Exploring the mechanism of bioactive components of Prunella vulgaris L. in treating hepatocellular carcinoma based on network pharmacology.

In traditional Chinese Medicine, Prunella vulgaris L. (PVL) is potentially effective in the treatment of some human malignancies including hepatocellular carcinoma (HCC). However, the detailed mechanism of action remains unclear. The purpose of this study was to decipher the constitutes of the bioactive ingredients of PVL, and its mechanism against HCC using network pharmacology and in vitro experiments. The bioactive components of PVL were obtained by Traditional Chinese Medicine System Pharmacology Database and Analysis platform database, and the targets of bioactive components of PVL was investigated by Swiss Target Prediction database. HCC related targets were obtained from GEO database, GeneCards database and DisGeNET database, and the gene ontology function annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were conducted for annotating the biological function of gene targets. A protein-protein interaction network was constructed using STRING database. Molecular docking of key bioactive ingredients was performed using AutoDock Vina. Cell proliferation and apoptosis were detected by cell counting kit-8 and flow cytometry, respectively. The expression level of the target genes of PI3K/Akt pathway were detected by qPCR. In the present work, 11 bioactive components of PVL were screened out, which acted on 177 potential targets. In addition, 13,517 genes were strongly associated with HCC pathogenesis, of which 158 targets are overlapped with PVL's targets. KEGG results identified 39 signaling pathways closely associated with the 158 targets. Molecular docking showed that the main bioactive components of PVL, kaempferol, morin, quercetin, luteolin, and spinasterol, had good binding activity with the core proteins in cancer biology such as AKT1, EGFR, SRC, ESR1, and PPARG. In vitro assays showed that quercetin, one of the main components of PVL extracts effectively inhibited HCC cell proliferation, and promoted apoptosis, which may be associated with PI3K/AKT signaling pathway. In summary, PVL may regulate HCC progression by regulating core targets such as AKT1, EGFR, SRC, ESR1, and PPARG, and acting on PI3K-Akt signaling pathway.

Association between internal carotid artery kinking and ischemic stroke: A population-based cross-sectional study.

AIM: Evidence for an association between Internal carotid artery (ICA) kinking and ischemic stroke has been controversial. We aimed to examine the association between ICA tortuosity and risk of ischemic stroke and specific ischemic stroke subtypes (large artery atherosclerosis, LAA; small artery occlusion, SAO). METHODS: A total of 419 outpatients were included in this cross-sectional study. ICA kinking was objectively assessed by head and neck computed tomography angiography (CTA). The risk of ischemic stroke for each patient was evaluated according to the Essen Stroke Risk Score (ESRS). Ischemic stroke subtypes (LAA and SAO) were measure with head magnetic resonance imaging (MRI). RESULTS: The average age of patients was 59.1 years (SD = 13.25) and 264 (63.0 %) were males. The prevalence of ICA kinking in this sample was 31.5 % (132 out of 419). Individuals with ICA kinking was associated with 0.55-points increase in ESRS score than those without ICA kinking (95 % CI, 0.28-0.81, p < 0.001) among patients over 50 years. In addition, right ICA kinking or left ICA kinking were associated with 0.35-points (95 % CI, 0.08-0.63) and 0.49-points (95 % CI, 0.23-0.76) increase in ESRS score, respectively. For specific ischemic stroke subtypes, individuals with ICA kinking had a 10.34-fold increased risk of SAO compared to those without ICA kinking (95 % CI, 6.22-20.68). Individuals with right ICA kinking had a 4.51-fold risk of SAO than those without kinking (95 % CI, 2.64-7.71), and had an 8.86-fold risk of SAO than those without kinking in the left ICA kinking (95 % CI, 4.97-15.79). CONCLUSION: Our findings support the role of ICA kinking on ischemic stroke. Early screening and proper treatment of carotid artery tortuosity could be a potential intervention strategy for the prevention of ischemic stroke later on.

