bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fecal microbiota transplantation and replenishment of short-chain fatty acids protect against chronic cerebral hypoperfusion-induced colonic dysfunction by regulating gut microbiota, differentiation of Th17 cells, and mitochondrial energy metabolism
Authors: Su Shao-Hua , Wu Yi-Fang , Lin Qi , Zhang Lin , Wang Da-Peng , Hai Jian 
Published: December 2022

Abstract
Background
Little is known about the association between gut microbiota and intestinal injury under a state of chronic cerebral hypoperfusion (CCH). Here, the effects of gut microbiota and short-chain fatty acids (SCFAs), as important metabolic products, on intestinal function and potential mechanisms after CCH were investigated.

Methods
Rats were subjected to bilateral common carotid artery occlusion (BCCAo) to induce CCH. The gut microbiota and metabolites of SCFAs were assessed by 16S rRNA sequencing and targeted metabolomics, respectively. Transcriptomic analysis of colon tissues was also conducted. Subsequently, potential molecular pathways and differentially expressed genes were verified by western blot, immunoprecipitation, and immunofluorescence analyses. Furthermore, the integrity of the colonic barrier was evaluated by hematoxylin and eosin and mucin 2 staining and expression levels of tight junction proteins. Besides, colonic inflammation was further assessed by flow cytometry and expression levels of inflammatory cytokines. In addition, colonic mitochondrial dysfunction was analyzed via membrane potential, reactive oxygen species, electron transport chain (ETC) activities, adenosine triphosphate content, and mitochondrial ultrastructure.

Results
CCH modified gut microbial composition and microbial metabolism of SCFAs, which may be associated with inhibition of mitochondrial ETC activities and oxidative phosphorylation, leading to dysregulation of mitochondrial energy metabolism. Furthermore, CCH induced differentiation of pathogenic Th17 cells, promoted the formation of complexes of interferon regulatory factor 4 and signal transducer and activator of transcription 3 (STAT3), and increased the phosphorylation of STAT3. This was associated with an impairment of colonic barrier function and chronic colonic inflammation. In contrast, FMT and SCFA replenishment ameliorated CCH-induced gut microbial dysbiosis by increasing the intestinal content of Ruminococcus_sp_N15_MGS_57 and modulating microbial metabolism of SCFAs by increasing acetic acid contents associated with an improvment of the balance between Tregs and Th17 cells, mitochondrial ETC activities, and oxidative phosphorylation to prevent colonic inflammation and dysregulation of mitochondrial energy metabolism.

Conclusion
These findings indicate that FMT and SCFA replenishment present a promising therapeutic strategy against colonic dysfunction under a state of chronic cerebral ischemia.
Exosomes derived from miR-338-3p-modified adipose stem cells inhibited inflammation injury of chondrocytes via targeting RUNX2 in osteoarthritis
Authors: Li ChunLiang , Li Wei , Pu GengZang , Wu JingWen , Qin Feng 
Published: December 2022

Abstract
Background
Osteoarthritis (OA) is a chronic degenerative disease that is one of the main causes of disability in middle-aged and elderly people. Adipose stem cell (ASC)-derived exosomes (ASC-Exo) could repair cartilage damage and treat OA. MiRNA-338-3p expression was confirmed to play a role in inhibiting proinflammatory cytokines. Herein, we aimed to explore the mechanism by which exosomes derived from miR-338-3p overexpressing ASCs protects chondrocytes from interleukin (IL)-1β-induced chondrocyte change.

Methods
Exosomes were extracted from ASCs transfected with miR-338-3p or its antisense inhibitor. The ASC-Exos (miR-338-3p silencing/overexpression) were incubated with IL-1β-induced ATDC5 cells, followed by evaluation of the chondrocyte proliferation, degradation, and inflammation injury.

Results
In vitro results revealed that ASC-Exos inhibited the expression of prostaglandin E2 (PGE2), IL-6, IL-1β, and TNF-α, as well as promoted the proliferation of ATDC5 cells. Moreover, ASC-Exos inhibited inflammation injury and degradation of ATDC5 cells by transferring miR-338-3p. Luciferase reporter assays showed that RUNX2 was a target gene of miR-338-3p. Additionally, RUNX2 overexpression in ATDC5 cells reversed the protective effect of miR-338-3p on chondrocytes. Taken together, this study demonstrated that exosomes secreted from miR-338-3p-modified ASCs were effective in the repair of IL-1β-induced chondrocyte change by inhibiting RUNX2 expression.

