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  • Lymphatic Drainage System of the Brain: A Novel Target for Intervention of Neurological Diseases
    Prog. Neurobiol. (IF 13.217) Pub Date : 2017-09-10
    Bao-Liang Sun, Li-hua Wang, Tuo Yang, Lei-lei Mao, Jing-yi Sun, Ming-feng Yang, Hui Yuan, Robert A. Colvin, Xiao-yi Yang

    The belief that the vertebrate brain functions normally without classical lymphatic drainage vessels has been held for many decades. On the contrary, new findings show that functional lymphatic drainage does exist in the brain. The brain lymphatic drainage system is composed of basement membrane-based perivascular pathway, a brain-wide glymphatic pathway, and cerebrospinal fluid (CSF) drainage routes including sinus-associated meningeal lymphatic vessels and olfactory/cervical lymphatic routes. The brain lymphatic systems function physiological as a route of drainage for interstitial fluid (ISF) from brain parenchyma to nearby lymph nodes. Brain lymphatic drainage helps maintain water and ion balance of the ISF, waste clearance, and reabsorption of macromolecular solutes. A second physiological function includes communication with the immune system modulating immune surveillance and responses of the brain. These physiological functions are influenced by aging, genetic phenotypes, sleep-wake cycle, and body posture. The impairment and dysfunction of the brain lymphatic system has crucial roles in age-related changes of brain function and the pathogenesis of neurovascular, neurodegenerative, and neuroinflammatory diseases, as well as brain injury and tumors. In this review, we summarize the key component elements (regions, cells, and water transporters) of the brain lymphatic system and their regulators as potential therapeutic targets in the treatment of neurologic diseases and their resulting complications. Finally, we highlight the clinical importance of ependymal route-based targeted gene therapy and intranasal drug administration in the brain by taking advantage of the unique role played by brain lymphatic pathways in the regulation of CSF flow and ISF/CSF exchange.

    更新日期:2017-09-10
  • The role of non-endothelial cells on the penetration of nanoparticles through the blood brain barrier
    Prog. Neurobiol. (IF 13.217) Pub Date : 2017-09-09
    Rui Pedro Moura, Andreia Almeida, Bruno Sarmento

    The blood brain barrier (BBB) is a well-established cell-based membrane that circumvents the central nervous system (CNS), protecting it from harmful substances. Due to its robustness and cell integrity, it is also an outstanding opponent when it comes to the delivery of several therapeutic agents to the brain, which requires the crossing through its highly-organized structure. This regulation and cell-cell communications occur mostly between astrocytes, pericytes and endothelial cells. Therefore, alternative ways to deliver drugs to the CNS, overcoming the BBB are required, to improve the efficacy of brain target drugs. Nanoparticles emerge here as a promising drug delivery strategy, due to their ability of high drug loading and the capability to exploit specific delivery pathways that most drugs are unable to when administered freely, increasing their bioavailability in the CNS. Thus, further attempts to assess the possible influence of non-endothelial may have on the BBB translocation of nanoparticles are here revised. Furthermore, the use of macrophages and/or monocytes as nanoparticle delivery cells are also approached. Lastly, the temporarily disruption of the overall organization and normal structure of the BBB to promote the penetration of nanoparticles aimed at the CNS is described, as a synergistic path.

    更新日期:2017-09-10
  • Progressing Neurobiological Strategies Against Proteostasis Failure: Challenges in Neurodegeneration
    Prog. Neurobiol. (IF 13.217) Pub Date : 2017-09-01
    Ayeman Amanullah, Arun Upadhyay, Vibhuti Joshi, Ribhav Mishra, Nihar Ranjan Jana, Amit Mishra
    更新日期:2017-09-04
  • Modelling iron mismanagement in neurodegenerative disease in vitro: paradigms, pitfalls, possibilities & practical considerations
    Prog. Neurobiol. (IF 13.217) Pub Date : 2017-08-30
    Sinead Healy, Jill M. McMahon, Una FitzGerald

