Blockade of CCR5 suppresses paclitaxel-induced peripheral neuropathic pain caused by increased deoxycholic acid.

Paclitaxel leads to peripheral neuropathy (paclitaxel-induced peripheral neuropathy [PIPN]) in approximately 50% of cancer patients. At present, there are no effective treatment strategies for PIPN, the mechanisms of which also remain unclear. In this study, we performed microbiome and metabolome analysis of feces and serum from breast cancer patients with different PIPN grades due to paclitaxel treatment. Our analysis reveals that levels of deoxycholic acid (DCA) are highly increased because of ingrowth of Clostridium species, which is associated with severe neuropathy. DCA, in turn, elevates serum level of C-C motif ligand 5 (CCL5) and induces CCL5 receptor 5 (CCR5) overexpression in dorsal root ganglion (DRG) through the bile acid receptor Takeda G-protein-coupled receptor 5 (TGR5), contributing to neuronal hyperexcitability. Consistent with this, administration of CCR5 antagonist maraviroc suppresses the development of neuropathic nociception. These results implicate gut microbiota/bile acids/CCR5 signaling in the induction of PIPN, thus suggesting a target for PIPN treatment.

Cross-Talking Pathways of Rapidly Accelerated Fibrosarcoma-1 (RAF-1) in Alzheimer's Disease.

Alzheimer's disease (AD) becomes one of the main global burden diseases with the aging population. This study was to investigate the potential molecular mechanisms of rapidly accelerated fibrosarcoma-1 (RAF-1) in AD through bioinformatics analysis. Differential gene expression analysis was performed in GSE132903 dataset. We used weight gene correlation network analysis (WGCNA) to evaluate the relations among co-expression modules and construct global regulatory network. Cross-talking pathways of RAF-1 in AD were identified by functional enrichment analysis. Totally, 2700 differentially expressed genes (DEGs) were selected between AD versus non-dementia control and RAF-1-high versus low group. Among them, DEGs in turquoise module strongly associated with AD and high expression of RAF-1 were enriched in vascular endothelial growth factor (VEGF), neurotrophin, mitogen-activated protein kinase (MAPK) signaling pathway, oxidative phosphorylation, GABAergic synapse, and axon guidance. Moreover, cross-talking pathways of RAF-1, including MAPK, VEGF, neurotrophin signaling pathways, and axon guidance, were identified by global regulatory network. The performance evaluation of AUC was 84.2%. The gene set enrichment analysis (GSEA) indicated that oxidative phosphorylation and synapse-related biological processes were enriched in RAF-1-high and AD group. Our findings strengthened the potential roles of high RAF-1 level in AD pathogenesis, which were mediated by MAPK, VEGF, neurotrophin signaling pathways, and axon guidance.

Effect of physical activity on risk of Alzheimer's disease: A systematic review and meta-analysis of twenty-nine prospective cohort studies.

OBJECTIVE: Physical activity (PA) is beneficial in reductions of all-cause mortality and dementia. However, whether Alzheimer's disease (AD) risk is modified by PA remains disputable. This meta-analysis aims to disclose the underlying relationship between PA and incident AD. METHODS: Pubmed, Embase, Cochrane Library, and Web of Science were retrieved from inception to June 2023. Random-effects models were employed to derive the effect size, represented by hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Twenty-nine prospective cohort studies involving 2068,519 participants were included. The pooled estimate showed a favorable effect of PA on AD risk decline (HR 0.72, 95% CI 0.65-0.80). This association remained robust after adjusting for maximum confounders (HR 0.85, 95% CI 0.79-0.91). Subgroup analysis of PA intensity demonstrated an inverse dose-response relationship between PA and AD, effect sizes of which were significant in moderate (HR 0.85, 95% CI 0.80-0.93) and high PA (HR 0.56, 95% CI 0.45-0.68), but not in low PA (HR 0.94, 95% CI 0.77-1.15). Regardless of all participants or the mid-life cohort, the protection of PA against AD appeared to be valid in shorter follow-up (<15 years) rather than longer follow-up (≥15 years). In addition to follow-up, the robustness of the estimates persisted in supplementary meta-analyses, meta-regression analyses, and sensitivity analyses. CONCLUSION: PA intervention reduces the incidence of AD, but merely in moderate to vigorous PA with follow-up of less than 15 years, thus conditionally recommending the popularization of PA as a modifiable lifestyle factor to prevent AD.

