Research trend of microbiota-gut-brain axis in Alzheimer's disease based on CiteSpace (2012-2021): A bibliometrics analysis of 608 articles.

Background: Recently, research on the microbiota-gut-brain axis (MGBA) has received increasing attention, and the number of studies related to Alzheimer's disease (AD) has increased rapidly, but there is currently a lack of summary of MGBA in AD. Objective: To capture research hotspots, grasp the context of disciplinary research, and explore future research development directions. Methods: In the core dataset of Web of Science, documents are searched according to specific subject words. CiteSpace software is used to perform statistical analysis on measurement indicators such as the number of published papers, publishing countries, institutions, subject areas, authors, cocited journals, and keywords, and to visualize of a network of relevant content elements. Results: The research of MGBA in AD has shown an upward trend year by year, and the cooperation between countries is relatively close, and mainly involves the intersection of neuroscience, pharmacy, and microbiology. This research focuses on the relationship between MGBA and AD symptoms. Keyword hotspots are closely related to new technologies. Alzheimer's disease, anterior cingulate cortex, inflammatory degeneration, dysbiosis, and other research are the focus of this field. Conclusion: The study revealed that the research and development of MGBA in AD rapidly progressed, but no breakthrough has been made in the past decade, it still needs to be closely combined with multidisciplinary technology to grasp the frontier hotspots. Countries should further strengthen cooperation, improve the disciplinary system, and increase the proportion of empirical research in all research.

Tß4 ameliorates oxidative damage and apoptosis through ERK/MAPK and 5-HT1A signaling pathway in Aß insulted SH-SY5Y cells.

AIMS: Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder seriously endangering the physical and mental health of the elderly, while no effective treatments and drugs in clinical practice are available. Thymosin ß4 (Tß4) is a multifunctional polypeptide involved in many physiological and pathological processes including AD. This study aims to understand the function and molecular mechanism of Tß4 in the development of AD. MAIN METHODS: Neuroblastoma cell line SH-SY5Y was treated with ß-amyloid (Aß) to induce AD-like pathological changes, which serves as Alzheimer's disease model. Tß4 was overexpressed in SH-SY5Y cells by lentivirus infection, and downregulated by siRNA transfection. Apoptosis of transfected SH-SY5Y cells after Aß-treatment was examined by western blot and flow cytometry. Apoptotic proteins and Tß4-related signaling pathways were also investigated by western blot. KEY FINDINGS: We found that Tß4 overexpression increased viability and suppressed apoptosis of Aß-treated SH-SY5Y cells. Tß4 ameliorated oxidative damage and suppressed reactive oxygen species production in Aß-treated SH-SY5Y cells. Consistently, Tß4 overexpression down-regulated the expression levels of pro-apoptotic markers such as Caspase-3, Caspase-8, and Bax, while up-regulated the expression level of anti-apoptotic gene Bcl-2 in Aß-stimulated SH-SY5Y cells. Mechanistically, we demonstrated that Tß4 dampened ERK/p38 MAPK signaling and enhanced 5-HTR1A expression in Aß-treated SH-SY5Y cells. Moreover, we revealed that Tß4 inhibited the activation of ERK pathway through up-regulating 5-HTR1A in Aß-treated SH-SY5Y cells. SIGNIFICANCE: Taken together, our findings provide evidences to support the neuroprotective role of Tß4 and might open up new therapeutic applications of Tß4 in AD treatment.

Thymosin ß4 reverses phenotypic polarization of glial cells and cognitive impairment via negative regulation of NF-κB signaling axis in APP/PS1 mice.

