Gravity Threshold and Dose Response Relationships: Health Benefits Using a Short Arm Human Centrifuge.

PURPOSE: Increasing the level of gravity passively on a centrifuge, should be equal to or even more beneficial not only to astronauts living in a microgravity environment but also to patients confined to bed. Gravity therapy (GT) may have beneficial effects on numerous conditions, such as immobility due to neuromuscular disorders, balance disorders, stroke, sports injuries. However, the appropriate configuration for administering the Gz load remains to be determined. METHODS: To address these issues, we studied graded G-loads from 0.5 to 2.0g in 24 young healthy, male and female participants, trained on a short arm human centrifuge (SAHC) combined with mild activity exercise within 40-59% MHR, provided by an onboard bicycle ergometer. Hemodynamic parameters, as cardiac output (CO), stroke volume (SV), mean arterial pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were analyzed, as well as blood gas analysis. A one-way repeated measures ANOVA and pairwise comparisons were conducted with a level of significance p < 0.05. RESULTS: Significant changes in heart rate variability (HRV) and its spectral components (Class, Fmax, and VHF) were found in all g loads when compared to standing (p < 0.001), except in 1.7 and 2.0g. There were significant changes in CO, cardiac index (CI), and cardiac power (CP) (p < 0.001), and in MAP (p = 0.003) at different artificial gravity (AG) levels. Dose-response curves were determined based on statistically significant changes in cardiovascular parameters, as well as in identifying the optimal G level for training, as well as the optimal G level for training. There were statistically significant gender differences in Cardiac Output/CO (p = 0.002) and Cardiac Power/CP (p = 0.016) during the AG training as compared to standing. More specifically, these cardiovascular parameters were significantly higher for male than female participants. Also, there was a statistically significant (p = 0.022) gender by experimental condition interaction, since the high-frequency parameter of the heart rate variability was attenuated during AG training as compared to standing but only for the female participants (p = 0.004). CONCLUSION: The comprehensive cardiovascular evaluation of the response to a range of graded AG loads, as compared to standing, in male and female subjects provides the dose-response framework that enables us to explore and validate the usefulness of the centrifuge as a medical device. It further allows its use in precisely selecting personalized gravity therapy (GT) as needed for treatment or rehabilitation of individuals confined to bed.

Human blood adenosine biomarkers and non-rapid eye movement sleep stage 3 (NREM3) cortical functional connectivity associations during a 30-day head-down-tilt bed rest analogue: Potential effectiveness of a reactive sledge jump as a countermeasure.

We investigated the alterations of sleep regulation and promotion biomarkers as adenosine through its enzymes total adenosine deaminase (tADA)/adenosine deaminase (ADA2) in a microgravity analogue environment of head-down-tilt bed rest and their association with brain connectivity networks during non-rapid eye movement sleep stage 3 (NREM3), as well as the effectiveness of the reactive sledge (RSL) jump countermeasure to promote sleep. A total of 23 healthy male volunteers were maintained in 6° head-down-tilt position for 30 days and assigned either to a control or to a RSL group. Blood collection and polysomnographic recordings were performed on data acquisition day 1, 14, 30 and -14, 21, respectively. Immunochemical techniques and network-based statistics were employed for adenosine enzymes and cortical connectivity estimation. Our findings indicate that human blood adenosine biomarkers as well as NREM3 cortical functional connectivity are impaired in simulated microgravity. RSL physical activity intervened in sleep quality via tADA/ADA2 fluctuations lack, minor cortical connectivity increases, and limited degree of node and resting-state networks. Statistically significant decreases in adenosine biomarkers and NREM3 functional connectivity involving regions (left superior temporal gyrus, right postcentral gyrus, precuneus, left middle frontal gyrus, left postcentral gyrus, left angular gyrus and precuneus) of the auditory, sensorimotor default-mode and executive networks highlight the sleep disturbances due to simulated microgravity and the sleep-promoting role of RSL countermeasure. The head-down-tilt environment led to sleep deterioration projected through NREM3 cortical brain connectivity or/and adenosine biomarkers shift. This decline was more pronounced in the absence of the RSL countermeasure, thereby highlighting its likely exploitation during space missions.

Therapeutic Benefits of Short-Arm Human Centrifugation in Multiple Sclerosis-A New Approach.

