Butyrate reduction and HDAC4 increase underlie maternal high fructose-induced metabolic dysfunction in hippocampal astrocytes in female rats.

Maternal nutrient intake influences the health of the offspring via microenvironmental systems in digestion and absorption. Maternal high fructose diet (HFD) impairs hippocampus-dependent memory in adult female rat offspring. However, the underlying mechanisms remain largely unclear. Maternal HFD causes microbiota dysbiosis. In this study, we find that the plasma level of butyrate, a major metabolite of microbiota, is significantly decreased in the adult female maternal HFD offspring. In these rats, GPR43, a butyrate receptor was downregulated in the hippocampus. Moreover, the expressions of mitochondrial transcription factor A (TFAM), and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) were downregulated in the hippocampus. The decreases of these functional proteins were reversed by fructooligosaccharides (FOS, a probiotic) treatment in adulthood. Astrocytes are critical for energy metabolism in the brain. Primary astrocyte culture from female maternal HFD offspring indicated that GPR43 and the mitochondrial biogenesis were significantly suppressed, which was reversed by supplemental butyrate incubation. The oxygen consumption rate (OCR) was reduced in the HFD group and rescued by butyrate. Intriguingly, the nuclear histone deacetylase 4 (HDAC4) was enhanced in the HFD group, suggesting an inhibitory role of butyrate on histone deacetylase activity. Inhibition of HDAC4 effectively restored the OCR, bioenergetics, and biogenesis of mitochondria. Together, these results suggested that the impaired butyrate signaling by maternal HFD could underlie the reduced mitochondrial functions in the hippocampus via HDAC4-mediated epigenetic changes.

Adult-Onset Genetic Leukoencephalopathies With Movement Disorders.

Genetic leukoencephalopathies (GLEs) are a group of white matter abnormalities with heterogeneous radiological and phenotypic features. Although these conditions have mostly been described in children, adult-onset cases are increasingly recognized owing to the widespread use of neuroimaging and advances in molecular genetic testing. The disease course is often progressive with a varied spectrum of presentations, trapping neurologists in the dilemma of differential diagnosis. Movement disorders are among the most common symptoms, and their diversity makes diagnosis challenging. In this review, we focus on adult-onset GLEs with movement disorders and offer a step-by-step diagnostic approach by clarifying the phenomenology of movement, advising investigations for acquired causes, describing the clinical and radiological clues to each disease, emphasizing the limitations of advanced molecular testing, and discussing the future application of artificial intelligence. We provide a list summarizing the leukoencephalopathies associated with different categories of movement disorders. In addition to guiding clinicians on how to narrow the list of differential diagnoses with the tools currently available, another aim of this review is to emphasize the inevitable trend toward applying advanced technology in diagnosing these difficult diseases.

Higher prevalence of idiopathic normal pressure hydrocephalus-like MRI features in progressive supranuclear palsy: An imaging reminder of atypical parkinsonism.

OBJECTIVES: The classic triad of idiopathic normal pressure hydrocephalus (NPH) encompass gait disturbance, cognitive impairment, and urinary incontinence. These symptoms overlap with parkinsonism but with distinct treatment. Lacking applicable differentiation also hampers the prediction to therapeutic response. Here, we try to clarify this issue among different Parkinsonian syndromes and propose some innovative thinking while approaching a patient with parkinsonism and hydrocephalus concomitantly. METHODS: Twenty-four patients with clinical probable multiple system atrophy (MSA), 34 with probable progressive supranuclear palsy (PSP), and 58 with sex- and age-matched Parkinson's disease (PD) were enrolled. Evans' index (EI), callosal angle (CA), antero-posterior (AP) diameter of the midbrain, length of the midbrain tegmentum diameter (MBTegm ), and disproportionately enlarged subarachnoid space hydrocephalus (DESH) were evaluated using the conventional MRI. Logistic regression was applied to identify the independent variables in hydrocephalus. RESULTS: Patients with PSP had higher mean EI than those with MSA and PD. Around 38.2% of patients with PSP had accompanied hydrocephalus (EI > 0.3). Parkinsonism subtypes (PD, MSA, or PSP), AP diameter of the midbrain, and MBTegm were significantly different among patients with and without hydrocephalus. After regression analysis, parkinsonism subtype stood out to be the most key risk factor of hydrocephalus. The comparison between patients with PSP with and without hydrocephalus did not disclose specific clinical characteristics or risk factors. CONCLUSIONS: This study demonstrates that the presence of NPH-like MRI features is much higher in PSP patients, and this tendency is decided upon the determination of parkinsonism subtype. Sharing pathophysiological characteristics in these two diseases is implied. More diagnostic tools are needed to better differentiate the two diseases and decide the treatment. To closely observe hydrocephalic parkinsonism patients and well inform the possible limited shunting benefits if PSP core features appear, will be more pivotal and practical at present clinical practice.

