ABSTRACT
Background: Donepezil in combination with memantine is a widely used clinical therapy for moderate to severe dementia. However, real-world population data on the long-term safety of donepezil in combination with memantine are incomplete and variable. Therefore, the aim of this study was to analyze the adverse events (AEs) of donepezil in combination with memantine according to US Food and Drug Administration Adverse Event Reporting System (FAERS) data to provide evidence for the safety monitoring of this therapy. Methods: We retrospectively analyzed reports of AEs associated with the combination of donepezil and memantine from 2004 to 2023 extracted from the FAERS database. Whether there was a significant association between donepezil and memantine combination therapy and AEs was assessed using four disproportionality analysis methods, namely, the reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker methods. To further investigate potential safety issues, we also analyzed differences and similarities in the time of onset and incidence of AEs stratified by sex and differences and similarities in the incidence of AEs stratified by age. Results: Of the 2,400 adverse drug reaction (ADR) reports in which the combination of donepezil and memantine was the primary suspected drug, most of the affected patients were female (54.96%) and older than 65 years of age (79.08%). We identified 22 different system organ classes covering 100 AEs, including some common AEs such as dizziness and electrocardiogram PR prolongation; fall, pleurothotonus and myoclonus were AEs that were not listed on the drug label. Moreover, we obtained 88 reports of AEs in men and 100 reports of AEs in women; somnolence was a common AE in both men and women and was more common in women, whereas pleurothotonus was a more common AE in men. In addition, we analyzed 12 AEs in patients younger than 18 years, 16 in patients between 18 and 65 years, and 113 in patients older than 65 years. The three age groups had distinctive AEs, but lethargy was the common AE among all age groups. Finally, the median time to AE onset was 19 days in all cases. In both men and women, most AEs occurred within a month of starting donepezil plus memantine, but some continued after a year of treatment. Conclusion: Our study identified potential and new AEs of donepezil in combination with memantine; some of these AEs were the same as in the specification, and some of the AE signals were not shown in the specification. In addition, there were sex and age differences in some of the AEs. Therefore, our findings may provide valuable insights for further studies on the safety of donepezil and memantine combination therapy, which are expected to contribute to the safe use of this therapy in clinical practice.
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Background: Previous studies have revealed that Galectin-9 (Gal-9) acts as an apoptosis modulator in autoimmunity and rheumatic inflammation. In the present study, we investigated the potential role of Gal-9 as a biomarker in patients with rheumatoid arthritis (RA), especially as an indicator of functional limitations and radiographic joint damage. Methods: A total of 146 patients with RA and 52 age- and sex-matched healthy controls were included in this study. Clinical data including disease activity, physical function, and radiographic joint damage were assessed. Functional limitation was defined as the Stanford Health Assessment Questionnaire (HAQ) disability index >1. Subjects with joint erosion >0 or joint space narrowing >0 were considered to have radiographic joint damage. Serum Gal-9 levels were detected by an enzyme-linked immunosorbent assay. Univariate and multivariate logistic regression analysis were used to evaluate the association between Gal-9 and high disease activity and functional limitations, and a prediction model was established to construct predictive nomograms. Results: Serum levels of Gal-9 were significantly increased in patients with RA compared to those in healthy controls (median 13.1 ng/mL vs. 7.6 ng/mL). Patients with RA who were older (>65 years), had a longer disease duration (>5 years), longer morning stiffness (>60mins), elevated serum erythrocyte sedimentation rate and C-reactive protein, and difficult-to-treat RA had significantly higher Gal-9 levels than those in the corresponding control subgroups (all p <0.05). Patients with RA were divided into two subgroups according to the cut-off value of Gal-9 of 11.6 ng/mL. Patients with RA with Gal-9 >11.6 ng/mL had a significantly higher core clinical disease activity index, HAQ scores, Sharp/van der Heijde modified Sharp scores, as well as a higher percentage of advanced joint damage (all p<0.05) than patients with Gal-9 ≤11.6 ng/mL. Accordingly, patients with RA presenting either functional limitations or radiographic joint damage had significantly higher serum Gal-9 levels than those without (both p <0.05). Furthermore, multivariate logistic regression analysis showed that a serum level of Gal-9 >11.6 ng/mL was an independent risk factor for high disease activity (OR=3.138, 95% CI 1.150-8.567, p=0.026) and presence of functional limitations (OR=2.455, 95% CI 1.017-5.926, p=0.046), respectively. Conclusion: Gal-9 could be considered as a potential indicator in patients with RA, especially with respect to functional limitations and joint damage.
