The Use of Transcranial Magnetic Stimulation in Attention Optimization Research: A Review from Basic Theory to Findings in Attention-Deficit/Hyperactivity Disorder and Depression.

This review explores the pivotal role of attention in everyday life, emphasizing the significance of studying attention-related brain functions. We delve into the development of methodologies for investigating attention and highlight the crucial role of brain neuroimaging and transcranial magnetic stimulation (TMS) in advancing attention research. Attention optimization theory is introduced to elucidate the neural basis of attention, identifying key brain regions and neural circuits involved in attention processes. The theory further explores neuroplasticity, shedding light on how the brain dynamically adapts and changes to optimize attention. A comprehensive overview of TMS is provided, elucidating the principles and applications of this technique in affecting brain activity through magnetic field stimulation. The application of TMS in attention research is discussed, outlining how it can be employed to regulate attention networks. The clinical applications of TMS are explored in attention-deficit/hyperactivity disorder (ADHD) and depression. TMS emerges as an effective clinical treatment for ADHD, showcasing its potential in addressing attention-related disorders. Additionally, the paper emphasizes the efficacy of TMS technology as a method for regulating depression, further underlining the versatility and therapeutic potential of TMS in clinical settings. In conclusion, this review underscores the interdisciplinary approach to attention research, integrating neuroimaging, neuroplasticity, and TMS. The presented findings contribute to our understanding of attention mechanisms and highlight the promising clinical applications of TMS in addressing attention-related disorders. This synthesis of theoretical and practical insights aims to propel further advancements in attention research and its therapeutic applications.

Exploring the Frontiers of Neuroimaging: A Review of Recent Advances in Understanding Brain Functioning and Disorders.

Neuroimaging has revolutionized our understanding of brain function and has become an essential tool for researchers studying neurological disorders. Functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) are two widely used neuroimaging techniques to review changes in brain activity. fMRI is a noninvasive technique that uses magnetic fields and radio waves to produce detailed brain images. An EEG is a noninvasive technique that records the brain's electrical activity through electrodes placed on the scalp. This review overviews recent developments in noninvasive functional neuroimaging methods, including fMRI and EEG. Recent advances in fMRI technology, its application to studying brain function, and the impact of neuroimaging techniques on neuroscience research are discussed. Advances in EEG technology and its applications to analyzing brain function and neural oscillations are also highlighted. In addition, advanced courses in neuroimaging, such as diffusion tensor imaging (DTI) and transcranial electrical stimulation (TES), are described, along with their role in studying brain connectivity, white matter tracts, and potential treatments for schizophrenia and chronic pain. Application. The review concludes by examining neuroimaging studies of neurodevelopmental and neurological disorders such as autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD), and Parkinson's disease (PD). We also described the role of transcranial direct current stimulation (tDCS) in ASD, ADHD, AD, and PD. Neuroimaging techniques have significantly advanced our understanding of brain function and provided essential insights into neurological disorders. However, further research into noninvasive treatments such as EEG, MRI, and TES is necessary to continue to develop new diagnostic and therapeutic strategies for neurological disorders.

Building Caregivers' Social Support on Social Network Sites Through Online Support Groups.

Online support groups (OSGs) provide caregivers of children with mental disorders, information, and advice, as well as the opportunity to exchange social support. This research explores the effects of social support on caregivers when they participate in OSGs. The research survey was conducted on OSGs for parents of children with mental disorders, including developmental delay, autism spectrum disorder, and attention-deficit/hyperactivity disorder. This study collected 204 questionnaires from caregivers for analysis. The results found that informational support and tangible support positively affect members' self-efficacy (SEF), while offering esteem support, emotional support, and companionship support, influencing positive affect (PA). Both SEF and PA improve with members' knowledge-sharing intentions and subjective well-being. In addition, PA impacts the release of stress and recovery from self-stigma. This study provides insights into members' behavior toward support groups. The findings also provide preliminary guidelines for health professionals in adopting strategies to support caregivers.

Exploring member's knowledge sharing intention in online health communities: The effects of social support and overload.