Polymorphisms of TRIB1 genes for coronary artery disease and stroke risk: A systematic review and meta-analysis.

BACKGROUND AND AIMS: In recent years, the results of the association between Tribbles Pseudokinase 1 (TRIB1) gene polymorphism and the risk of coronary artery disease (CAD) and stroke are inconsistent. This study aimed to systematically review the literature on TRIB1 gene polymorphisms and susceptibility to coronary atherosclerotic heart disease (CAD) and stroke. METHODS: This study collected studies published until May 2022 through a systematic search of PubMed, Web of Science, and Google Scholar databases. After a systematic literature search, pooled odds ratio (OR) and their corresponding 95 % confidence interval (CI) were used to assess the strength of the association. RESULTS: We identified 6 studies on rs17321515, including 12,892 controls and 4583 patients, and 3 on rs2954029, including 1732 controls and 1305 patients. In different genetic models, the rs2954029 genetic polymorphism significantly increased the risk of CAD and stroke. In the codominant model, the AA genotype increased the risk of CAD and stroke (OR = 1.74, 95 % CI = 1.39-2.17, P < 0.001); the TA genotype also increased the prevalence of CAD and stroke risk (OR = 1.39, 95 % CI = 1.18-1.64, P < 0.001). Compared with the control group, the TT + TA genotype increased the risk of CAD and stroke in the dominant genetic model (OR = 1.46, 95 %CI = 1.25-1.71, P < 0.001), and in the recessive model, the TA + AA genotype increased the risk of CAD and stroke (OR = 1.41, 95 % CI = 1.15-1.72, P < 0.001). In addition, the TRIB1 rs17321515 polymorphism was not found to be associated with the risk of CAD and stroke, which may be related to other factors such as race. CONCLUSIONS: The rs2954029 A allele was significantly associated with an increased risk of CAD and stroke, according to the present meta-analysis. However, the association of rs17321515 polymorphism with susceptibility to CAD and stroke has not been found in this study.

Contribution of intracranial artery stenosis to white matter hyperintensities progression in elderly Chinese patients: A 3-year retrospective longitudinal study.

Background and purpose: There have been controversial results in previous studies for the association between intracranial artery stenosis (ICAS) and white matter hyperintensities (WMHs), and the correlation of ICAS with the progression of WMHs is uncertain. The aim of this study was to investigate the association between ICAS and the progression of WMHs. Methods: In this retrospective longitudinal study, we enrolled 302 patients aged 60 years and older who had received two brain MRI scans with a 3-year interval and was examined by CTA in the first MRI scan. We measured the stenosis of major intracranial arteries by CTA and assessed the progression of WMHs using the modified Rotterdam Progression scale (mRPS). We performed binary logistic regression analyses and established linear regression model to determine the relationship between the degree of ICAS and the progression of WMHs. Results: A total of 302 patients were enrolled, of which 48.3% experienced WMHs progression. After adjustment for confounding factors, the patients with Grade 2 ICAS had an OR of 2.8 (95% CI 1.4-5.5), and those with Grade 3 ICAS had an OR of 3.0 (95% CI 1.2-7.3) for the progression of WMHs. The ICAS degree remained associated with PVWMHs but had an attenuated relation to SCWMHs. ICAS severity was significantly associated with WMHs progression scores, higher for Grade 3 ICAS [ß (SE) = 0.18 (0.18)] followed by Grade 2 ICAS [ß (SE) = 0.10 (0.15)] compared with Grade 1 ICAS. Conclusions: Patients with more severe ICAS are more likely to have WMHs progression and have distinct relevancy to PVWMHs and SCWMHs, which may provide clues for understanding mechanisms of WMHs progression.

Characterization of placental and decidual cell development in early pregnancy loss by single-cell RNA sequencing.