Prognostic Signature for Human Umbilical Cord Mesenchymal Stem Cell Treatment of Ischemic Cerebral Infarction by Integrated Bioinformatic Analysis.

In recent studies, stem cell-based therapy is a potential new approach in the treatment of stroke. The mechanism of human umbilical cord mesenchymal stem cell (hUMSC) transplantation as one of the new approaches in the treatment of ischemic stroke is still unclear. The aim of this study was to determine the traits of immune responses during stroke progression after treatment with human umbilical cord blood MSCs by bioinformatics, to predict potential prognostic biomarkers that could lead to sex differences, and to reveal potential therapeutic targets. The microarray dataset GSE78731 (mRNA profile) of middle cerebral artery occlusion (MCAO) rats was obtained from the Gene Expression Omnibus (GEO) database. First, two potentially expressed genes (DEGs) were screened using the Bioconductor R package. Ultimately, 30 specific DEGs were obtained (22 upregulated and 353 downregulated). Next, bioinformatic analysis was performed on these specific DEGs. We performed a comparison for the differentially expressed genes screened from between the hUMSC and MCAO groups. Gene Ontology enrichment and pathway enrichment analyses were then performed for annotation and visualization. Gene Ontology (GO) functional annotation analysis shows that DEGs are mainly enriched in leukocyte migration, neutrophil activation, neutrophil degranulation, the external side of plasma membrane, cytokine receptor binding, and carbohydrate binding. KEGG pathway enrichment analysis showed that the first 5 enrichment pathways were cytokine-cytokine receptor interaction, chemokine signal pathway, viral protein interaction with cytokine and cytokine receptor, cell adhesion molecules (CAMs), and phagosome. The top 10 key genes of the constructed PPI network were screened, including Cybb, Ccl2, Cd68, Ptprc, C5ar1, Il-1b, Tlr2, Itgb2, Itgax, and Cd44. In summary, hUMSC is likely to be a promising means of treating IS by immunomodulation.

Down-Regulation of Insulin Like Growth Factor 1 Involved in Alzheimer's Disease via MAPK, Ras, and FoxO Signaling Pathways.

The inability to halt or even delay the course of Alzheimer's disease (AD) forces the development of new molecular signatures and therapeutic strategies. Insulin like growth factor 1 (IGF1) is a promising target for AD treatment, yet exact mechanisms of AD ascribed to IGF1 remain elusive. Herein, gene expression profiles of 195 samples were analyzed and 19,245 background genes were generated, among which 4,424 differentially expressed genes (DEGs) were overlapped between AD/control and IGF1-low/high groups. Based on such DEGs, seven co-expression modules were established by weight gene correlation network analysis (WGCNA). The turquoise module had the strongest correlation with AD and IGF1-low expression, the DEGs of which were enriched in GABAergic synapse, long-term potentiation, mitogen-activated protein kinase (MAPK), Ras, and forkhead box O (FoxO) signaling pathways. Furthermore, cross-talking pathways of IGF1, including MAPK, Ras, and FoxO signaling pathways were identified in the protein-protein interaction network. According to the area under the curve (AUC) analysis, down-regulation of IGF1 exhibited good diagnostic performance in AD prediction. Collectively, our findings highlight the involvement of low IGF1 in AD pathogenesis via MAPK, Ras, and FoxO signaling pathways, which might advance strategies for the prevention and therapy of AD based on IGF1 target.

Molecular Signatures of Mitochondrial Complexes Involved in Alzheimer's Disease via Oxidative Phosphorylation and Retrograde Endocannabinoid Signaling Pathways.