This study explores the determinants of members' participation intention in online health communities (OHC) from both the facilitators and barriers points of view. From the facilitators perspective, each member's subjective well-being plays a crucial role in sharing intention. On the other hand, from the barriers point of view, social network site exhaustion would negatively affect. The survey was conducted on two online support groups, including parents of children with autism spectrum disorder and caregivers of dementia disease. This study collected 330 questionnaires from social network sites to examine the research model. The results showed that social support positively affects members' self-efficacy; in turn, self-efficacy has a positive effect on subjective well-being. Overload has an impact on psychological distress. Moreover, members' subjective well-being determined their knowledge sharing intention.

Nanogold induces anti-inflammation against oxidative stress induced in human neural stem cells exposed to amyloid-beta peptide.

Alzheimer's disease (AD) is a neurodegenerative disorder with progressive memory loss resulting in dementia. Amyloid-beta (Aß) peptides play a critical role in the pathogenesis of the disease by promoting inflammation and oxidative stress, leading to neurodegeneration in the brains of AD patients. Numerous in vitro 3D cell culture models are useful mimics for understanding cellular changes that occur during AD under in vivo conditions. The 3D Bioprinter developed at the CELLINK INKREDIBLE was used in this study to directly investigate the influence of 3D conditions on human neural stem cells (hNSCs) exposed to Aß. The development of anti-AD drugs is usually difficult, mainly due to a lack of therapeutic efficacy and enhanced serious side effects. Gold nanoparticles (AuNPs) demonstrate benefits in the treatment of several diseases, including AD, and may provide a novel therapeutic approach for AD patients. However, the neuroprotective mechanisms by which AuNPs exert these beneficial effects in hNSCs treated with Aß are still not well understood. Therefore, we tested the hypothesis that AuNPs protect against Aß-induced inflammation and oxidative stress in hNSCs under 3D conditions. Here, we showed that AuNPs improved the viability of hNSCs exposed to Aß, which was correlated with the reduction in the expression of inflammatory cytokines, such as TNF-α and IL-1ß. In addition, AuNPs rescued the levels of the transcripts of inhibitory kappa B kinase (IKK) in Aß-treated hNSCs. The Aß-mediated increases in mRNA, protein, and nuclear translocation levels of NF-κB (p65), a key transcription factor involved in inflammatory responses, were all significantly abrogated following co-treatment of hNSCs with AuNPs. In addition, treatment with AuNPs significantly restored iNOS and COX-2 levels in Aß-treated hNSCs. Importantly, hNSCs co-treated with AuNPs were significantly protected from Aß-induced oxidative stress, as detected using the DCFH-DA and DHE staining assays. Furthermore, hNSCs co-treated with AuNPs were significantly protected from the Aß-induced reduction in the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf2 downstream antioxidant target genes (SOD-1, SOD-2, Gpx1, GSH, Catalase, and HO-1). Moreover, AuNPs reduced the aggregates and increased the proteasome activity and the expression of HSP27 and HSP70 genes in Aß-treated hNSCs. Taken together, these findings provide the first evidence extending our understanding of the molecular mechanisms under 3D scaffold conditions by which AuNPs reverse the inflammation and oxidative stress-induced in hNSCs exposed to Aß. These findings may facilitate the development of novel treatments for AD.

Examining the effect of online advertisement cues on human responses using eye-tracking, EEG, and MRI.

