Nanotechnologies meeting natural sources:Engineered lipoproteins for precise brain disease theranostics

Biological nanotechnologies have provided considerable opportunities in the management of malignancies with delicate design and negligible toxicity,from preventive and diagnostic to therapeutic fields.Lipoproteins,because of their inherent blood-brain barrier permeability and lesion-homing capability,have been identified as promising strategies for high-performance theranostics of brain diseases.However,the application of natural lipoproteins remains limited owing to insufficient accumulation and complex purification processes,which can be critical for individual therapeutics and clinical translation.To address these issues,lipoprotein-inspired nano drug-delivery systems(nano-DDSs),which have been learned from nature,have been fabricated to achieve synergistic drug delivery involving site-specific accumulation and tractable preparation with versatile physicochemical functions.In this review,the barriers in brain disease treatment,advantages of state-of-the-art lipoprotein-inspired nano-DDSs,and bio-interactions of such nano-DDSs are highlighted.Furthermore,the characteristics and advanced applications of natural lipoproteins and tailor-made lipoprotein-inspired nano-DDSs are summarized.Specifically,the key designs and current applications of lipoprotein-inspired nano-DDSs in the field of brain disease therapy are intensively discussed.Finally,the current challenges and future perspectives in the field of lipoprotein-inspired nano-DDSs combined with other vehicles,such as exosomes,cell membranes,and bacteria,are discussed.

Neural stem cell therapy for brain disease

Brain diseases, including brain tumors, neurodegenerative disorders, cerebrovasculardiseases, and traumatic brain injuries, are among the major disordersinfluencing human health, currently with no effective therapy. Due to the lowregeneration capacity of neurons, insufficient secretion of neurotrophic factors,and the aggravation of ischemia and hypoxia after nerve injury, irreversible lossof functional neurons and nerve tissue damage occurs. This damage is difficult torepair and regenerate the central nervous system after injury. Neural stem cells(NSCs) are pluripotent stem cells that only exist in the central nervous system.They have good self-renewal potential and ability to differentiate into neurons,astrocytes, and oligodendrocytes and improve the cellular microenvironment.NSC transplantation approaches have been made for various neurodegenerativedisorders based on their regenerative potential. This review summarizes anddiscusses the characteristics of NSCs, and the advantages and effects of NSCs inthe treatment of brain diseases and limitations of NSC transplantation that need tobe addressed for the treatment of brain diseases in the future.

Using induced pluripotent stem cells derived neurons to model brain diseases

The ability to use induced pluripotent stem cells（i PSC）to model brain diseases is a powerful tool for unraveling mechanistic alterations in these disorders.Rodent models of brain diseases have spurred understanding of pathology but the concern arises that they may not recapitulate the full spectrum of neuron disruptions associated with human neuropathology.iPSC derived neurons,or other neural cell types,provide the ability to access pathology in cells derived directly from a patient＇s blood sample or skin biopsy where availability of brain tissue is limiting.Thus,utilization of iPSC to study brain diseases provides an unlimited resource for disease modelling but may also be used for drug screening for effective therapies and may potentially be used to regenerate aged or damaged cells in the future.Many brain diseases across the spectrum of neurodevelopment,neurodegenerative and neuropsychiatric are being approached by iPSC models.The goal of an iPSC based disease model is to identify a cellular phenotype that discriminates the disease-bearing cells from the control cells.In this mini-review,the importance of iPSC cell models validated for pluripotency,germline competency and function assessments is discussed.Selected examples for the variety of brain diseases that are being approached by iPSC technology to discover or establish the molecular basis of the neuropathology are discussed.

Nano-imaging agents for brain diseases: Environmentally responsive imaging and therapy

Precise imaging is essential for the accurate diagnosis and surgical guidance of brain diseases but it is challenging due to the difficulties in crossing the blood-brain barrier(BBB),the difficulties in disease lesion targeting,and the limited contrast in the brain environment.Nano-imaging agents were characterized by functionalized modifications,high contrast,small size,and high biocompatibility,thus providing advantages in BBB crossing,brain targeting,imaging resolution,and real-time monitoring,holding great potential in brain disease imaging.Specific characteristics in brain environment and brain diseases(e.g.,marker proteins on the BBB,the pathogenic proteins in the neurodegenerative diseases or brain tumors,and the tumor and inflammatory microenvironment)provide opportunities for the functionalized nano-imaging agents to improve BBB crossing and disease targeting.Moreover,the versatile nano-imaging agents are endowed with therapeutic agents to facilitate the theranostics of brain diseases.Here,we summarized the common materials and imaging techniques of nano-imaging agents and their imaging treatment applications.We discussed their BBB penetration,environmental response for disease targeting,and therapeutic effects.We also provided insights on the advantages,challenges,and application of nano-imaging agents in detecting and treating brain diseases such as neurodegenerative diseases,brain tumors,stroke,and traumatic brain injury.These discussions will help develop nano-imaging agents-based theranostic platforms for the precise diagnosis and treatment of brain diseases.

