Beneficial effects of saffron(Crocus sativus L.) in ocular pathologies,particularly neurodegenerative retinal diseases

Saffron(Crocus sativus L.)has been traditionally used in food preparation and as a medicinal plant.It currently has numerous therapeutic properties attributed to it,such as protection against ischemia,as well as anticonvulsant,antidepressant,anxiolytic,hypolipidemic,anti-atherogenic,anti-hypertensive,antidiabetic,and anti-cancer properties.In addition,saffron has remarkable beneficial properties,such as anti-apoptotic,anti-inflammatory and antioxidant activities,due to its main metabolites,among which crocin and crocetin stand out.Furthermore,increasing evidence underwrites the possible neuroprotective role of the main bioactive saffron constituents in neurodegenerative diseases,such as Parkinson’s and Alzheimer’s diseases,both in experimental models and in clinical studies in patients.Currently,saffron supplementation is being tested for ocular neurodegenerative pathologies,such as diabetic retinopathy,retinitis pigmentosa,age-related macular degeneration and glaucoma,among others,and shows beneficial effects.The present article provides a comprehensive and up to date report of the investigations on the beneficial effects of saffron extracts on the main neurodegenerative ocular pathologies and other ocular diseases.This review showed that saffron extracts could be considered promising therapeutic agents to help in the treatment of ocular neurodegenerative diseases.     

Prefrontal cortical dopamine from an evolutionary perspective

In this article, we propose the hypothesis that the prefrontal cortex(PFC) acquired neotenic development as a consequence of mesocortical dopamine(DA) innervation, which in turn drove evolution of the PFC into becoming a complex functional system. Accordingly, from the evolutionary perspective, decreased DA signaling in the PFC associated with such adverse conditions as chronic stress may be considered as an environmental adaptation strategy. Psychiatric disorders such as schizophrenia and attention deficit/hyperactivity disorder may also be understood as environmental adaptation or a by-product of such a process that has emerged through evolution in humans. To investigate the evolutionary perspective of DA signaling in the PFC, domestic animals such as dogs may be a useful model.     

All roads lead to Rome-a review of the potential mechanisms by which exerkines exhibit neuroprotective effects in Alzheimer’s disease

Age-related neurodegenerative disorders such as Alzheimer’s disease(AD)have become a critical public health issue due to the significantly extended human lifespan,leading to considerable economic and social burdens.Traditional therapies for AD such as medicine and surgery remain ineffective,impractical,and expensive.Many studies have shown that a variety of bioactive substances released by physical exercise(called“exerkines”)help to maintain and improve the normal functions of the brain in terms of cognition,emotion,and psychomotor coordination.Increasing evidence suggests that exerkines may exert beneficial effects in AD as well.This review summarizes the neuroprotective effects of exerkines in AD,focusing on the underlying molecular mechanism and the dynamic expression of exerkines after physical exercise.The findings described in this review will help direct research into novel targets for the treatment of AD and develop customized exercise therapy for individuals of different ages,genders,and health conditions.     

Mounting evidence of FKBP12 implication in neurodegeneration

Intrinsically disordered proteins, such as tau or α-synuclein, have long been associated with a dysfunctional role in neurodegenerative diseases. In Alzheimer's and Parkinson's' diseases, these proteins, sharing a common chemical-physical pattern with alternating hydrophobic and hydrophilic domains rich in prolines, abnormally aggregate in tangles in the brain leading to progressive loss of neurons. In this review, we present an overview linking the studies on the implication of the peptidyl-prolyl isomerase domain of immunophilins, and notably FKBP12, to a variety of neurodegenerative diseases, focusing on the molecular origin of such a role. The involvement of FKBP12 dysregulation in the aberrant aggregation of disordered proteins pinpoints this protein as a possible therapeutic target and, at the same time, as a predictive biomarker for early diagnosis in neurodegeneration, calling for the development of reliable, fast and cost-effective detection methods in body fluids for community-based screening campaigns.     