Subject(s)
Arthritis, Rheumatoid , Biomarkers , Galectins , Humans , Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/diagnostic imaging , Galectins/blood , Female , Male , Middle Aged , Biomarkers/blood , Aged , Adult , Severity of Illness Index , Case-Control Studies , Joints/diagnostic imaging , Joints/pathologyABSTRACT
Purpose: To investigate the predictive factors of pathologic complete response (pCR) in locally advanced rectal cancer (LARC) patients who had been treated with neoadjuvant chemoradiation (nCRT). Methods and materials: For this retrospective study, 53 LARC patients (37 males and 16 females; age range 25 to 79 years) were selected. Clinical characteristics, baseline mrTNM staging, MR gross tumor volumes (GTV), and pCR were evaluated. The diagnostic accuracy of GTV for predicting pCR was calculated. Results: Among 53 LARC patients, 15 patients achieved pCR (28.3%), while 38 patients achieved non-pCR. Only three (5.7%) out of 53 patients did not downstage after nCRT. GTV and tumor differentiation were the significant prognostic parameters for predicting pCR. A tumor volume threshold of 21.1 cm3 was determined as a predictor for pCR, with a sensitivity of 84% and specificity of 47%. In addition, GTV was associated with mrN stage, circumferential resection margin (CRM) status, extramural vascular invasion (EMVI) status, and pretreatment serum CEA level. Conclusion: Tumor volume and tumor differentiation have significant predictive values in preoperative assessment of pCR among LARC patients. These findings aid clinicians to discriminate those patients who may likely benefit from preoperative regimens and to make optimal treatment plans.
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Objective: This systematic review and meta-analysis aimed to evaluate the relationship between the prognostic nutritional index (PNI) and intravenous immunoglobulin (IVIG) resistance and coronary artery lesion (CAL) in Kawasaki disease (KD). Methods: The relevant literature was searched on PubMed, Embase, Cochrane Library, Web of Science, and Google Scholar up to August 5, 2023. A pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under curve (AUC) were calculated to assess the predicted values of PNI in KD patients with IVIG resistance and CAL. Results: A total of 8 articles containing 10 studies involving 7,047 participants were included. The pooled results revealed a pooled sensitivity of 0.44 (0.25-0.65), a pooled specificity of 0.87 (0.73-0.94), a pooled PLR of 3.4 (2.0-5.9), a pooled NLR of 0.65 (0.48-0.87), a pooled DOR of 5.26 (2.76-10.02), and a pooled AUC of 0.75 (0.71-0.78) in the diagnosis of KD with CAL. The pooled results suggested that a pooled sensitivity was 0.69 (0.60-0.77), specificity was 0.76 (0.69-0.82), PLR was 2.9 (2.1-4.1), NLR was 0.40 (0.29-0.56), DOR was 7.27 (3.89-13.59), and AUC was 0.79 (0.75-0.82) in the diagnosis of KD with IVIG resistance. The combined results revealed the pooled sensitivity was 0.63 (0.58-0.67), specificity was 0.82 (0.80-0.83), PLR was 3.09 (1.06-8.98), NLR was 0.38 (0.07-2.02), DOR was 8.23 (0.81-83.16) in differentiating KD from febrile patients. These findings demonstrated low sensitivity and relatively high specificity of PNI for KD, KD-CAL, and IVIG-resistant KD. Conclusion: In conclusion, this study was the first systematic review and meta-analysis of the diagnostic value of PNI in KD with IVIG resistance and CAL. The results suggested that PNI could be used as biomarkers for distinguish KD, KD with CAL, and KD with IVIG resistance.
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Effective therapeutics is much needed for amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease mainly affecting motor neurons. By screening chemical compounds in human patient-derived and aging-relevant motor neurons, we identify a neuroprotective compound and show that MAP4Ks may serve as therapeutic targets for treating ALS. The lead compound broadly improves survival and function of motor neurons directly converted from human ALS patients. Mechanistically, it works as an inhibitor of MAP4Ks, regulates the MAP4Ks-HDAC6-TUBA4A-RANGAP1 pathway, and normalizes subcellular distribution of RANGAP1 and TDP-43. Finally, in an ALS mouse model we show that inhibiting MAP4Ks preserves motor neurons and significantly extends animal lifespan.