    Although aberrant metabolism and deposition of iron has been associated with aging and neurodegeneration, the contribution of iron to neuropathology is unclear. Well-designed model systems that are suited to studying the putative pathological effect of iron are likely to be essential if such unresolved details are to be clarified. In this review, we have evaluated the utility and effectiveness of the reductionist in vitro platform to study the molecular mechanisms putatively underlying iron perturbations of neurodegenerative disease. The expression and function of iron metabolism proteins in glia and neurons and the extent to which this iron regulatory system is replicated in in vitro models has been comprehensively described followed by an appraisal of the inherent suitability of different in vitro and ex vivo models that have been, or might be, used for iron loading. Next, we have identified and critiqued the relevant experimental parameters that have been used in in vitro iron loading experiments, including the choice of iron reagent, relevant iron loading concentrations and supplementation with serum or ascorbate, and propose optimal iron loading conditions. Finally, we have provided a synthesis of the differential iron accumulation and toxicity in glia and neurons from reported iron loading paradigms. In summary, this review has amalgamated the findings and paradigms of the published reports modelling iron loading in monocultures, discussed the limitations and discrepancies of such work to critically propose a robust, relevant and reliable model of iron loading to be used for future investigations.

    更新日期:2017-08-31
  • Chronic Traumatic Encephalopathy-Integration of Canonical Traumatic Brain Injury Secondary Injury Mechanisms with Tau Pathology
    Prog. Neurobiol. (IF 13.217) Pub Date : 2017-08-26
    Jacqueline R. Kulbe, Edward D. Hall
    更新日期:2017-08-31
  • Impact of microRNAs on ischemic stroke: From pre- to post-disease
    Prog. Neurobiol. (IF 13.217) Pub Date : 2017-08-24
    Guangwen Li, Kahlilia C. Morris-Blanco, Mary S. Lopez, Tuo Yang, Haiping Zhao, Raghu Vemuganti, Yumin Luo

    Stroke is the number one cause of neurological dysfunction in adults and has a heavy socioeconomic burden worldwide. The etiological origins of ischemic stroke and resulting pathological processes are mediated by a multifaceted cascade of molecular mechanisms that are in part modulated by posttranscriptional activity. Accumulating evidence has revealed a role for microRNAs (miRNAs) as essential mediators of posttranscriptional gene silencing in both the physiology of brain development and pathology of ischemic stroke. In this review, we compile miRNAs that have been reported to regulate various stroke risk factors and pre-disease mechanisms, including hypertension, atherosclerosis, and diabetes, followed by an in-depth analysis of miRNAs in ischemic stroke pathogenesis, such as excitotoxicity, oxidative stress, inflammation, apoptosis, angiogenesis and neurogenesis. Since promoting or suppressing expression of miRNAs by specific pharmaceutical and non-pharmaceutical therapies may be beneficial to post-stroke recovery, we also highlight the potential therapeutic value of miRNAs in clinical settings.

    更新日期:2017-08-31
  • Astrocytes and endoplasmic reticulum stress: A bridge between obesity and neurodegenerative diseases
    Prog. Neurobiol. (IF 13.217) Pub Date : 2017-08-10
    Cynthia A. Martin-Jiménez, Ángela García-Vega, Ricardo Cabezas, Gjumrakch Aliev, Valentina Echeverria, Janneth González, George E. Barreto

    Endoplasmic reticulum (ER) is a subcellular organelle involved in protein folding and processing. ER stress constitutes a cellular process characterized by accumulation of misfolded proteins, impaired lipid metabolism and induction of inflammatory responses. ER stress has been suggested to be involved in several human pathologies, including neurodegenerative diseases and obesity. Different studies have shown that both neurodegenerative diseases and obesity trigger similar cellular responses to ER stress. Moreover, both diseases are assessed in astrocytes as evidences suggest these cells as key regulators of brain homeostasis. However, the exact contributions to the effects of ER stress in astrocytes in the various neurodegenerative diseases and its relation with obesity are not well known. Here, we discuss recent advances in the understanding of molecular mechanisms that regulate ER stress-related disorders in astrocytes such as obesity and neurodegeneration. Moreover, we outline the correlation between the activated proteins of the unfolded protein response (UPR) in these pathological conditions in order to identify possible therapeutic targets for ER stress in astrocytes. We show that ER stress in astrocytes shares UPR activation pathways during both obesity and neurodegenerative diseases, demonstrating that UPR related proteins like ER chaperone GRP 78/Bip, PERK pathway and other exogenous molecules ameliorate UPR response and promote neuroprotection.