This study sought to emphasize how disciplines such as neuroscience and marketing can be applied in advertising and consumer behavior. The application of neuroscience methods in analyzing and understanding human behavior related to the Elaboration Likelihood Model (ELM) and brain activity has recently garnered attention. This study examines brain processes while participants attempted to elicit preferences for a product, and demonstrates factors that influence consumer behavior using eye-tracking, electroencephalography (EEG), and magnetic resonance imaging (MRI) from a neuroscience approach. We planned two conditions of online advertising, namely, peripheral cues without argument and central cues with argument strength. Thirty respondents participated in the experiment, consisting of eye-tracking, EEG, and MRI instruments to explore brain activity in central cue conditions. We investigated whether diffusion tensor imaging (DTI) analysis could detect regional brain changes. Using eye-tracking, we found that the responses were mainly in the mean fixation duration, number of fixations, mean saccade duration, and number of saccade durations for the central cue condition. Moreover, the findings show that the fusiform gyrus and frontal cortex are significantly associated with building a relationship by inferring central cues in the EEG assay. The MRI images show that the fusiform gyrus and frontal cortex are significantly active in the central cue condition. DTI analysis indicates that the corpus callosum has changed in the central cue condition. We used eye-tracking, EEG, MRI, and DTI to understand that these connections may apprehend responses when viewing advertisements, especially in the fusiform gyrus, frontal cortex, and corpus callosum.

Nanogold Neuroprotection in Human Neural Stem Cells Against Amyloid-beta-induced Mitochondrial Dysfunction.

Alzheimer's disease (AD) is a neuronal dementia with progressive memory loss. Amyloid-beta (Aß) peptides has major effect in the neurodegenerative disorder, which are thought to promote mitochondrial dysfunction in AD brains. Anti-AD drugs acting upon the brain are generally difficult to develop, often cause serious side effects or lack therapeutic efficacy. Numerous studies have shown the beneficial therapeutic applications of gold nanoparticles (AuNPs), including for neuroprotective events and AD. The aim of this study is to understand how AuNPs could exert their neuroprotective role in AD, for which cell model have chosen human neural stem cells (hNSCs) as the experimental tool. We hypothesize AuNPs protect against Aß-induced cellular impairment and mitochondrial dysfunction in hNSCs. Here, we show AuNPs increase the survival of hNSCs treated with Aß via downregulation of caspase 3 and 9 activities. Moreover, AuNPs abrogated the Aß-mediated decrease neuroprotective (CREB and Bcl-2) and mitochondrial (PGC1α, NRF-1 and Tfam) gene expressions in treated hNSCs. Importantly, co-treatment with AuNPs significantly rescued hNSCs from Aß-mediated mitochondrial function and morphology. AuNPs also significantly normalizes the immunostaining of mitochondrial marker and mass in differentiated hNSCs with Aß. The effects may be exerted by the AuNPs, as supported by its protective reversal of Aß-induced cellular impairment and mitochondrial dysfunction in hNSCs. In fact, the results presented extend our understanding of the mechanisms through which AuNPs could exert their neuroprotective role in hNSCs treated with Aß.

Neuroprotective effects of resveratrol against oxygen glucose deprivation induced mitochondrial dysfunction by activation of AMPK in SH-SY5Y cells with 3D gelatin scaffold.

Ischemic stroke arising from the sudden blockage of arteries in the brain, is a common and serious brain damaging problem worldwide, often leading to disability or death. The oxygen glucose deprivation (OGD) model was created to improve understanding of hypoxia- and hypoglycemia-induced neuronal cell injury, and provide an in vitro surrogate to assess novel treatments for cerebral hypoxia-ischemia. AMP-activated protein kinase (AMPK) is a critical neuroprotective regulator of energy homeostasis, metabolism and cell survival. However, the neuroprotective mechanisms by which AMPK achieves these beneficial effects in human SH-SY5Y neural cells exposed to OGD are still not well understood. Resveratrol is a potent activator of AMPK suggesting it may have therapeutic potential as a neuroprotective agent. Therefore, we hypothesized the AMPK activator resveratrol protects against OGD-mediated impairment of human SH-SY5Y neuronal cells. The novelty of the experiment using a 3D gelatin scaffold cell culture assay, we have tested the potential of 3D systems to mimic the endogenous neuronal environment and have applied these systems to study the effect of OGD on neuronal cells with/without resveratrol. Here we show resveratrol reverses, via AMPK-dependent downregulation of caspase 3 and 9 activity, the OGD-mediated decreases in SH-SY5Y cell viability on a 3D gelatin scaffold. In addition, treatment with OGD decreases mRNA levels of AMPK and the neuroprotective genes (Bcl-2 and CREB); however, co-treatment with resveratrol significantly normalizes these effects. Importantly, resveratrol improves the expression of AMPK and p-AMPK in OGD-exposed SH-SY5Y cells. Resveratrol also significantly rescues SH-SY5Y cells from OGD-mediated mitochondrial deficiency (lower D-loop level, mitochondrial mass, maximal respiratory function, COX activity, and mitochondrial membrane potential). Resveratrol also rescues the transcript expression levels of PGC1α and mitochondrial genes (NRF-1 and Tfam) in OGD-treated SH-SY5Y cells. These findings extend our mechanistic understanding of the central role of AMPK in OGD-related neuronal impairment, and may serve as basis for implementing new therapeutic strategies in the treatment of ischemic stroke.