BACKGROUND: Thymosin ß4 (Tß4) is the most abundant member of the ß-thymosins and plays an important role in the control of actin polymerization in eukaryotic cells. While its effects in multiple organs and diseases are being widely investigated, the safety profile has been established in animals and humans, currently, little is known about its influence on Alzheimer's disease (AD) and the possible mechanisms. Thus, we aimed to evaluate the effects and mechanisms of Tß4 on glial polarization and cognitive performance in APP/PS1 transgenic mice. METHODS: Behavior tests were conducted to assess the learning and memory, anxiety and depression in APP/PS1 mice. Thioflavin S staining, Nissl staining, immunohistochemistry/immunofluorescence, ELISA, qRT-PCR, and immunoblotting were performed to explore Aß accumulation, phenotypic polarization of glial cells, neuronal loss and function, and TLR4/NF-κB axis in APP/PS1 mice. RESULTS: We demonstrated that Tß4 protein level elevated in all APP/PS1 mice. Over-expression of Tß4 alone alleviated AD-like phenotypes of APP/PS1 mice, showed less brain Aß accumulation and more Insulin-degrading enzyme (IDE), reversed phenotypic polarization of microglia and astrocyte to a healthy state, improved neuronal function and cognitive behavior performance, and accidentally displayed antidepressant-like effect. Besides, Tß4 could downregulate both TLR4/MyD88/NF-κB p65 and p52-dependent inflammatory pathways in the APP/PS1 mice. While combination drug of TLR4 antagonist TAK242 or NF-κB p65 inhibitor PDTC exerted no further effects. CONCLUSIONS: These results suggest that Tß4 may exert its function by regulating both classical and non-canonical NF-κB signaling and is restoring its function as a potential therapeutic target against AD.

PNU282987 alleviates Aß-induced anxiety and depressive-like behaviors through upregulation of α7nAChR by ERK-serotonin receptors pathway.

Patients with Alzheimer's disease often undergo anxiety and depression. Our previous studies have shown that α7nAChR protects against Aß-induced neurotoxicity via downregulation of p38 and JNK MAPKs, but the role of α7nAChR on Aß-induced anxiety and depressive-like behaviors and the effect of α7nAChR on the regulation of MAPKs pathways remain unknown. To examine the effects of α7nAChR and MAPKs pathways on Aß-induced anxiety and depression-like behaviors and to explore their relationships between them, elevated plus maze, open field and forced swim tests were performed. Protein levels of 5-HT1A receptor, 5-HT2C receptor, α7nAChR, t-ERK1/2 and p-ERK1/2 in the amygdala were analyzed by western blotting and immunostaining. Our study found out that Aß oligomers induced anxiety and depression-like behaviors in C56BL/6 mice with open field, elevated plus maze and forced swim tests. However, activation of α7nAChR or inhibition of ERK pathways showed significant antidepressant and anxiolytic-like effects on Aß-injected mice. Moreover, Aß significantly decreased the level of 5-HT1A receptor but increased the level of 5-HT2C receptor in the basolateral amygdala. Treatment with α7nAChR agonist PNU282987 or ERK inhibitor U0126 reversed Aß-induced 5-HT1A and 5-HT2C receptor changes. Moreover, activation of α7nAChR inhibited ERK pathway in the amygdala of Aß1-42-injected mice. Our study provides a new insight into the mechanism of α7nAChR in Aß-induced depression and anxiety-related symptoms through the regulation of ERK1/2 pathway and the potential association with serotonin receptors. Together, our data suggests that α7nAChR is protective against Aß-induced anxiety and depression-like behaviors in mice.

5-HT1AR alleviates Aß-induced cognitive decline and neuroinflammation through crosstalk with NF-κB pathway in mice.

The 5-hydroxytryptamine (5-HT) receptor is significant for the regulation of mood and memory. However, the role of 5-HT1AR in ß-Amyloid protein (Aß)-induced cognitive decline, neuroinflammation and the possible mechanism remains elusive. Thus, we aimed to evaluate the effects of 5-HT1AR on Aß-induced learning and memory decline and neuroinflammation in mice. Novel object recognition and Morris water maze tests were performed to observe learning and memory behavior in mice. Protein levels of Iba1, GFAP, MAP2, TNF-α, Tß4, C-fos, IKK-ß, IKB-α, NF-κBp65, phospho-NF-κBp65 in the hippocampus were examined by immunostaining or western blotting. Aß1-42-treatment inducing learning and memory decline was shown in novel object recognition and Morris water maze tests; neuroinflammation shown in immunostaining. Our study found out that 5-HT1AR inhibitor WAY100635 showed significant improvement in Aß-induced learning and memory decline. Moreover, WAY100635 decreases levels of Iba1, GFAP, and TNF-α in the hippocampus, which were related to neuroinflammation. While treatment with 5-HT1AR agonist 8-OH-DPAT or ERK inhibitor U0126 exerted no effects or even aggravated Aß-induced learning and memory decline. In addition, WAY100635 could downregulate phospho-NF-κB in the hippocampus of Aß1-42-injected mice. These results provide new insight into the mechanism, for 5-HT1AR in Aß-induced cognitive impairments through crosstalk with the NF-κB signaling pathway. Our data indicated that WAY100635 was involved in the protective effects against neuroinflammation and improvement of learning and memory in Alzheimer's disease.