    更新日期:2017-08-31
  • Impact of aging immune system on neurodegeneration and potential immunotherapies
    Prog. Neurobiol. (IF 13.217) Pub Date : 2017-08-04
    Zhanfeng Liang, Yang Zhao, Linhui Ruan, Linnan Zhu, Kunlin Jin, Qichuan Zhuge, Dong-Ming Su, Yong Zhao

    The interaction between the nervous and immune systems during aging is an area of avid interest, but many aspects remain unclear. This is due, not only to the complexity of the aging process, but also to a mutual dependency and reciprocal causation of alterations and diseases between both the nervous and immune systems. Aging of the brain drives whole body systemic aging, including aging-related changes of the immune system. In turn, the immune system aging, particularly immunosenescence and T cell aging initiated by thymic involution that are sources of chronic inflammation in the elderly (termed inflammaging), potentially induces brain aging and memory loss in a reciprocal manner. Therefore, immunotherapeutics including modulation of inflammation, vaccination, cellular immune therapies and “protective autoimmunity” provide promising approaches to rejuvenate neuroinflammatory disorders and repair brain injury. In this review, we summarize recent discoveries linking the aging immune system with the development of neurodegeneration. Additionally, we discuss potential rejuvenation strategies, focusing aimed at targeting the aging immune system in an effort to prevent acute brain injury and chronic neurodegeneration during aging.

    更新日期:2017-08-31
  • Functional integration of complex miRNA networks in central and peripheral lesion and axonal regeneration
    Prog. Neurobiol. (IF 13.217) Pub Date : 2017-08-03
    M. Ghibaudi, M. Boido, A. Vercelli

    New players are emerging in the game of peripheral and central nervous system injury since their physiopathological mechanisms remain partially elusive. These mechanisms are characterized by several molecules whose activation and/or modification following a trauma is often controlled at transcriptional level. In this scenario, microRNAs (miRNAs/miRs) have been identified as main actors in coordinating important molecular pathways in nerve or spinal cord injury (SCI). miRNAs are small non-coding RNAs whose functionality at network level is now emerging as a new level of complexity. Indeed they can act as an organized network to provide a precise control of several biological processes. Here we describe the functional synergy of some miRNAs in case of SCI and peripheral damage. In particular we show how several small RNAs can cooperate in influencing simultaneously the molecular pathways orchestrating axon regeneration, inflammation, apoptosis and remyelination. We report about the networks for which miRNA-target bindings have been experimentally demonstrated or inferred based on target prediction data: in both cases, the connection between one miRNA and its downstream pathway is derived from a validated observation or is predicted from the literature. Hence, we discuss the importance of miRNAs in some pathological processes focusing on their functional structure as participating in a cooperative and/or convergence network.

    更新日期:2017-08-31
  • Stem Cell Therapy for Abrogating Stroke-Induced Neuroinflammation and Relevant Secondary Cell Death Mechanisms
    Prog. Neurobiol. (IF 13.217) Pub Date : 2017-07-23
    Connor Stonesifer, Sydney Corey, Shaila Ghanekar, Zachary Diamandis, Sandra A. Acosta, Cesar V. Borlongan

    Ischemic stroke is a leading cause of death worldwide. A key secondary cell death mechanism mediating neurological damage following the initial episode of ischemic stroke is the upregulation of endogenous neuroinflammatory processes to levels that destroy hypoxic tissue local to the area of insult, induce apoptosis, and initiate a feedback loop of inflammatory cascades that can expand the region of damage. Stem cell therapy has emerged as an experimental treatment for stroke, and accumulating evidence supports the therapeutic efficacy of stem cells to abrogate stroke-induced inflammation. In this review, we investigate clinically relevant stem cell types, such as hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), very small embryonic-like stem cells (VSELs), neural stem cells (NSCs), extraembryonic stem cells, adipose tissue-derived stem cells, breast milk-derived stem cells, menstrual blood-derived stem cells, dental tissue-derived stem cells, induced pluripotent stem cells (iPSCs), teratocarcinoma-derived Ntera2/D1 neuron-like cells (NT2N), c-mycER(TAM) modified NSCs (CTX0E03), and notch-transfected mesenchymal stromal cells (SB623), comparing their potential efficacy to sequester stroke-induced neuroinflammation and their feasibility as translational clinical cell sources. To this end, we highlight that MSCs, with a proven track record of safety and efficacy as a transplantable cell for hematologic diseases, stand as an attractive cell type that confers superior anti-inflammatory effects in stroke both in vitro and in vivo. That stem cells can mount a robust anti-inflammatory action against stroke complements the regenerative processes of cell replacement and neurotrophic factor secretion conventionally ascribed to cell-based therapy in neurological disorders.

