Shilajit: A Natural Phytocomplex with Potential Procognitive Activity

Shilajit is a natural substance found mainly in the Himalayas, formed for centuries by the gradual decomposition of certain plants by the action of microorganisms. It is a potent and very safe dietary supplement, restoring the energetic balance and potentially able to prevent several diseases. Recent investigations point to an interesting medical application toward the control of cognitive disorders associated with aging, and cognitive stimulation. Thus, fulvic acid, the main active principle, blocks tau self-aggregation, opening an avenue toward the study of Alzheimer's therapy. In essence, this is a nutraceutical product of demonstrated benefits for human health. Considering the expected impact of shilajit usage in the medical field, especially in the neurological sciences, more investigations at the basic biological level as well as clinical trials are necessary, in order to understand how organic molecules of shilajit and particularly fulvic acid, one of the active principles, and oligoelements act at both the molecular and cellular levels and in the whole organism

Neuroinflammation and Neurodegeneration

Pathophysiological processes of neurodegenerative diseases are not clearly defined. However, an important body of evidence points toward the role of various inflammatory processes. The microglial cell is the main representative of the immune system in the central nervous system (CNS). This cell type can sense foreign or harmful pathogens and trigger its own activation and the generation of neuroinflammatory processes through phagocytosis and the release of cytokines, in order to maintain the cellular microenvironment. However, after maintaining a permanent state of activation due to sustained stimulation over time, microglial cells may generate a focus of persistent inflammation that in some cases precedes or enhances the neurodegenerative process. Thus, neuroinflammatory microenvironment becomes toxic and harmful for the neuronal cell, which degenerates and releases various factors that in turn activate the inflammatory response of microglia, potentiating the neurodegenerative cycle. In this chapter, we discuss the evidence on the role of microglial cell activation in neurodegenerative conditions and the association between neuroinflammatory processes and age-related neurological diseases. Finally, we outline how this new approach can help us to find new ways to understand neurodegenerative processes and to orientate the search for new therapies

Neuroimmune Dynamics in Alzheimer’s Disease Progression

Alzheimer’s disease (AD) is a neurodegenerative disease, the most common cause of dementia in senile population. According to the World Health Organization, AD represents around 12% of people over 65 worldwide. Due to its etiological agents, neurofibrillary tangles (NFT) and amyloid plaques (AP), several attempts to explain the genesis and progression of AD have been proposed. Pathological variants of tau protein, are the main precursor for AD onset, with a molecular mechanism based on neuroinflammatory processes in the context of the neuroimmunomodulation theory. Microglial cells play preponderant roles in innate immunity and are the main source of proinflammatory factors in the central nervous system (CNS), the links between microglia and neurons are the main focus on AD pathogenesis. Depending on these factors, either a neuroprotective or a proinflammatory effect could be triggered. In AD, a persistently active microglial condition generates neuronal damage and death, causing the release of pathological tau toward the extracellular environment. This causes the activation of microglia, promoting a feedback mechanism and generating a continuous cellular damage. After activation of microglia, generation of NF‐kB occurs, thus promoting the expression and release of proinflammatory cytokines. As a consequence, short‐lived cytotoxic factors, such as O2, NO and other reactive oxygen species, are released. In normal physiological conditions, tau’s kinases play a role in regulating normal tau functions in neurons. Glycogen synthase kinase 3‐beta (GSK3β)‐mediated tau phosphorylation promotes N‐methyl‐D aspartate receptor (NMDAr)‐mediated long‐term depression. The increase of proinflammatory cytokines during AD by microglia leads to an increase in kinase expression and activity of cyclin‐dependent kinase 5 (Cdk‐5) and GSK3‐β. On the other hand, TNF‐α and IL‐8 increase expression and activity of Cdk5, whereas IL‐1β hyperactivates GSK3‐β, leading to tau hyperphosphorylation and impairing its normal function. Tau hyperphosphorylation results in microtubule destabilization, impaired axonal transport, NMDAr‐mediated neurotoxicity, synaptic dysfunction and cell death. Finally, the previously summarized mechanisms could explain the onset and progression of AD, opening a new projection to focus research on therapeutic agents that could modulate the interactions between tau and microglial cells. The neuroimmunomodulation mechanism has been the conceptual framework for the search of therapeutic approaches for AD and other neurodegenerative disorders

Roles of Cholesterol and Lipids in the Etiopathogenesis of Alzheimer's Disease

Alzheimer's disease is the principal cause of dementia throughout the world and the fourth cause of death in developed economies.This brain disorder is characterized by the formation of brain protein aggregates, namely, the paired helical filaments and senile plaques. Oxidative stress during life, neuroinflamamtion, and alterations in neuron-glia interaction patterns have been also involved in the etiopathogenesis of this disease. In recent years, cumulative evidence has been gained on the involvement of alteration in neuronal lipoproteins activity, as well as on the role of cholesterol and other lipids in the pathogenesis of this neurodegenerative disorder. In this review, we analyze the links between changes in cholesterol homeostasis, and the changes of lipids of major importance for neuronal activity and Alheimer's disease. The investigation on the fine molecular mechanisms underlying the lipids influence in the etiopathogenesis of Alzheimer's disease may shed light into its treatment and medical management