Objective: The inability to intervene in Alzheimer's disease (AD) forces the search for promising gene-targeted therapies. This study was aimed at exploring molecular signatures and mechanistic pathways to improve the diagnosis and treatment of AD. Methods: Microarray datasets were collected to filter differentially expressed genes (DEGs) between AD and nondementia controls. Weight gene correlation network analysis (WGCNA) was employed to analyze the correlation of coexpression modules with AD phenotype. A global regulatory network was established and then visualized using Cytoscape software to determine hub genes and their mechanistic pathways. Receiver operating characteristic (ROC) analysis was conducted to estimate the diagnostic performance of hub genes in AD prediction. Results: A total of 2,163 DEGs from 13,049 background genes were screened in AD relative to nondementia controls. Among the six coexpression modules constructed by WGCNA, DEGs of the key modules with the strongest correlation with AD were extracted to build a global regulatory network. According to the Maximal Clique Centrality (MCC) method, five hub genes associated with mitochondrial complexes were chosen. Further pathway enrichment analysis of hub genes, such as oxidative phosphorylation and retrograde endocannabinoid signaling, was identified. According to the area under the curve (AUC) of about 70%, each hub gene exhibited a good diagnostic performance in predicting AD. Conclusions: Our findings highlight the perturbation of mitochondrial complexes underlying AD onset, which is mediated by molecular signatures involved in oxidative phosphorylation (COX5A, NDUFAB1, SDHB, UQCRC2, and UQCRFS1) and retrograde endocannabinoid signaling (NDUFAB1) pathways.

Cross-Talking Pathways of Forkhead Box O1 (FOXO1) Are Involved in the Pathogenesis of Alzheimer's Disease and Huntington's Disease.

Alzheimer's disease (AD) and Huntington's disease (HD) are destructive worldwide diseases. Efforts have been made to elucidate the process of these two diseases, yet the pathogenesis remains elusive as it involves a combination of multiple factors, including genetic and environmental ones. To explore the potential role of forkhead box O1 (FOXO1) in the development of AD and HD, we identified 1,853 differentially expressed genes (DEGs) from 19,414 background genes in both the AD&HD/control and FOXO1-low/high groups. Four coexpression modules were predicted by the weighted gene coexpression network analysis (WGCNA), among which blue and turquoise modules had the strongest correlation with AD&HD and high expression of FOXO1. Functional enrichment analysis showed that DEGs in these modules were enriched in phagosome, cytokine-cytokine receptor interaction, cellular senescence, FOXO signaling pathway, pathways of neurodegeneration, GABAergic synapse, and AGE-RAGE signaling pathway in diabetic complications. Furthermore, the cross-talking pathways of FOXO1 in AD and HD were jointly determined in a global regulatory network, such as the FOXO signaling pathway, cellular senescence, and AGE-RAGE signaling pathway in diabetic complications. Based on the performance evaluation of the area under the curve of 85.6%, FOXO1 could accurately predict the onset of AD and HD. We then identified the cross-talking pathways of FOXO1 in AD and HD, respectively. More specifically, FOXO1 was involved in the FOXO signaling pathway and cellular senescence in AD; correspondingly, FOXO1 participated in insulin resistance, insulin, and the FOXO signaling pathways in HD. Next, we use GSEA to validate the biological processes in AD&HD and FOXO1 expression. In GSEA analysis, regulation of protein maturation and regulation of protein processing were both enriched in the AD&HD and FOXO1-high groups, suggesting that FOXO1 may have implications in onset and progression of these two diseases through protein synthesis. Consequently, a high expression of FOXO1 is a potential pathogenic factor in both AD and HD involving mechanisms of the FOXO signaling pathway, AGE-RAGE signaling pathway in diabetic complications, and cellular senescence. Our findings provide a comprehensive perspective on the molecular function of FOXO1 in the pathogenesis of AD and HD.

Exploring the potential biomarkers for prognosis of glioblastoma via weighted gene co-expression network analysis.