MicroRNA-144 represses gliomas progression and elevates susceptibility to Temozolomide by targeting CAV2 and FGF7.

Malignant gliomas are the most common tumor in central nervous system with poor prognosis. Due to the limitation of histological classification in earlier diagnosis and individualized medicine, it is necessary to combine the molecular signatures and the pathological characteristics of gliomas. Lots of microRNAs presented abnormal expression in gliomas and modulated gliomas development. Exploration the miRNAs profile is helpful for the diagnosis, therapy and prognosis of gliomas. It has been demonstrated that miR-144 plays important roles in solid tumors. However, the detail mechanisms remained unrevealed. In this study, we have demonstrated the level of miR-144 decreased in glioma tissues from patients, especially in gliomas with higher grades. MiR-144 was also validated have lower expression in glioma cell lines compared with cortical neuron cell by using qRT-PCR. The in vitro functional experiment indicated miR-144 improved gliomas progression through repressing proliferation, sensitizing to chemotherapeutics and inhibiting metastasis. We further identified fibroblast growth factor 7 (FGF7) and Caveolin 2 (CAV2) were target genes of miR-144 by luciferase reporter assay and western blotting. The mechanisms study suggested forced FGF7 expression elevated Akt activation and decreased reactive oxygen species (ROS) generation. The MTT and cell cycle assay indicated miR-144 suppressed glioma cells proliferation through modulating FGF mediated Akt signaling pathway. Meanwhile, miR-144 promoted Temozolomide (TMZ) induced apoptosis in glioma cells via increasing ROS production by using FACS. On the other hand, CAV2, as another target of miR-144, accelerated glioma cells migration and invasion via promoting glioma cells EMT progress. Retrieved expression of FGF7 or CAV2 rescued the proliferation and migration function mediated by miR-144. Furthermore, the in vivo experiments in PDX models displayed the anti-tumor function of miR-144, which could be retrieved by overexpression of FGF7 and CAV2. Taken together, these findings indicated miR-144 acted as a potential target against gliomas progression and uncovered a novel regulatory mechanism, which may provide a new therapeutic strategy and prognostic indicator for gliomas.

Modulation of the MAPKs pathways affects Aß-induced cognitive deficits in Alzheimer's disease via activation of α7nAChR.

Cognitive impairment in Alzheimer's disease (AD) is characterized by being deficient at learning and memory. Aß1-42 oligomers have been shown to impair rodent cognitive function. We previously demonstrated that activation of α7nAChR, inhibition of p38 or JNK could alleviate Aß-induced memory deficits in Y maze test. In this study, we investigated whether the effects of α7nAChR and MAPKs on Y maze test is reproducible with a hippocampus-dependent spatial memory test such as Morris water maze. We also assessed the possible co-existence of hippocampus-independent recognition memory dysfunction using a novel object recognition test and an alternative and stress free hippocampus-dependent recognition memory test such as the novel place recognition. Besides, previous research from our lab has shown that MAPKs pathways regulate Aß internalization through mediating α7nAChR. In our study, whether MAPKs pathways exert their functions in cognition by modulating α7nAChR through regulating glutamate receptors and synaptic protein, remain little known. Our results showed that activation of α7nAChR restored spatial memory, novel place recognition memory, and short-term and long-term memory in novel object recognition. Inhibition of p38 restored spatial memory and short-term and long-term memory in novel object recognition. Inhibition of ERK restored short-term memory in novel object recognition and novel place recognition memory. Inhibition of JNK restored spatial memory, short-term memory in novel object recognition and novel place recognition memory. Beside this, the activation of α7nAChR, inhibition of p38 or JNK restored Aß-induced levels of NMDAR1, NMDAR2A, NMDAR2B, GluR1, GluR2 and PSD95 in Aß-injected mice without influencing synapsin 1. In addition, these treatments also recovered the expression of acetylcholinesterase (AChE). Finally, we found that the inhibition of p38 or JNK resulted in the upregulation of α7nAChR mRNA levels in the hippocampus. Our results indicated that inhibition of p38 or JNK MAPKs could alleviate Aß-induced spatial memory deficits through regulating activation of α7nAChR via recovering memory-related proteins. Moreover, p38, ERK and JNK MAPKs exert different functions in spatial and recognition memory.