Feature Enhanced Stacked Auto Encoder for Diseases Detection in Brain MRI

The detection of brain disease is an essential issue in medical and research areas.Deep learning techniques have shown promising results in detecting and diagnosing brain diseases using magnetic resonance imaging(MRI)images.These techniques involve training neural networks on large datasets of MRI images,allowing the networks to learn patterns and features indicative of different brain diseases.However,several challenges and limitations still need to be addressed further to improve the accuracy and effectiveness of these techniques.This paper implements a Feature Enhanced Stacked Auto Encoder(FESAE)model to detect brain diseases.The standard stack auto encoder’s results are trivial and not robust enough to boost the system’s accuracy.Therefore,the standard Stack Auto Encoder(SAE)is replaced with a Stacked Feature Enhanced Auto Encoder with a feature enhancement function to efficiently and effectively get non-trivial features with less activation energy froman image.The proposed model consists of four stages.First,pre-processing is performed to remove noise,and the greyscale image is converted to Red,Green,and Blue(RGB)to enhance feature details for discriminative feature extraction.Second,feature Extraction is performed to extract significant features for classification using DiscreteWavelet Transform(DWT)and Channelization.Third,classification is performed to classify MRI images into four major classes:Normal,Tumor,Brain Stroke,and Alzheimer’s.Finally,the FESAE model outperforms the state-of-theart,machine learning,and deep learning methods such as Artificial Neural Network(ANN),SAE,Random Forest(RF),and Logistic Regression(LR)by achieving a high accuracy of 98.61% on a dataset of 2000 MRI images.The proposed model has significant potential for assisting radiologists in diagnosing brain diseases more accurately and improving patient outcomes.

Rethinking neurodegenerative diseases:neurometabolic concept linking lipid oxidation to diseases in the central nervous system

Currently,there is a lack of effective medicines capable of halting or reve rsing the progression of neurodegenerative disorde rs,including amyotrophic lateral sclerosis,Parkinson s disease,multiple sclerosis,or Alzheimer s disease.Given the unmet medical need,it is necessary to reevaluate the existing para digms of how to to rget these diseases.When considering neurodegenerative diseases from a systemic neurometabolic perspective,it becomes possible to explain the shared pathological features.This innovative approach presented in this paper draws upon exte nsive research conducted by the authors and researchers worldwide.In this review,we highlight the importance of metabolic mitochondrial dysfunction in the context of neurodegenerative diseases.We provide an overview of the risk factors associated with developing neurodegenerative disorders,including genetic,epigenetic,and environmental fa ctors.Additionally,we examine pathological mechanisms implicated in these diseases such as oxidative stress,accumulation of misfolded proteins,inflammation,demyelination,death of neurons,insulin resistance,dysbiosis,and neurotransmitter disturbances.Finally,we outline a proposal for the restoration of mitochondrial metabolism,a crucial aspect that may hold the key to facilitating curative therapeutic interventions for neurodegenerative disorders in forthcoming advancements.

Evolution of blood-brain barrier in brain diseases and related systemic nanoscale brain-targeting drug delivery strategies

Bloode-brain barrier(BBB)strictly controls matter exchange between blood and brain,and severely limits brain penetration of systemically administered drugs,resulting in ineffective drug therapy of brain diseases.However,during the onset and progression of brain diseases,BBB alterations evolve inevitably.In this review,we focus on nanoscale brain-targeting drug delivery strategies designed based on BBB evolutions and related applications in various brain diseases including Alzheimer’s disease,Parkinson’s disease,epilepsy,stroke,traumatic brain injury and brain tumor.The advances on optimization of small molecules for BBB crossing and non-systemic administration routes(e.g.,intranasal treatment)for BBB bypassing are not included in this review.

Urinary Biomarkers of Brain Diseases

Biomarkers are the measurable changes associated with a physiological or pathophysio- logical process. Unlike blood, urine is not subject to homeostatic mechanisms. Therefore, greater fluctuations could occur in urine than in blood, better reflecting the changes in human body. The roadmap of urine biomarker era was proposed. Although urine analysis has been attempted for clin- ical diagnosis, and urine has been monitored during the progression of many diseases, particularly urinary system diseases, whether urine can reflect brain disease status remains uncertain. As some biomarkers of brain diseases can be detected in the body fluids such as cerebrospinal fluid and blood, there is a possibility that urine also contain biomarkers of brain diseases. This review summarizes the clues of brain diseases reflected in the urine proteome and metabolome.