Rosiglitazone rescues human neural stem cells from amyloid-beta induced ER stress via PPARγ dependent signaling.

Peroxisome proliferator-activated receptor gamma (PPARγ) belongs to a family of ligand-activated nuclear receptors known to regulate many crucial physiological and pathological conditions. Indeed, altered PPARγ transcriptional activity contributes to metabolic syndromes (obesity and hyperglycemia associated with type 2 diabetes mellitus), stroke and neurodegenerative diseases. Various studies suggest that PPARγ agonists influence neuronal deficits in Alzheimer's Disease (AD) patients and rodent models of AD. Expression of amyloid-beta (Aß), a neuropathological marker associated with the pathogenesis of AD neuronal impairment, is inversely correlated with the activation of PPARγ-dependent neuroprotective responses. Nevertheless, molecular mechanisms by which the effects of PPARγ agonists in AD remain to be clarified. Here, we explore the PPARγ signaling pathways and networks that protect against Aß-induced endoplasmic reticulum (ER) stress (e.g., caspase 4, Bip, CHOP, ASK1 and ER calcium), cell death (e.g., viability and cytochrome c) and mitochondrial deficiency (e.g., maximal respiratory function, COX activity, and mitochondrial membrane potential) events in the human neural stem cells (hNSCs) treated with Aß. Co-treatment with GW9662 (an antagonist of PPARγ) effectively blocked these protective effects by rosiglitazone, providing strong evidence that PPARγ-dependent signaling rescues hNSCs from Aß-mediated toxicity. Together, our data suggest activation of PPARγ pathway might be critical to protecting against AD-related ER stress, ER disequilibrium and mitochondrial deficiency. These findings also improve our understanding of the role of PPARγ in hNSCs, and may aid in the development and implementation of new therapeutic strategies for the treatment of AD.

Activation of AMPK is neuroprotective in the oxidative stress by advanced glycosylation end products in human neural stem cells.

Advanced glycosylation end products (AGEs) formation is correlated with the pathogenesis of diabetic neuronal damage, but its links with oxidative stress are still not well understood. Metformin, one of the most widely used anti-diabetic drugs, exerts its effects in part by activation of AMP-activated protein kinase (AMPK). Once activated, AMPK regulates many pathways central to metabolism and energy balance including, glucose uptake, glycolysis and fatty acid oxidation. AMPK is also present in neurons, but its role remains unclear. Here, we show that AGE exposure decreases cell viability of human neural stem cells (hNSCs), and that the AMPK agonist metformin reverses this effect, via AMPK-dependent downregulation of RAGE levels. Importantly, hNSCs co-treated with metformin were significantly rescued from AGE-induced oxidative stress, as reflected by the normalization in levels of reactive oxygen species. In addition, compared to AGE-treated hNSCs, metformin co-treatment significantly reversed the activity and mRNA transcript level changes of SOD1/2 and Gpx. Furthermore, hNSCs exposed to AGEs had significantly lower mRNA levels among other components of normal cellular oxidative defenses (GSH, Catalase and HO-1), which were all rescued by co-treatment with metformin. This metformin-mediated protective effect on hNSCs for of both oxidative stress and oxidative defense genes by co-treatment with metformin was blocked by the addition of an AMPK antagonist (Compound C). These findings unveil the protective role of AMPK-dependent metformin signaling during AGE mediated oxidative stress in hNSCs, and suggests patients undergoing AGE-mediated neurodegeneration may benefit from the novel therapeutic use of metformin.