BACKGROUND: Glioblastoma (GBM) is the most common malignant tumor in the central system with a poor prognosis. Due to the complexity of its molecular mechanism, the recurrence rate and mortality rate of GBM patients are still high. Therefore, there is an urgent need to screen GBM biomarkers to prove the therapeutic effect and improve the prognosis. RESULTS: We extracted data from GBM patients from the Gene Expression Integration Database (GEO), analyzed differentially expressed genes in GEO and identified key modules by weighted gene co-expression network analysis (WGCNA). GSE145128 data was obtained from the GEO database, and the darkturquoise module was determined to be the most relevant to the GBM prognosis by WGCNA (r =  - 0.62, p = 0.01). We performed enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) to reveal the interaction activity in the selected modules. Then Kaplan-Meier survival curve analysis was used to extract genes closely related to GBM prognosis. We used Kaplan-Meier survival curves to analyze the 139 genes in the darkturquoise module, identified four genes (DARS/GDI2/P4HA2/TRUB1) associated with prognostic GBM. Low expression of DARS/GDI2/TRUB1 and high expression of P4HA2 had a poor prognosis. Finally, we used tumor genome map (TCGA) data, verified the characteristics of hub genes through Co-expression analysis, Drug sensitivity analysis, TIMER database analysis and GSVA analysis. We downloaded the data of GBM from the TCGA database, the results of co-expression analysis showed that DARS/GDI2/P4HA2/TRUB1 could regulate the development of GBM by affecting genes such as CDC73/CDC123/B4GALT1/CUL2. Drug sensitivity analysis showed that genes are involved in many classic Cancer-related pathways including TSC/mTOR, RAS/MAPK.TIMER database analysis showed DARS expression is positively correlated with tumor purity (cor = 0.125, p = 1.07e-02)), P4HA2 expression is negatively correlated with tumor purity (cor =-0.279, p = 6.06e-09). Finally, GSVA analysis found that DARS/GDI2/P4HA2/TRUB1 gene sets are closely related to the occurrence of cancer. CONCLUSION: We used two public databases to identify four valuable biomarkers for GBM prognosis, namely DARS/GDI2/P4HA2/TRUB1, which have potential clinical application value and can be used as prognostic markers for GBM.

Downregulation of PIK3CB Involved in Alzheimer's Disease via Apoptosis, Axon Guidance, and FoxO Signaling Pathway.

OBJECTIVE: To investigate the molecular function of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB) underlying Alzheimer's disease (AD). METHODS: RNA sequencing data were used to filtrate differentially expressed genes (DEGs) in AD/nondementia control and PIK3CB-low/high groups. An unbiased coexpression network was established to evaluate module-trait relationships by using weight gene correlation network analysis (WGCNA). Global regulatory network was constructed to predict the protein-protein interaction. Further cross-talking pathways of PIK3CB were identified by functional enrichment analysis. RESULTS: The mean expression of PIK3CB in AD patients was significantly lower than those in nondementia controls. We identified 2,385 DEGs from 16,790 background genes in AD/control and PIK3CB-low/high groups. Five coexpression modules were established using WGCNA, which participated in apoptosis, axon guidance, long-term potentiation (LTP), regulation of actin cytoskeleton, synaptic vesicle cycle, FoxO, mitogen-activated protein kinase (MAPK), and vascular endothelial growth factor (VEGF) signaling pathways. DEGs with strong relation to AD and low PIK3CB expression were extracted to construct a global regulatory network, in which cross-talking pathways of PIK3CB were identified, such as apoptosis, axon guidance, and FoxO signaling pathway. The occurrence of AD could be accurately predicted by low PIK3CB based on the area under the curve of 71.7%. CONCLUSIONS: These findings highlight downregulated PIK3CB as a potential causative factor of AD, possibly mediated via apoptosis, axon guidance, and FoxO signaling pathway.

DL-3-n-butylphthalide promotes hippocampal neurogenesis and reduces mossy fiber sprouting in chronic temporal lobe epilepsy rats.