Clearing the corpses： regulatory mechanisms, novel tools, and therapeutic potential of harnessing microglial phagocytosis in the diseased brain

Apoptosis is a widespread phenomenon that occurs in the brain in both physiological and pathological conditions. Dead ceils must be quickly removed to avoid the further toxic effects they exert in the pa- renchyma, a process executed by microglia, the brain professional phagocytes. Although phagocytosis is critical to maintain tissue homeostasis, it has long been either overlooked or indirectly assessed based on microglial morphology, expression of classical activation markers, or engulfment of artificial phagocytic targets in vitro. Nevertheless, these indirect methods present several limitations and, thus, direct obser- vation and quantification of microglial phagocytosis is still necessary to fully grasp its relevance in the diseased brain. To overcome these caveats and obtain a comprehensive, quantitative picture of microglial phagocytosis we have developed a novel set of parameters. These parameters have allowed us to identify the different strategies utilized by microglia to cope with apoptotic challenges induced by excitotoxicity or inflammation. In contrast, we discovered that in mouse and human epilepsy microglia failed to find and engulf apoptotic ceils, resulting in accumulation of debris and inflammation. Herein, we advocate that the efficiency of microglial phagocytosis should be routinely tested in neurodegenerative and neuro- logical disorders, in order to determine the extent to which it contributes to apoptosis and inflammation found in these conditions. Finally, our findings point towards enhancing microglial phagocytosis as a novel therapeutic strategy to control tissue damage and inflammation, and accelerate recovery in brain diseases.

An abnormal resting-state functional brain network indicates progression towards Alzheimer's disease

Brain structure and cognitive function change in the temporal lobe, hippocampus, and prefrontal cortex of patients with mild cognitive impairment and Alzheimer＇s disease, and brain network-connection strength, network efficiency, and nodal attributes are abnormal. However, existing research has only analyzed the differences between these patients and normal controls. In this study, we constructed brain networks using resting-state functional MRI data that was extracted from four populations （nor- mal controls, patients with early mild cognitive impairment, patients with late mild cognitive impairment, and patients with Alzheimer＇s disease） using the Alzheimer＇s Disease Neuroimaging Initiative data set. The aim was to analyze the characteristics of resting-state functional neural networks, and to observe mild cognitive impairment at different stages before the transformation to Alzheimer＇s disease. Results showed that as cognitive deficits increased across the four groups, the shortest path in the rest- ing-state functional network gradually increased, while clustering coefficients gradually decreased. This evidence indicates that dementia is associated with a decline of brain network efficiency. In addi- tion, the changes in functional networks revealed the progressive deterioration of network function across brain regions from healthy elderly adults to those with mild cognitive impairment and AIz- heimer＇s disease. The alterations of node attributes in brain regions may reflect the cognitive functions in brain regions, and we speculate that early impairments in memory, hearing, and language function can eventually lead to diffuse brain injury and other cognitive impairments.

Bifurcations for counterintuitive post-inhibitory rebound spike related to absence epilepsy and Parkinson disease

Seizures are caused by increased neuronal firing activity resulting from reduced inhibitory effect and enhancement of inhibitory modulation to suppress this activity is used as a therapeutic tool.However,recent experiments have shown a counterintuitive phenomenon that inhibitory modulation does not suppress but elicit post-inhibitory rebound(PIR)spike along with seizure to challenge the therapeutic tool.The nonlinear mechanism to avoid the PIR spike can present theoretical guidance to seizure treatment.This paper focuses on identifying credible bifurcations that underlie PIR spike by modulating multiple parameters in multiple theoretical models.The study identifies a codimension-2 bifurcation called saddle-node homoclinic orbit(SNHOB),which is an intersection between saddle node bifurcation on invariant cycle(SNIC)and other two bifurcations.PIR spike cannot be evoked for the SNIC far from the SNHOBbut induced for the SNIC close to the SNHOB,which extends the bifurcation condition for PIR spike from the well-known Hopf to SNIC.Especially,in a thalamic neuron model,increases of conductance of T-type Ca^(2+)(TC a)channel induce SNIC bifurcation approaching to the SNHOB to elicit PIR spikes,closely matching experimental results of the absence seizure or Parkinson diseases.Such results imply that,when inhibition is employed to relieve absence seizure and Parkinson diseases related to PIR spike,modulating SNIC to get far from the SNHOBto avoid PIR spike is the principle.The study also addresses the complex roles of TCacurrent and comprehensive relationships between PIR spike and nonlinear conceptions such as bifurcation types and shapes of threshold curve.