Short-arm human centrifugation (SAHC) is proposed as a robust countermeasure to treat deconditioning and prevent progressive disability in a case of secondary progressive multiple sclerosis. Based on long-term physiological knowledge derived from space medicine and missions, artificial gravity training seems to be a promising physical rehabilitation approach toward the prevention of musculoskeletal decrement due to confinement and inactivity. So, the present study proposes a novel infrastructure based on SAHC to investigate the hypothesis that artificial gravity ameliorates the degree of disability. The patient was submitted to a 4-week training programme including three weekly sessions of 30 min of intermittent centrifugation at 1.5-2 g. During sessions, cardiovascular, muscle oxygen saturation (SmO2) and electroencephalographic (EEG) responses were monitored, whereas neurological and physical performance tests were carried out before and after the intervention. Cardiovascular parameters improved in a way reminiscent of adaptations to aerobic exercise. SmO2 decreased during sessions concomitant with increased g load, and, as training progressed, SmO2 of the suffering limb dropped, both effects suggesting increased oxygen use, similar to that seen during hard exercise. EEG showed increased slow and decreased fast brain waves, with brain reorganization/plasticity evidenced through functional connectivity alterations. Multiple-sclerosis-related disability and balance capacity also improved. Overall, this study provides novel evidence supporting SAHC as a promising therapeutic strategy in multiple sclerosis, based on mechanical loading, thereby setting the basis for future randomized controlled trials.

A review on current trends in automatic sleep staging through bio-signal recordings and future challenges.

Sleep staging is a vital process conducted in order to analyze polysomnographic data. To facilitate prompt interpretation of these recordings, many automatic sleep staging methods have been proposed. These methods rely on bio-signal recordings, which include electroencephalography, electrocardiography, electromyography, electrooculography, respiratory, pulse oximetry and others. However, advanced, uncomplicated and swift sleep-staging-evaluation is still needed in order to improve the existing polysomnographic data interpretation. The present review focuses on automatic sleep staging methods through bio-signal recording including current and future challenges.

Modified magnetic core-shell mesoporous silica nano-formulations with encapsulated quercetin exhibit anti-amyloid and antioxidant activity.

Targeted tissue drug delivery is a challenge in contemporary nanotechnologically driven therapeutic approaches, with the interplay interactions between nanohost and encapsulated drug shaping the ultimate properties of transport, release and efficacy of the drug at its destination. Prompted by the need to pursue the synthesis of such hybrid systems, a family of modified magnetic core-shell mesoporous silica nano-formulations was synthesized with encapsulated quercetin, a natural flavonoid with proven bioactivity. The new nanocarriers were produced via the sol-gel process, using tetraethoxysilane as a precursor and bearing a magnetic core of surface-modified monodispersed magnetite colloidal superparamagnetic nanoparticles, subsequently surface-modified with polyethylene glycol 3000 (PEG3k). The arising nano-formulations were evaluated for their textural and structural properties, exhibiting enhanced solubility and stability in physiological media, as evidenced by the loading capacity, entrapment efficiency results and in vitro release studies of their load. Guided by the increased bioavailability of quercetin in its encapsulated form, further evaluation of the biological activity of the magnetic as well as non-magnetic core-shell nanoparticles, pertaining to their anti-amyloid and antioxidant potential, revealed interference with the aggregation of ß-amyloid peptide (Aß) in Alzheimer's disease, reduction of Aß cellular toxicity and minimization of Aß-induced Reactive Oxygen Species (ROS) generation. The data indicate that the biological properties of released quercetin are maintained in the presence of the host nanocarriers. Collectively, the findings suggest that the emerging hybrid nano-formulations can function as efficient nanocarriers of hydrophobic natural flavonoids in the development of multifunctional nanomaterials toward therapeutic applications.

The Pattern of Mu Rhythm Modulation During Emotional Destination Memory: Comparison Between Mild Cognitive Impairment Patients and Healthy Controls.