BACKGROUND: A decrease in hippocampal neurogenesis is considered an important cause of cognitive impairment, while changes in mossy fiber sprouting are closely related to development of spontaneous recurrent seizures in chronic temporal lobe epilepsy (TLE). Racemic l-3-n-butylphthalide (DL-NBP) can alleviate cognitive impairment in ischemic stroke and Alzheimer's disease by promoting neurogenesis. DL-NBP treatment can also improve cognitive function and reduce seizure incidence in chronic epileptic mice. However, the mechanisms of action of DL-NBP remain unclear. The aim of the present study was to examine the effects of DL-NBP on mossy fiber sprouting, hippocampal neurogenesis, spontaneous epileptic seizures, and cognitive functioning in the chronic phase of TLE. METHODS: Nissl staining was used to evaluate hippocampal injury, while immunofluorescent staining was used to analyze hippocampal neurogenesis. The duration of spontaneous seizures was measured by electroencephalography. The Morris water maze was used to evaluate cognitive function. Timm staining was used to assess mossy fiber sprouting. RESULTS: TLE animals showed reduced proliferation of newborn neurons, cognitive dysfunction, and spontaneous seizures. Treatment with DL-NBP after TLE increased the proliferation and survival of newborn neurons in the dentate gyrus, reversed the neural loss in the hippocampus, alleviated cognitive impairments, and decreased mossy fiber sprouting and long-term spontaneous seizure activity. CONCLUSIONS: We provided pathophysiological and morphological evidence that DL-NBP might be a useful therapeutic for the treatment of TLE.

Integrative genomic analysis of PPP3R1 in Alzheimer's disease: a potential biomarker for predictive, preventive, and personalized medical approach.

Alzheimer's disease (AD) is associated with abnormal calcium signaling, a pathway regulated by the calcium-dependent protein phosphatase. This study aimed to investigate the molecular function of protein phosphatase 3 regulatory subunit B (PPP3R1) underlying AD, which may provide novel insights for the predictive diagnostics, targeted prevention, and personalization of medical services in AD by targeting PPP3R1. A total of 1860 differentially expressed genes (DEGs) from 13,049 background genes were overlapped in AD/control and PPP3R1-low/high cohorts. Based on these DEGs, six co-expression modules were constructed by weight gene correlation network analysis (WGCNA). The turquoise module had the strongest correlation with AD and low PPP3R1, in which DEGs participated in axon guidance, glutamatergic synapse, long-term potentiation (LTP), mitogen-activated protein kinase (MAPK), Ras, and hypoxia-inducible factor 1 (HIF-1) signaling pathways. Furthermore, the cross-talking pathways of PPP3R1, such as axon guidance, glutamatergic synapse, LTP, and MAPK signaling pathways, were identified in the global regulatory network. The area under the curve (AUC) analysis showed that low PPP3R1 could accurately predict the onset of AD. Therefore, our findings highlight the involvement of PPP3R1 in the pathogenesis of AD via axon guidance, glutamatergic synapse, LTP, and MAPK signaling pathways, and identify downregulation of PPP3R1 as a potential biomarker for AD treatment in the context of 3P medicine-predictive diagnostics, targeted prevention, and personalization of medical services. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13167-021-00261-2.

Integrative Functional Genomic Analysis of Molecular Signatures and Mechanistic Pathways in the Cell Cycle Underlying Alzheimer's Disease.

OBJECTIVE: Alzheimer's disease (AD) is associated with cell cycle reentry of mature neurons that subsequently undergo degeneration. This study is aimed to identify key regulators of the cell cycle and their underlying pathways for developing optimal treatment of AD. METHODS: RNA sequencing data were profiled to screen for differentially expressed genes in the cell cycle. Correlation of created modules with AD phenotype was computed by weight gene correlation network analysis (WGCNA). Signature genes for trophic factor receptors were determined using Pearson correlation coefficient (PCC) analysis. RESULTS: Among the 13,679 background genes, 775 cell cycle genes and 77 trophic factor receptors were differentially expressed in AD versus nondementia controls. Four coexpression modules were constructed by WGCNA, among which the turquoise module had the strongest correlation with AD. According to PCC analysis, 10 signature trophic receptors most strongly interacting with cell cycle genes were filtered and subsequently displayed in the global regulatory network. Further cross-talking pathways of signature receptors, such as glutamatergic synapse, long-term potentiation, PI3K-Akt, and MAPK signaling pathways, were identified. CONCLUSIONS: Our findings highlighted the mechanistic pathways of signature trophic receptors in cell cycle perturbation underlying AD pathogenesis, thereby providing new molecular targets for therapeutic intervention in AD.