Conclusions
Our result provided valuable data for understanding the mechanism of ASC-Exos in OA treatment.

Graphical abstract
Divergent impacts on the gut microbiome and host metabolism induced by traditional Chinese Medicine with Cold or Hot properties in mice
Authors: Li Bingbing , Tao Xin , Sheng Lili , Li Yan , Zheng Ningning , Li Houkai 
Published: December 2022

Abstract
Background
Traditional Chinese Medicine (TCM) has been practiced and developed in China over thousands of years under the guidance of a series of complicated traditional theories. Herbs within TCM usually are classified according to their different properties ranging from cold, cool, warm to hot, which are simplified as Cold and Hot properties. TCM with either Cold or Hot properties are used in various formulae designed for the purpose of restoring the balance of patients. Emerging evidence has highlighted that an altered gut microbiota or host metabolism are critically involved in affecting the healing properties of TCM. However, at present the exact influences and crosstalk on the gut microbiota and host metabolism remain poorly understood.

Methods
In the present study, the divergent impacts of six TCMs with either Cold or Hot properties on gut microbiome and host metabolism during short- or long-term intervention in mice were investigated. Six typical TCMs with Hot or Cold properties including Cinnamomi Cortex (rougui, RG), Zingiberis Rhizoma (ganjiang, GJ), Aconiti Lateralis Radix Praeparata (fuzi, FZ), Rhei Radix et Rhizoma (dahuang, DH), Scutellariae Radix (huangqin, HQ), and Copitdis Rhizoma (huanglian, HL) were selected and orally administered to male C57BL/6J mice for a short- or a long-term (7 or 35 days). At the end of experiments, serum and cecal contents were collected for metabolomic and gut microbiome analyses using gas chromatography–tandem mass spectrometry (GC–MS) or 16S ribosomal deoxyribonucleic acid (16S rDNA) sequencing.

Results
The results revealed that the gut microbiome underwent divergent changes both in its composition and functions after short-term intervention with TCM possessing either Cold or Hot properties. Interestingly, the number of changed genus and bacteria pathways was reduced in Hot_LT, but was increased in Cold_LT, especially in the HL group. Increased α diversity and a reduced F/B ratio revealed the changes in Hot_ST, but a reduced Shannon index and increased altered bacteria function was evident in Cold_LT. The serum metabolic profile showed that the influence of TCM on host metabolism was gradually reduced over time. Glycolipid metabolism related pathways were specifically regulated by Hot_ST, but also surprisingly by Cold_LT. Reduced lactic acid in Cold_ST, increased tryptophan concentrations and decreased proline and threonine concentrations in Cold_LT perhaps highlighting the difference between the two natures influence on serum metabolism. These metabolites were closely correlated with altered gut microbiota shown by further correlation analyses.

Conclusion
The results indicated that TCM properties could be, at least partially characterized by an alteration in the gut microbiota and metabolic profile, implying that the divergent responses of gut microbiome and host metabolism are involved in different responses to TCM.

Graphic Abstract
Early neurodevelopmental outcomes in children with asymptomatic congenital CMV infection
Authors: Novelli Maria , Natale Fabio , Di Norcia Anna , Boiani Arianna , Temofonte Sara , Calandriello Francesca , Zitarelli Cristina , Caravale Barbara 
Published: December 2022

Abstract
Background
Approximately 85–90% of congenital cytomegalovirus infections (cCMV) are asymptomatic. Few studies have investigated early and long-term neurodevelopmental outcomes in children with asymptomatic cCMV (acCMV), and the data is contradictory. In the present study, we did investigate the effect of cCMV asymptomatic infection on neurological outcomes and in cognitive, language and motor development at 6 months of age.

Methods
Fifty-six children with cCMV asymptomatic infection were followed for 6 months, as part of a long-term surveillance program, examining their neurological and developmental outcomes. Neurological examination and Bayley-III Scales were performed.

Results
Clinical evaluation revealed that early neurological outcomes were essentially normal, with minor neurological deficits (i.e., tone abnormalities) in a subgroup of patients. Bayley-III scores were substantially in the normal range, with 14% showing a score less than 85 (-1SD) in the Motor Scale. Children's neurological and neurodevelopmental outcomes at 6 months of age did not differ according to the trimester of infection.