BACKGROUND: Early pregnancy loss (EPL) presents as sporadic or recurrent miscarriage during the first trimester. In addition to chromosomal defects, EPL may result from impairment of the placental-decidual interface at early gestational age due to gene-environmental interactions. METHODS: To better understand the pathogenesis associated with this impairment, cell development in chorionic villi and decidua of different forms of EPL (sporadic or recurrent) was investigated with single-cell RNA sequencing and compared to that of normal first-trimester tissue. RESULTS: Unique gene expression signatures were obtained for the different forms of EPL and for normal tissue and the composition of placental and decidual cell clusters in each form was established. In particular, the involvement of macrophages in the EPL phenotypes was identified revealing an immunoactive state. CONCLUSION: Differential gene expression and unique marker genes among cell clusters from chorionic villi and decidua of miscarried and normal pregnancies, may lead to identification of biomarker for EPL.

Based on molecular structures: Amyloid-ß generation, clearance, toxicity and therapeutic strategies.

Amyloid-ß (Aß) has long been considered as one of the most important pathogenic factors in Alzheimer's disease (AD), but the specific pathogenic mechanism of Aß is still not completely understood. In recent years, the development of structural biology technology has led to new understandings about Aß molecular structures, Aß generation and clearance from the brain and peripheral tissues, and its pathological toxicity. The purpose of the review is to discuss Aß metabolism and toxicity, and the therapeutic strategy of AD based on the latest progress in molecular structures of Aß. The Aß structure at the atomic level has been analyzed, which provides a new and refined perspective to comprehend the role of Aß in AD and to formulate therapeutic strategies of AD.

ß-Patchoulene represses hypoxia-induced proliferation and epithelial-mesenchymal transition of liver cancer cells.

Hepatocellular carcinoma (HCC) is a malignant tumor originating from liver epithelial cells with a high clinical mortality rate. ß-Patchoulene (ß-PAE) is a compound extracted from patchouli, which has analgesic, anti-inflammatory and antioxidant effects. This research aims to probe the impacts of ß-PAE on hypoxia-induced HCC cell proliferation and epithelial-mesenchymal transition (EMT). Firstly, hypoxic injury models were constructed in HCC Huh-7 and MHCC97 cells, and the hypoxic injury cell models were then treated with different concentrations of ß-PAE. The cell viability, proliferation, migration, invasion and apoptosis were checked by the cell counting kit-8 (CCK-8) assay, colony formation assay, Transwell assay, flow cytometry and terminal deoxyribonucleotide transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay. The expression of Survivin protein, EMT markers and the NF-κB/HIF-1α pathway was gauged by Western blot (WB) or cellular immunofluorescence or reverse transcription-polymerase chain reaction (RT-PCR). The in-vivo experiment was conducted to confirm the anti-tumor role of ß-PAE. As a result, ß-PAE abated hypoxia-induced HCC cell growth, proliferation, migration, invasion and EMT and facilitated apoptosis in vitro and in vivo dose-dependently. Further mechanism studies displayed that ß-PAE inactivated the NF-κB/HIF-1α pathway, and HIF-1α activation significantly reversed the ß-PAE-mediated tumor inhibition. ß-PAE repressed the proliferation and EMT of hypoxia-induced HCC cells by choking the NF-κB/HIF-1α pathway, suggesting that ß-PAE was a potential drug for HCC treatment.

Corrigendum: Association Between Metabolic Syndrome and Mild Parkinsonian Signs Progression in the Elderly.

[This corrects the article DOI: 10.3389/fnagi.2021.722836.].

Association Between Metabolic Syndrome and Mild Parkinsonian Signs Progression in the Elderly.

