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Adult neurogenesis is the life-long process of neural stem cell proliferation, differentiation into neurons, migration, and incorporation into the existing neuronal circuits. After decades of research, it is now widely accepted that mammals and birds retain the capacity to regenerate neurons even after their subadult ontogeny. Cerebrospinal fluid participates in the regulation of the neurogenic niches of the vertebrate brain through signaling pathways not fully elucidated. Proteomic studies of cerebrospinal fluid have the potential to allow the in-depth characterization of its molecular composition. Comparative studies help to delineate those pathways that are universally critical for the regulation of neurogenesis in adulthood. In this review, we performed literature-based data mining in studies using liquid chromatography-tandem mass spectroscopy that analyzed cerebrospinal fluid samples from healthy adult humans (Homo sapiens); mice (Mus musculus); sheep (Ovis aries); chickens (Gallus gallus); and two parrot species, the budgerigar (Melopsittacus undulatus) and cockatiel (Nymphicus hollandicus). We identified up to 911 proteins represented in cerebrospinal fluid, involved in various pathways regulating adult neurogenesis. However, only 196 proteins were common across humans, mice, and birds. Pathway components involved in nervous system development, cell migration, and axonal guidance were commonly evident in all species investigated so far. Extensive bioinformatic analysis revealed that the universally over-represented pathways involved L1 cell adhesion molecule protein interactions, cell-adhesion molecules, signals regulating extracellular matrix remodeling, regulation of insulin growth factor signaling, axonal guidance, programmed cell death, immune signaling, and post-translational modifications. Most of the reported proteins are part of extracellular vesicles enriched in cerebrospinal fluid. However, the information presently available is still highly fragmentary, and far more questions persist than are answered. Technological advances will allow cerebrospinal fluid comparative proteomic research to delve into the fundamental processes of adult neurogenesis and eventually translate this research into any regenerative interventions.
- Klíčová slova
- adult neurogenesis, birds, cerebrospinal fluid, chicken, comparative proteomics, human, mammals, mass spectrometry, parrots,
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- časopisecké články MeSH
- přehledy MeSH
Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are a heterogeneous group of debilitating disorders with multifactorial etiologies and pathogeneses that manifest distinct molecular mechanisms and clinical manifestations with abnormal protein dynamics and impaired bioenergetics. Mitochondrial dysfunction is emerging as an important feature in the etiopathogenesis of these age-related neurodegenerative diseases. The prevalence and incidence of these diseases is on the rise with the increasing global population and average lifespan. Although many therapeutic approaches have been tested, there are currently no effective treatment routes for the prevention or cure of these diseases. We present the current status of our knowledge and understanding of the involvement of mitochondrial dysfunction in these diseases and highlight recent advances in novel therapeutic strategies targeting neuronal bioenergetics as potential approach for treating these diseases.
Alzheimer's disease (AD) is the most common type of dementia, but it is very difficult to diagnose with certainty, so many AD studies have attempted to find early and relevant diagnostic markers. Regulated upon activation, normal T cell expressed and secreted (RANTES, also known as C-C chemokine ligand) is a chemokine involved in the migration of T cells and other lymphoid cells. Changes in RANTES levels and its expression in blood or in cerebrospinal fluid have been reported in some neurodegenerative diseases, such as Parkinson's disease and multiple sclerosis, but also in metabolic diseases in which inflammation plays a role. The aim of this observational study was to assess RANTES levels in peripheral blood as clinical indicators of AD. Plasma levels of RANTES were investigated in 85 AD patients in a relatively early phase of AD (median 8.5 months after diagnosis; 39 men and 46 women; average age 75.7 years), and in 78 control subjects (24 men and 54 women; average age 66 years). We found much higher plasma levels of RANTES in AD patients compared to controls. A negative correlation of RANTES levels with age, disease duration, Fazekas scale score, and the medial temporal lobe atrophy (MTA) score (Scheltens's scale) was found in AD patients, i.e., the higher levels corresponded to earlier stages of the disease. Plasma RANTES levels were not correlated with cognitive scores. In AD patients, RANTES levels were positively correlated with the levels of pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-α, which is consistent with the well-known fact that AD is associated with inflammatory processes. RANTES levels were also positively correlated with insulin levels in AD patients, with insulin resistance (HOMA-R) and pancreatic beta cell function (HOMA-F). This study evaluated several clinical and metabolic factors that may affect plasma levels of RANTES, but these factors could not explain the increases in RANTES levels observed in AD patients. Plasma levels of RANTES appear to be an interesting peripheral marker for early stages of AD. The study was approved by the Ethics Committee of Institute of Endocrinology, Prague, Czech Republic on July 22, 2011.