Lipopolysaccharide-induced Autophagy Increases SOX2-positive Astrocytes While Decreasing Neuronal Differentiation in the Adult Hippocampus.

Inflammation alters the neural stem cell (NSC) lineage from neuronal to astrogliogenesis. However, the underlying mechanism is elusive. Autophagy contributes to the decline in adult hippocampal neurogenesis under E. coli lipopolysaccharide (LPS) stimulation. SRY-box transcription Factor 2 (SOX2) is critical for NSC self-renewal and proliferation. In this study, we investigated the role of SOX2 in induced autophagy and hippocampal adult neurogenesis under LPS stimulation. LPS (5 ng•100 g-1•hour-1 for 7 days) was intraperitoneally infused into male Sprague-Dawley rats (8 weeks old) to induce mild systemic inflammation. Beclin 1 and autophagy protein 12 (Atg12) were significantly upregulated concurrent with decreased numbers of Ki67- and doublecortin (DCX)-positive cells in the dentate gyrus. Synchronically, the levels of phospho(p)-mTOR, the p-mTOR/mTOR ratio, p-P85s6k, and the p-P85s6k/P85s6k ratio were suppressed. In contrast, SOX2 expression was increased. The fluorescence micrographs indicated that the colocalization of Beclin 1 and SOX2 was increased in the subgranular zone (SGZ) of the dentate gyrus. Moreover, increased S100ß-positive astrocytes were colocalized with SOX2 in the SGZ. Intracerebroventricular infusion of 3-methyladenine (an autophagy inhibitor) effectively prevented the increases in Beclin 1, Atg12, and SOX2. The SOX2+-Beclin 1+ and SOX2+-S100ß+ cells were reduced. The levels of p-mTOR and p-P85s6k were enhanced. Most importantly, the number of DCX-positive cells was preserved. Altogether, these data suggest that LPS induced autophagy to inactivate the mTOR/P85s6k pathway, resulting in a decline in neural differentiation. SOX2 was upregulated to facilitate the NSC lineage, while the autophagy milieu could switch the SOX2-induced NSC lineage from neurogenesis to astrogliogenesis.

Fructose milieu undermines the therapeutic effect of Tribulus terrestris extract on neuroblastoma cell line via maintaining mitochondrial function.

Fructose overconsumption promotes tumor progression. Neuroblastoma is a common extracranial tumor with about 50% 5-year survival rate in high-risk children. The anti-tumor effect of Tribulus terrestris might bring new hope to neuroblastoma therapy. However, whether fructose disturbs the therapeutic effect of T. terrestris is currently unknown. In this study, the mouse neuroblastoma cell line, Neuro 2a (N2a) cells, was used to investigate the therapeutic effects of T. terrestris extract at various dosages (0.01, 1, 100 ng/ml) in regular EMEM medium or extra added fructose (20 mM) for 24 h. 100 ng/ml T. terrestris treatment significantly reduced the cell viability, whereas the cell viabilities were enhanced at the dosages of 0.01 or 1 ng/ml T. terrestris in the fructose milieu instead. The inhibition effect of T. terrestris on N2a migration was blunted in the fructose milieu. Moreover, T. terrestris effectively suppressed mitochondrial functions, including oxygen consumption rates, the activities of electron transport enzymes, the expressions of mitochondrial respiratory enzymes, and mitochondrial membrane potential. These suppressions were reversed in the fructose group. In addition, the T. terrestris-suppressed mitofusin and the T. terrestris-enhance mitochondrial fission 1 protein were maintained at basal levels in the fructose milieu. Together, these results demonstrated that T. terrestris extract effectively suppressed the survival and migration of neuroblastoma via inhibiting mitochondrial oxidative phosphorylation and disturbing mitochondrial dynamics. Whereas, the fructose milieu blunted the therapeutic effect of T. terrestris, particularly, when the dosage is reduced.