Background: This study investigated the impact of metabolic syndrome on the progression from mild parkinsonian signs (MPS) to Parkinson's disease (PD). Methods: A total of 1,563 participants with MPS completed 6 years of follow-up. The diagnosis of metabolic syndrome was made according to Adult Treatment Panel III of the National Cholesterol Education Program. The evaluations of MPS and PD were based on the motor portion of the Unified Parkinson's Disease Rating Scale. Cox proportional hazard models were used to identify the association between metabolic syndrome and PD conversion. Results: Of the 1,563 participants, 482 (30.8%) with MPS developed PD at the end of the follow-up. Metabolic syndrome (HR: 1.69, 95% CI: 1.29-2.03) was associated with the risk of PD conversion. Metabolic syndrome was associated with the progression of bradykinesia (HR: 1.85, 95% CI: 1.43-2.34), rigidity (HR: 1.36, 95% CI: 1.19-1.57), tremor (HR: 1.98, 95% CI: 1.73-2.32), and gait/balance impairment (HR: 1.66, 95% CI: 1.25-2.11). The effect of metabolic syndrome on the progression of bradykinesia and tremor was nearly two fold. Participants treated for two or three to four components of metabolic syndrome, including high blood pressure, high fasting plasma glucose, hypertriglyceridemia, and low HDL-C, had a lower risk of PD conversion. Conclusion: Metabolic syndrome increased the risk of progression from MPS to PD. Participants treated for two or more components of metabolic syndrome had a lower risk of PD conversion.

LncRNA DARS-AS1 aggravates the growth and metastasis of hepatocellular carcinoma via regulating the miR-3200-5p-Cytoskeleton associated protein 2 (CKAP2) axis.

Accumulating signs have found that long noncoding RNAs (lncRNAs) contribute to hepatocellular carcinoma (HCC). Here, we probed the effect and mechanism of lncRNA DARS-AS1 in HCC. The profiles of DARS-AS1 and Cytoskeleton associated protein 2 (CKAP2) in 50 HCC tissues and non-tumor tissues were examined by real-time quantitative polymerase chain reaction (RT-qPCR). DARS-AS1 and CKAP2 overexpression and/or knockdown cell models were established. The proliferation, apoptosis, invasion and epithelial-mesenchymal transition (EMT) were determined. CKAP2, and focal adhesion kinase (FAK)-extracellular signal-regulated kinase (ERK) was tested by Western blot (WB). The relationship between DARS-AS1 and CKAP2 was predicted by Bioinformatics, and the dual-luciferase reporter assay was applied to verify the targeting association between miR-3200-5p and DARS-AS1 and CKAP2. DARS-AS1 was overexpressed in HCC tissues (vs. that in non-tumor tissues) and was closely correlated with the patients' tumor stage. DARS-AS1 facilitated HCC cell proliferation and hampered apoptosis. HCC cell migration and EMT were enhanced by DARS-AS1. DARS-AS1 up-regulated CKAP2, which aggravated HCC. Further investigation illustrated that either DARS-AS1 or CKAP2 activated FAK-ERK pathway, and miR-3200-5p was competitively restrained by DARS-AS1. miR-3200-5p exerted tumor-suppressive effects in HCC and inactivated CKAP2 and FAK-ERK pathway. All in all, this study corroborates that DARS-AS1 facilitates HCC proliferation and metastasis by regulating miR-3200-5p-mediated CKAP2, which provides a potential target for HCC diagnosis and treatment.Abbreviations: CCK-8: cell counting kit-8; CKAP2: Cytoskeleton associated protein 2; cDNA:complementary DNA; DAPI: 4',6-diamidino-2-phenylindole; DARS-AS1: DARS1 antisense RNA 1; DEPC: diethyl pyrocarbonate; DMEM-F12: Dulbecco's minimal essential medium/Ham's-F12; EMT: epithelial-mesenchymal transition; ERK: extracellular signal-regulated kinase; FAK: focal adhesion kinase; FBS: fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HCC: hepatocellular carcinoma; HE: hematoxylin-eosin; IHC: Immunohistochemistry; LIHC: Liver hepatocellular carcinoma; lncRNAs: long noncoding RNAs; MIAT: lncRNA myocardial infarction-related transcripts; MT: Mutant; NC: negative control; PBS: phosphate-buffered saline; PMSF: Phenylmethylsulfonyl fluoride; PVDF: polyvinylidene difluoride; RT: room temperature; RT-qPCR: real-time quantitative polymerase chain reaction; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SPF: specific pathogen-free; TMAP: tumor-associated microtubule-associated protein; TUNEL: TdT-mediated dUTP nick end labeling; V: volume; WT: wild type.