Single housing-induced effects on cognitive impairment and depression-like behavior in male and female mice involve neuroplasticity-related signaling.

Single-housed stress elicits a range of social isolation-related behavioral and neurobiological abnormalities. To investigate single housing-induced behavioral changes and sex differences on stress outcomes, we examined single-housed stress-induced learning and memory impairment, depression-like behaviors, neuroplasticity abnormalities and underlying mechanism. The results showed that male and female mice socially isolated for 8 weeks had significantly decreased memory acquisition, as demonstrated in the learning curve of the Morris water maze task. Memory consolidation and retrieval were also decreased in both the single-housed male and female mice. These findings were corroborated further by the two classical animal models, Y-maze and novel object recognition tests, as demonstrated by reduced spontaneous alternation and recognition index in both sexes of single-housed mice. Subsequent studies suggested that single-housed male mice exhibited increased immobility time in both the forced swim and tail suspension tests, while the female mice only exhibited increased immobility time in the tail suspension test. Moreover, single-housed stress significantly decreased the apical and basal branch points, dendritic length, and spine density in the CA1 of hippocampal neurons in both male and female mice. These effects were consistent with decreased neuroplasticity and neuroprotective-related molecules such as synaptophysin, PSD95, PKA, pCREB and BDNF expression. These findings suggest that loss of neuronal remodeling and neuroprotective mechanisms due to single housing are involved in behavioral changes in both male and female mice. The results provide further evidence that neuroplasticity-related signaling plays a crucial role in isolation-induced effects on neuropsychiatric behavioral deficits in both sexes.

Alpha 7 nicotinic acetylcholine receptor and its effects on Alzheimer's disease.

Alzheimer's disease (AD) is one of the major disabling and lethal diseases for aged individuals worldwide. To date, there are more than 10 hypotheses proposed for AD pathology. The beta-amyloid (Aß) cascade hypothesis is the most widely accepted and proposes that the accumulation of Aß in the brain is one potential mechanism for AD pathogenesis. Because some Aß-overloaded patients do not have AD syndrome, this hypothesis is challenged from time to time. More recently, it has been shown that intracellular Aß plays a key role in AD pathology. Aß is internalized by receptors distributed on the cell membrane. Among these receptors, the alpha7 nicotinic acetylcholine receptor (α7 nAChR) has been shown to play an important role in AD. The α7 nAChR is a ligand-gated ion channel and is expressed in pivotal brain regions (e.g., the cerebral cortex and hippocampus) responsible for cognitive functions. The α7 nAChR is localized both presynaptically and postsynaptically, where it activates intracellular signaling cascades. Its agonist has been investigated in clinical studies to improve cognitive functions in AD. Although many studies have shown the importance of the α7 nAChR in AD, little is known regarding its role in AD pathology. Therefore, in the current review, we summarized the basic information regarding the structures and functions of the α7 nAChR, the distribution and expression of the α7 nAChR, and the role of the α7 nAChR in mediating Aß internalization. We subsequently focused on introducing the comprehensive α7 nAChR related signaling pathways and how these signaling pathways are integrated with the α7 nAChR to play a role in AD. Finally, we stressed the AD therapy that targets the α7 nAChR.

Activation of α7 nicotinic acetylcholine receptor alleviates Aß1-42-induced neurotoxicity via downregulation of p38 and JNK MAPK signaling pathways.