Serum Levels of Soluble Triggering Receptor Expressed on Myeloid Cells-1 Associated with the Severity and Outcome of Acute Ischemic Stroke.

Stroke is a neurological emergency, where the mechanism of the blood supply to the brain is impaired, resulting in brain cell ischemia and death. Neuroinflammation is a key component in the ischemic cascade that results in cell damage and death after cerebral ischemia. The triggering receptor expressed on myeloid cells-1 (TREM-1) modulates neuroinflammation after acute ischemic stroke. In the present study, 60 patients with acute ischemic stroke, who had been subjected to neurological examinations and National Institutes of Health Stroke Scale (NIHSS) and brain magnetic resonance imaging studies, were enrolled in the emergency room of Kaohsiung Chang Gung Memorial Hospital. Twenty-four healthy volunteers were recruited as controls. The serum levels of soluble TREM-1 (sTREM-1), human S100 calcium-binding protein B (S100B), and proinflammatory cytokines and chemokines, including tumor necrosis α (TNF-α), interleukin 1ß, interleukin 6 (IL-6), interleukin 8, and interferon-γ were measured immediately after acute ischemic stroke. The serum levels of sTREM-1, TNFα, IL-6, and S100B were correlated with the stroke volume and NIHSS, after acute ischemic stroke. Additionally, the serum levels of sTREM-1 were significantly positively correlated with S100B. The functional outcomes were evaluated 6 months after ischemic stroke by the Barthel index, which was correlated with the age and levels of sTREM-1 and S100B. We suggest that acute ischemic stroke induces neuroinflammation by the activation of the TREM-1 signaling pathway and the downstream inflammatory machinery that modulates the inflammatory response and ischemic neuronal cell death. From a translational perspective, our results may allow for the development of a new therapeutic strategy for acute ischemic stroke by targeting the TREM-1 signaling pathway.

Environmental Stimulation Counteracts the Suppressive Effects of Maternal High-Fructose Diet on Cell Proliferation and Neuronal Differentiation in the Dentate Gyrus of Adult Female Offspring via Histone Deacetylase 4.

Maternal high-fructose diets (HFD) impair the learning and memory capacity of adult female offspring via histone deacetylase 4 (HDAC4). Hippocampal adult neurogenesis is important for supporting the function of existing neural circuits. In this study, we investigated the effects of maternal HFD on hippocampal neural stem cell (NSC) proliferation and neuronal differentiation in adult offspring. Increased nuclear HDAC4 enzyme activity was detected in the hippocampus of HFD female offspring. The Western blot analyses indicated that the expressions of sex-determining region Y box2 (SOX2) and the transcription factor Paired Box 6 (PAX6), which are critical for the progression of NSC proliferation and differentiation, were downregulated. Concurrently, the expression of Ki67 (a cellular marker for proliferation) and doublecortin (DCX), which are related to NSC division and neuronal differentiation, was suppressed. Intracerebroventricular infusion with class II HDAC inhibitor (Mc1568, 4 weeks) led to the upregulation of these proteins. Environmental stimulation reversed the expression of Ki67 and DCX and the counts of Ki67- and DCX-positive cells in the hippocampi of HFD offspring as a result of providing the enriched housing for 4 weeks. Together, these results demonstrate that the suppressive effects of maternal HFD on hippocampal NSC proliferation and neuronal differentiation are reversibly mediated through HDAC4 and can be effectively reversed by environmental stimulation. The advantageous effects of environmental enrichment were possibly mediated by HDAC4 suppression.

