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Purpose: Cumulating evidence supports the close association between periodontal diseases, neuroinflammation and neurodegenerative pathologies, except for peri-implantitis (PI). Thus, this study explored the association between experimental PI and neuropathological changes in the rat brain. Materials and methods: After bilateral first molars extraction, experimental PI was induced at titanium implants placed in the maxillae by lipopolysaccharide injections and ligature placement. Following 28-weeks of disease progression, the maxillae and brains were retrieved from 6 rats. Healthy brains from 3 rats were used as control. Brains were analyzed by immunohistochemistry to detect signs of neuroinflammation (interleukin (IL)-6 and tumor necrosis factor (TNF)-α)), microglial activation (IBA-1) and astrogliosis (GFAP). To explore signs of neurodegeneration, hematoxylin/eosin and Nissl stainings were used. Also, four different antibodies against amyloid beta (Aβ 1–42) were tested. Results: Chronic PI lesions showed peri-implant bone resorption accompanied by large inflammatory infiltrates. IL-6+ and TNF-α+ cells were found within the CA1 and Dentate Gyrus regions of the hippocampus of the PI-affected group, while almost no immune-positivity was detected in the control (p < 0.05). Detection of activated GFAP+ microglia and IBA-1+ astrocytes surface were significantly higher at the CA areas, and cerebral cortex of the PI-affected group, in comparison with control (p < 0.05). Shrunk neurons with pyknotic nuclei were inconsistently found among the PI-affected group, and these were almost not detected in control. No positive Aβ reactivity was detected in any of the samples. Conclusion: Chronic experimental PI lesions led to an increased detection of IL-6 and TNF-α, GFAP+ microgliosis and IBA-1+ astrocytosis, and in some cases, neurodegeneration, in the rat brain. [ABSTRACT FROM AUTHOR]

Background: Chronic migraine is closely related to the dysregulation of neurochemical substances in the brain, with metabolic imbalance being one of the proposed causes of chronic migraine. This study aims to evaluate the metabolic changes between energy metabolism and excitatory and inhibitory neurotransmitters in key brain regions of mice with chronic migraine-like state and to uncover the dysfunctional pathways of migraine. Methods: A chronic migraine-like state mouse model was established by repeated administration of nitroglycerin (NTG). We used von Frey filaments to assess the mechanical thresholds of the hind paw and periorbital in wild-type and familial hemiplegic migraine type 2 mice. After the experiments, tissue was collected from five brain regions: the somatosensory cortex (SSP), hippocampus, thalamus (TH), hypothalamus, and the spinal trigeminal nucleus caudalis (TNC). Proton magnetic resonance spectroscopy (1H-MRS) was employed to study the changes in brain metabolites associated with migraine, aiming to explore the mechanisms underlying metabolic imbalance in chronic migraine-like state. Results: In NTG-induced chronic migraine-like state model, we observed a significant reduction in energy metabolism during central sensitization, an increase in excitatory neurotransmitters such as glutamate, and a tendency for inhibitory neurotransmitters like GABA to decrease. The TNC and thalamus were the most affected regions. Furthermore, the consistency of N-acetylaspartate levels highlighted the importance of the TNC-TH-SSP pathway in the ascending nociceptive transmission of migraine. Conclusion: Abnormal energy metabolism and neurotransmitter imbalance in the brain region of NTG-induced chronic migraine-like state model are crucial mechanisms contributing to the chronicity of migraine. [ABSTRACT FROM AUTHOR]