Metformin activation of AMPK suppresses AGE-induced inflammatory response in hNSCs.

A growing body of evidence suggests type 2 diabetes mellitus (T2DM) is linked to neurodegenerative diseases such as Alzheimer's disease (AD). Although the precise mechanisms remain unclear, T2DM may exacerbate neurodegenerative processes. AMP-activated protein kinase (AMPK) signaling is an evolutionary preserved pathway that is important during homeostatic energy biogenesis responses at both the cellular and whole-body levels. Metformin, a ubiquitously prescribed anti-diabetic drug, exerts its effects by AMPK activation. However, while the roles of AMPK as a metabolic mediator are generally well understood, its performance in neuroprotection and neurodegeneration are not yet well defined. Given hyperglycemia is accompanied by an accelerated rate of advanced glycosylation end product (AGE) formation, which is associated with the pathogenesis of diabetic neuronal impairment and, inflammatory response, clarification of the role of AMPK signaling in these processes is needed. Therefore, we tested the hypothesis that metformin, an AMPK activator, protects against diabetic AGE induced neuronal impairment in human neural stem cells (hNSCs). In the present study, hNSCs exposed to AGE had significantly reduced cell viability, which correlated with elevated inflammatory cytokine expression, such as IL-1α, IL-1ß, IL-2, IL-6, IL-12 and TNF-α. Co-treatment with metformin significantly abrogated the AGE-mediated effects in hNSCs. In addition, metformin rescued the transcript and protein expression levels of acetyl-CoA carboxylase (ACC) and inhibitory kappa B kinase (IKK) in AGE-treated hNSCs. NF-κB is a transcription factor with a key role in the expression of a variety of genes involved in inflammatory responses, and metformin did prevent the AGE-mediated increase in NF-κB mRNA and protein levels in the hNSCs exposed to AGE. Indeed, co-treatment with metformin significantly restored inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) levels in AGE-treated hNSCs. These findings extend our understanding of the central role of AMPK in AGE induced inflammatory responses, which increase the risk of neurodegeneration in diabetic patients.

Metformin activation of AMPK-dependent pathways is neuroprotective in human neural stem cells against Amyloid-beta-induced mitochondrial dysfunction.

Alzheimer's disease (AD) is the general consequence of dementia and is diagnostic neuropathology by the cumulation of amyloid-beta (Aß) protein aggregates, which are thought to promote mitochondrial dysfunction processes leading to neurodegeneration. AMP-activated protein kinase (AMPK), a critical regulator of energy homeostasis and a major player in lipid and glucose metabolism, is potentially implied in the mitochondrial deficiency of AD. Metformin, one of the widespread used anti- metabolic disease drugs, use its actions in part by stimulation of AMPK. While the mechanisms of AD are well established, the neuronal roles for AMPK in AD are still not well understood. In the present study, human neural stem cells (hNSCs) exposed to Aß had significantly reduced cell viability, which correlated with decreased AMPK, neuroprotective genes (Bcl-2 and CREB) and mitochondria associated genes (PGC1α, NRF-1 and Tfam) expressions, as well as increased activation of caspase 3/9 activity and cytosolic cytochrome c. Co-treatment with metformin distinct abolished the Aß-caused actions in hNSCs. Metformin also significantly rescued hNSCs from Aß-mediated mitochondrial deficiency (lower D-loop level, mitochondrial mass, maximal respiratory function, COX activity, and mitochondrial membrane potential). Importantly, co-treatment with metformin significantly restored fragmented mitochondria to almost normal morphology in the hNSCs with Aß. These findings extend our understanding of the central role of AMPK in Aß-related neuronal impairment. Thus, a better understanding of AMPK might assist in both the recognition of its critical effects and the implementation of new therapeutic strategies in the treatment of AD.