Recessively-Inherited Adult-Onset Alexander Disease Caused by a Homozygous Mutation in the GFAP Gene.

BACKGROUND: Alexander disease (AxD) is an autosomal-dominant leukodystrophy caused by heterozygous mutations in the glial fibrillary acidic protein (GFAP) gene. OBJECTIVES: The objective of this report is to characterize the clinical phenotype and identify the genetic mutation associated with adult-onset AxD. METHODS: A man presented with progressive unsteadiness since age 16. Magnetic resonance imaging findings revealed characteristic features of AxD. The GFAP gene was screened, and a candidate variant was functionally tested to evaluate causality. RESULTS: A homozygous c.197G > A (p.Arg66Gln) mutation was found in the proband, and his asymptomatic parents were heterozygous for the same mutation. This mutation affected GFAP solubility and promoted filament aggregation. The presence of the wild-type protein rescued mutational effects, consistent with the recessive nature of this mutation. CONCLUSIONS: This study is the first report of AxD caused by a homozygous mutation in GFAP. The clinical implication is while examining patients with characteristic features on suspicion of AxD, GFAP screening is recommended even without a supportive family history. © 2020 International Parkinson and Movement Disorder Society.

Maternal high fructose-induced hippocampal neuroinflammation in the adult female offspring via PPARγ-NF-κB signaling.

The mechanisms beneath the initiation of neuroinflammation are still inconclusive. Growing evidence proposes the maternal effect on the development of neuroinflammation. In this study, we evaluated the upstream regulators and the indices of neuroinflammation in the hippocampi of female offspring at 3 months old. The accumulation of nuclear factor-κB (NF-κB, 65 kDa), a cytokine-encoding transcription factor, was increased in microglia. The enhanced microglial activation was detected in CA1, CA3 and dentate gyrus (DG) HFD group with upregulation of CD11b and ionized calcium binding adaptor molecule 1 (Iba-1). Moreover, proinflammatory cytokines (including TNFα, IL-1ß and IL-6) were significantly increased in HFD group. Peroxisome proliferator-activated receptors γ (PPARγ) is a transcription factor involved in the suppression of NF-κB expression and in encoding endogenous antioxidants (such as catalase and glutathione peroxidases). On the contrary, the expression of nuclear PPARγ was suppressed in hippocampal neurons of the HFD group. In addition, the expressions of glutathione peroxidase 1 (GPx1) was suppressed in HFD group. Oral application with pioglitazone, a PPARγ agonist, effectively ceased the neuroinflammation and reversed the expression of antioxidants in HFD group. Together, these results for the first time demonstrated that maternal HFD triggered the waxing and waning of NF-κB and PPARγ may initiate neuroinflammation in the hippocampus of adult female offspring. Our findings further suggest that PPARγ could be the feasible targets to reprogram the hippocampal impairment induced by maternal HFD.

Anti-neuroinflammation ameliorates systemic inflammation-induced mitochondrial DNA impairment in the nucleus of the solitary tract and cardiovascular reflex dysfunction.