Conclusions
Some infants with cCMV asymptomatic infection may present minor neurological abnormalities in early stages of life. It seems useful to monitor this population for early and late neurodevelopmental sequelae.
StudyMe: a new mobile app for user-centric N-of-1 trials
Authors: Zenner Alexander M. , Böttinger Erwin , Konigorski Stefan 
Published: December 2022

AbstractN-of-1 trials are multi-crossover self-experiments that allow individuals to systematically evaluate the effect of interventions on their personal health goals. Although several tools for N-of-1 trials exist, there is a gap in supporting non-experts in conducting their own user-centric trials. In this study, we present StudyMe, an open-source mobile application that is freely available from https://play.google.com/store/apps/details?id=health.studyu.me and offers users flexibility and guidance in configuring every component of their trials. We also present research that informed the development of StudyMe, focusing on trial creation. Through an initial survey with 272 participants, we learned that individuals are interested in a variety of personal health aspects and have unique ideas on how to improve them. In an iterative, user-centered development process with intermediate user tests, we developed StudyMe that features an educational part to communicate N-of-1 trial concepts. A final empirical evaluation of StudyMe showed that all participants were able to create their own trials successfully using StudyMe and the app achieved a very good usability rating. Our findings suggest that StudyMe provides a significant step towards enabling individuals to apply a systematic science-oriented approach to personalize health-related interventions and behavior modifications in their everyday lives.
A combined miRNA–piRNA signature in the serum and urine of rabbits infected with Toxoplasma gondii oocysts
Authors: Xie Shi-Chen , Zhou Chun-Xue , Zhai Bin-Tao , Zheng Wen-Bin , Liu Guo-Hua , Zhu Xing-Quan 
Published: December 2022

AbstractBackgroundIncreasing evidence has shown that non-coding RNA (ncRNA) molecules play fundamental roles in cells, and many are stable in body fluids as circulating RNAs. Study on these ncRNAs will provide insights into toxoplasmosis pathophysiology and/or help reveal diagnostic biomarkers.MethodsWe performed a high-throughput RNA-Seq study to comprehensively profile the microRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs) in rabbit serum and urine after infection withToxoplasma gondiioocysts during the whole infection process.ResultsTotal RNA extracted from serum and urine samples of acutely infected [8 days post-infection (DPI)], chronically infected (70 DPI) and uninfected rabbits were subjected to genome-wide small RNA sequencing. We identified 2089 miRNAs and 2224 novel piRNAs from the rabbit sera associated withT. gondiiinfection. Meanwhile, a total of 518 miRNAs and 4182 novel piRNAs were identified in the rabbit urine associated withT. gondiiinfection. Of these identified small ncRNAs, 1178 and 1317 serum miRNAs and 311 and 294 urine miRNAs were identified as differentially expressed (DE) miRNAs in the acute and chronic stages of infections, respectively. A total of 1748 and 1814 serum piRNAs and 597 and 708 urine piRNAs were found in the acute and chronic infection stages, respectively. Of these dysregulated ncRNAs, a total of 88 common DE miRNAs and 120 DE novel piRNAs were found in both serum and urine samples of infected rabbits.ConclusionsThese findings provide valuable data for revealing the physiology of herbivore toxoplasmosis caused by oocyst infection. Circulating ncRNAs identified in this study are potential novel diagnostic biomarkers for the detection/diagnosis of toxoplasmosis in herbivorous animals.Graphical Abstract
Association of glucagon-like peptide-1 receptor agonists with cardiac arrhythmias in patients with type 2 diabetes or obesity: a systematic review and meta-analysis of randomized controlled trials
Authors: Wu Sijin , Lu Wenzhao , Chen Zhongli , Dai Yan , Chen Keping , Zhang Shu 
Published: December 2022

Abstract
Background
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been highly recommended for glycemic control and weight reduction. However, evidence has accumulated that GLP-1 RAs treatment is related to an increase in heart rate, which could potentially induce cardiac arrhythmias. This study aims to investigate the association of GLP-1 RAs therapy with incident arrhythmias in diabetic and obese patients.