Subject(s)
Amyotrophic Lateral Sclerosis , Neurodegenerative Diseases , Mice , Animals , Adult , Humans , Amyotrophic Lateral Sclerosis/drug therapy , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/metabolism , Neurodegenerative Diseases/metabolism , Motor Neurons/metabolism , Aging , Disease Models, Animal , Mice, TransgenicABSTRACT
A Cu/Pd-cocatalyzed 1,5-boroacylation of cyclopropyl-substituted ACPs with B2pin2 and acid chlorides has been developed. Using cyclopropyl-substituted ACPs as the starting material, a broad range of 1,5-boroacylated products with multiple functional groups was prepared in good yields with excellent regio- and stereoselectively. Both aromatic and aliphatic acid chlorides were tolerated in this reaction.
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Whether peripheral immunity prospectively influences brain health remains controversial. This study aims to investigate the longitudinal associations between peripheral immunity markers with incident brain disorders. A total of 161,968 eligible participants from the UK Biobank were included. We investigated the linear and non-linear effects of peripheral immunity markers including differential leukocytes counts, their derived ratios and C-reactive protein (CRP) on the risk of dementia, Parkinson's disease (PD), stroke, schizophrenia, bipolar affective disorder (BPAD), major depressive disorder (MDD) and anxiety, using Cox proportional hazard models and restricted cubic spline models. Linear regression models were used to explore potential mechanisms driven by brain structures. During a median follow-up of 9.66 years, 16,241 participants developed brain disorders. Individuals with elevated innate immunity markers including neutrophils, monocytes, platelets, neutrophil-to-lymphocyte ratio (NLR), and systemic immune-inflammation index (SII) had an increased risk of brain disorders. Among these markers, neutrophils exhibited the most significant correlation with risk of dementia (hazard ratio 1.08, 95% confidence interval 1.04-1.12), stroke (HR 1.06, 95% CI 1.03-1.09), MDD (HR 1.13, 95% CI 1.10-1.16) and anxiety (HR 1.07, 95% CI 1.04-1.10). Subgroup analysis revealed age-specific and sex-specific associations between innate immunity markers with risk of dementia and MDD. Neuroimaging analysis highlighted the associations between peripheral immunity markers and alterations in multiple cortical, subcortical regions and white matter tracts, typically implicated in dementia and psychiatric disorders. These findings support the hypothesis that neuroinflammation is important to the etiology of various brain disorders, offering new insights into their potential therapeutic approaches.
Subject(s)
Dementia , Depressive Disorder, Major , Stroke , Male , Female , Humans , Depressive Disorder, Major/epidemiology , Prospective Studies , Brain/diagnostic imaging , BiomarkersABSTRACT
BACKGROUND: Recent genetic research identified a protective factor against late-onset Alzheimer's disease (AD) in Caucasians, a variant called rs3747742-C in the TREML2 gene. However, the roles of other TREML2 variants in AD have not been fully explored. OBJECTIVE: We conducted a focused analysis of 16 TREML2 variants, examining their connection to AD by studying their correlation with cerebrospinal fluid (CSF) proteins, neuroimage, and cognition in the Alzheimer's Disease Neuroimaging Initiative database (ADNI). METHODS: A multiple linear regression model was utilized to estimate potential associations between TREML2 genotypes and various endophenotypes in the entire ADNI sample at baseline, with age, gender, years of education, and APOE É4 status included as covariates. To examine changes in clinical outcomes over time, linear mixed-effects models were employed. RESULTS: We found that the SNP rs17328707-A was associated with higher ADNI-VS scores, smaller ventricles, and larger middle temporal volume at baseline. The SNP rs6915083-G was linked to lower CSF t-tau and p-tau levels, and higher CSF Aß levels. The SNP rs9394766-G was associated with a smaller hippocampus and larger ventricles at baseline. In longitudinal cohorts, the rs6915083-G SNP was associated with changes in ADNI-MEM and ADNI-EF scores, as well as the rate of hippocampal and middle temporal atrophy. CONCLUSION: Our findings reveal that TREML2 gene variants have different effects on AD. Two variants are protective, while one may be a risk factor. This enhances our understanding of AD genetics and could guide future research and personalized treatments.