- Klíčová slova
- Alzheimer’s disease, RANTES, biomarker, central nervous system, cognitive impairment, inflammation,
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- časopisecké články MeSH
Systematic inflammatory response after spinal cord injury (SCI) is one of the factors leading to lesion development and a profound degree of functional loss. Anti-inflammatory compounds, such as curcumin and epigallocatechin gallate (EGCG) are known for their neuroprotective effects. In this study, we investigated the effect of combined therapy of curcumin and EGCG in a rat model of acute SCI induced by balloon compression. Immediately after SCI, rats received curcumin, EGCG, curcumin + EGCG or saline [daily intraperitoneal doses (curcumin, 6 mg/kg; EGCG 17 mg/kg)] and weekly intramuscular doses (curcumin, 60 mg/kg; EGCG 17 mg/kg)] for 28 days. Rats were evaluated using behavioral tests (the Basso, Beattie, and Bresnahan (BBB) open-field locomotor test, flat beam test). Spinal cord tissue was analyzed using histological methods (Luxol Blue-cresyl violet staining) and immunohistochemistry (anti-glial fibrillary acidic protein, anti-growth associated protein 43). Cytokine levels (interleukin-1β, interleukin-4, interleukin-2, interleukin-6, macrophage inflammatory protein 1-alpha, and RANTES) were measured using Luminex assay. Quantitative polymerase chain reaction was performed to determine the relative expression of genes (Sort1, Fgf2, Irf5, Mrc1, Olig2, Casp3, Gap43, Gfap, Vegf, NfκB, Cntf) related to regenerative processes in injured spinal cord. We found that all treatments displayed significant behavioral recovery, with no obvious synergistic effect after combined therapy of curcumin and ECGC. Curcumin and EGCG alone or in combination increased axonal sprouting, decreased glial scar formation, and altered the levels of macrophage inflammatory protein 1-alpha, interleukin-1β, interleukin-4 and interleukin-6 cytokines. These results imply that although the expected synergistic response of this combined therapy was less obvious, aspects of tissue regeneration and immune responses in severe SCI were evident.
- Klíčová slova
- curcumin, epigallocatechin gallate, inflammatory response, neural regeneration, spinal cord injury,
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- časopisecké články MeSH
Among the macromolecular drug targets in neurodegenerative disorders, the neurotrophin brain-derived neurotrophic factor (BDNF) and its high-affinity tropomyosin-related kinase receptor (TrkB) present strong interest for nanomedicine development aiming at neuronal and synaptic repair. Currently, BDNF is regarded as the neurotrophic factor of highest therapeutic significance. However, BDNF has delivery problems as a protein drug. The enhanced activation of the transcription factor CREB (cAMP response element-binding protein) has been evidenced to increase the BDNF gene expression and hence the production of endogenous BDNF. We assume that BDNF delivery by nanocarriers and mitochondrial protection may provide high potential for therapeutic amelioration of the neuroregenerative strategies. Beneficial therapeutic outcomes may be expected for synergistic dual or multi-drug action aiming at (i) neurotrophic protein regulation in the central and peripheral nervous systems, and (ii) diminishment of the production of reactive oxygen species (ROS) and the oxidative damage in mitochondria. Our research strategy is based on a nanoarchitectonics approach for the design of nanomedicine assemblies by hierarchical self-assembly. We explore nanoarchitectonics concepts in soft-matter nanotechnology towards preparation of biodegradable self-assembled lipid nanostructures for safe neuro-therapeutic applications of multi-target nanomedicines.
- Klíčová slova
- BDNF delivery, CREB, combination therapy, macromolecular drugs, nanomedicine, neuroprotective lipid nanocarriers, neurotrophic factor,
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- přehledy MeSH
Distribution and activity of mitochondria are key factors in neuronal development, synaptic plasticity and axogenesis. The majority of energy sources, necessary for cellular functions, originate from oxidative phosphorylation located in the inner mitochondrial membrane. The adenosine-5'- triphosphate production is regulated by many control mechanism-firstly by oxygen, substrate level, adenosine-5'-diphosphate level, mitochondrial membrane potential, and rate of coupling and proton leak. Recently, these mechanisms have been implemented by "second control mechanisms," such as reversible phosphorylation of the tricarboxylic acid cycle enzymes and electron transport chain complexes, allosteric inhibition of cytochrome c oxidase, thyroid hormones, effects of fatty acids and uncoupling proteins. Impaired function of mitochondria is implicated in many diseases ranging from mitochondrial myopathies to bipolar disorder and schizophrenia. Mitochondrial dysfunctions are usually related to the ability of mitochondria to generate adenosine-5'-triphosphate in response to energy demands. Large amounts of reactive oxygen species are released by defective mitochondria, similarly, decline of antioxidative enzyme activities (e.g. in the elderly) enhances reactive oxygen species production. We reviewed data concerning neuroplasticity, physiology, and control of mitochondrial oxidative phosphorylation and reactive oxygen species production.
- Klíčová slova
- calcium, electron transport chain complex, fatty acid, membrane potential, metabolic pathway, mitochondria, neural regeneration, neuroregeneration, oxidative phosphorylation, reactive oxygen species, respiratory state, reviews, uncoupling protein,
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- časopisecké články MeSH