Provision of nutrients after acute spinal cord injury：the implications of feast and famine

<正>Traumatic spinal cord injury(SCI)often leaves patients with devastating neurological deficits.The traumatic event–or primary injury–can be due to mechanisms such as compression,distraction,shear,laceration or(rarely)even transection.Thereafter SCI patients are vulnerable to progressive,delayed damage as a result of secondary insults and secondary injury.Secondary insults such as hypoxia and hypotension occur at the level of the organism from a myriad of causes.Secondary injury occurs at the molecular level and includes processes such as ischemia,excitotoxicity,ionic dysregulation,free radical formation,inflammation,oxidative damage,and activation of necrotic and apoptotic cell death signaling events.Despite the great progress     

Neuronal autophagy in cerebral ischemia

Autophagy has evolved as a conserved process for the bulk degradation and recycling of cytosolic components, such as long-lived proteins and organelles. In neurons, autophagy is important for homeostasis and protein quality control and is maintained at relatively low levels under normal conditions, while it is upregulated in response to pathophysiological conditions, such as cerebral ischemic injury. However, the role of autophagy is more complex. It depends on age or brain maturity, region, severity of insult, and the stage of ischemia. Whether autophagy plays a beneficial or a detrimental role in cerebral ischemia depends on various pathological conditions. In this review, we elucidate the role of neuronal autophagy in cerebral ischemia.     

Cadmium-induced neurotoxicity: still much ado

Cadmium(Cd) is a highly toxic heavy metal that accumulates in living system and as such is currently one of the most important occupational and environmental pollutants. Cd reaches into the environment by anthropogenic mobilization and it is absorbed from tobacco consumption or ingestion of contaminated substances. Its extremely long biological half-life(approximately 20–30 years in humans) and low rate of excretion from the body cause cadmium storage predominantly in soft tissues(primarily, liver and kidneys) with a diversity of toxic effects such as nephrotoxicity, hepatotoxicity, endocrine and reproductive toxicities. Moreover, a Cd-dependent neurotoxicity has been also related to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, and multiple sclerosis. At the cellular level, Cd affects cell proliferation, differentiation, apoptosis and other cellular activities. Among all these mechanisms, the Cd-dependent interference in DNA repair mechanisms as well as the generation of reactive oxygen species, seem to be the most important causes of its cellular toxicity. Nevertheless, there is still much to find out about its mechanisms of action and ways to reduce health risks. This article gives a brief review of the relevant mechanisms that it would be worth investigating in order to deep inside cadmium toxicity.     

Dysregulation of neurogenesis by neuroinflammation:key differences in neurodevelopmental and neurological disorders

Embryonic neurogenesis is the process of generating neurons, the functional units of the brain. Because of its sensitivity to adverse intrauterine environment such as infection, dysregulation of this process has emerged as a key mechanism underlying many neurodevelopmental disorders such as autism spectrum disorders (ASD). Adult neurogenesis, although is restricted to a few neurogenic niches, plays pivotal roles in brain plasticity and repair. Increasing evidence suggests that impairments in adult neurogenesis are in-volved in major neurodegenerative disorders such as Alzheimer's disease. A hallmark feature of these brain disorders is neuroinflammation, which can either promote or inhibit neurogenesis depending upon the context of brain microenvironment. In this review paper, we present evidence from both experimental and human studies to show a complex picture of relationship between these two events, and discussed potential factors contributing to different or even opposing actions of neuroinflammation on neurogenesis in neuro-developmental and neurological disorders.     

Recent advances in RNA-targeting therapy for neurological diseases

<正>Advances in sequencing and molecular technology now allow us to understand the genetic underpinnings of complex diseases such as neurological disorders.Genetic variations(or mutations) in the DNA sequence of single genes have been implicated in neurological diseases such as Huntington’s disease and spinal muscular atrophy.As a result,the development of gene therapies for neurological diseases is now a feasible endeavor.     