Subject(s)
Alzheimer Disease , Humans , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/genetics , Alzheimer Disease/cerebrospinal fluid , Cognition , Biomarkers/cerebrospinal fluid , Neuroimaging , Genotype , Amyloid beta-Peptides/cerebrospinal fluid , tau Proteins/genetics , tau Proteins/cerebrospinal fluid , Receptors, Immunologic/geneticsABSTRACT
BACKGROUND: In recent years, many studies have focused on the relationship between noncoding RNAs (ncRNAs) and Kawasaki disease (KD). Studies have indicated that ncRNAs are associated with the occurrence and development of KD. Thus, we performed a systematic review and meta-analysis to investigate the diagnostic value of ncRNAs in KD patients. METHODS: We searched the PubMed, Web of Science, Embase and Cochrane Library, China National Knowledge Infrastructure, VIP, China Biology Medicine disc databases, and Wanfang databases until August 25, 2023 and screened all eligible studies focusing on the diagnostic performance of ncRNAs in KD patients. RESULTS: In total, 535 articles were found, and 28 articles were included in this systematic review and meta-analysis. The calculated area under the curve value was 0.880 (95% confidence intervals, 0.840-0.900). The pooled sensitivity, specificity, positive likelihood ratio and negative likelihood ratio were 0.790, 0.830, 4.610, and 0.260, respectively. The pooled diagnostic odds ratio was 17.890 (95% confidence intervals, 13.110-24.420), indicating a relatively good diagnostic performance of the ncRNAs for detecting KD. In addition, the diagnostic value of micro RNAs in KD was better than that of long noncoding RNAs and circular noncoding RNAs. A subgroup analysis by specimen indicated a better diagnostic value of ncRNAs in plasma and platelet than serum. The diagnostic accuracy of ncRNAs was better in febrile controls than in healthy control groups, indicating a relatively good accuracy in distinguishing KD patients from febrile diseases. CONCLUSIONS: This systematic review and meta-analysis demonstrated that ncRNAs could be used as novel biomarkers for detecting KD. More studies should be conducted in the future to verify the diagnostic values of ncRNAs in KD.
Subject(s)
MicroRNAs , Mucocutaneous Lymph Node Syndrome , Humans , Mucocutaneous Lymph Node Syndrome/diagnosis , Mucocutaneous Lymph Node Syndrome/genetics , Sensitivity and Specificity , Biomarkers , RNA, CircularABSTRACT
MicroRNA-29a (miR-29a) is a well characterized fibro-inflammatory molecule and its aberrant expression is linked to a variety of pathological liver conditions. The long-term effects of a high-fat diet (HFD) in combination with different levels of EtOH consumption on miR-29a expression and liver pathobiology are unknown. Mice at 8 weeks of age were divided into five groups (calorie-matched diet plus water (CMD) as a control group, HFD plus water (HFD) as a liver disease group, HFD plus 2% EtOH (HFD + 2% E), HFD + 10% E, and HFD + 20% E as intervention groups) and fed for 4, 13, 26, or 39 weeks. At each time point, analyses were performed for liver weight/body weight (BW) ratio, AST/ALT ratio, as well as liver histology assessments, which included inflammation, estimated fat deposition, lipid area, and fibrosis. Hepatic miR-29a was measured and correlations with phenotypic traits were determined. Four-week feeding produced no differences between the groups on all collected phenotypic traits or miR-29a expression, while significant effects were observed after 13 weeks, with EtOH concentration-specific induction of miR-29a. A turning point for most of the collected traits was apparent at 26 weeks, and miR-29a was significantly down-regulated with increasing liver injury. Overall, miR-29a up-regulation was associated with a lower liver/BW ratio, fat deposition, inflammation, and fibrosis, suggesting a protective role of miR-29a against liver disease progression. A HFD plus increasing concentrations of EtOH produces progressive adverse effects on the liver, with no evidence of beneficial effects of low-dose EtOH consumption. Moreover, miR-29a up-regulation is associated with less severe liver injury.