Ketogenic diet prevents paclitaxel-induced neuropathic nociception through activation of PPARγ signalling pathway and inhibition of neuroinflammation in rat dorsal root ganglion.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect during the course of cancer treatment, which is mainly manifested as a series of sensory abnormalities. At present, there are no recommended prevention or treatment strategies, and the underlying mechanisms are unclear. The ketogenic diet (KD), a special diet that is high in fat and low in carbohydrate intake, shows good therapeutic potential in children with epilepsy. In this study, it was found that KD significantly prevented paclitaxel-induced neuropathic nociception. Using the GSE113941 database, 281 differentially expressed genes (DEGs) were found in an animal model of CIPN and controls. The DEGs were mainly enriched in peroxisome proliferator activated receptor (PPAR) and oxidative phosphorylation signalling pathways. As a main regulatory pathway of lipid metabolism, the PPARγ signalling pathway was significantly upregulated in the KD model. In addition, KD also inhibited the expression of pro-inflammatory cytokines and the TLR4/NF-κB signalling pathway in the dorsal root ganglion (DRG) in paclitaxel-treated rats. In vitro, rat primary DRG neurons were used to investigate the role of PPARγ in paclitaxel-induced neurotoxicity. It was found that PPARγ agonist rosiglitazone significantly protected DRG neurons against cell apoptosis and reactive oxygen species generation induced by paclitaxel administration. Therefore, KD is a prospective treatment option when applied as a dietary intervention in the prevention and treatment of paclitaxel-induced neuropathic nociception, possibly through the activation of PPARγ and its neuroprotective functions.

Downregulation of ATP6V1A Involved in Alzheimer's Disease via Synaptic Vesicle Cycle, Phagosome, and Oxidative Phosphorylation.

OBJECTIVE: The objective of this study was to investigate the potential molecular mechanisms of ATPase H+ transporting V1 subunit A (ATP6V1A) underlying Alzheimer's disease (AD). METHODS: Microarray expression data of human temporal cortex samples from the GSE118553 dataset were profiled to screen for differentially expressed genes (DEGs) between AD/control and ATP6V1A-low/high groups. Correlations of coexpression modules with AD and ATP6V1A were assessed by weight gene correlation network analysis (WGCNA). DEGs strongly interacting with ATP6V1A were extracted to construct global regulatory network. Further cross-talking pathways of ATP6V1A were identified by functional enrichment analysis. Diagnostic performance of ATP6V1A in AD prediction was evaluated using area under the curve (AUC) analysis. RESULTS: The mean expression of ATP6V1A was significantly downregulated in AD compared with nondementia controls. A total of 1,364 DEGs were overlapped from AD/control and ATP6V1A-low/high groups. Based on these DEGs, four coexpression modules were predicted by WGCNA. The blue, brown, and turquoise modules were significantly correlated with AD and low ATP6V1A, whose DEGs were enriched in phagosome, oxidative phosphorylation, synaptic vesicle cycle, focal adhesion, and gamma-aminobutyric acidergic (GABAergic) synapse. Global regulatory network was constructed to identify the cross-talking pathways of ATP6V1A, such as synaptic vesicle cycle, phagosome, and oxidative phosphorylation. According to the AUC value of 74.2%, low ATP6V1A expression accurately predicted the occurrence of AD. CONCLUSIONS: Our findings highlighted the pleiotropic roles of low ATP6V1A in AD pathogenesis, possibly mediated by synaptic vesicle cycle, phagosome, and oxidative phosphorylation.