Effects and prognostic values of miR-30c-5p target genes in gastric cancer via a comprehensive analysis using bioinformatics.

Gastric cancer (GC) is a common cancer and the leading cause of cancer-related death worldwide. To improve the diagnosis and treatment of GC, it is necessary to identify new biomarkers by investigating the cellular and molecular mechanisms. In this study, miR-30c-5p expression was significantly down-regulated in GC tissues by comprehensive analysis using multiple databases. The target genes of miR-30c-5p with up-regulated expression level in GC were identified, including ADAM12 (a disintegrin and metalloproteinase12), EDNRA (the Endothelin receptor type A), STC1 (stanniocalcin 1), and CPNE8 (the calcium-dependent protein, copine 8). The expression level of ADAM12 was significantly related to depth of invasion (p = 0.036) in GC patients. The expression level of EDNRA was significantly related to grade (P = 0.003), depth of invasion (P = 0.019), and lymphatic metastasis (P = 0.001). The expression level of CPNE8 was significantly related to grade (P = 0.043) and TNM stage (P = 0.027).Gene set enrichment analysis showed that they might participate in GC progression through cancer-related pathways. CIBERSORT algorithm analysis showed that their expressions were related to a variety of tumor-infiltrating immune cells. The higher expression of those target genes might be the independent risk factor for poor survival of GC patients, and they might be potential prognostic markers in GC patients.

Effect of High Cholesterol Regulation of LRP1 and RAGE on Aß Transport Across the Blood-Brain Barrier in Alzheimer's Disease.

BACKGROUND: High cholesterol aggravates the risk development of Alzheimer's disease (AD). AD is closely related to the transport impairment of Amyloid-ß (Aß) in the blood-brain barrier. It is unclear whether high cholesterol affects the risk of cognitive impairment in AD by affecting Aß transport. The purpose of the study is to investigate whether high cholesterol regulates Aß transport through low-density Lipoprotein Receptor-Related Protein 1 (LRP1) and Receptor for Advanced Glycation End products (RAGE) in the risk development of AD. METHODS: We established high cholesterol AD mice model. The learning and memory functions were evaluated by Morris Water Maze (MWM). Cerebral microvascular endothelial cells were isolated, cultured, and observed. The expression levels of LRP1 and RAGE of endothelial cells and their effect on Aß transport in vivo were observed. The expression level of LRP1 and RAGE was detected in cultured microvessels after using Wnt inhibitor DKK-1 and ß-catenin inhibitor XAV-939. RESULTS: Hypercholesterolemia exacerbated spatial learning and memory impairment. Hypercholesterolemia increased serum Aß40 level, while serum Aß42 level did not change significantly. Hypercholesterolemia decreased LRP1 expression and increased RAGE expression in cerebral microvascular endothelial cells. Hypercholesterolemia increased brain apoptosis in AD mice. In in vitro experiment, high cholesterol decreased LRP1 expression and increased RAGE expression, increased Aß40 expression in cerebral microvascular endothelial cells. High cholesterol regulated the expressions of LRP1 and RAGE and transcriptional activity of LRP1 and RAGE promoters by the Wnt/ß-catenin signaling pathway. CONCLUSION: High cholesterol decreased LRP1 expression and increased RAGE expression in cerebral microvascular endothelial cells, which led to Aß transport disorder in the blood-brain barrier. Increased Aß deposition in the brain aggravated apoptosis in the brain, resulting to cognitive impairment of AD mice.

Exercise-induced muscle damage: multi-parametric MRI quantitative assessment.