Subject(s)
MicroRNAs , Non-alcoholic Fatty Liver Disease , Mice , Animals , Diet, High-Fat/adverse effects , Liver/metabolism , Ethanol/toxicity , Ethanol/metabolism , Non-alcoholic Fatty Liver Disease/metabolism , Liver Cirrhosis/metabolism , Inflammation/metabolism , MicroRNAs/metabolism , Water/metabolism , Mice, Inbred C57BLABSTRACT
Objective: It is a challenge to differentiate multiple system atrophy parkinsonism (MSA-P), Parkinson's disease (PD), and progressive supranuclear palsy (PSP). We aimed to explore the value of external anal-sphincter electromyography (EAS-EMG) and urethral-sphincter electromyography (US-EMG) in differential diagnosis with MSA-P, PD, and PSP. Methods: A total of 149 subjects, including 27 MSA-P, 100 PD, and 22 PSP, were recruited. The average duration and amplitude of motor unit potentials (MUPs), percentage of polyphasic MUPs, amplitude during strong contraction, and recruitment pattern during maximal voluntary contraction were recorded. The differences in EAS-EMG and US-EMG results between MSA-P, PD, and PSP were analyzed. Results: In EAS-EMG examination, the average duration of MUPs of MSA-P was significantly longer than that of PD and PSP; the percentage of polyphasic MUPs and the ratio of simple phase and simple-mix phase of MSA-P and PSP were significantly higher than that of PD; the amplitude during strong contraction of MSA-P was significantly lower than that of PD. In US-EMG examination, the average duration of MUPs in male MSA-P was significantly longer than that in male PD and PSP; the ratio of simple phase and simple-mix phase in male MSA-P was significantly higher than that in male PD; there was no statistical difference in US-EMG indexes between male PD and PSP male. And because only one female PSP was examined, only female MSA-P and PD were compared, the average duration of MUPs in female MSA-P was significantly longer than that in female PD; the ratio of simple phase and simple-mix phase in female MSA-P was significantly higher than that in female PD. Conclusion: The average duration of MUPs and the ratio of the simple phase and simple-mix phase of EAS-EMG and US-EMG all can provide the basis for the differential diagnosis between MSA-P and PD. US-EMG can be used as a supplement to differentiate MSA-P from PD when EAS-EMG is limited. The only discriminating indicator between MSA-P and PSP seems to be the average duration of MUPs of EAS-EMG and US-EMG. There is still a lack of diagnostic electromyography indicators between PD and PSP.
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Aim: To investigate the potential microbiome profile of a mouse model with heart failure (HF) during dapagliflozin treatment. Method: An HF model was constructed in 8-week-old male mice, and cardiac tissues were analyzed using histological staining. Hemodynamic indexes were measured, and fecal samples were collected for 16S rDNA sequencing. Chao1, Shannon, and Simpson were used for α-diversity analysis. b-Diversity analysis was conducted using principal coordinate analysis (PCoA) and non-metric multidimensional scaling (NMDS) based on the Bray-Curtis distance. Linear discriminant analysis coupled with effect size measurements (LEfSe) was used to identify signature gut microbiota, and phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) was used to predict the function of altered gut microbiota. Result: Dapagliflozin treatment reduced inflammation, infarction area, and cardiac fibrosis in HF mice. It also increased endothelial-dependent dilation and inflammation in mice with HF. Dapagliflozin decreased the ratio of Firmicutes/Bacteroidetes, which was increased in HF mice. There was no significant statistical difference in α-diversity among the control, HF, and HF+dapagliflozin groups. Desulfovibrio, AF12, and Paraprevotella were enriched in HF+dapagliflozin, while Rikenella and Mucispirillum were enriched in HF based on LEfSe. KEGG analysis revealed that altered gut microbiota was associated with fermentation, amino acid biosynthesis, nucleoside and nucleotide biosynthesis/degradation, fatty acid and lipid biosynthesis, carbohydrate biosynthesis/degradation, and cofactor/prosthetic group/electron carrier/vitamin biosynthesis. Conclusion: Understanding the microbiome profile helps elucidate the mechanism of dapagliflozin for HF. The signature genera identified in this study could be used as a convenient method to distinguish between HF patients and healthy individuals.
Subject(s)
Gastrointestinal Microbiome , Heart Failure , Vascular Diseases , Male , Animals , Mice , Gastrointestinal Microbiome/genetics , Phylogeny , Heart Failure/drug therapy , Bacteroidetes , InflammationABSTRACT
The C-X-C motif ligand 16, or CXCL16, is a chemokine that belongs to the ELR - CXC subfamily. Its function is to bind to the chemokine receptor CXCR6, which is a G protein-coupled receptor with 7 transmembrane domains. The CXCR6/CXCL16 axis has been linked to the development of numerous autoimmune diseases and is connected to clinical parameters that reflect disease severity, activity, and prognosis in conditions such as multiple sclerosis, autoimmune hepatitis, rheumatoid arthritis, Crohn's disease, and psoriasis. CXCL16 is expressed in various immune cells, such as dendritic cells, monocytes, macrophages, and B cells. During autoimmune diseases, CXCL16 can facilitate the adhesion of immune cells like monocytes, T cells, NKT cells, and others to endothelial cells and dendritic cells. Additionally, sCXCL16 can regulate the migration of CXCR6-expressing leukocytes, which includes CD8+ T cells, CD4+ T cells, NK cells, constant natural killer T cells, plasma cells, and monocytes. Further investigation is required to comprehend the intricate interactions between chemokines and the pathogenesis of autoimmune diseases. It remains to be seen whether the CXCR6/CXCL16 axis represents a new target for the treatment of these conditions.