Sex-biased autophagy as a potential mechanism mediating sex differences in ischemic stroke outcome

Stroke is the second leading cause of death and a major cause of disability worldwide, and biological sex is an important determining factor in stroke incidence and pathology. From childhood through adulthood, men have a higher incidence of stroke compared with women. Abundant research has confirmed the beneficial effects of estrogen in experimental ischemic stroke but genetic factors such as the X-chromosome complement can also play an important role in determining sex differences in stroke. Au...     

Transforming growth factor β1-mediated anti-inflammation slows progression of midbrain dopaminergic neurodegeneration in Parkinson's disease?

<正>Parkinson’s disease(PD)is characterized by the progressive loss of midbrain dopaminergic(m DA)neurons and a subsequent decrease in striatal dopamine levels,which cause the typical clinical motor symptoms such as muscle rigidity,bradykinesia and tremor.Although a subset of     

Thinking outside the black box:are the brain endothelial cells the new main target in Alzheimer's disease?

The blood-brain barrier is the interface through which the brain interacts with the milieu and consists mainly of a sophisticated network of brain endothelial cells that forms blood vessels and selectively moves molecules inside and outside the brain through multiple mechanisms of transport. Although brain endothelial cell function is crucial for brain homeostasis, their role in neurodegenerative diseases has historically not been considered with the same importance as other brain cells such as ...     

Pharmacological interventions targeting nuclear factor-kappa B signaling in multiple sclerosis

Multiple sclerosis(MS)is an inflammatory neurodegenerative disease of the central nervous system(CNS).Pathological characteristics of the disease include activation of CNS-intrinsic immune cells,such as microglia and astrocytes,and loss of neuronal connections,myelin and blood-brain barrier(BBB)integrity as well as peripheral immune cell infiltration into the brain.MS has long been considered a predominantly immunological disease,which has led to the development of essentially only immune-directed medications.Within this traditional“outside-in”MS hypothesis,a dysregulation of the peripheral immune system causes immune cell infiltration into the CNS,leading to autoreactivity against myelin sheath components and secondary BBB dysfunction.However,recent findings indicate that overactivation of microglia and astrocytes represents an important first step in MS pathology,as appears to be the case for other neurodegenerative diseases such as Alzheimer’s disease(AD)and Parkinson’s disease(PD).     

Role of exosomes in the pathogenesis of inflammation in Parkinson’s disease

Inflammatory responses,including glial cell activation and peripheral immune cell infiltration,are involved in the pathogenesis of Parkinson’s disease(PD).These inflammatory responses appear to be closely related to the release of extracellular vesicles,such as exosomes.However,the relationships among different forms of glial cell activation,synuclein dysregulation,mitochondrial dysfunction,and exosomes are complicated.This review discusses the multiple roles played by exosomes in PD-associated inflammation and concludes that exosomes can transport toxicα-synuclein oligomers to immature neurons and into the extracellular environment,inducing the oligomerization ofα-synuclein in normal neurons.Misfoldedα-synuclein causes microglia and astrocytes to activate and secrete exosomes.Glial cell-derived exosomes participate in communications between glial cells and neurons,triggering anti-stress and anti-inflammatory responses,in addition to axon growth.The production and release of mitochondrial vesicles and exosomes establish a new mechanism for linking mitochondrial dysfunction to systemic inflammation associated with PD.Given the relevance of exosomes as mediators of neuron-glia communication in neuroinflammation and neuropathogenesis,new targeted treatment strategies are currently being developed that use these types of extracellular vesicles as drug carriers.Exosome-mediated inflammation may be a promising target for intervention in PD patients.     

Nuclear sphingomyelin in neurodegenerative diseases

Introduction:Recently,sphingolipids(SphLs)have become increasingly appreciated as a family of molecules involved in the growth,differentiation,and death of the central nervous system cells.The disequilibrium among the different SphLs leads to changes in the neuronal cell physiology and induces the development of neurodegenerative diseases(Alessenko and Albi,2020).Sphingomyelin(SM),sphinganin(Sphn),sphingosine(Sph),sphingosine-1-phosphate(S1P)and ceramide(Cer)are the most well-studied group of SphLs responsible for neurodegeneration,as well as derived molecules such as glucosylceramide or cerebroside(GCer)and galactosylceramide(GalCer)and finally more complex molecules such as as gangliosides.     