Serum Uric Acid and the Risk of Dementia: A Systematic Review and Meta-Analysis.

Background: This meta-analysis aimed to evaluate the relationship between serum uric acid (UA) and the risk of dementia and its subtypes. Methods: Embase, PubMed, and Web of Science were searched from inception to July 2020. Random-effect models were employed to analyze the standard mean difference (SMD) with the corresponding 95% confidence intervals (CI). Results: Twenty-three eligible studies involving 5,575 participants were identified. The overall results showed lower levels of UA in dementia relative to non-dementia controls [SMD = -0.32 (-0.64; -0.01) p = 0.04]. The subgroup analysis of the type of dementia demonstrated a significant association of UA with Alzheimer's disease (AD) [SMD = -0.58 (-1.02; -0.15) p = 0.009] and Parkinson's disease with dementia (PDD) [SMD = -0.33 (-0.52; -0.14) p = 0.001] but not with vascular dementia (VaD). The stratification analysis of the concentrations of UA revealed that the UA quartile 1-2 was negatively correlated with dementia and neurodegenerative subtypes (p < 0.05), whereas a positive correlation of UA quartile 4 with dementia was noted (p = 0.028). Additionally, the meta-regression analysis on confounders showed that not age, body mass index, diabetes mellitus, hypertension, or smoking but education (p = 0.003) exerted an influence of the UA in the risk estimate of dementia. Conclusions: Low concentrations of UA (< 292 µmol/L or 4.91 mg/dL) is a potential risk factor for AD and PDD but not for VaD. The mechanism of different concentrations of the UA in dementia needs to be confirmed through further investigation.

Functional analysis of brain derived neurotrophic factor (BDNF) in Huntington's disease.

The aim of this study is to determine the molecular functions of brain derived neurotrophic factor (BDNF) in Huntington's disease (HD). A total of 1,675 differentially expressed genes (DEGs) were overlapped from HD versus control and BDNF-low versus high groups. Five co-expression modules were constructed using weight gene correlation network analysis, among which the blue and turquoise modules were most strongly correlated with HD and low BDNF. Functional enrichment analyses revealed DEGs in these modules significantly enriched in GABAergic synapse, phagosome, cyclic adenosine monophosphate (cAMP), mitogen-activated protein kinase (MAPK), renin-angiotensin system (Ras), Ras-associated protein-1 and retrograde endocannabinoid signaling pathways. The intersection pathways of BDNF, such as cAMP, MAPK and Ras signaling pathways, were identified in global regulatory network. Further performance evaluation of low BDNF accurately predicted HD occurrence according to the area under the curve of 82.4%. In aggregate, our findings highlighted the involvement of low BDNF expression in HD pathogenesis, potentially mediated by cAMP, MAPK and Ras signaling pathways.

The Polygenic Map of Keloid Fibroblasts Reveals Fibrosis-Associated Gene Alterations in Inflammation and Immune Responses.

Due to many inconsistencies in differentially expressed genes (DEGs) related to genomic expression changes during keloid formation and a lack of satisfactory prevention and treatment methods for this disease, the critical biomarkers related to inflammation and the immune response affecting keloid formation should be systematically clarified. Normal skin/keloid scar tissue-derived fibroblast genome expression data sets were obtained from the Gene Expression Omnibus (GEO) and ArrayExpress databases. Hub genes have a high degree of connectivity and gene function aggregation in the integration network. The hub DEGs were screened by gene-related protein-protein interactions (PPIs), and their biological processes and signaling pathways were annotated to identify critical biomarkers. Finally, eighty-one hub DEGs were selected for further analysis, and some noteworthy signaling pathways and genes were found to be closely related to keloid fibrosis. For example, IL17RA is involved in IL-17 signal transduction, TIMP2 and MMP14 activate extracellular matrix metalloproteinases, and TNC, ITGB2, and ITGA4 interact with cell surface integrins. Furthermore, changes in local immune cell activity in keloid tissue were detected by DEG expression, immune cell infiltration, and mass CyTOF analyses. The results showed that CD4+ T cells, CD8+ T cells and NK cells were abnormal in keloid tissue compared with normal skin tissue. These findings not only support the key roles of fibrosis-related pathways, immune cells and critical genes in the pathogenesis of keloids but also expand our understanding of targets that may be useful for the treatment of fibrotic diseases.