BACKGROUND: Decreased heart rate variability (HRV) leads to cardiovascular diseases and increased mortality in clinical studies. However, the underlying mechanisms are still inconclusive. Systemic inflammation-induced neuroinflammation is known to impair the autonomic center of cardiovascular regulation. The dynamic stability of blood pressure and heart rate (HR) is regulated by modulation of the reciprocal responses of sympathetic and parasympathetic tone by the baroreflex, which is controlled by the nucleus of the solitary tract (NTS). METHODS: Systemic inflammation was induced by E. coli lipopolysaccharide (LPS, 1.2 mg/kg/day, 7 days) peritoneal infusion via an osmotic minipump in normotensive Sprague-Dawley rats. Systolic blood pressure (SBP) and HR were measured by femoral artery cannulation and recorded on a polygraph under anesthesia. The low-frequency (LF; 0.25-0.8 Hz) and high-frequency (HF; 0.8-2.4 Hz) components of SBP were adopted as the indices for sympathetic vasomotor tone and parasympathetic vasomotor tone, while the baroreflex effectiveness index (BEI) was adopted from the analysis of SBP and pulse interval (PI). The plasma levels of proinflammatory cytokines and mitochondrial DNA (mtDNA) oxidative damage were analyzed by ELISA. Protein expression was evaluated by Western blot. The distribution of oxidative mtDNA was probed by immunofluorescence. Pharmacological agents were delivered via infusion into the cisterna magna with an osmotic minipump. RESULTS: The suppression of baroreflex sensitivity was concurrent with increased SBP and decreased HR. Neuroinflammatory factors, including TNF-α, CD11b, and Iba-1, were detected in the NTS of the LPS group. Moreover, indices of mtDNA damage, including 8-OHdG and γ-H2AX, were significantly increased in neuronal mitochondria. Pentoxifylline or minocycline intracisternal (IC) infusion effectively prevented mtDNA damage, suggesting that cytokine and microglial activation contributed to mtDNA damage. Synchronically, baroreflex sensitivity was effectively protected, and the elevated blood pressure was significantly relieved. In addition, the mtDNA repair mechanism was significantly enhanced by pentoxifylline or minocycline. CONCLUSION: These results suggest that neuronal mtDNA damage in the NTS induced by neuroinflammation could be the core factor in deteriorating baroreflex desensitization and subsequent cardiovascular dysfunction. Therefore, the enhancement of base excision repair (BER) signaling in mitochondria could be a potential therapeutic strategy for cardiovascular reflex dysregulation.

Pioglitazone reversed the fructose-programmed astrocytic glycolysis and oxidative phosphorylation of female rat offspring.

Excessive maternal high-fructose diet (HFD) during pregnancy and lactation has been reported to cause metabolic disorders in the offspring. Whether the infant's brain metabolism is disturbed by maternal HFD is largely unknown. Brain energy metabolism is elevated dramatically during fetal and postnatal development, whereby maternal nutrition is a key factor that determines cellular metabolism. Astrocytes, a nonneuronal cell type in the brain, are considered to support the high-energy demands of neurons by supplying lactate. In this study, the effects of maternal HFD on astrocytic glucose metabolism were investigated using hippocampal primary cultures of female infants. We found that glycolytic capacity and mitochondrial respiration and electron transport chain were suppressed by maternal HFD. Mitochondrial DNA copy number and mitochondrial transcription factor A expression were suppressed by maternal HFD. Western blots and immunofluorescent images further indicated that the glucose transporter 1 was downregulated whereas the insulin receptor-α, phospho-insulin receptor substrate-1 (Y612) and the p85 subunit of phosphatidylinositide 3-kinase were upregulated in the HFD group. Pioglitazone, which is known to increase astrocytic glucose metabolism, effectively reversed the suppressed glycolysis, and lactate release was restored. Moreover, pioglitazone also normalized oxidative phosphorylation with an increase of cytosolic ATP. Together, these results suggest that maternal HFD impairs astrocytic energy metabolic pathways that were reversed by pioglitazone.

Nrf2 activation attenuates the early suppression of mitochondrial respiration due to the α-synuclein overexpression.