    更新日期:2017-08-31
  • Nanomaterial applications for neurological diseases and central nervous system injury
    Prog. Neurobiol. (IF 13.217) Pub Date : 2017-07-22
    Lijie Huang, Jiangnan Hu, Shengwei Huang, Brian Wang, Felix Siaw-Debrah, Mark Nyanzu, Yu Zhang, Qichuan Zhuge

    The effectiveness of noninvasive treatment for neurological disease is generally limited by the poor entry of therapeutic agents into the central nervous system (CNS). Most CNS drugs cannot permeate into the brain parenchyma because of the blood-brain barrier thus, overcoming this problem has become one of the most significant challenges in the development of neurological therapeutics. Nanotechnology has emerged as an innovative alternative for treating neurological diseases. In fact, rapid advances in nanotechnology have provided promising solutions to this challenge. This review highlights the applications of nanomaterials in the developing neurological field and discusses the evidence for their efficacies.

    更新日期:2017-08-31
  • Neural Reuse Of Action Perception Circuits For Language, Concepts And Communication
    Prog. Neurobiol. (IF 13.217) Pub Date : 2017-07-20
    Friedemann Pulvermüller

    Neurocognitive and neurolinguistics theories make explicit statements relating specialized cognitive and linguistic processes to specific brain loci. These linking hypotheses are in need of neurobiological explanation. Recent mathematical models of human language mechanisms constrained by fundamental neuroscience principles and established knowledge about comparative neuroanatomy offer explanations for where, when and how language is processed in the human brain. In these models, network structure and connectivity along with action- and perception-induced correlation of neuronal activity co-determine neurocognitive mechanisms. Language learning leads to the formation of action perception circuits (APCs) with specific distributions across cortical areas. Cognitive and linguistic processes such as speech production, comprehension, verbal working memory and prediction are modelled by activity dynamics in these APCs, and combinatorial and communicative-interactive knowledge is organized in the dynamics within, and connections between APCs. The network models and, in particular, the concept of distributionally-specific circuits, can account for some previously not well understood facts about the cortical ‘hubs’ for semantic processing and the motor system’s role in language understanding and speech sound recognition. A review of experimental data evaluates predictions of the APC model and alternative theories, also providing detailed discussion of some seemingly contradictory findings. Throughout, recent disputes about the role of mirror neurons and grounded cognition in language and communication are assessed critically.

    更新日期:2017-08-31
  • Criticality in the brain: A synthesis of neurobiology, models and cognition
    Prog. Neurobiol. (IF 13.217) Pub Date : 2017-07-19
    Luca Cocchi, Leonardo L. Gollo, Andrew Zalesky, Michael Breakspear

    Cognitive function requires the coordination of neural activity across many scales, from neurons and circuits to large-scale networks. As such, it is unlikely that an explanatory framework focused upon any single scale will yield a comprehensive theory of brain activity and cognitive function. Modelling and analysis methods for neuroscience should aim to accommodate multiscale phenomena. Emerging research now suggests that multi-scale processes in the brain arise from so-called critical phenomena that occur very broadly in the natural world. Criticality arises in complex systems perched between order and disorder, and is marked by fluctuations that do not have any privileged spatial or temporal scale. We review the core nature of criticality, the evidence supporting its role in neural systems and its explanatory potential in brain health and disease.

    更新日期:2017-08-31
  • Autophagy in hemorrhagic stroke: Mechanisms and clinical implications
    Prog. Neurobiol. (IF 13.217) Pub Date : 2017-04-13
    Haiying Li, Jiang Wu, Haitao Shen, Xiyang Yao, Chenglin Liu, S. Pianta, J. Han, C.V. Borlongan, Gang Chen