Amyloid ß peptide 1-42 (Aß1-42) could induce cognitive deficits through oxidative stress, inflammation, and neuron death in Alzheimer's disease (AD). MAPK pathways have been thought to mediate Aß1-42-induced neuroinflammation responses, neuron death and cognitive decline in AD. The α7 nicotinic acetylcholine receptor (α7nAChR) exerts a neuroprotective effect. However, whether α7nAChR alleviates Aß1-42-induced neurotoxicity through MAPKs (p38, ERK, JNK) in vivo remains unclear. In our study, memory was assessed in C57BL/6 mice using a Y-maze test. Cell death was assessed by Nissl and Hoechst staining and Bax, Bcl-2, Caspase 3, and Cytochrome C levels using Western blotting. Oxidative stress was assayed by superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) levels. Inflammation was examined with GFAP and Iba1 using immunohistochemistry. The Aß degrading enzymes insulin degrading enzyme (IDE) and neprilysin (NEP) were tested using Western blotting. We found that activating α7nAChR or inhibiting p38 or JNK pathway alleviated Aß1-42-induced cognitive deficits and neuron loss and death by reducing oxidative stress. In addition, activating α7nAChR or inhibiting p38 or JNK pathway also reduced inflammation, which was observed as reduced GFAP and Iba1 levels with different effects on Aß degrading enzymes. Finally, we found that the activation of α7nAChR led to the downregulation of pp38 and pJNK levels. Conversely, the inhibition of p38 or JNK resulted in the upregulation of α7nAChR levels in the hippocampus and cortex. Our data indicate that the activation of α7nAChR alleviates Aß1-42-induced neurotoxicity, and this protective effect might act through the downregulation of p38 and JNK MAPKs.

The p38 mitogen activated protein kinase regulates ß-amyloid protein internalization through the α7 nicotinic acetylcholine receptor in mouse brain.

Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders. Intracellular ß-amyloid protein (Aß) is an early event in AD. It induces the formation of amyloid plaques and neuron damage. The α7 nicotinic acetylcholine receptor (α7nAChR) has been suggested to play an important role in Aß caused cognition. It has high affinity with Aß and could mediate Aß internalization in vitro. However, whether in mouse brain the p38 MAPK signaling pathway is involved in the regulation of the α7nAChR mediated Aß internalization and their role in mitochondria remains little known. Therefore, in this study, we revealed that Aß is internalized by cholinergic and GABAergic neurons. The internalized Aß were found deposits in lysosomes/endosomes and mitochondria. Aß could form Aß-α7nAChR complex with α7nAChR, activates the p38 mitogen activated protein kinase (MAPK). And the increasing of α7nAChR could in return mediate Aß internalization in the cortex and hippocampus. In addition, by using the α7nAChR agonist PNU282987, the p38 phosphorylation level decreases, rescues the biochemical changes which are tightly associated with Aß-induced apoptosis, such as Bcl2/Bax level, cytochrome c (Cyt c) release. Collectively, the p38 MAPK signaling pathway could regulate the α7nAChR-mediated internalization of Aß. The activation of α7nAChR or the inhibition of p38 MAPK signaling pathway may be a beneficial therapy to AD.

Tongxinluo improves cognition by decreasing ß-amyloid in spontaneous hypertensive rats.

ß-Amyloid (Aß) accumulation in the brain is the major pathophysiology of Alzheimer disease (AD). Hypertension is a risk factor for AD by promoting Aß deposition. Traditional Chinese medicinal compound tongxinluo (TXL) can improve blood circulation and endothelium-dependent vasodilation. This study investigates the effects of TXL on cognition and Aß using spontaneously hypertensive rats (SHRs). TXL was intragastrically administered to SHRs at low-dose, mid-dose and high-dose for 15, 30 or 60days. Cognition was evaluated with a Morris Water Maze (MWM). Aß in the brain was detected by western blot, ELISA and Thioflavin-S staining. Western blot and RT-PCR were employed to exam the expression of receptor for advanced glycation end products (RAGE), low-density lipoprotein receptor-related protein-1 (LRP-1) and amyloid precursor protein (APP). After TXL treatment for 60days, compared with the vehicle, the number of crossed platform and the time spent in the target quadrant increased in parallel with the increasing length of treatment in MWM. Moreover, the Aß in the hippocampus significantly decreased compared to the vehicle group, both in western blot and ELISA. Additionally, TXL reduced RAGE expression in a dose- and time-depended manner, but LRP-1 expression had no difference between TXL groups and vehicle groups. Furthermore, the ß-secretase expression was significantly decreased compared to the vehicle group, but APP expression had no difference. In conclusion, TXL improved cognition and decreased Aß in SHRs in a dose- and time-dependent manner, the underlying mechanism may involved in inhibiting RAGE and ß-secretase expression.