Methods
MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov were systematically searched from inception up to May 25, 2022. Randomized controlled trials (RCTs) comparing GLP-1 RAs with placebo or active control for adults with type 2 diabetes or obesity were included. The outcomes of interest were prespecified as incident atrial fibrillation (AF), atrial flutter (AFL), ventricular arrhythmias (VAs), and sudden cardiac death (SCD). Mantel-Haenszel relative risk (MH-RR) with a corresponding 95% confidence interval (95% CI) was estimated using a fixed-effects model.

Results
A total of 56 RCTs involving 79,720 participants (44,028 GLP-1 RAs vs 35,692 control: mean age 57.3 years) were included from 7692 citations. GLP-1 RAs use overall did not significantly increase the risk of AF (RR 0.97, 95% CI 0.83–1.12), AFL (RR 0.83, 95% CI 0.59–1.17), VAs (RR 1.24, 95% CI 0.92–1.67), and SCD (RR 0.89, 95% CI 0.67–1.19), compared with controls. In further subgroup analyses, we observed an increasing trend toward incident AF with dulaglutide (RR 1.40, 95% CI 1.03–1.90) while an inverse trend with oral semaglutide (RR 0.43, 95% CI 0.21–0.87). Additionally, higher doses of GLP-1 RAs (RR 1.63, 95% CI 1.11–2.40) and higher baseline BMI (RR 1.60, 95% CI 1.04–2.48) might significantly increase the risk of VAs. No significant differences were identified in other subgroup analyses.

Conclusions
GLP-1 RAs therapy was not associated with an overall higher risk of arrhythmias, demonstrating an assuring cardiovascular safety profile. Further studies are required to determine whether the potential antiarrhythmic or arrhythmogenic effect of GLP-1 RAs is drug-specific and varies from doses or baseline BMI.
Trial registration: PROSPERO Identifier: CRD42022339389.
Genome-wide distribution of histone trimethylation reveals a global impact of bisphenol A on telomeric binding proteins and histone acetyltransferase factors: a pilot study with human and in vitro data
Authors: D’Cruz Shereen Cynthia , Hao Chunxiang , Labussiere Martin , Mustieles Vicente , Freire Carmen , Legoff Louis , Magnaghi-Jaulin Laura , Olivas-Martinez Alicia , Rodriguez-Carrillo Andrea , Jaulin Christian , David Arthur , Fernandez Mariana F. , Smagulova Fatima 
Published: December 2022

AbstractObjectiveTo assess the genetic and epigenetic effects promoted by Bisphenol A (BPA) exposure in adolescent males from the Spanish INMA-Granada birth cohort, and in human cells.MethodsDNA methylation was analysed using MEDIP. Repeat number variation in genomic DNA was evaluated, along with the analysis of H3K4me3 by using chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq). Analyses were performed with material extracted from whole blood of the adolescents, complemented by in vitro assessments of human (HeLa) cells exposed to 10 nM BPA, specifically, immunofluorescence evaluation of protein levels, gene expression analysis and ChIP‒qPCR analysis.ResultsAdolescents in the high urinary BPA levels group presented a higher level of Satellite A (SATA) repetitive region copy numbers compared to those in the low BPA group and a tendency towards increase in telomere length. We also observed decreased DNA methylation at the promoters of the imprinted genesH19, KCNQ1,andIGF2; atLINE1retroelements; and at theARID2, EGFRandESRRAandTERTgenes. Genome-wide sequencing revealed increased H3K4me3 occupancy at the promoters of genes encoding histone acetyltransferases, telomeric DNA binding factors and DNA repair genes. Results were supported in HeLa cells exposed to 10 nM BPA in vitro. In accordance with the data obtained in blood samples, we observed higher H3K4me3 occupancy and lower DNA methylation at some specific targets in HeLa cells. In exposed cells, changes in the expression of genes encoding DNA repair factors (ATM, ARID2, TRP53) were observed, and increased expression of several genes encoding telomeric DNA binding factors (SMG7, TERT, TEN1, UPF1, ZBTB48) were also found. Furthermore, an increase in ESR1/ERa was observed in the nuclei of HeLa cells along with increased binding of ESR1 toKAT5, KMT2EandTERF2IPpromoters and decreased ESR1 binding at theRARApromoter. The DNA damage marker p53/TP53 was also increased.ConclusionIn this pilot study, genome-wide analysis of histone trimethylation in adolescent males exposed to BPA revealed a global impact on the expression of genes encoding telomeric binding proteins and histone acetyltransferase factors with similar results in HeLa cells. Nevertheless, larger studies should confirm our findings.
BDNF exon IV promoter methylation and antidepressant action: a complex interplay
Authors: Pathak Hansi , Borchert Anton , Garaali Sara , Burkert Alexandra , Frieling Helge 
Published: December 2022