Artesunate attenuates traumatic brain injury-induced impairments in rats.

BACKGROUND: Blood-brain barrier (BBB) dysfunction and neuroinflammation induced by traumatic brain injuries (TBIs) cause a succession of secondary brain damage events and finally lead to a massive and progressive cerebral neuronal destruction. Artesunate, a semisynthetic artemisinin derivative, is a potential candidate for the management of cerebral damage induced by TBI due to its protective function to BBB and cerebral neurons. METHODS: To demonstrate the effect of artesunate to TBI-induced BBB dysfunction and neural damage, TBI rat model was constructed by cortical impact injury. Behavioral experiments were used to estimate the impact of the combined treatment on rats. Western blotting was performed to demonstrate the protein levels in the brain tissues of rats. Quantitative real-time PCRs were utilized to investigate the alteration in the expression of various RNA levels. The chemokine levels were estimated by ELISA. RESULTS: Artesunate treatment attenuated the impact caused by TBI on rat brain and improved the long-term neurological recover. Artesunate treatment protected the integrity of BBB and inhibited neuroinflammation. Artesunate treatment promoted the phosphorylation of Akt and inhibited the phosphorylation of glycogen synthase kinase (GSK)-3ß in TBI rat model. CONCLUSION: Artesunate protected rats from TBI-induced impairments of BBB and improved longer-term neurological outcomes.

Molecular identification of protein kinase C beta in Alzheimer's disease.

The purpose of this study was to investigate the potential roles of protein kinase C beta (PRKCB) in the pathogenesis of Alzheimer's disease (AD). We identified 2,254 differentially expressed genes from 19,245 background genes in AD versus control as well as PRKCB-low versus high group. Five co-expression modules were constructed by weight gene correlation network analysis. Among them, the 1,222 genes of the turquoise module had the strongest relation to AD and those with low PRKCB expression, which were enriched in apoptosis, axon guidance, gap junction, Fc gamma receptor (FcγR)-mediated phagocytosis, mitogen-activated protein kinase (MAPK) and vascular endothelial growth factor (VEGF) signaling pathways. The intersection pathways of PRKCB in AD were determined, including gap junction, FcγR-mediated phagocytosis, MAPK and VEGF signaling pathways. Based on the performance evaluation of the area under the curve of 75.3%, PRKCB could accurately predict the onset of AD. Therefore, low expressions of PRKCB was a potential causative factor of AD, which might be involved in gap junction, FcγR-mediated phagocytosis, MAPK and VEGF signaling pathways.

Forced forelimb use following stroke enhances oligodendrogenesis and functional recovery in the rat.

Forced limb use, which forces the use of the impaired arm following stroke, improves functional recovery. The study was designed to investigate the mechanisms of recovery underlying forced impaired limbuse. Furthermore, forced unimpaired arm use was also performed in order to explore its effect on functional behavior. We hypothesized that forced forelimb use could improve functional recovery in rats that have had an experimentally induced ischemic stroke, through promoting the recruitment and differentiation of the oligodendrocyte progenitor cells (OPCs). Indeed the proliferation of Olig2 and NG2 positive cells, as well as the expression of myelin basic protein (MBP)were increased in the perilesional striatum, whereas quantitative changes of Olig2+ and NG2+ oligodendrocyte progenitor cells was not observed in the subventricular zone. Through comparing rats forced to rely on affected or unaffected forelimb, the results demonstrated that forced impaired limb use boosted functional recovery. At the same time forced unimpaired limb use deteriorated limb movement of injured side. In addition, the expression of NogoA is reduced, when the injured limb was used more, suggesting that it played a role in the repair of white matter.