    Accumulating evidence advances the critical role of autophagy in brain pathology after stroke. Investigations employing autophagy induction or inhibition using pharmacological tools or autophagy-related gene knockout mice have recently revealed the biological significance of intact and functional autophagy in stroke. Most of the reported cases attest to a pro-survival role for autophagy in stroke, by facilitating removal of damaged proteins and organelles, which can be recycled for energy generation and cellular defenses. However, these observations are difficult to reconcile with equally compelling evidence demonstrating stroke-induced upregulation of brain cell death index that parallels enhanced autophagy. This begs the question of whether drug-induced autophagy during stroke culminates in improved or worsened pathological outcomes. A corollary fascinating hypothesis, but presents as a tricky conundrum, involves the effects of autophagy on cell death and inflammation, which are two main culprits in the disease progression of stroke-induced brain injury. Evidence has extended the roles of autophagy in inflammation via cytokine regulation in an unconventional secretion manner or by targeting inflammasomes for degradation. Moreover, in the recently concluded Vancouver Autophagy Symposium (VAS) held in 2014, the potential of selective autophagy for clinical treatment has been recognized. The role of autophagy in ischemic stroke has been reviewed previously in detail. Here, we evaluate the strength of laboratory and clinical evidence by providing a comprehensive summary of the literature on autophagy, and thereafter we offer our perspectives on exploiting autophagy as a drug target for cerebral ischemia, especially in hemorrhagic stroke.

    更新日期:2017-08-31
  • Stem cell transplantation therapy for multifaceted therapeutic benefits after stroke
    Prog. Neurobiol. (IF 13.217) Pub Date : 2017-03-18
    Ling Wei, Zheng Z. Wei, Michael Qize Jiang, Osama Mohamad, Shan Ping Yu

    One of the exciting advances in modern medicine and life science is cell-based neurovascular regeneration of damaged brain tissues and repair of neuronal structures. The progress in stem cell biology and creation of adult induced pluripotent stem (iPS) cells has significantly improved basic and pre-clinical research in disease mechanisms and generated enthusiasm for potential applications in the treatment of central nervous system (CNS) diseases including stroke. Endogenous neural stem cells and cultured stem cells are capable of self-renewal and give rise to virtually all types of cells essential for the makeup of neuronal structures. Meanwhile, stem cells and neural progenitor cells are well-known for their potential for trophic support after transplantation into the ischemic brain. Thus, stem cell-based therapies provide an attractive future for protecting and repairing damaged brain tissues after injury and in various disease states. Moreover, basic research on naïve and differentiated stem cells including iPS cells has markedly improved our understanding of cellular and molecular mechanisms of neurological disorders, and provides a platform for the discovery of novel drug targets. The latest advances indicate that combinatorial approaches using cell based therapy with additional treatments such as protective reagents, preconditioning strategies and rehabilitation therapy can significantly improve therapeutic benefits. In this review, we will discuss the characteristics of cell therapy in different ischemic models and the application of stem cells and progenitor cells as regenerative medicine for the treatment of stroke.

    更新日期:2017-08-31
  • Preconditioning in neuroprotection: From hypoxia to ischemia
    Prog. Neurobiol. (IF 13.217) Pub Date : 2017-01-18
    Sijie Li, Adam Hafeez, Fatima Noorulla, Xiaokun Geng, Guo Shao, Changhong Ren, Guowei Lu, Heng Zhao, Yuchuan Ding, Xunming Ji

    Sublethal hypoxic or ischemic events can improve the tolerance of tissues, organs, and even organisms from subsequent lethal injury caused by hypoxia or ischemia. This phenomenon has been termed hypoxic or ischemic preconditioning (HPC or IPC) and is well established in the heart and the brain. This review aims to discuss HPC and IPC with respect to their historical development and advancements in our understanding of the neurochemical basis for their neuroprotective role. Through decades of collaborative research and studies of HPC and IPC in other organ systems, our understanding of HPC and IPC-induced neuroprotection has expanded to include: early- (phosphorylation targets, transporter regulation, interfering RNA) and late- (regulation of genes like EPO, VEGF, and iNOS) phase changes, regulators of programmed cell death, members of metabolic pathways, receptor modulators, and many other novel targets. The rapid acceleration in our understanding of HPC and IPC will help facilitate transition into the clinical setting.