BACKGROUND: α-synuclein (SNCA) accumulation in the substantia nigra is one of the characteristic pathologies of Parkinson's disease (PD). A53T missense mutations in the SNCA gene has been proved to enhance the expression of SNCA and accelerate the onset of PD. Mitochondrial dysfunction in SNCA aggregation has been under debate for decades but the causal relationship remains uncertain. At a later stage of PD, the cellular dysfunctions are complicated and multiple factors are tangled. Our aim here is to investigate the mitochondrial functional changes and clarify the main causal mechanism at earlier-stage of PD. METHODS: We used the mutant A53T SNCA-expressed neuro 2a (N2a) cells without detectable cell death to investigate: 1) whether SNCA overexpression impairs the mitochondrial respiration and biogenesis. 2) The role of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signal in SNCA-induced mitochondria dysfunction. RESULTS: Accompanying with the increment of SNCA, reactive oxygen species (ROS) accumulation was increased. The maximal respiratory capacity was suppressed. Meanwhile, mitochondrial complex 1 activity and the activity of nicotinamide adenine dinucleotide (NADH) cytochrome C reductase (NCCR) were decreased. Moreover, the mitochondrial DNA (mtDNA) copy number was decreased. On the other hand, the nuclear peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α), Nrf2, and the cytosolic mitochondrial transcription factor A (TFAM) were increased at an early stage and declined thereafter. Above factors triggered by SNCA were reversed by tBHQ, a Nrf2 activator. CONCLUSION: These results suggested that at an early stage, SNCA-overexpressed increase mtROS accumulation, mitochondrial dysfunction and mtDNA decrement. Nrf2, PGC-1α and TFAM were upregulated to compromise mitochondrial dysfunction. tBHQ effectively reversed the SNCA-induced mitochondrial dysfunction.

Effects of Home-Based Versus Clinic-Based Rehabilitation Combining Mirror Therapy and Task-Specific Training for Patients With Stroke: A Randomized Crossover Trial.

OBJECTIVE: We investigated the treatment effects of a home-based rehabilitation program compared with clinic-based rehabilitation in patients with stroke. DESIGN: A single-blinded, 2-sequence, 2-period, crossover-designed study. SETTING: Rehabilitation clinics and participant's home environment. PARTICIPANTS: Individuals with disabilities poststroke. INTERVENTIONS: During each intervention period, each participant received 12 training sessions, with a 4-week washout phase between the 2 periods. Participants were randomly allocated to home-based rehabilitation first or clinic-based rehabilitation first. Intervention protocols included mirror therapy and task-specific training. MAIN OUTCOME MEASURES: Outcome measures were selected based on the International Classification of Functioning, Disability and Health. Outcomes of impairment level were the Fugl-Meyer Assessment, Box and Block Test, and Revised Nottingham Sensory Assessment. Outcomes of activity and participation levels included the Motor Activity Log, 10-meter walk test, sit-to-stand test, Canadian Occupational Performance Measure, and EuroQoL-5D Questionnaire. RESULTS: Pretest analyses showed no significant evidence of carryover effect. Home-based rehabilitation resulted in significantly greater improvements on the Motor Activity Log amount of use subscale (P=.01) and the sit-to-stand test (P=.03) than clinic-based rehabilitation. The clinic-based rehabilitation group had better benefits on the health index measured by the EuroQoL-5D Questionnaire (P=.02) than the home-based rehabilitation group. Differences between the 2 groups on the other outcomes were not statistically significant. CONCLUSIONS: The home-based and clinic-based rehabilitation groups had comparable benefits in the outcomes of impairment level but showed differential effects in the outcomes of activity and participation levels.

Functional Role of Matrix gla Protein in Glioma Cell Migration.

Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor subtype. Despite that metastasis of GBM beyond the central nervous system (CNS) is rare, its malignancy is attributed to the highly infiltration trait, leading to the difficulty of complete surgical excision. Matrix gla protein (MGP) is a vitamin K-dependent small secretory protein, and functions as a calcification inhibitor. The involvement of MGP function in glioma cell dynamics remains to be clarified. The study showed that a low proliferative rat C6 glioma cell line named as C6-2 exhibited faster migratory and invasive capability compared to that observed in a high tumorigenic rat C6 glioma cell line (called as C6-1). Interestingly, C6-2 cells expressed higher levels of MGP molecules than C6-1 cells did. Lentivirus-mediated short hairpin RNA (shRNA) against MGP gene expression (MGP-KD) in C6-2 cells or lentivirus-mediated overexpression of MGP transcripts in C6-1 cells resulted in the morphological alteration of the two cell lines. Moreover, MGP-KD caused a decline in cell migration and invasion ability of C6-2 cells. In contrast, increased expression of MGP in C6-1 cells promoted their cell migration and invasion. The observations were further verified by the results from the implantation of C6-1 and C6-2 cells into ex vivo brain slice and in vivo rat brain. Thus, our results demonstrate that the manipulation of MGP expression in C6 glioma cells can mediate glioma cell migratory activity. Moreover, our findings indicate the possibility that high proliferative glioma cells expressing a high level of MGP may exist and contribute to tumor infiltration and recurrence.