Leading theories of affect development and empirical studies suggest that emotion can enhance memory in older adults. Destination memory which is defined as the ability to remember to whom we told a piece of information is being found to be compromised in aging. In the present study, we sought to assess destination memory using emotional stimuli (Emotional Destination Memory, EDM) in 16 older adults with mild cognitive impairment (MCI) and 16 healthy controls and shed light onto its potential neurophysiological aspects. We measured Mu suppression in frontal and temporal regions via EEG in real time while participants performed the task of EDM. Results showed no group differences in task performance but significant differences in fronto-temporal activations, specifically in electrodes F7 and F8. Differential Mu rhythm pattern was observed between healthy controls and MCI with the first exhibiting Mu suppression and the last Mu enhancement. Furthermore, Mu enhancement in temporal electrodes within the MCI group was associated with lower scores on EDM. The absence of group differences in the task can be explained by the fact that even if there are underlying structural or functional deficits in the MCI group, these deficits are manifested only at neurophysiological level and not at a behavioral level, which is a common pattern in the process of cognitive decline in its initial phases. The overall findings reveal that, even if there are not any behavioral decrements in MCI patients, they show reduced activations in fronto-temporal regions and this can be attributed to general impairment in emotional destination memory due to possible mirror neuron deficiency.

Current trends and future perspectives of space neuroscience towards preparation for interplanetary missions.

This review addresses central nervous system (CNS) physiological changes during inter-planetary missions, specifically sensorimotor processing and sleep disorders. Isolation, confinement and induced stress factors also have a detrimental effect on cognitive and mental well-being, which could jeopardize mission accomplishment. Although countermeasures have been proposed, they mostly focus on cardiovascular and/or musculoskeletal systems. Long-term space flights require optimal cognitive performance of crew members during weightlessness for longer time periods independent of ground support. The present study describes various countermeasures trends in neuroscientific data acquisition and future perspectives of advanced analysis through functional connectivity and graph theory. These could be used to identify early deterioration patterns and evaluate the robustness of countermeasures employed.

Neurophysiological changes in simulated microgravity: An animal model.

Microgravity (MG) is one of the main problems that astronauts have to cope with during space missions. Long-duration space travel can have detrimental effects on human neurophysiology. Despite scientific efforts, these effects are still insufficiently investigated. Animal earth-based analogs are used to investigate potential nervous system associated perturbations that might occur during prolonged space missions. Hindlimb unloading, Tail suspension and Pelvic suspension models are currently used in MG studies. Loss of homeostasis of certain biological pathways in the nervous system can lead to the functioning and expression of receptors/genes, and the release and functioning of neurotransmitters and neuronal membrane ion channels into specific brain regions. The potential impact of MG on molecular mechanisms linked to neurophysiology through animal earth-based analogs is reviewed. The effect of molecular signalling pathways on the decline of neuronal connectivity and cognitive and neuroplasticity function under MG simulated conditions will be studied. The role of biomarkers including neurotransmitters, genes or receptors will be highlighted in the healthy and MG-affected brain. MG-mediated neurodegenerative mechanisms linked to learning and memory impairment will be highlighted. This review depicts the current rodent models applied to simulate MG ground based approaches and investigates the MG induced changes in the nervous system. The neuropathological profile of the above animal MG ground-based models can be comparable to the effects of ageing, anxiety and other neurological disorders. The advantages and limitations of the existing approaches are discussed. MG induced neurophysiology outcomes can be extrapolated to study other clinical applications.

Naringin nanoparticles against neurodegenerative processes: A preliminary work.

It is well established that during Alzheimer disease (AD), gradual loss of neuronal networks occurs in the brain, consequently, affecting cognition and memory tasks of the patients. Among other causative factors, oxidative stress induces changes that are eventually accompanied by an irreversible disruption of synaptic connectivity and death of neurons. Moreover, aging and oxidative stress cause alterations to the blood brain barrier, leading to increased permeability, which are thought to further aggravate the underlying pathology. Up to date, no effective treatment is available to Alzheimer's disease patients. Lately, scientific efforts are focusing on exploiting the antioxidant properties that natural polyphenol agents such as flavonoids possess and their potential beneficial effect against neurodegenerative diseases. For that reason, the current investigation, aims at developing more effective flavonoid agents by encapsulating naringin into modified PEG 3000 Silica nanoparticles before its use at cellular level. Overall, our findings suggest an enhanced protective capacity of naringin pegylated nanoparticles against Aß amyloid linked oxidative stress mediated neurodegeneration in primary rat neuronal and glial hippocampal cultures for a certain incubation period. The functional biological reactivities of the novel flavonoid nanoparticles were in line with their physicochemical features and reflect the a) differential nature of the structural assemblies of the new nanoparticles, thereby distinguishing them from other polymeric and liposomal drug carriers, and b) significance and impact of PEG chemistry in the synthetic assembly of the nanocarriers. The ability of the employed nanoparticles to entrap a relatively high dose of otherwise insoluble drugs and their biological activity highlight their potential as brain targeting therapeutics.