Background: Chronic alcohol users often exhibit an increased minimum alveolar concentration (MAC) of sevoflurane, yet the specific mechanism remains unclear. It has been reported that ethanol exposure can upregulate the protein expression and enzyme activity of cytochrome P450 2E1 (CYP2E1). CYP2E1 is a key enzyme that converts 2–5% of sevoflurane into equimolar amounts of hexafluoroisopropanol (HFIP) and F−. This study aims to explore whether ethanol exposure could alter sevoflurane metabolism through CYP2E1 modulation, potentially explaining the increased MAC observed in alcohol users. Methods: Eighty adult male Sprague-Dawley (SD) rats were randomly divided into two groups and received either 50% ethanol (dose: 3 g/kg) or 0.9% saline twice daily by gavage. After 1, 2, 3, and 4 weeks of gavage, ten rats were randomly selected from each group to undergo 1-hour anesthesia with 2.3% sevoflurane. Blood samples were collected after anesthesia to measure the concentration of free HFIP using gas chromatography. Additionally, the left lobe tissue of the liver was collected for the analysis of CYP2E1 protein expression by Western blot and CYP2E1 enzyme activity by colorimetric assay. Correlations between these parameters were analyzed using Pearson's correlation. Results: In the ethanol group, CYP2E1 expression, activity, and the concentration of free HFIP were significantly higher at all time points compared to the control group (P < 0.05), except for protein expression in the first week (P > 0.05). Within-group comparisons indicated no significant changes in any of the parameters for the control group (P > 0.05). In the ethanol group, there was no difference in free HFIP concentration between the first and second weeks (P > 0.05), but a significant increase was observed in the third and fourth weeks (P < 0.01); protein expression and enzyme activity significantly varied over time, especially showing a notable increase from the first to the third and fourth weeks (P < 0.05). Correlation analysis revealed strong positive correlations between free HFIP concentration and CYP2E1 activity (r = 0.7898), free HFIP concentration and CYP2E1 expression (r = 0.8418), and CYP2E1 activity and expression (r = 0.8740), all with P < 0.001. Conclusions: Ethanol exposure increased both the expression and enzymatic activity of CYP2E1, consequently enhancing the metabolism of sevoflurane. [ABSTRACT FROM AUTHOR]

Objective: In the face of the ongoing circulation of SARS‐CoV‐2, the durability of neutralization post–COVID‐19 vaccination in immune‐mediated inflammatory disease (IMID) is a key issue, as are the effects of medications. Methods: Adults (n = 112) with inflammatory bowel disease, psoriasis/psoriatic arthritis, rheumatoid arthritis, spondylarthritis, and systemic lupus were recruited from participating Canadian medical centers from 2021 to 2023. We focused on log‐transformed neutralization (lentivirus methods) as a continuous outcome, with separate models for wild‐type and Omicron strains BA.1 and BA.5. Results: Compared with 30 to 120 days postvaccination, subsequent periods were associated with greater neutralization in unadjusted models for wild‐type, BA.1, and BA.5 strains and against the BA.1 strain in adjusted models. Rituximab was associated with lower neutralization for the BA.1 strain in adjusted models, with a similar trend for BA.5. In methotrexate users, there were trends for less neutralization of BA.1 and BA.5 in all unadjusted models, whereas in adjusted models, there was significantly lower neutralization only for the wild type. Three or more doses and Omicron‐specific vaccines were both independently associated with better neutralization ability for all three strains. A COVID‐19 infection within six months before sampling was associated with higher neutralization of wild type and BA.1 in adjusted analyses. Anti–tumor necrosis factor agents were associated with lower neutralization ability for BA.5 in adjusted analyses. Conclusion: Neutralization responses in immunosuppressed individuals with IMID were durable over time and were augmented by more than three doses and Omicron‐specific vaccines. Less neutralization was seen with certain medications. Our work clarifies the joint effects of vaccine history, infection, and medications on COVID‐19 immunity. [ABSTRACT FROM AUTHOR]