Subject(s)
Autoimmune Diseases , Chemokines, CXC , Humans , Receptors, Scavenger , CD8-Positive T-Lymphocytes , Endothelial Cells , Receptors, CXCR6 , Receptors, Virus , Chemokine CXCL16ABSTRACT
AIMS: Complex cellular communications between glial cells and neurons are critical for brain normal function and disorders, and single-cell level RNA-sequencing datasets display more advantages for analyzing cell communications. Therefore, it is necessary to systematically explore brain cell communications when considering factors such as sex and brain region. METHODS: We extracted a total of 1,039,459 cells derived from 28 brain single-cell RNA-sequencing (scRNA-seq) or single-nucleus RNA-sequencing (snRNA-seq) datasets from the GEO database, including 12 human and 16 mouse datasets. These datasets were further divided into 71 new sub-datasets when considering disease, sex, and region conditions. In the meanwhile, we integrated four methods to evaluate ligand-receptor interaction score among six major brain cell types (microglia, neuron, astrocyte, oligodendrocyte, OPC, and endothelial cell). RESULTS: For Alzheimer's disease (AD), disease-specific ligand-receptor pairs when compared with normal sub-datasets, such as SEMA4A-NRP1, were identified. Furthermore, we explored the sex- and region-specific cell communications and identified that WNT5A-ROR1 among microglia cells displayed close communications in male, and SPP1-ITGAV displayed close communications in the meninges region from microglia to neurons. Furthermore, based on the AD-specific cell communications, we constructed a model for AD early prediction and confirmed the predictive performance using multiple independent datasets. Finally, we developed an online platform for researchers to explore brain condition-specific cell communications. CONCLUSION: This research provided a comprehensive study to explore brain cell communications, which could reveal novel biological mechanisms involved in normal brain function and neurodegenerative diseases such as AD.
Subject(s)
Alzheimer Disease , Neurodegenerative Diseases , Semaphorins , Male , Humans , Animals , Mice , RNA, Small Nuclear , Gene Expression Profiling/methods , Ligands , Single-Cell Gene Expression Analysis , Alzheimer Disease/genetics , Solitary NucleusABSTRACT
Oral intake of 1,4-naphthoquinones could be a potential risk factor for hyperuricemia and gout via activation of xanthine oxidase (XO). Herein, 1,4-naphthoquinones derived from food and food-borne pollutants were selected to investigate the structure and activity relationship (SAR) and the relative mechanism for activating XO in liver S9 fractions from humans (HLS9) and rats (RLS9). The SAR analysis showed that introduction of electron-donating substituents on the benzene ring or electron-withdrawing substituents on the quinone ring improved the XO-activating effect of 1,4-naphthoquinones. Different activation potential and kinetics behaviors were observed for activating XO by 1,4-naphthoquinones in HLS9/RLS9. Molecular docking simulation and density functional theory calculations showed a good correlation between -LogEC50 and docking free energy or HOMO-LUMO energy gap. The risk of exposure to the 1,4-naphthoquinones was evaluated and discussed. Our findings are helpful to guide diet management in clinic and avoid adverse events attributable to exposure to food-derived 1,4-naphthoquinones.