Oral pioglitazone ameliorates fructose-induced peripheral insulin resistance and hippocampal gliosis but not restores inhibited hippocampal adult neurogenesis.

Diet-associated insulin resistance (IR) is intimately correlated with the progression of metabolic syndrome and hippocampal dysfunction. Pioglitazone (PIO), a selective peroxisome proliferator-activated receptor gamma (PPARγ) agonist, has been applied to enhance insulin sensitivity. With limited permeability to blood-brain-barrier, it is unclear that whether oral PIO available to cure both the peripheral IR and the impairment in the hippocampus. We evaluated the levels of peripheral and hippocampal IR via the homeostatic model assessment of insulin resistance and hippocampal IRS-1/Akt phosphorylation, respectively, of Wistar Kyoto rats fed with a regular chew or high fructose diet (HFD) for 12weeks. Gavage with PIO (30mg/kg/day, 2weeks) significantly reduced the peripheral IR and reversed the level of hippocampal PPARγ. Moreover, HFD-activated microglia and astrocyte were effectively relieved by PIO. The suppressed brain-derived neurotrophic factor, CaMKIIα, and postsynaptic density protein 95 in the hippocampus were effectively reversed by PIO. However, the hippocampal IR and inhibition of adult neurogenesis in dentate gyrus were not restored by PIO. Together, PIO oral application may reverse the HFD-induced peripheral IR and maintain the existed neuronal circuit by ameliorating glial activation and enhancing synaptic density through BDNF but failed to restore adult neurogenesis in the hippocampus.

Stem cell transplantation therapy in Parkinson's disease.

Ineffective therapeutic treatments and inadequate repair ability in the central nervous system are disturbing problems for several neurological diseases. Fortunately, the development of clinically applicable populations of stem cells has provided an avenue to overcome the failure of endogenous repair systems and substitute new cells into the damaged brain. However, there are still several existing obstacles to translating into clinical application. Here we review the stem-cell based therapies for Parkinson's disease and discuss the potential advantages and drawbacks. We hope this review may provide suggestions for viable strategies to overcome the current technical and biological issues associated with the application of stem cells in Parkinson's disease.

The Potential Regulatory Mechanisms of miR-196a in Huntington's Disease through Bioinformatic Analyses.

High throughput screening is a powerful tool to identify the potential candidate molecules involved during disease progression. However, analysis of complicated data is one of the most challenging steps on the way to obtaining useful results from this approach. Previously, we showed that a specific miRNA, miR-196a, could ameliorate the pathological phenotypes of Huntington's disease (HD) in different models, and performed high throughput screening by using the striatum of transgenic mice. In this study, we further tried to identify the potential regulatory mechanisms using different bioinformatic tools, including Database for Annotation, Visualization and Integrated Discovery (DAVID), Molecular Signatures Database (MSigDB), TargetScan and MetaCore. The results showed that miR-196a dominantly altered "ABC transporters", "RIG-I-like receptor signaling pathway", immune system", "adaptive immune system","tissue remodeling and wound repair" and "cytoskeleton remodeling". In addition, miR-196a also changed the expression of several well-defined pathways of HD, such as apoptosis and cell adhesion. Since these analyses showed the regulatory pathways are highly related to the modification of the cytoskeleton, we further confirmed that miR-196a could enhance the neurite outgrowth in neuroblastoma cells, suggesting miR-196a might provide beneficial functions through the alteration of cytoskeleton structures. Since impairment of the cytoskeleton has been reported in several neuronal diseases, this study will provide not only the potential working mechanisms of miR-196a but also insights for therapeutic strategies for use with different neuronal diseases.