Magnetic chrysin silica nanomaterials behavior in an amyloidogenic environment.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with brain damage induced by ß-amyloid and tau accumulation. One of the hallmarks of amyloidogenesis, is the aggregation of amyloid proteins into a specific cross-ß sheet structure, which alters their biological activity thereby affecting neuronal connectivity and function. Despite significant progress in the management of AD over the recent years, the early diagnostic and treatment options still remain limited. Recently, great attention has been focused on the advancement of therapeutic strategies exploiting the antioxidant properties of naturally occurring compounds. Flavonoids, a major class of phytochemicals, have been found to possess a multiple range of health promoting effects, including neuroprotection. Chrysin (ChR) is a flavonoid of the flavone class with potent neuroprotective and anti-inflammatory activity. In addition, ChR improves cognitive decline by exerting anti-amyloidogenic and neurotrophic effects. Magnetic nanoparticles allow binding of drugs by entrapment on the particles, adsorption, or covalent attachment. In our study, well characterized ChR-loaded magnetic PEGylated silica nanospheres (MChRPNPs) were employed with potential enhanced protective characteristics against amyloid induced oxidative stress. The interactions of MChRPNPs with ß-amyloid were demonstrated in rat hippocampal cell cultures. Overall, the findings regarding the biological activity profile of MChRPNPs in a cellular amyloidogenic environment suggest an improved specificity of antioxidant properties counteracting amyloid mediated oxidative stress reactivity.

Advanced network neuroscience approaches in sleep neurobiology on extreme environments.

In this paper we propose a novel methodology for investigating pathological sleep patterns through network neuroscience approaches. It consists of initial identification of statistically significant alterations in cortical functional connectivity patterns. The resulting sub-network is then analyzed by employing graph theory for estimating both global performance metrics (integration and specialization) as well as the significance of specific network nodes and their hierarchical organization. So, nodes with important role in network structure are recognized and their functionality is correlated with adenosine biomarker which is important in sleep regulation and promotion. The aforementioned pipeline is applied in a dataset of sleep data gathered during a microgravity simulation experiment. The analysis was performed on cortical resting-state networks involved in sleep physiology. It demonstrated the detrimental effects of microgravity which were more prominent for the group which did not perform reactive sledge jumps as a countermeasure.

Shared pathological pathways of Alzheimer's disease with specific comorbidities: current perspectives and interventions.

Alzheimer's disease (AD) belongs to one of the most multifactorial, complex and heterogeneous morbidity-leading disorders. Despite the extensive research in the field, AD pathogenesis is still at some extend obscure. Mechanisms linking AD with certain comorbidities, namely diabetes mellitus, obesity and dyslipidemia, are increasingly gaining importance, mainly because of their potential role in promoting AD development and exacerbation. Their exact cognitive impairment trajectories, however, remain to be fully elucidated. The current review aims to offer a clear and comprehensive description of the state-of-the-art approaches focused on generating in-depth knowledge regarding the overlapping pathology of AD and its concomitant ailments. Thorough understanding of associated alterations on a number of molecular, metabolic and hormonal pathways, will contribute to the further development of novel and integrated theranostics, as well as targeted interventions that may be beneficial for individuals with age-related cognitive decline.

Chitosan encapsulation of essential oil "cocktails" with well-defined binary Zn(II)-Schiff base species targeting antibacterial medicinal nanotechnology.