Subject(s)
Enzyme Inhibitors , Naphthoquinones , Humans , Rats , Animals , Enzyme Inhibitors/chemistry , Molecular Docking Simulation , Xanthine Oxidase/chemistry , Risk Assessment , DietABSTRACT
OBJECTIVE: To observe the effect of transcutaneous electrical acupoint stimulation (TEAS) on the histomorphological manifestations of hippocampal CA1 region and the expression of extracellular regulatory protein kinase (ERK), cyclic adenosine response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in chronic fatigue syndrome (CFS) rats, so as to explore the mechanisms of TEAS in improving the learning and memory abilities of CFS rats. METHODS: Forty male Wistar rats were randomly divided into normal group (10 rats) and modeling group (30 rats); then after modeling, they were selected and randomly divided into model group (10 rats) and TEAS group (10 rats). CFS rats model was prepared by sleep deprivation combined with weight-bearing swimming. Rats in the TEAS group were stimulated with Han's acupoint nerve stimulator at bilateral "Zusanli" (ST36) and "Shenshu" (BL23) (2 Hz/15 Hz, 1-2 mA), 20 min each time, once a day for 4 weeks with 1 d rest every 6 d. The score of general conditions of rats was evaluated. The learning and memory ability was tested with Morris water maze. The morphology and ultrastructure of hippocampal CA1 region were observed by HE staining and transmission electron microscopy. The expression levels of ERK, CREB and BDNF mRNAs and proteins in hippocampus were detected by real time quantitative PCR and Western blot, respectively. RESULTS: Compared with the normal group, the score of general condition was increased (P<0.01); the escape latency was prolonged (P<0.05, P<0.01) and the times of crossing the original platform was decreased (P<0.05); the expression levels of ERK, CREB and BDNF mRNAs and proteins in hippocampus were decreased (P<0.05, P<0.01) in the model group. Compared with the model group, the scores of general condition on the 42nd and 49th day were decreased (P<0.05, P<0.01); the escape latency was shortened (P<0.01, P<0.05)and the times of crossing the original platform were increased (P<0.05); the expression levels of ERK, CREB and BDNF mRNAs and proteins in hippocampus were increased (P<0.01, P<0.05) in the TEAS group. The morphology of neurons in hippocampal CA1 region was normal in the normal group. In the model group, the number of neurons in hippocampal CA1 region decreased, the arrangement of nerve cells was scattered, the number of apoptotic cells increased, some nuclear structures disappeared, nuclear heterochromatin increased, the cell membrane wrinkled, the chromatin appeared empty bright area, and the crista was incomplete. Compared with the model group, the nerve cells morphology in hippocampal CA1 region was more regular, the number of apoptotic cells decreased, the chromatin and the cytoplasm were uniformly distributed, and the crista was relatively intact in the TEAS group. CONCLUSION: TEAS can improve the learning and memory ability of CFS rats, the mechanisms may be related to improving the neural structure of hippocampal CA1 region and up-regulating the expression levels of ERK/CREB/BDNF.
Subject(s)
Electroacupuncture , Fatigue Syndrome, Chronic , Rats , Male , Animals , Brain-Derived Neurotrophic Factor/genetics , Fatigue Syndrome, Chronic/genetics , Fatigue Syndrome, Chronic/therapy , Rats, Sprague-Dawley , Acupuncture Points , Rats, Wistar , Hippocampus , ChromatinABSTRACT
Effective therapeutics is much needed for amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease mainly affecting motor neurons. By screening chemical compounds in human patient-derived and aging-relevant motor neurons, we identify a neuroprotective compound and show that MAP4Ks may serve as therapeutic targets for treating ALS. The lead compound broadly improves survival and function of motor neurons directly converted from human ALS patients. Mechanistically, it works as an inhibitor of MAP4Ks, regulates the MAP4Ks-HDAC6-TUBA4A-RANGAP1 pathway, and normalizes subcellular distribution of RANGAP1 and TDP-43. Finally, in an ALS mouse model we show that inhibiting MAP4Ks preserves motor neurons and significantly extends animal lifespan.
ABSTRACT
OBJECTIVES: To determine whether sTREM2 is changed during the pathogenesis of PD and reflect motor decline in PD individuals. METHODS: The cerebrospinal fluid (CSF) from PD and healthy individuals were obtained to measure the expression of sTREM2 and further to evaluate the motor function at baseline and after four years of follow-up using the Parkinson's Progression Markers Initiative (PPMI) database. The relationship between motor disease progression at baseline and longitudinal CSF sTREM2 was evaluated by linear mixed-effects (LME) and multiple linear regression (MLR) models. The change rates of the motor symptoms and sTREM2 level in CSF were further rigorously analyzed using the LME model. Cox proportional-hazards regression models were used to evaluate the predictive values of sTREM2 in CSF for motor progression. The regulatory role of CSF α-syn and Tau between sTREM2 and motor assessments was evaluated by Mediating effect analysis. RESULTS: We found no significant difference in CSF sTREM2 levels between the PD and HC groups (p = 0.155). However, late-onset PD patients had higher CSF sTREM2 levels than early-onset PD patients (p = 0.044). The basal levels of sTREM2 could predict motor progression over the four years of follow-up. The change rate of CSF sTREM2 was correlated with the progressive deterioration of motor function in PD individuals. Our observations also showed that CSF Tau was a significant mediator of the association between CSF sTREM2 and total UPDRS scores and UPDRS III and tremor at baseline with 26.5% and 33.5%, and 28.7% mediation, respectively. CONCLUSION: Our results indicated that CSF sTREM2 was associated with the prognosis of PD motor symptoms. Besides, CSF Tau could effectively mediate the association of sTREM2 with motor progression.