The Differential Profiling of Ubiquitin-Proteasome and Autophagy Systems in Different Tissues before the Onset of Huntington's Disease Models.

Huntington's disease (HD) is a genetic and neurodegenerative disease, leading to motor and cognitive dysfunction in HD patients. At cellular level, this disease is caused by the accumulation of mutant huntingtin (HTT) in different cells, and finally results in the dysfunction of different cells. To clean these mutant proteins, ubiquitin-proteasome system (UPS) and autophagy system are two critical pathways in the brain; however, little is known in other peripheral tissues. As mutant HTT affects different tissues progressively and might influence the UPS and autophagy pathways at early stages, we attempted to examine two clearance systems in HD models before the onset. Here, in vitro results showed that the accumulation of UPS signals with time was observed obviously in neuroblastoma and kidney cells, not in other cells. In HD transgenic mice, we observed the impairment of UPS, but not autophagy, over time in the cortex and striatum. In heart and muscle tissues, disturbance of autophagy was observed, whereas dysfunction of UPS was displayed in liver and lung. These results suggest that two protein clearance pathways are disturbed differentially in different tissues before the onset of HD, and enhancement of protein clearance at early stages might provide a potential stratagem to alleviate the progression of HD.

Churg-Strauss Syndrome Following Vaccination Against 2010 Influenza A (H1N1): A Case Report.

PURPOSE AND BACKGROUND: Churg-Strauss syndrome (CSS) is a systemic inflammatory disorder characterized by asthma, transient pulmonary infiltration, hyper-eosinophilia, and systemic vasculitis. Reported triggering factors include infections, drugs, allergic desensitization, and vaccinations, although cases involving the latter two are extremely rare. Herein, we describe a patient who developed CSS after receiving an H1N1 vaccination. CASE REPORT: A 55-year-old woman presented with fever, skin eruptions, and sensory impairment of her feet within one week after an H1N1 vaccine injection. A chest X-ray showed pulmonary infiltrations in both lower lung fields. Eosinophilia was noted in a hematological test, and an electrophysiological study revealed a pattern of mononeuritis multiplex. A skin biopsy was performed which revealed palisading necrotizing granuloma around a degenerated dermis and eosinophilic infiltration of the blood vessel walls. These findings combined with the hematological and electrophysiological findings met the criteria of CSS according to the American College of Rheumatology. The patient recovered well after steroid treatment. CONCLUSION: This case highlights the possibility that the H1N1 vaccination can trigger CSS. Due to the rarity of reported autoimmune events after vaccine administration and the obscure causal association between autoimmunity and a vaccine, further post-marketing surveillance and research are necessary to clarify the relationship and identify risk factors.

Recurrent ischemic stroke is predicted by intracranial large artery stenosis identified by brain MRA: an observational study of 693 patients from Kaohsiung, Taiwan.

PURPOSE: This study aimed to explore the incidence, severity and risk factors of recurrent stroke after stroke stratified by intracranial large artery stenosis (ILAS). METHODS: This was an observational study of 693 ischemic stroke patients recruited in a medical center in southern Taiwan. ILAS was identified by MRA. Vascular risk factors, therapeutic conditions and stroke severity were evaluated prospectively. Risk of events was estimated by Kaplan-Meier survival analysis and adjusted for sex, age along with all the variables of interest by Cox proportional hazard models. RESULTS: The mean observation period was 1.1 year with no lost to follow up. There were 57 (8.2%) patients suffered from recurrent ischemic stroke with 6 (10.5%) dead. Recurrent stroke rate was 2.3% within first month after stroke, 1.5% 31-90 days, 3% 91-365 days, and 1.2% within 365-730 days. Annual stroke recurrence was 8.6% (95%CI, 7.7-9.5). History of ischemic stroke (HR 2.793, 1.550-5.043) and ILAS (HR 2.193, 1.197-4.018) were associated with increased risk of recurrence. CONCLUSION: History of ischemic stroke along with ILAS related to the recurrence. Most of the recurrent stroke was mild in severity. Possibly due to the short interval of observation, recurrent stroke was not related to increased mortality.