Inhibition of CCR7 promotes NF-κB-dependent apoptosis and suppresses epithelial-mesenchymal transition in non-small cell lung cancer.

Activation of C-C chemokine receptor type 7 (CCR7) has been demonstrated to mediate the occurrence and progression of non-small cell lung cancer (NSCLC). However, the potential therapeutic role of CCR7 inhibition in NSCLC is still obscure. Thus, the present study was conducted to investigate the molecular mechanism underlying the inhibition of CCR7 on cell apoptosis and epithelial-mesenchymal transition (EMT) in NSCLC A549 cells. Chemokine ligand 21 (CCL21) was used to activate CCR7 and the results revealed that CCR7 upregulation inhibited cell apoptosis and affected apoptosis­related protein levels. However, CCR7-siRNA treatment markedly promoted apoptosis and suppressed inflammatory response and transforming growth factor ß1 (TGF-ß1)-induced EMT. In addition, CCR7­siRNA inactivated the NF-κB signaling pathway and inhibition of NF-κB via its specific antagonist, pyrrolidine dithiocarbamate, indicated that NF-κB was involved in the CCR7-mediated apoptosis. In conclusion, upregulation of CCR7 promoted cell proliferation and inflammation in A549 cells. In conclusion, inhibition of CCR7 via siRNA treatment promoted cell apoptosis and suppressed the inflammatory response and TGF-ß1­induced EMT, which may be associated with NF-κB signaling.

The p38 mitogen-activated protein kinase signaling pathway is involved in regulating low-density lipoprotein receptor-related protein 1-mediated ß-amyloid protein internalization in mouse brain.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. Recently, increasing evidence suggests that intracellular ß-amyloid protein (Aß) alone plays a pivotal role in the progression of AD. Therefore, understanding the signaling pathway and proteins that control Aß internalization may provide new insight for regulating Aß levels. In the present study, the regulation of Aß internalization by p38 mitogen-activated protein kinases (MAPK) through low-density lipoprotein receptor-related protein 1 (LRP1) was analyzed in vivo. The data derived from this investigation revealed that Aß1-42 were internalized by neurons and astrocytes in mouse brain, and were largely deposited in mitochondria and lysosomes, with some also being found in the endoplasmic reticulum. Aß1-42-LRP1 complex was formed during Aß1-42 internalization, and the p38 MAPK signaling pathway was activated by Aß1-42 via LRP1. Aß1-42 and LRP1 were co- localized in the cells of parietal cortex and hippocampus. Furthermore, the level of LRP1-mRNA and LRP1 protein involved in Aß1-42 internalization in mouse brain. The results of this investigation demonstrated that Aß1-42 induced an LRP1-dependent pathway that related to the activation of p38 MAPK resulting in internalization of Aß1-42. These results provide evidence supporting a key role for the p38 MAPK signaling pathway which is involved in the regulation of Aß1-42 internalization in the parietal cortex and hippocampus of mouse through LRP1 in vivo.

Ginsenoside-Rd Promotes Neurite Outgrowth of PC12 Cells through MAPK/ERK- and PI3K/AKT-Dependent Pathways.

Panax ginseng is a famous herbal medicine widely used in Asia. Ginsenosides have been identified as the principle active ingredients for Panax ginseng's biological activity, among which ginsenoside Rd (Rd) attracts extensive attention for its obvious neuroprotective activities. Here we investigated the effect of Rd on neurite outgrowth, a crucial process associated with neuronal repair. PC12 cells, which respond to nerve growth factor (NGF) and serve as a model for neuronal cells, were treated with different concentrations of Rd, and then their neurite outgrowth was evaluated. Our results showed that 10 µM Rd significantly increased the percentages of long neurite- and branching neurite-bearing cells, compared with respective controls. The length of the longest neurites and the total length of neurites in Rd-treated PC12 cells were much longer than that of respective controls. We also showed that Rd activated ERK1/2 and AKT but not PKC signalings, and inhibition of ERK1/2 by PD98059 or/and AKT by LY294002 effectively attenuated Rd-induced neurite outgrowth. Moreover, Rd upregulated the expression of GAP-43, a neuron-specific protein involved in neurite outgrowth, while PD98059 or/and LY294002 decreased Rd-induced increased GAP-43 expression. Taken together, our results provided the first evidence that Rd may promote the neurite outgrowth of PC12 cells by upregulating GAP-43 expression via ERK- and ARK-dependent signaling pathways.

