety profile. The study demonstrated MR309 usefulness in decreasing acute OIN, by reducing cold hypersensitivity experienced by patients, and pointed to the amelioration of chronic OIN by lowering the proportion of patients who developed severe chronic OIN. In addition, we provide a summary and discussion on the pathways that can be modulated by the S1R to explain the observed clinical benefits in the OIN.
基金supported by the Spanish Ministry of Science and Innovation SAF2017-84283-R,PI2016/01,CB06/05/0024(Biomedical Research Networking Centre in Neurodegenerative Diseases)the European Regional Development Founds(all to AC)
文摘Alzheimer’s disease(AD)is a progressive neurodegenerative disease that was histopathologically characterized in the brain by the presence of extracellular senile plaques made of amyloid β peptides and intracellular neurofibrillary tangles composed of hyperphosphorylated Tau protein.Over the years,AD has been classified in two subgroups:early onset or familial AD and late onset or sporadic AD.On the one hand,familial AD has been described to be the result of genetic mutations that cause,in some cases,for the overproduction of amyloid β.On the other,the cause of late onset or sporadic AD is still unclear even though several hypotheses have been proposed to explain the process of severe and progressive memory and cognitive loss.In the present review,some of the current hypotheses that try to explain the origin of late onset or sporadic AD have been summarized.Also,their potential implication in the development of new drugs for the presymptomatic treatment of late onset or sporadic AD has been considered.