Subject(s)
Parkinson Disease , Humans , Parkinson Disease/complications , Amyloid beta-Peptides/cerebrospinal fluid , tau Proteins/cerebrospinal fluid , Tremor , Biomarkers/cerebrospinal fluid , Disease Progression , Membrane Glycoproteins , Receptors, ImmunologicABSTRACT
Immunotherapy has greatly changed the status of cancer treatment, and many patients do not respond or develop acquired resistance. The related research is blocked by lacking of comprehensive resources for researchers to discovery and analysis signatures, then further exploring the mechanisms. Here, we first offered a benchmarking dataset of experimentally supported signatures of cancer immunotherapy by manually curated from published literature works and provided an overview. We then developed CiTSA ( http://bio-bigdata.hrbmu.edu.cn/CiTSA/ ) which stores 878 entries of experimentally supported associations between 412 signatures such as genes, cells, and immunotherapy across 30 cancer types. CiTSA also provides flexible online tools to identify and visualize molecular/cell feature and interaction, to perform function, correlation, and survival analysis, and to execute cell clustering, cluster activity, and cell-cell communication analysis based on single cell and bulk datasets of cancer immunotherapy. In summary, we provided an overview of experimentally supported cancer immunotherapy signatures and developed CiTSA which is a comprehensive and high-quality resource and is helpful for understanding the mechanism of cancer immunity and immunotherapy, developing novel therapeutic targets and promoting precision immunotherapy for cancer.
Subject(s)
Neoplasms , Single-Cell Gene Expression Analysis , Humans , Neoplasms/genetics , Neoplasms/therapy , ImmunotherapyABSTRACT
Objective: Anti-Ro60 and anti-Ro52 antibodies are associated with different connective tissue diseases (CTDs). However, the clinical significance of anti-Ro antibodies is not always consistent among different global regions. The aim of this study was to investigate the clinical characteristics of patients with anti-Ro antibodies. Methods: A total of 1596 inpatients with anti-Ro antibodies were included in the study. Demographic, clinical, and serological data were compared between individuals with different profiles of anti-Ro antibodies: patients with anti-Ro52 antibodies alone, patients with anti-Ro60 antibodies alone, and patients with combined anti-Ro52 and anti-Ro60 antibodies. Results: Of the 1596 patients, 1362 (85.3%) were female, the mean age was 45.5 years, and systemic lupus erythematosus (SLE) (46.0%) and Sjogren's syndrome (SS) (19.0%) were the most common CTD diagnoses. Among the patients with anti-Ro52 antibodies alone, idiopathic inflammatory myopathy (18.8%) and SLE (17.6%) were the most common CTD diagnoses. The coexistent autoantibodies of this group were significantly lower compared with those of the other two groups, while the presence of anti-Jo1 antibodies were significantly higher compared with those of the other two groups (3.7% vs. 0.6% vs. 1.9%, p = 0.029). In addition, the patients with isolated anti-Ro52 antibodies were more likely to suffer from interstitial lung disease (35.5% vs. 11.3% vs. 13.7%, p < 10-4) and pulmonary arterial hypertension (10.1% vs. 5.3% vs. 3.6%, p = 0.001) compared with the other two groups of patients. Compared with patients with isolated anti-Ro52 or anti-Ro60 antibodies, the patients with combined anti-Ro52 and anti-Ro60 antibodies were more likely to suffer from xerophthalmia and xerostomia. Furthermore, hypocomplementemia, hyperglobulinemia, and proteinuria were particularly prevalent in patients with anti-Ro60 antibodies. Conclusion: Different profiles of anti-Ro antibodies were significantly associated with clinical phenotypic features in CTDs, indicating the potential diagnostic and prognostic value of these antibodies in clinical practice.