Study on the adult physique with the Heath-Carter anthropometric somatotype in the Han of Xi'an, China.

The study of somatotypes has important significance for medical and physical anthropology as well as sports science. The aim of this study was to understand the somatotype components of the Han population in Xi'an and compare the somatotypes of the Han and five other nationalities in China. The study sample consisted of 429 people of Han nationality (207 males, 222 females) from Xi'an, China, aged ≥20 years old. The Heath-Carter anthropometric method was employed. We evaluated the differences in age and sex by one-way ANOVA and t test. A comparison of somatotypes between the Han and other nationalities was made using the U test. The results showed that the male and female samples all could be classified as having a mesomorphic endomorph profile. The difference in endomorphy was strongest between sexes in all age groups (P < 0.01). There were prominent differences in mesomorphy and ectomorphy between males and females in the 50-59- and ≥60-year-old age groups. In females, the differences in somatotype components appeared to be distinguished between ages (P < 0.01 or P < 0.05). However, in males, there were prominent differences in somatotype components between the 20-29 year olds and all other age groups (P < 0.01 or P < 0.05) except for between those 20-29 and ≥60 years old in endomorphy. Compared with the other five nationalities, there were prominent differences in somatotype components between males and females. These results suggest that the somatotype of the Han population in Xi'an, China, has a predominantly mesomorphic endomorph profile. The endomorphic component shows distinct differences between ages and genders, respectively. Additionally, there are distinct differences in the somatotype components between Xi'an Han and five other nationalities in China in males and females.

Vasoactive intestinal peptide administration after stroke in rats enhances neurogenesis and improves neurological function.

The aim of this study was to investigate the effects of vasoactive intestinal peptide (VIP) on neurogenesis and neurological function after cerebral ischemia. Rats were intracerebroventricular administered with VIP after a 2h middle cerebral artery occlusion (MCAO) and sacrificed at 7, 14 and 28 days after MCAO. Functional outcome was studied with the modified neurological severity score. The infarct volume was evaluated via histology. Neurogenesis, angiogenesis and the protein expression of vascular endothelial growth factor (VEGF) were measured by immunohistochemistry and Western blotting analysis, respectively. The treatment with VIP significantly reduced the neurological severity score and the infarc volume, and increased the numbers of bromodeoxyuridine (BrdU) immunoreactive cells and doublecortin immunoreactive area in the subventricular zone (SVZ) at 7, 14 and 28 days after ischemia. The cerebral protein levels of VEGF and VEGF expression in the SVZ were also enhanced in VIP-treated rats at 7 days after stroke. VIP treatment obviously increased the number of BrdU positive endothelial cells in the SVZ and density of cerebral microvessels in the ischemic boundary at 28 days after ischemia. Our study suggests that in the ischemic rat brain VIP reduces brain damage and promotes neurogenesis by increasing VEGF. VIP-enhanced neurogenesis is associated with angiogenesis. These changes may contribute to improvement in functional outcome.

Mitogen-activated protein kinase signaling pathways promote low-density lipoprotein receptor-related protein 1-mediated internalization of beta-amyloid protein in primary cortical neurons.