The advent of biodegradable nanomaterials with enhanced antibacterial activity stands as a challenge to the global research community. In an attempt to pursue the development of novel antibacterial medicinal nanotechnology, we herein a) synthesized ionic-gelated chitosan nanoparticles, b) compared and evaluated the antibacterial activity of essential oils extracted from nine different herbs (Greek origin) and their combinations with a well-defined antibacterial Zn(II)-Schiff base compound, and c) encapsulated the most effective hybrid combination of Zn(II)-essential oils inside the chitosan matrix, thereby targeting well-formulated nanoparticles of distinct biological impact. The empty and loaded chitosan nanoparticles were physicochemically characterized by FT-IR, Thermogravimetric Analysis (TGA), Scanning Electron Microscopy (SEM), with the entrapment and drug release studies being conducted through UV-Visible and atomic absorption techniques. The antimicrobial properties of the novel hybrid materials were demonstrated against Gram positive (S. aureus, B. subtilis, and B. cereus) and Gram negative (E. coli and X. campestris) bacteria using modified agar diffusion methods. The collective physicochemical profile of the hybrid Zn(II)-essential oil cocktails, formulated so as to achieve optimal activity when loaded to chitosan nanoparticles, signifies the importance of design in the development of efficient nanomedicinal pharmaceuticals a) based on both natural products and biogenic metal ionic cofactors, and b) targeting bacterial infections and drug resistance.

Mechanisms and applications of interleukins in cancer immunotherapy.

Over the past years, advances in cancer immunotherapy have resulted in innovative and novel approaches in molecular cancer diagnostics and cancer therapeutic procedures. However, due to tumor heterogeneity and inter-tumoral discrepancy in tumor immunity, the clinical benefits are quite restricted. The goal of this review is to evaluate the major cytokines-interleukins involved in cancer immunotherapy and project their basic biochemical and clinical applications. Emphasis will be given to new cytokines in pre-clinical development, and potential directions for future investigation using cytokines. Furthermore, current interleukin-based approaches and clinical trial data from combination cancer immunotherapies will also be discussed. It appears that continuously increasing comprehension of cytokine-induced effects, cancer stemness, immunoediting, immune-surveillance as well as understanding of molecular interactions emerging in the tumor microenvironment and involving microRNAs, autophagy, epithelial-mesenchymal transition (EMT), inflammation, and DNA methylation processes may hold much promise in improving anti-tumor immunity. To this end, the emerging in-depth knowledge supports further studies on optimal synergistic combinations and additional adjuvant therapies to realize the full potential of cytokines as immunotherapeutic agents.

Quercetin encapsulation in modified silica nanoparticles: potential use against Cu(II)-induced oxidative stress in neurodegeneration.

Neurodegenerative diseases entail deeply complex processes, intimately associated with progressive brain damage reflecting cellular demise. Biochemical reactivity linked to such processes in Alzheimer's disease involves, among others, metal-induced oxidative stress contributing to neuronal cell death. Prominent among redox active metals inducing oxidative stress is Cu(II). Poised to develop molecular technology counteracting oxidative stress, efforts were launched to prepare bioactive hybrid nanoparticles, capable of working as host-carriers of potent antioxidants, such as the natural flavonoid quercetin. Employing synthetic protocols consistent with the assembly of silica nanoparticles, PEGylated and CTAB-modified materials were synthesized. Subsequent concentration-dependent loading of quercetin led to well-defined molecular carriers, the antioxidant efficiency of which was determined through drug release studies using UV-visible spectroscopy. The physicochemical characterization (elemental analysis, particle size, z-potential, FT-IR, thermogravimetric analysis, scanning electron microscopy) of the empty and loaded silica nanoparticles led to the formulation of optimized material linked to the delivery of the encapsulated antioxidant to primary rat hippocampal cultures under oxidative stress. Entrapment and drug release studies showed a) the competence of hybrid nanoparticles as far as the loading capacity in quercetin (concentration dependence), b) congruence with the physicochemical features determined, and c) the release profile of the nanoparticle load under oxidative stress in neuronal cultures. The bio-activity profile of quercetin nanoparticles in a neurodegenerative environment brought on by Cu(II) a) denotes the improved specificity of antioxidant reactivity counteracting oxidative stress, and b) sets the stage for the development of molecular protection and preventive medical nanotechnology of relevance to neurodegenerative Alzheimer's disease.

In vitro neurotoxic Fe(III) and Fe(III)-chelator activities in rat hippocampal cultures. From neurotoxicity to neuroprotection prospects.