Rosiglitazone activation of PPARγ-dependent pathways is neuroprotective in human neural stem cells against amyloid-beta-induced mitochondrial dysfunction and oxidative stress.

Neuronal cell impairment, such as that induced by amyloid-beta (Aß) protein, is a process with limited therapeutic interventions and often leads to long-term neurodegeneration common in disorders such as Alzheimer's disease. Interestingly, peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated nuclear receptor whose ligands control many physiological and pathologic processes, and may be neuroprotective. We hypothesized that rosiglitazone, a PPARγ agonist, would prevent Aß-mediated effects in human neural stem cells (hNSCs). Here, we show that rosiglitazone reverses, via PPARγ-dependent downregulation of caspase 3 and 9 activity, the Aß-mediated decreases in hNSC cell viability. In addition, Aß decreases hNSC messenger RNA (mRNA) levels of 2 neuroprotective factors (Bcl-2 and CREB), but co-treatment with rosiglitazone significantly rescues these effects. Rosiglitazone co-treated hNSCs also showed significantly increased mitochondrial function (reflected by levels of adenosine triphosphate and Mit mass), and PPARγ-dependent mRNA upregulation of PGC1α and mitochondrial genes (nuclear respiratory factor-1 and Tfam). Furthermore, hNSCs co-treated with rosiglitazone were significantly rescued from Aß-induced oxidative stress and correlates with reversal of the Aß-induced mRNA decrease in oxidative defense genes (superoxide dismutase 1, superoxide dismutase 2, and glutathione peroxidase 1). Taken together, these novel findings show that rosiglitazone-induced activation of PPARγ-dependent signaling rescues Aß-mediated toxicity in hNSCs and provide evidence supporting a neuroprotective role for PPARγ activating drugs in Aß-related diseases such as Alzheimer's disease.

Rosiglitazone activation of PPARγ-dependent signaling is neuroprotective in mutant huntingtin expressing cells.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a crucial transcription factor for neuroprotection in several brain diseases. Using a mouse model of Huntington's Disease (HD), we recently showed that PPARγ not only played a major function in preventing HD, but also oral intake of a PPARγ agonist (thiazolidinedione, TZD) significantly reduced the formation of mutant Huntingtin (mHtt) aggregates in the brain (e.g., cortex and striatum). The molecular mechanisms by which PPARγ exerts its HD neuroprotective effects remain unresolved. We investigated whether the PPARγ agonist (rosiglitazone) mediates neuroprotection in the mHtt expressing neuroblastoma cell line (N2A). Here we show that rosiglitazone upregulated the endogenous expression of PPARγ, its downstream target genes (including PGC1α, NRF-1 and Tfam) and mitochondrial function in mHtt expressing N2A cells. Rosiglitazone treatment also significantly reduced mHtt aggregates that included ubiquitin (Ub) and heat shock factor 1 (HSF1), as assessed by a filter-retardation assay, and increased the levels of the functional ubiquitin-proteasome system (UPS), HSF1 and heat shock protein 27/70 (HSP27/70) in N2A cells. Moreover, rosiglitazone treatment normalized endoplasmic reticulum (ER) stress sensors Bip, CHOP and ASK1, and significantly increased N2A cell survival. Taken together, these findings unveil new insights into the mechanisms by which activation of PPARγ signaling protects against the HD-mediated neuronal impairment. Further, our data also support the concept that PPARγ may be a novel therapeutic target for treating HD.

The neuroprotective role of metformin in advanced glycation end product treated human neural stem cells is AMPK-dependent.