Interleukin-3 prevents neuronal death induced by amyloid peptide

<p>Abstract</p> <p>Background</p> <p>Interleukin-3 (IL-3) is an important glycoprotein involved in regulating biological responses such as cell proliferation, survival and differentiation. Its effects are mediated via interaction with cell surface receptors. Several studies have demonstrated the expression of IL-3 in neurons and astrocytes of the hippocampus and cortices in normal mouse brain, suggesting a physiological role of IL-3 in the central nervous system. Although there is evidence indicating that IL-3 is expressed in some neuronal populations, its physiological role in these cells is poorly known.</p> <p>Results</p> <p>In this study, we demonstrated the expression of IL-3 receptor in cortical neurons, and analyzed its influence on amyloid β (Aβ)-treated cells. In these cells, IL-3 can activate at least three classical signalling pathways, Jak/STAT, Ras/MAP kinase and the PI 3-kinase. Viability assays indicated that IL-3 might play a neuroprotective role in cells treated with Aβ fibrils. It is of interest to note that our results suggest that cell survival induced by IL-3 required PI 3-kinase and Jak/STAT pathway activation, but not MAP kinase. In addition, IL-3 induced an increase of the anti-apoptotic protein Bcl-2.</p> <p>Conclusion</p> <p>Altogether these data strongly suggest that IL-3 neuroprotects neuronal cells against neurodegenerative agents like Aβ.</p

Cognitive impairment and Alzheimer’s disease: Links with oxidative stress and cholesterol metabolism

Oxidative stress has been implicated in the progression of a number of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease and amyotrophic lateral sclerosis. We carried out an in-depth study of cognitive impairment and its relationships with oxidative stress markers such as ferric-reducing ability of plasma (FRAP), plasma malondialdehyde and total antioxidative capacity (TAC), as well as cholesterol parameters, in two subsets of subjects, AD patients (n = 59) and a control group of neurologically normal subjects (n = 29), attending the University Hospital Salvador in Santiago, Chile. Cognitive impairment was assessed by a set of neuropsychological tests (Mini-Mental State Examination, Boston Naming Test, Ideomotor Praxia by imitation, Semantic Verbal Fluency of animals or words with initial A, Test of Memory Alteration, Frontal Assessment Battery), while the levels of those oxidative stress markers and cholesterol metabolism parameters were determined according with standard bioassays in fresh plasma samples of the two subgroups of patients. No significant differences were observed when the cholesterol parameters (low-, high-density lipoprotein, total cholesterol) of the AD group were compared with normal controls. Interestingly, a correlation was evidenced when the levels of cognitive impairment were analyzed with respect to the plasma antioxidant capacity (AOC) of patients. In this context, the subset of subjects exhibiting cognitive impairment were divided into two subgroups according with their Global Dementia Scale performance: a subgroup with mild AD and a subgroup with moderate to severe AD. Significant differences in AOC were found between subgroups. The different correlations between cognitive impairment of subgroups of subjects with the oxidative stress profile are discussed in the context of AD pathogenesis

DIMENSIONES BIOÉTICAS DE LA INVESTIGACIÓN SOBRE EL GENOMA HUMANO

El desciframiento del genoma humano es un paradigma de la ciencia. Además de impactar en el conocimiento puede cambiar el curso de la medicina, con un enfoque personalizado y un énfasis en lo preventivo. Como los hallazgos que abren nuevas avenidas de pensamiento, ha despertado la atención sobre los riesgos éticos. Se plantea si es ético que le revelen a un individuo que podría llegar a padecer una enfermedad incurable, lo que impactaría negativamente en su calidad de vida. Sobre quién tendrá acceso a la información genética. Desde los inicios de la carrera del genoma humano se planteó la necesidad de asegurar la privacidad de la información genética. Se hace necesario situar la discusión en un contexto amplio, pues se crean mitos que es importante aplacar. Es esencial sembrar la confianza promoviendo que la comunidad científica, junto con diferentes sectores de la sociedad, realicen un debate abierto sobre los aspectos positivos y negativos de cada nueva tecnología que derive del genoma human