    更新日期:2017-08-31
  • Mitochondrial function in hypoxic ischemic injury and influence of aging
    Prog. Neurobiol. (IF 13.217) Pub Date : 2016-06-16
    P. Benson Ham, Raghavan Raju

    Mitochondria are a major target in hypoxic/ischemic injury. Mitochondrial impairment increases with age leading to dysregulation of molecular pathways linked to mitochondria. The perturbation of mitochondrial homeostasis and cellular energetics worsens outcome following hypoxic-ischemic insults in elderly individuals. In response to acute injury conditions, cellular machinery relies on rapid adaptations by modulating posttranslational modifications. Therefore, post-translational regulation of molecular mediators such as hypoxia-inducible factor 1α (HIF-1α), peroxisome proliferator-activated receptor γ coactivator α (PGC-1α), c-MYC, SIRT1 and AMPK play a critical role in the control of the glycolytic-mitochondrial energy axis in response to hypoxic-ischemic conditions. The deficiency of oxygen and nutrients leads to decreased energetic reliance on mitochondria, promoting glycolysis. The combination of pseudohypoxia, declining autophagy, and dysregulation of stress responses with aging adds to impaired host response to hypoxic-ischemic injury. Furthermore, intermitochondrial signal propagation and tissue wide oscillations in mitochondrial metabolism in response to oxidative stress are emerging as vital to cellular energetics. Recently reported intercellular transport of mitochondria through tunneling nanotubes also play a role in the response to and treatments for ischemic injury. In this review we attempt to provide an overview of some of the molecular mechanisms and potential therapies involved in the alteration of cellular energetics with aging and injury with a neurobiological perspective.

    更新日期:2017-08-31
  • Astrocyte elevated gene-1 (AEG-1) and the A(E)Ging HIV/AIDS-HAND☆
    Prog. Neurobiol. (IF 13.217) Pub Date : 2016-04-14
    Neha Vartak-Sharma, Shruthi Nooka, Anuja Ghorpade

    Recent attempts to analyze human immunodeficiency virus (HIV)-1-induced gene expression changes in astrocytes uncovered a multifunctional oncogene, astrocyte elevated gene-1 (AEG-1). Our previous studies revealed that AEG-1 regulates reactive astrocytes proliferation, migration and inflammation, hallmarks of aging and CNS injury. Moreover, the involvement of AEG-1 in neurodegenerative disorders, such as Huntington’s disease and migraine, and its induction in the aged brain suggest a plausible role in regulating overall CNS homeostasis and aging. Therefore, it is important to investigate AEG-1 specifically in aging-associated cognitive decline. In this study, we decipher the common mechanistic links in cancer, aging and HIV-1-associated neurocognitive disorders that likely contribute to AEG-1-based regulation of astrocyte responses and function. Despite AEG-1 incorporation into HIV-1 virions and its induction by HIV-1, tumor necrosis factor-α and interleukin-1β, the specific role(s) of AEG-1 in astrocyte-driven HIV-1 neuropathogenesis are incompletely defined. We propose that AEG-1 plays a central role in a multitude of cellular stress responses involving mitochondria, endoplasmic reticulum and the nucleolus. It is thus important to further investigate AEG-1-based cellular and molecular regulation in order to successfully develop better therapeutic approaches that target AEG-1 to combat cancer, HIV-1 and aging.

    更新日期:2017-08-31
  • HIV/neuroAIDS biomarkers
    Prog. Neurobiol. (IF 13.217) Pub Date : 2016-04-12
    Pejman Rahimian, Johnny J. He
    更新日期:2017-08-31
  • The application of information theory for the research of aging and aging-related diseases
    Prog. Neurobiol. (IF 13.217) Pub Date : 2016-03-19
    David Blokh, Ilia Stambler

    This article reviews the application of information-theoretical analysis, employing measures of entropy and mutual information, for the study of aging and aging-related diseases. The research of aging and aging-related diseases is particularly suitable for the application of information theory methods, as aging processes and related diseases are multi-parametric, with continuous parameters coexisting alongside discrete parameters, and with the relations between the parameters being as a rule non-linear. Information theory provides unique analytical capabilities for the solution of such problems, with unique advantages over common linear biostatistics. Among the age-related diseases, information theory has been used in the study of neurodegenerative diseases (particularly using EEG time series for diagnosis and prediction), cancer (particularly for establishing individual and combined cancer biomarkers), diabetes (mainly utilizing mutual information to characterize the diseased and aging states), and heart disease (mainly for the analysis of heart rate variability). Few works have employed information theory for the analysis of general aging processes and frailty, as underlying determinants and possible early preclinical diagnostic measures for aging-related diseases. Generally, the use of information-theoretical analysis permits not only establishing the (non-linear) correlations between diagnostic or therapeutic parameters of interest, but may also provide a theoretical insight into the nature of aging and related diseases by establishing the measures of variability, adaptation, regulation or homeostasis, within a system of interest. It may be hoped that the increased use of such measures in research may considerably increase diagnostic and therapeutic capabilities and the fundamental theoretical mathematical understanding of aging and disease.