BACKGROUND: To explore the value of magnetic resonance quantitative analysis using diffusion tensor imaging, T2 mapping, and intravoxel incoherent motion in the evaluation of eccentric exercise-induced muscle damage and to compare the effects of various eccentric exercise modes at different time points in rats. METHODS: A total of 174 Sprague-Dawley male rats were randomly divided into five groups: control, once-only exercise, continuous exercise, intermittent exercise, and once-fatigue exercise groups. Each experimental group was divided into seven time-subgroups: 0.5 h, 24 h, 48 h, 72 h, 96 h, 120 h and 168 h after exercise. The quadriceps femoris muscles were then scanned using magnetic resonance imaging. The apparent diffusion coefficient and fractional anisotropy values of diffusion tensor imaging, T2 values of T2 mapping, D and D* values of intravoxel incoherent motion and optical density values of desmin were measured. Associations among different eccentric exercise programmes, magnetic resonance imaging findings, and histopathological results were evaluated. Dunnett's test, two-way repeated measures analysis of variance, and Pearson correlation analysis were used for statistical analysis. RESULTS: Diffusion tensor imaging showed that the number of muscle fibre bundles decreased to varying degrees with different time points and eccentric exercises. Apparent diffusion coefficient values of the exercise groups showed a trend that first increased and then decreased, the opposite of fractional anisotropy. The specimens in all eccentric exercise programmes showed high signal T2 values after exercise, the highest among which was in the once-fatigue exercise group. D and D* in the experimental groups were significantly higher than those in the control group at 0.5-48 h after exercise. The apparent diffusion coefficient, fractional anisotropy, T2, D and D* values correlated with the optical density values of desmin. CONCLUSIONS: Diffusion tensor imaging, T2 mapping, and intravoxel incoherent motion technology accurately reflect the degree of skeletal muscle damage and recovery associated with eccentric exercise. The degree of muscle damage was the lowest in the continuous exercise group and the highest in the once-fatigue exercise group, which may provide more information and guidance for the formulation of physical and athletic training programmes.

Association of naturally occurring antibodies to ß-amyloid with cognitive decline and cerebral amyloidosis in Alzheimer's disease.

The pathological relevance of naturally occurring antibodies to ß-amyloid (NAbs-Aß) in Alzheimer's disease (AD) remains unclear. We aimed to investigate their levels and associations with Aß burden and cognitive decline in AD in a cross-sectional cohort from China and a longitudinal cohort from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. NAbs-Aß levels in plasma and cerebrospinal fluid (CSF) were tested according to their epitopes. Levels of NAbs targeting the amino terminus of Aß increased, and those targeting the mid-domain of Aß decreased in both CSF and plasma in AD patients. Higher plasma levels of NAbs targeting the amino terminus of Aß and lower plasma levels of NAbs targeting the mid-domain of Aß were associated with higher brain amyloidosis at baseline and faster cognitive decline during follow-up. Our findings suggest a dynamic response of the adaptive immune system in the progression of AD and are relevant to current passive immunotherapeutic strategies.

Blood cell-produced amyloid-ß induces cerebral Alzheimer-type pathologies and behavioral deficits.

It is traditionally believed that cerebral amyloid-beta (Aß) deposits are derived from the brain itself in Alzheimer's disease (AD). Peripheral cells such as blood cells also produce Aß. The role of peripherally produced Aß in the pathogenesis of AD remains unknown. In this study, we established a bone marrow transplantation model to investigate the contribution of blood cell-produced Aß to AD pathogenesis. We found that bone marrow cells (BMCs) transplanted from APPswe/PS1dE9 transgenic mice into wild-type (Wt) mice at 3 months of age continuously expressed human Aß in the blood, and caused AD phenotypes including Aß plaques, cerebral amyloid angiopathy (CAA), tau hyperphosphorylation, neuronal degeneration, neuroinflammation, and behavioral deficits in the Wt recipient mice at 12 months after transplantation. Bone marrow reconstitution in APPswe/PS1dE9 mice with Wt-BMCs at 3 months of age reduced blood Aß levels, and alleviated brain Aß burden, neuronal degeneration, neuroinflammation, and behavioral deficits in the AD model mice at 12 months after transplantation. Our study demonstrated that blood cell-produced Aß plays a significant role in AD pathogenesis, and the elimination of peripheral production of Aß can decrease brain Aß deposition and represents a novel therapeutic approach for AD.