Dimensões bioéticas da pesquisa sobre o genoma humano

The elucidation of the human genome constitutes a major paradigm. Besides its impact on our biological nowledge, the elucidation of the human genome will certainly exert a driving force on both medical research and practice in the future. As a paradigmatic discovery impacting medical research, the human genome has also increased public awareness concerning the risks and ethical problems associated with this advancement. Questions such as whether it is ethical to reveal to a patient that he may be suffering an incurable disease, that this information may negatively impact his quality of life are among the many concerns. From the beginning of the race to elucidate the human genome, it was agreed upon that it is necessary to assure the privacy of an individual genetic information. Therefore, it is critical to focus the discussion in a wide scope and integrative perspective, since myths appear that may produce distortions in the analysis. It is also important to trust that the scientific community, together with other public sectors of the society, will promote a debate associated with the positive and negative aspects of any new technology arising from the discoveries around human genome. It is not the scientific advances that cause bioethical problems, it is the decisions that society takes in terms of how this technology will be used.El desciframiento del genoma humano es un paradigma de la ciencia. Además de impactar en el conocimiento puede cambiar el curso de la medicina, con un enfoque personalizado y un énfasis en lo preventivo. Como los hallazgos que abren nuevas avenidas de pensamiento, ha despertado la atención sobre los riesgos éticos. Se plantea si es ético que le revelen a un individuo que podría llegar a padecer una enfermedad incurable, lo que impactaría negativamente en su calidad de vida. Sobre quién tendrá acceso a la información genética. Desde los inicios de la carrera del genoma humano se planteó la necesidad de asegurar la privacidad de la información genética. Se hace necesario situar la discusión en un contexto amplio, pues se crean mitos que es importante aplacar. Es esencial sembrar la confianza promoviendo que la comunidad científica, junto con diferentes sectores de la sociedad, realicen un debate abierto sobre los aspectos positivos y negativos de cada nueva tecnología que derive del genoma humano.O mapeamento do genoma humano é uma paradigma para a ciência. Além de impactar no conhecimento, pode mudar o curso da medicina, com um enfoque personalizado e ênfase no preventivo. Como os hallazgos que abrem novas avenidas de pensamento, desertou a atenção sobre os riscos éticos. Pergunta-se de é ético que se revele a um indivíduo que poderia chegar a padecer de uma enfermidade incurável, o que impactaria negativamente sua qualidade de vida. Quem terá acesso à informação genética? Desde o início do processo de mapeamento do genoma humano se colocou a necessidade de assegurar a privacidade da informação genética. Torna-se necessário situar a discussão num contexto mais amplo, pois se criam mitos que é importante enfrentar. É essencial semear a confiança promovendo que a comunidade científica, junto com os diferentes setores da sociedade, realizem um debate aberto sobre os aspectos positivos e negativos de cada nova tecnologia que derive do genoma humano

Dimensões bioéticas da pesquisa sobre o genoma humano

The elucidation of the human genome constitutes a major paradigm. Besides its impact on our biological nowledge, the elucidation of the human genome will certainly exert a driving force on both medical research and practice in the future. As a paradigmatic discovery impacting medical research, the human genome has also increased public awareness concerning the risks and ethical problems associated with this advancement. Questions such as whether it is ethical to reveal to a patient that he may be suffering an incurable disease, that this information may negatively impact his quality of life are among the many concerns. From the beginning of the race to elucidate the human genome, it was agreed upon that it is necessary to assure the privacy of an individual genetic information. Therefore, it is critical to focus the discussion in a wide scope and integrative perspective, since myths appear that may produce distortions in the analysis. It is also important to trust that the scientific community, together with other public sectors of the society, will promote a debate associated with the positive and negative aspects of any new technology arising from the discoveries around human genome. It is not the scientific advances that cause bioethical problems, it is the decisions that society takes in terms of how this technology will be used.El desciframiento del genoma humano es un paradigma de la ciencia. Además de impactar en el conocimiento puede cambiar el curso de la medicina, con un enfoque personalizado y un énfasis en lo preventivo. Como los hallazgos que abren nuevas avenidas de pensamiento, ha despertado la atención sobre los riesgos éticos. Se plantea si es ético que le revelen a un individuo que podría llegar a padecer una enfermedad incurable, lo que impactaría negativamente en su calidad de vida. Sobre quién tendrá acceso a la información genética. Desde los inicios de la carrera del genoma humano se planteó la necesidad de asegurar la privacidad de la información genética. Se hace necesario situar la discusión en un contexto amplio, pues se crean mitos que es importante aplacar. Es esencial sembrar la confianza promoviendo que la comunidad científica, junto con diferentes sectores de la sociedad, realicen un debate abierto sobre los aspectos positivos y negativos de cada nueva tecnología que derive del genoma humano.O mapeamento do genoma humano é uma paradigma para a ciência. Além de impactar no conhecimento, pode mudar o curso da medicina, com um enfoque personalizado e ênfase no preventivo. Como os hallazgos que abrem novas avenidas de pensamento, desertou a atenção sobre os riscos éticos. Pergunta-se de é ético que se revele a um indivíduo que poderia chegar a padecer de uma enfermidade incurável, o que impactaria negativamente sua qualidade de vida. Quem terá acesso à informação genética? Desde o início do processo de mapeamento do genoma humano se colocou a necessidade de assegurar a privacidade da informação genética. Torna-se necessário situar a discussão num contexto mais amplo, pois se criam mitos que é importante enfrentar. É essencial semear a confiança promovendo que a comunidade científica, junto com os diferentes setores da sociedade, realizem um debate aberto sobre os aspectos positivos e negativos de cada nova tecnologia que derive do genoma humano