    更新日期:2017-08-31
  • Hibernation-like neuroprotection in stroke by attenuating brain metabolic dysfunction
    Prog. Neurobiol. (IF 13.217) Pub Date : 2016-03-07
    Brian Forreider, David Pozivilko, Qingwen Kawaji, Xiaokun Geng, Yuchuan Ding

    Many mammalian species naturally undergo hibernation, a process that is associated with drastic changes in metabolism and systemic physiology. Their ability to retain an undamaged central nervous system during severely reduced cerebral blood flow has been studied for possible therapeutic application in human ischemic stroke. By inducing a less extreme ‘hibernation-like’ state, it has been hypothesized that similar neuroprotective effects reduce ischemia-mediated tissue damage in stroke patients. This manuscript includes reviews and evaluations of: (1) true hibernation, (2) hibernation-like state and its neuroprotective characteristics, (3) the preclinical and clinical methods for induction of artificial hibernation (i.e., therapeutic hypothermia, phenothiazine drugs, and ethanol), and (4) the mechanisms by which cerebral ischemia leads to tissue damage and how the above-mentioned induction methods function to inhibit those processes.

    更新日期:2017-08-31
  • Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury
    Prog. Neurobiol. (IF 13.217) Pub Date : 2016-02-15
    E.B. Engler-Chiurazzi, C.M. Brown, J.M. Povroznik, J.W. Simpkins

    There is ample empirical evidence to support the notion that the biological impacts of estrogen extend beyond the gonads to other bodily systems, including the brain and behavior. Converging preclinical findings have indicated a neuroprotective role for estrogen in a variety of experimental models of cognitive function and brain insult. However, the surprising null or even detrimental findings of several large clinical trials evaluating the ability of estrogen-containing hormone treatments to protect against age-related brain changes and insults, including cognitive aging and brain injury, led to hesitation by both clinicians and patients in the use of exogenous estrogenic treatments for nervous system outcomes. That estrogen-containing therapies are used by tens of millions of women for a variety of health-related applications across the lifespan has made identifying conditions under which benefits with estrogen treatment will be realized an important public health issue. Here we provide a summary of the biological actions of estrogen and estrogen-containing formulations in the context of aging, cognition, stroke, and traumatic brain injury. We have devoted special attention to highlighting the notion that estrogen appears to be a conditional neuroprotectant whose efficacy is modulated by several interacting factors. By developing criteria standards for desired beneficial peripheral and neuroprotective outcomes among unique patient populations, we can optimize estrogen treatments for attenuating the consequences of, and perhaps even preventing, cognitive aging and brain injury.

    更新日期:2017-08-31
  • The biphasic function of microglia in ischemic stroke
    Prog. Neurobiol. (IF 13.217) Pub Date : 2016-02-02
    Yuanyuan Ma, Jixian Wang, Yongting Wang, Guo-Yuan Yang

    Microglia are brain resident macrophages originated from primitive progenitor cells in the yolk sac. Microglia can be activated within hours and recruited to the lesion site. Traditionally, microglia activation is considered to play a deleterious role in ischemic stroke, as inhibition of microglia activation attenuates ischemia induced brain injury. However, increasing evidence show that microglia activation is critical for attenuating neuronal apoptosis, enhancing neurogenesis, and promoting functional recovery after cerebral ischemia. Differential polarization of microglia could likely explain the biphasic role of microglia in ischemia. We comprehensively reviewed the mechanisms involved in regulating microglia activation and polarization. The latest discoveries of microRNAs in modulating microglia function are discussed. In addition, the interaction between microglia and other cells including neurons, astrocytes, oligodendrocytes, and stem cells were also reviewed. Future therapies targeting microglia may not exclusively aim at suppressing microglia activation, but also at modulating microglia polarization at different stages of ischemic stroke. More work is needed to elucidate the cellular and molecular mechanisms of microglia polarization under ischemic environment. The roles of microRNAs and transplanted stem cells in mediating microglia activation and polarization during brain ischemia also need to be further studied.