White matter hyperintensities and the progression from mild parkinsonian signs to parkinsonism and Parkinson's disease.

This study investigated the impact of white matter hyperintensities (WMHs) on the progression from mild parkinsonian signs (MPS) to parkinsonism and Parkinson's disease (PD). Participants with MPS completed 5 years of follow-up. WMHs were divided into periventricular WMHs and deep WMHs according to magnetic resonance imaging scans. The diagnosis of MPS, parkinsonism, and PD was based on the motor portion of the Unified Parkinson's Disease Rating Scale. Cox proportional hazard models were used to identify the association between WMHs and MPS progression. Of the 636 participants, 166 (26.1%) with MPS developed parkinsonism and PD after follow-up. After adjusting for potential factors, severe WMHs were associated with an increased risk of MPS progression, moderate and severe periventricular WMHs and severe deep WMHs were associated with the risk of MPS progression, and severe WMHs were associated with the progression of gait/balance impairment, bradykinesia, and rigidity. Additionally, participants treated for vascular risk factors such as hypertension, diabetes mellitus, and hypercholesterolemia had a lower risk of MPS progression.

A phase II randomized trial of sodium oligomannate in Alzheimer's dementia.

BACKGROUND: Sodium oligomannate (GV-971), a marine-derived oligosaccharide, is a novel agent that may improve cognition in AD patients. METHODS: The 24-week multicenter, randomized, double-blind, placebo parallel controlled clinical trial was conducted in AD in China between 24 October 2011 and 10 July 2013. The study included a 4-week screening/washout period, followed by a 24-week treatment period. Patients were randomized in a 1:1:1 ratio to receive GV-971 900 mg, 600 mg, or placebo capsule in treatment period, respectively. The primary outcome was cognitive improvement as assessed by changes in Alzheimer's Disease Assessment Scale-cognitive subscale 12-item (ADAS-cog12) scores from baseline to week 24. The secondary efficacy outcomes included CIBIC-Plus, ADCS-ADL, and NPI at 24 weeks after treatment compared with baseline. A subgroup study was assessment of the change in cerebral glucose metabolism by fluorodeoxyglucose positron emission tomography measurements. RESULTS: Comparing with the placebo group (n = 83, change - 1.45), the ADAS-cog12 score change in the GV-971 600-mg group (n = 76) was - 1.39 (p = 0.89) and the GV-971 900-mg group (n = 83) was - 2.58 (p = 0.30). The treatment responders according to CIBIC-Plus assessment were significantly higher in the GV-971 900-mg group than the placebo group (92.77% vs. 79.52%, p < 0.05). The GV-971 900-mg subgroup showed a lower decline of cerebral metabolic rate for glucose than the placebo subgroup at the left precuneus, right posterior cingulate, bilateral hippocampus, and bilateral inferior orbital frontal at uncorrected p = 0.05. The respective rates of treatment-related AEs were 5.9%, 14.3%, and 3.5%. CONCLUSIONS: GV-971 was safe and well tolerated. GV-971 900 mg was chosen for phase III clinical study. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01453569 . Registered on October 18, 2011.

Capsaicin consumption reduces brain amyloid-beta generation and attenuates Alzheimer's disease-type pathology and cognitive deficits in APP/PS1 mice.