Abstract
Background
BDNF exon IV promoter methylation is a potential biomarker for treatment response to antidepressants in MDD. We have previously shown CpG-87 methylation as a successful biomarker for the prediction of non-response to monoaminergic antidepressants like the SSRI Fluoxetine or the SNRI Venlafaxine. This study aimed to dissect the biological evidence and mechanisms for the functionality of CpG-87 methylation in a cell culture model.

Results
We observed a significant interaction between methylation and antidepressant-mediated transcriptional activity in BDNF exon IV promoter. In addition, antidepressant treatment increased the promoter methylation in a concentration-dependent manner. Further single CpG methylation of -87 did not change the promoter activity, but methylation of CREB domain CpG-39 increased the transcriptional activity in an antidepressant-dependent manner. Interestingly, DNMT3a overexpression also increases the BDNF exon IV transcription and more so in Venlafaxine-treated cells.

Conclusions
The study strengthens the previously reported association between antidepressant treatment and BDNF exon IV promoter methylation as well as hints toward the mechanism of action. We argue that potential CpG methylation biomarkers display a complex synergy with the molecular changes at the neighboring CpG positions, thus highlighting the importance of epiallele analyses.
ApoJ/Clusterin concentrations are determinants of cerebrospinal fluid cholesterol efflux capacity and reduced levels are associated with Alzheimer’s disease
Authors: Ko Yi-An , Billheimer Jeffrey T. , Lyssenko Nicholas N. , Kueider-Paisley Alexandra , Wolk David A. , Arnold Steven E. , Leung Yuk Yee , Shaw Leslie M. , Trojanowski John Q. , Kaddurah-Daouk Rima F. , Kling Mitchel A. , Rader Daniel J. 
Published: December 2022

Abstract
Background
Alzheimer’s disease (AD) shares risk factors with cardiovascular disease (CVD) and dysregulated cholesterol metabolism is a mechanism common to both diseases. Cholesterol efflux capacity (CEC) is an ex vivo metric of plasma high-density lipoprotein (HDL) function and inversely predicts incident CVD independently of other risk factors. Cholesterol pools in the central nervous system (CNS) are largely separate from those in blood, and CNS cholesterol excess may promote neurodegeneration. CEC of cerebrospinal fluid (CSF) may be a useful measure of CNS cholesterol trafficking. We hypothesized that subjects with AD and mild cognitive impairment (MCI) would have reduced CSF CEC compared with Cognitively Normal (CN) and that CSF apolipoproteins apoA-I, apoJ, and apoE might have associations with CSF CEC.

Methods
We retrieved CSF and same-day ethylenediaminetetraacetic acid (EDTA) plasma from 108 subjects (40 AD; 18 MCI; and 50 CN) from the Center for Neurodegenerative Disease Research biobank at the Perelman School of Medicine, University of Pennsylvania. For CSF CEC assays, we used N9 mouse microglial cells and SH-SY5Y human neuroblastoma cells, and the corresponding plasma assay used J774 cells. Cells were labeled with [3H]-cholesterol for 24 h, had ABCA1 expression upregulated for 6 h, were exposed to 33 μl of CSF, and then were incubated for 2.5 h. CEC was quantified as percent [3H]-cholesterol counts in medium of total counts medium+cells, normalized to a pool sample. ApoA-I, ApoJ, ApoE, and cholesterol were also measured in CSF.

Results
We found that CSF CEC was significantly lower in MCI compared with controls and was poorly correlated with plasma CEC. CSF levels of ApoJ/Clusterin were also significantly lower in MCI and were significantly associated with CSF CEC. While CSF ApoA-I was also associated with CSF CEC, CSF ApoE had no association with CSF CEC. CSF CEC is significantly and positively associated with CSF Aβ. Taken together, ApoJ/Clusterin may be an important determinant of CSF CEC, which in turn could mitigate risk of MCI and AD risk by promoting cellular efflux of cholesterol or other lipids. In contrast, CSF ApoE does not appear to play a role in determining CSF CEC.