    更新日期:2017-08-31
  • The brain interstitial system: Anatomy, modeling, in vivo measurement, and applications
    Prog. Neurobiol. (IF 13.217) Pub Date : 2016-02-01
    Yiming Lei, Hongbin Han, Fan Yuan, Aqeel Javeed, Yong Zhao

    Although neurons attract the most attention in neurobiology, our current knowledge of neural circuit can only partially explain the neurological and psychiatric conditions of the brain. Thus, it is also important to consider the influence of brain interstitial system (ISS), which refers to the space among neural cells and capillaries. The ISS is the major compartment of the brain microenvironment that provides the immediate accommodation space for neural cells, and it occupies 15% to 20% of the total brain volume. The brain ISS is a dynamic and complex space connecting the vascular system and neural networks and it plays crucial roles in substance transport and signal transmission among neurons. Investigation of the brain ISS can provide new perspectives for understanding brain architecture and function and for exploring new strategies to treat brain disorders. This review discussed the anatomy of the brain ISS under both physiological and pathological conditions, biophysical modeling of the brain ISS and in vivo measurement and imaging techniques, including recent findings on brain ISS divisions. Moreover, the implications of ISS knowledge for basic neuroscience and clinical applications are addressed.

    更新日期:2017-08-31
  • The therapeutic potential of cell identity reprogramming for the treatment of aging-related neurodegenerative disorders
    Prog. Neurobiol. (IF 13.217) Pub Date : 2016-02-01
    Derek K. Smith, Miao He, Chun-Li Zhang, Jialin C. Zheng

    Neural cell identity reprogramming strategies aim to treat age-related neurodegenerative disorders with newly induced neurons that regenerate neural architecture and functional circuits in vivo. The isolation and neural differentiation of pluripotent embryonic stem cells provided the first in vitro models of human neurodegenerative disease. Investigation into the molecular mechanisms underlying stem cell pluripotency revealed that somatic cells could be reprogrammed to induced pluripotent stem cells (iPSCs) and these cells could be used to model Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease, and Parkinson disease. Additional neural precursor and direct transdifferentiation strategies further enabled the induction of diverse neural linages and neuron subtypes both in vitro and in vivo. In this review, we highlight neural induction strategies that utilize stem cells, iPSCs, and lineage reprogramming to model or treat age-related neurodegenerative diseases, as well as, the clinical challenges related to neural transplantation and in vivo reprogramming strategies.

    更新日期:2017-08-31
  • Alternative mitochondrial electron transfer for the treatment of neurodegenerative diseases and cancers: Methylene blue connects the dots
    Prog. Neurobiol. (IF 13.217) Pub Date : 2015-11-18
    Shao-Hua Yang, Wenjun Li, Nathalie Sumien, Michael Forster, James W. Simpkins, Ran Liu

    Brain has exceptional high requirement for energy metabolism with glucose as the exclusive energy source. Decrease of brain energy metabolism and glucose uptake has been found in patients of Alzheimer's, Parkinson's and other neurodegenerative diseases, providing a clear link between neurodegenerative disorders and energy metabolism. On the other hand, cancers, including glioblastoma, have increased glucose uptake and rely on aerobic glycolysis for energy metabolism. The switch of high efficient oxidative phosphorylation to low efficient aerobic glycolysis pathway (Warburg effect) provides macromolecule for biosynthesis and proliferation. Current research indicates that methylene blue, a century old drug, can receive electron from NADH in the presence of complex I and donates it to cytochrome c, providing an alternative electron transfer pathway. Methylene blue increases oxygen consumption, decrease glycolysis, and increases glucose uptake in vitro. Methylene blue enhances glucose uptake and regional cerebral blood flow in rats upon acute treatment. In addition, methylene blue provides protective effect in neuron and astrocyte against various insults in vitro and in rodent models of Alzheimer's, Parkinson's, and Huntington's disease. In glioblastoma cells, methylene blue reverses Warburg effect by enhancing mitochondrial oxidative phosphorylation, arrests glioma cell cycle at s-phase, and inhibits glioma cell proliferation. Accordingly, methylene blue activates AMP-activated protein kinase, inhibits downstream acetyl-coA carboxylase and cyclin-dependent kinases. In summary, there is accumulating evidence providing a proof of concept that enhancement of mitochondrial oxidative phosphorylation via alternative mitochondrial electron transfer may offer protective action against neurodegenerative diseases and inhibit cancers proliferation.

    更新日期:2017-08-31
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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