Alzheimer's disease (AD) is the most common cause of age-related dementia and is currently incurable. The failures of current clinical trials and the establishment of modifiable risk factors have shifted the AD intervention from treatment to prevention in the at-risk population. Previous studies suggest that there is a geographic overlap between AD incidence and spicy food consumption. We previously reported that capsaicin-rich diet consumption was associated with better cognition and lower serum Amyloid-beta (Aß) levels in people aged 40 years and over. In the present study, we found that intake of capsaicin, the pungent ingredient in chili peppers, reduced brain Aß burden and rescued cognitive decline in APP/PS1 mice. Our in vivo and in vitro studies revealed that capsaicin shifted Amyloid precursor protein (APP) processing towards α-cleavage and precluded Aß generation by promoting the maturation of a disintegrin and metalloproteinase 10 (ADAM10). We also found that capsaicin alleviated other AD-type pathologies, such as tau hyperphosphorylation, neuroinflammation and neurodegeneration. The present study suggests that capsaicin is a potential therapeutic candidate for AD and warrants clinical trials on chili peppers or capsaicin as dietary supplementation for the prevention and treatment of AD.

Analysis of risk factors for depression in Alzheimer's disease patients.

Purpose: Depression, which affects about 52% of Alzheimer's disease (AD) patients, can worsen cognitive impairment and increase mortality and suicide rates. We hope to provide clinical evidence for the prevention and treatment of depression in AD patients by investigating related risk factors of depression in AD patients.Methods: 158 AD inpatients of the Department of Neurology, Daping Hospital from September 2017 to March 2019 were enrolled. General information, laboratory tests, cognitive and emotional function assessments of the inpatients were collected. Logistic regression was used to analyze the risk factors of depression in AD patients, and the relationship between 17 Hamilton depression scale scores and HbA1c levels in AD patients was further analyzed.Results: The prevalence of age, gender, hypertension, hyperlipidemia, Type 2 diabetes mellitus (T2DM), and white matter lesions (WML) in the AD with depression group was significantly different from without depression group. Hypertension, T2DM, and WML are independent risk factors for depression in AD patients. The depression scores of AD patients with HbA1c>6.5% were significantly higher than AD patients with HbA1c ≤ 6.5%, and there were significant difference in depression scale scores between using anti-diabetes drugs group and not using anti-diabetes drugs group whose HbA1c level is >6.5%, while no difference in depression scores between using anti-diabetes drugs group and not using anti-diabetes drugs group whose HbA1c level is ≤6.5%.Conclusion: T2DM is an independent risk factor for AD patients with depression. Increased HbA1c levels aggravate depression in AD patients, and controlling HbA1c levels and anti-diabetes drugs can reduce the severity of depression in AD patients.

Frequency distribution of apolipoprotein E genotypes in elderly population and relationship with senile dementia.

BACKGROUND: The aim of this study was to determine the relationship between apolipoprotein E (ApoE)-ε4 genotype and senile dementia (SD) by analyzing the ApoE allelic frequency distributions among the elderly Han Chinese population. METHODS: For this purpose, a total of 316 Chongqing residents aged ≥60 years were classified as SD or control groups following the criteria of National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association. Genomic DNA was isolated from the peripheral blood lymphocytes and exon 4 of the ApoE gene with polymorphism sites was amplified by PCR and genotypes determined by restriction fragment length polymorphism (RFLP). RESULTS: We found that the most prevalent genotype was ApoE-ε3/3, followed in order by ApoE-ε3/4 and ApoE-ε2/2. The estimated ApoE allelic frequencies in individuals with SD were 0.095, 0.560, and 0.345 for ε2, ε3, and ε4, respectively. In controls, the corresponding ApoE allelic frequencies were 0.146, 0.699, and 0.155. The percentage of ε4 allele carriers in SD group was significantly higher than that in control group (P<0.01); while those of ε2 and ε3 genotypes were lower in SD group as compared with control group. CONCLUSIONS: We concluded that in the elderly Han Chinese residents of Chongqing aged 60 years and over, ApoE-ε3/3 and ApoE-ε2/2 were the most and least prevalent genotypes, respectively. Further, based on strong linkage, ApoEε4 allele might be a significant risk factor for the development of senile dementia.