Diabetic neuronal damage results from hyperglycemia followed by increased formation of advanced glycosylation end products (AGEs), which leads to neurodegeneration, although the molecular mechanisms are still not well understood. Metformin, one of the most widely used anti-diabetic drugs, exerts its effects in part by activation of AMP-activated protein kinase (AMPK). AMPK is a critical evolutionarily conserved enzyme expressed in the liver, skeletal muscle and brain, and promotes cellular energy homeostasis and biogenesis by regulating several metabolic processes. While the mechanisms of AMPK as a metabolic regulator are well established, the neuronal role for AMPK is still unknown. In the present study, human neural stem cells (hNSCs) exposed to AGEs had significantly reduced cell viability, which correlated with decreased AMPK and mitochondria associated gene/protein (PGC1α, NRF-1 and Tfam) expressions, as well as increased activation of caspase 3 and 9 activities. Metformin prevented AGEs induced cytochrome c release from mitochondria into cytosol in the hNSCs. Co-treatment with metformin significantly abrogated the AGE-mediated effects in hNSCs. Metformin also significantly rescued hNSCs from AGE-mediated mitochondrial deficiency (lower ATP, D-loop level, mitochondrial mass, maximal respiratory function, COX activity, and mitochondrial membrane potential). Furthermore, co-treatment of hNSCs with metformin significantly blocked AGE-mediated reductions in the expression levels of several neuroprotective genes (PPARγ, Bcl-2 and CREB). These findings extend our understanding of the molecular mechanisms of both AGE-induced neuronal toxicity, and AMPK-dependent neuroprotection by metformin. This study further suggests that AMPK may be a potential therapeutic target for treating diabetic neurodegeneration.

Rosiglitazone promotes neurite outgrowth and mitochondrial function in N2A cells via PPARgamma pathway.

Several pieces of evidence indicate that peroxisome proliferator-activated receptor gamma (PPARγ) stimulation promotes neuronal differentiation. However, to date, the effects of a synthetic PPARγ agonist (Rosiglitazone, Rosi) on neurite outgrowth have not yet been well described. Here we have evaluated the effects of Rosi on neurite outgrowth and mitochondrial function in the mouse neuroblastoma Neuro 2a (N2A) cell line. Our results show that Rosi promotes neurite outgrowth of N2A cells and significantly increases the population of neurite-bearing cells, with apparent increase of intracellular calcium and the expression of calmodulin-dependent kinase I (CaMKI). Rosi also increases the intracellular cAMP and expression of both protein kinase A (PKA) and cAMP response element binding protein (CREB). Phosphorylation of CREB was also detected in the Rosi treated N2A cells. Moreover, Rosi significantly increases the transcription of AMP-activated kinase (AMPK) and Sirtuin 1 (SIRT1). Besides, the expression of PPAR coactivator 1α (PGC1α), as well as the mRNA level its downstream genes, including nuclear respiratory factors 1 and 2 (NRF1 and NRF2) and mitochondrial transcription factor A (Tfam) were induced by Rosi treatments. Furthermore, Rosi increases the level of ATP, D-loop, and mitochondrial mass in N2A cells. Collectively, these findings provide an array of evidence that PPARγ activation provides beneficial neuronal networks within neurite outgrowth.

ß-adrenoceptor pathway enhances mitochondrial function in human neural stem cells via rotary cell culture system.

The structure and function of the human nervous system are altered in space when compared with their state on earth. To investigate directly the influence of simulated microgravity conditions which may be beneficial for cultivation and proliferation of human neural stem cells (hNSCs), the rotary cell culture system (RCCS) developed at the National Aeronautics and Space Administration (NASA) was used. RCCS allows the creation of a unique microgravity environment of low shear force, high-mass transfer and enables three-dimensional (3D) cell culture of dissimilar cell types. The results show that simulated microgravity using an RCCS would induce ß-adrenoceptor, upregulate cAMP formation and activate both PKA and CREB (cAMP response element binding protein) pathways. The expression of intracellular mitochondrial genes, including PGC1α (PPAR coactivator 1α), nuclear respiratory factors 1 and 2 (NRF1 and NRF2) and mitochondrial transcription factor A (Tfam), regulated by CREB, were all significantly increased at 72 h after the onset of microgravity. Accordingly and importantly, the ATP level and amount of mitochondrial mass were also increased. These results suggest that exposure to simulated microgravity using an RCCS would induce cellular proliferation in hNSCs via an increased mitochondrial function. In addition, the RCCS bioreactor would support hNSCs growth, which may have the potential for cell replacement therapy in neurological disorders.