The Janus face of N-terminal lysines in α-synuclein

Parkinson’s disease(PD)is the second most prevalent progressive neurodegenerative disorder after Alzheimer’s disease.PD usually starts with a tremor in the extremities(usually in the hands)and gradually evolves with other symptoms such as bradykinesia,muscle stiffness,impaired posture,loss of automatic movements or speech changes.These symptoms worsen as the condition progresses and eventually lead to death.     

Microglia regulation of synaptic plasticity and learning and memory

Microglia are the resident macrophages of the central nervous system.Microglia possess varied morphologies and functions.Under normal physiological conditions,microglia mainly exist in a resting state and constantly monitor their microenvironment and survey neuronal and synaptic activity.Through the C1 q,C3 and CR3"Eat Me"and CD47 and SIRPα"Don't Eat Me"complement pathways,as well as other pathways such as CX3 CR1 signaling,resting microglia regulate synaptic pruning,a process crucial for the promotion of synapse formation and the regulation of neuronal activity and synaptic plasticity.By mediating synaptic pruning,resting microglia play an important role in the regulation of experience-dependent plasticity in the barrel cortex and visual cortex after whisker removal or monocular deprivation,and also in the regulation of learning and memory,including the modulation of memory strength,forgetfulness,and memory quality.As a response to brain injury,infection or neuroinflammation,microglia become activated and increase in number.Activated microglia change to an amoeboid shape,migrate to sites of inflammation and secrete proteins such as cytokines,chemokines and reactive oxygen species.These molecules released by microglia can lead to synaptic plasticity and learning and memory deficits associated with aging,Alzheimer's disease,traumatic brain injury,HIV-associated neurocognitive disorder,and other neurological or mental disorders such as autism,depression and post-traumatic stress disorder.With a focus mainly on recently published literature,here we reviewed the studies investigating the role of resting microglia in synaptic plasticity and learning and memory,as well as how activated microglia modulate disease-related plasticity and learning and memory deficits.By summarizing the function of microglia in these processes,we aim to provide an overview of microglia regulation of synaptic plasticity and learning and memory,and to discuss the possibility of microglia manipulation as a therapeutic to ameliorate cognitive deficits associated with aging,Alzheimer's disease,traumatic brain injury,HIV-associated neurocognitive disorder,and mental disorders.     

Ferroptosis: copper-iron connection in cuprizone-induced demyelination

Redox active metals such as iron,copper,zinc,and manganese play important roles in promoting a variety of biochemical reactions essential for cellular function.This is made possible by the ability of these metals to accept and donate electrons.Iron in the form of iron-sulfur clusters and heme plays a key role in adenosine triphosphate generation in mitochondria as well as numerous other enzymatic reactions.On the other hand.     

Protocadherin gamma C3: a new player in regulating vascular barrier function

Defects in the endothelial cell barrier accompany diverse malfunctions of the central nervous system such as neurodegenerative diseases, stroke, traumatic brain injury, and systemic diseases such as sepsis, viral and bacterial infections, and cancer. Compromised endothelial sealing leads to leaking blood vessels, followed by vasogenic edema. Brain edema as the most common complication caused by stroke and traumatic brain injury is the leading cause of death. Brain microvascular endothelial cells...     

Cortical Astrocyte-neuronal Metabolic Coupling Emerges as a Critical Modulator of Stress-induced Hopelessness

Stress is a major risk factor for the development of mental illness,such as major depression disorder (MDD)[1].Despite decades of progress,including findings that stressinduced depression corresponds with numerous morphological and functional neuronal changes within brain structures associated with cognition and mood,such as the medial prefrontal cortex (mPFC)[1-3],a thorough understanding of how stress induces the core symptoms of depression,such as hopelessness,is still lacking.In an exciting new paper in mice,Yin et al.show that astrocyteneuronal metabolic coupling in the mPFC is critically involved in the stress-induced passive coping response in mice [4].