Eating Less Seems To Fend Off Brain Diseases

民间有种说法:饭胀傻瓜,酒醉智汉。当然,这更多地是酒桌上酒友们互相鼓劲的一种说法。不过,威斯康星-麦迪逊大学最近的一项研究表明,这种说法还颇富科学意蕴。该研究认为老年人节食可能对健脑有益,尤其是可减少患某些神经系统疾病(如帕金森和早老性痴呆症)的风险。当然节食应该是适当的。至于对小孩来说节食是不是可以利脑现在没有明证。因而那些因小孩厌食而成心病的父母也不应因此而有太多放松。

Not only a bad guy:potential proneurogenic role of the RAGE/NF-κB axis in Alzheimer's disease brain

The receptor for advanced glycation endproducts（RAGE）is a receptor of the immunoglobulin superfamily of cell surface molecules which plays important contributions under both physiological and pathological conditions.Over the years extensive research work supported the detrimental role of RAGE in Alzheimer’s disease（AD）pathophysiology,ranging from its involvement in beta amyloid（Aβ）brain influx and clearance,

The treatment of Parkinson's disease with deep brain stimulation: current issues

Deep brain stimulation has become a well-established symptomatic treatment for Parkinson＇s disease during the last 25 years. Besides improving motor symptoms and long-term motor complications, positive effects on patients＇ mobility, activities of daily living, emotional well-being and health-related quality of life have been recognized. Apart from that, numerous clinical trials analyzed effects on non-motor symptoms and side effects of deep brain stimulation. Several technical issues and stimulation paradigms have been and are still being developed to optimize the therapeutic effects, minimize the side effects and facilitate handling. This review summarizes current therapeutic issues, i.e., patient and target selection, surgical procedure and programming paradigms. In addition it focuses on neuropsychological effects and side effects of deep brain stimulation.

Staining neurons with Golgi techniques in degenerative diseases ofthe brain

A detailed morphological study of neurons in healthy and pathological conditions requires reasonably a number of special techniques, which may visualize the majority of neu- rons in a thick three-dimensional arrangement. A detailed visualization of neurons must include the cell body, most of the dendritic arbor, the dendritic spines, the axon, the axonal collaterals and the synapses. An ideal morphological technique for the study of degeneration and regeneration processes of the central nervous system must also visualize clearly the long and short neuronal circuits, as well as the dendritic and axonal bands and tracks.

Dopaminergic mediation in the brain aging and neurodegenerative diseases:a role of senescent cells

Aging is well known to be the main risk factor for the neurodegenerative pathologies,in particular,Parkinson’s disease（PD）and Alzheimer’s disease（AD）.In aging and in the diseases,similar changes in various hallmarks of neurodegeneration（lipofuscin accumulation,autophagia weakening,and disturbances in functions of mitochondriaand lysosomes） were shown （Tan et al., 2014）. Furthermore, dopami- nergic system （DAS） involvement in mechanisms of aging, PD, and AD were revealed （Martorana and Koch, 2014）.

Cholinergic input from the pedunculopontine nucleus to the cerebellum: implications for deep brain stimulation in Parkinson's disease

Deep brain stimulation（DBS）is a well established electrophysiological treatment initially applied to treat medication-refractory motor symptoms in Parkinson＇s disease（PD）,and is now being explored for several neurological and psychiatric disorders.The specific physiological mechanisms underlying the effectiveness of DBS are not fully understood.

Nose-to-brain drug delivery approach：a key to easily accessing the brain for the treatment of Alzheimer＇s disease

Alzheimer＇s disease（AD）：AD,a neurodegenerative disorder and a significant cause of dementia throughout the world mostly affects the older adults but sometimes also seen in young age（early state AD）（Agrawal et al.,2017）.

The brain compensatory mechanisms and Alzheimer's disease progression:a new protective strategy

Compensatory/adaptive mechanisms in the brain are hy- pothesized to be involved in its protection from the Alz- heimer＇s disease （AD） progression. These mechanisms are activated by malfunctioning of various brain systems： anti- oxidant, neurotrophic, neurotransmitter, immune, and oth- ers. Detailed analysis of compensatory^adaptive capabilities of these systems might be a start point for further discovery and development of perspective approaches for early diag- nostics and treatment of AD and associated neurodegenera- tive disorders.

Need for multiple biomarkers to adjust parameters of closed-loop deep brain stimulation for Parkinson's disease

Closed-loop deep brain stimulation（DBS）：DBS has been established as a surgical therapy for movement disorders and select neuropsychiatric disorders.Various efforts to improve the clinical outcomes of the procedure have been previously made.Several factors affect the DBS clinical outcomes such as lead position,programming technique,