It is well known that iron dysregulation is involved in a number of processes involving genetic and non-genetic factors leading to neurodegeneration. Molecules bearing iron or influencing iron metabolism reflect directly into the levels of that redox active metal, present as Fe(II)/Fe(III), in the brain. In turn, iron level variations are associated with chemical reactivity disrupting iron homeostasis, generating variable neurotoxic iron forms and contributing to the vulnerability of cells toward oxidative stress and neuronal death in Alzheimer's disease (AD). Efforts to delineate the interactions of neurotoxic Fe(III) with low molecular mass substrates, relevant to cellular processes, led to the discovery of specific well-defined binary iron-quinate (FeQ) species. Poised to investigate the specific effects of a) well-defined forms of labile soluble Fe(III), b) the nature and chemistry of the ligand bound to Fe(III), and c) a natural metal ion binder - quinic acid - acting as a potential neuroprotectant toward iron toxicity, FeCl(3), FeQ, and free quinate were employed in in vitro studies involving primary rat hippocampal cultures. Three hour and 24-hour exposures of such cultures to Fe(III) reveal significant differential effects on both glial and neuronal cell survival linked to neurotoxicity of the specific yet variably composed complex forms of iron. The use of quinic acid both in the free and bound form to Fe(III) a) exemplifies essential structural and chemical attributes of naturally encountered metal ion binders promoting well-defined interactions with neurotoxic Fe(III), and b) signifies the potential linkage of labile Fe(III) chemical reactivity in neurodegeneration with natural substrate neuroprotection.

Aluminum does not enhance beta-amyloid toxicity in rat hippocampal cultures.

A number of environmental factors have been implicated in neurodegenerative disorders, including metallotoxins such as aluminum (Al). In the present study, the toxicity of Al-quinate (AlQ), a well-characterized Al complex, was investigated in primary rat hippocampal cultures in comparison to inorganic Al (Al-S). AlQ was significantly less toxic than Al-S during both short- (3h) and long-term (24h) incubations. The neuroprotective properties of quinic acid (which constitutes the quinate moiety of AlQ) against short-term incubations with Al-S were subsequently assessed, and the organic compound was found to provide full protection, comparable to synthetic metal chelating agents desferrioxamine and clioquinol. Finally, potential synergistic actions between Al (AlQ and Al-S) and beta-amyloid (Abeta) were investigated. Neither Al form appeared to enhance Abeta toxicity, in fact, AlQ significantly reduced Abeta toxicity. Collectively, this study highlights further the impact of structural features and physiological ligands of metal complexes on toxicity profiles, and reveals promising properties of quinic acid as a metal chelator. Despite previous reports suggesting synergistic toxicity between Al and Abeta, we could not identify such a mechanism in our investigation.

Aluminium interferes with hippocampal calcium signaling in a species-specific manner.

Aluminium (Al) has been implicated in a number of neurodegenerative disorders and the disruption of calcium homeostasis has been proposed as a possible mechanism. To investigate ligand- and structure-specific effects of Al species, calcium imaging was used to probe the influence of five Al complexes - in comparison to inorganic Al (Al-S) - on N-methyl d-aspartate receptor (NMDAR) and voltage-dependent calcium channel (VDCC) function in hippocampal neurontos. The Al complexes utilized comprised three Al-citrate species (AlCit1-3), Al-quinate (AlQ) and Al-N-phosphonomethyliminodiacetate (AlNTAP). Our results suggest variable toxicity among the Al compounds tested: Al-S most potently affected neurons, with a full and irreversible inhibition of NMDAR and VDCC signaling at 500 microM. At all concentrations tested (10, 100, and 500 microM), all Al compounds investigated inhibited NMDA responses, however, no dose-dependency was evident. Furthermore, striking differences were noted with respect to calcium responses via VDCC activation. AlCit2 reduced calcium responses at all concentrations tested, AlQ at 10 and 100 microM, and AlNTAP at 500 microM only. In contrast, AlCit1 and AlCit3 had no significant effect. Collectively, diversely structured Al-ligand species selectively affect neuronal membrane channel function. The distinct chemical reactivity of the various Al forms reflects their unique interactions with neuronal structures and is poised to explain the diverse facets of Al toxicity.