Mounting evidence suggests that the pathological hallmarks of Alzheimer's disease (AD) are caused by the intraneuronal accumulation of beta-amyloid protein (Aß). Reuptake of extracellular Aß is believed to contribute significantly to the intraneuronal Aß pool in the early stages of AD. Published reports have claimed that the low-density lipoprotein receptor-related protein 1 (LRP1) mediates Aß1-42 uptake and lysosomal trafficking in GT1-7 neuronal cells and mouse embryonic fibroblast non-neuronal cells. However, there is no direct evidence supporting the role of LRP1 in Aß internalization in primary neurons. Our recent study indicated that p38 MAPK and ERK1/2 signaling pathways are involved in regulating α7 nicotinic acetylcholine receptor (α7nAChR)-mediated Aß1-42 uptake in SH-SY5Y cells. This study was designed to explore the regulation of MAPK signaling pathways on LRP1-mediated Aß internalization in neurons. We found that extracellular Aß1-42 oligomers could be internalized into endosomes/lysosomes and mitochondria in cortical neurons. Aß1-42 and LRP1 were also found co-localized in neurons during Aß1-42 internalization, and they could form Aß1-42-LRP1 complex. Knockdown of LRP1 expression significantly decreased neuronal Aß1-42 internalization. Finally, we identified that p38 MAPK and ERK1/2 signaling pathways regulated the internalization of Aß1-42 via LRP1. Therefore, these results demonstrated that LRP1, p38 MAPK and ERK1/2 mediated the internalization of Aß1-42 in neurons and provided evidence that blockade of LRP1 or inhibitions of MAPK signaling pathways might be a potential approach to lowering brain Aß levels and served a potential therapeutic target for AD.

The effects of valsartan on cognitive deficits induced by aluminum trichloride and d-galactose in mice.

OBJECTIVES: Valsartan has been reported to reduce brain beta-amyloid protein levels and improve spatial learning in the Tg2576 transgenic mouse model of Alzheimer's disease (AD). However, the exact mechanism of neuroprotective effects of valsartan has not been properly studied especially in cholinergic function and oxidative damage, the essential factors that undergo impairment in AD. Therefore, the present study examined the effects of valsartan on memory impairment, cholinergic dysfunction, and oxidative stress in aluminum trichloride (AlCl3) and d-galactose (d-gal)-induced experimental sporadic dementia of Alzheimer's type. METHODS: Valsartan was administered intragastrically (i.g.) (20 mg/kg/day) for 60 days after mice were given AlCl3 (10 mg/kg/day) and d-gal (150 mg/kg/day) intraperitoneally (i.p.) once daily for 90 days. Then, memory function was evaluated by Morris water maze test. Acetylcholinesterase (AChE), superoxide dismutases (SOD) and glutathione peroxidase (GSH-Px) activities and malondialdehyde (MDA) level in cortex and hippocampus were also assessed with biochemical technique. RESULTS: Chronic administration of valsartan not only improved learning and memory but also restored the elevation of AChE activity induced by AlCl3 and d-gal in cortex and hippocampus. In addition, valsartan significantly restored SOD and GSH-Px activities and reduced MDA level in cortex and hippocampus indicating attenuation of oxidative stress. DISCUSSION: Our results indicate that valsartan prevents AlCl3- and d-gal-induced cognitive decline partly to restore cholinergic function and attenuate oxidative damage. These findings further support the potential of valsartan to be used in AD treatment.

The effects of perindopril on cognitive impairment induced by d-galactose and aluminum trichloride via inhibition of acetylcholinesterase activity and oxidative stress.

Preclinical and clinical studies indicate involvement of renin angiotensin system (RAS) in memory functions. However, exact role of RAS in cognition is still ambiguous. The present study investigated the effects of perindopril on dementia of Alzheimer's type induced by d-galactose (d-gal) and aluminum trichloride (AlCl3). Perindopril, an angiotensin converting enzyme inhibitor, was administered intragastrically (0.5mg/kg/day) for 60days after mice were given d-gal (150mg/kg/day) and AlCl3 (10mg/kg/day) intraperitoneally for 90days. Then, memory function was evaluated by Morris water maze test. The biochemical studies were conducted in cerebral cortex and hippocampus of mouse brain after the behavioral studies. d-Gal and AlCl3 caused significant memory impairment along with significant elevation of acetylcholinesterase (AChE) activity in cerebral cortex and hippocampus. Further, a significant reduction of superoxide dismutases (SOD) and glutathione peroxidase (GSH-Px) activities, and elevation of malondialdehyde (MDA) level in cerebral cortex and hippocampus were observed. Perindopril not only improved cognitive impairment but also restored the elevation of AChE activity induced by d-gal and AlCl3. In addition, perindopril significantly increased SOD and GSH-Px activities, reduced MDA level in cerebral cortex and hippocampus. Taken together, the above findings indicate that perindopril improves learning and memorizing probably by restoring cholinergic function and attenuating oxidative damage.