BI 187004, a selective small‐molecule inhibitor of 11β‐hydroxysteroid dehydrogenase‐1 (11β‐HSD1), displayed complex nonlinear pharmacokinetics (PK) in humans. Following nine single oral doses, BI 187004 exhibited nonlinear PK at low doses and linear PK at higher doses. Notably, substantial hepatic 11β‐HSD1 inhibition (50%) was detected in a very low‐dose group, achieving a consistent 70% hepatic enzyme inhibition in subsequent ascending doses without any dose‐dependent effects. The unusual PK and PD profiles of BI 187004 suggest the presence of pharmacological target‐mediated drug disposition (TMDD), arising from the saturable binding of BI 187004 compound to its high‐affinity and low‐capacity target 11β‐HSD1. The non‐intuitive dose, exposure, and response relationship for BI 187004 pose a significant challenge in rational dose selection. This study aimed to construct a TMDD model to explain the complex nonlinear PK behavior and underscore the importance of recognizing TMDD in this small‐molecule compound. Among the various models explored, the best model was a two‐compartment TMDD model with three transit absorption components. The final model provides insights into 11β‐HSD1 binding‐related parameters for BI 187004, including the total amount of 11β‐HSD1 in the liver (estimated to be 8000 nmol), the second order association rate constant (estimated to be 0.102 nM−1h−1), and the first‐order dissociation rate constant (estimated to be 0.11 h−1). Our final population PK model successfully characterized the intricate nonlinear PK of BI 187004 across a wide dose range. This modeling work serves as a valuable reference for the rational selection of the dose regimens for BI 187004's future clinical trials. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common fatal neurodegenerative disease among the elderly worldwide, characterized by memory and cognitive impairment. The identification of biomarkers for AD is crucial and urgent to facilitate the diagnosis and intervention. The aim of this study was to evaluate the diagnostic value of acyl-Coenzyme A thioesterase 7 (ACOT7) as a serum biomarker for the prediction of AD. In our study, we observed a significant increase in ACOT7 expression in patients (n = 366) with AD and animal (n = 8-12) models of AD, compared to the control group. A significant negative correlation was found between ACOT7 levels and Mini-Mental State Examination (MMSE) scores (r = -0.85; p < 0.001). The analysis of the receiver operating characteristic curve (ROC) showed that the area under the curve (AUC) for ACOT7 was 0.83 (95% confidence intervals: 0.80-0.86). The optimal cut-off point of 62.5 pg./mL was selected with the highest sum of sensitivity and specificity. The diagnostic accuracy of serum ACOT7 for AD was 77% (95% confidence intervals: 72-82%), with a sensitivity of 80% (95% confidence intervals: 75-84%) and a specificity of 74% (95% confidence intervals: 69-79%). Moreover, the ROC analysis showed that the AUC of Aβ42/40 ratio is 0.70, and the diagnostic accuracy was 72%, with 69% sensitivity and 76% specificity. Compared with the AD traditional marker Aβ42/40 ratio, ACOT7 shows better superiority as a new serum candidate biomarker of AD. By suppressing the ACOT7 gene, our study provides evidence of the involvement of ACOT7 in the metabolism of amyloid precursor protein (APP), resulting in alterations in the expression levels of Aβ42, BACE1 and βCTF. ACOT7 has the ability to modulate the amyloidogenic pathway of APP metabolism, while it does not have an impact on the non-amyloidogenic pathway. In conclusion, the findings of our study suggest that serum ACOT7 may serve as a promising and non-invasive biomarker for AD. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus (T2DM) is a prevalent chronic disease often accompanied by low-grade inflammation. Recently, the neutrophil-to-lymphocyte ratio (NLR) has garnered researchers' interest as an emerging inflammation biomarker. This study aimed to comprehensively explore the relationship between NLR and T2DM using the National Health and Nutrition Examination Survey (NHANES) database. Method: We employed a cross-sectional study design to analyze data from five NHANES cycles from 2007 to 2016, excluding individuals with incomplete data. This study utilized a weighted logistic regression model, subgroup analyses, and restricted cubic spline (RCS) analysis to assess the potential relationship between NLR and T2DM. Results: A total of 9903 participants were eligible for the analysis, of which 1280 were diagnosed with T2DM. The T2DM group exhibited significantly higher NLR levels than the non-T2DM group. After adjusting for potential confounders, elevated NLR levels were associated with an increased risk of developing T2DM, indicated by an odds ratio (OR) of 1.14, 95% CI: (1.05,1.24), P = 0.003. The results of the subgroup analyses revealed a significant interaction effect between NLR and T2DM concerning race and hypertension (P for interaction < 0.05). In contrast, no significant interactions were found for age, sex, education level, body mass index (BMI), smoking status, recreational activities, and alcohol drinker (P for interaction > 0.05). RCS analysis showed a significant non-linear relationship between NLR and T2DM, with an inflection point at 2.27 (all P for non-linearity < 0.05). Conclusion: Our study indicates that an elevated neutrophil-to-lymphocyte ratio is associated with a higher risk of T2DM. [ABSTRACT FROM AUTHOR]

The importance of Se in human health has received much attention due to its antioxidant properties when it is consumed at an appropriate level. However, the existing evidence is limited to obtain an effective conclusion for colorectal cancer (CRC). Notably, an adequate intake of Se was reported for Koreans. Furthermore, cytokine secretion and immune function may be affected by dietary Se. Our study aimed to explore whether Se potentially reduces CRC risk and whether the IL10 rs1800871 polymorphism has an effect on this association. We designed a case–control study with 1420 cases and 2840 controls. A semi-quantitative FFQ was used to obtain information on Se intake. We determined IL10 rs1800871 through genetic analysis. Different models were developed to explore Se intake related to CRC risk by calculating OR and 95 % CI using unconditional logistic regression. A reduced risk of CRC was found as Se intake increased, with an OR (95 % CI) of 0·44 (0·35, 0·55) (P for trend < 0·001). However, this association seems to be allele-specific and only present among risk variant allele carriers (GA/GG) with a significant interaction between dietary Se and IL10 rs1800871 (P for interaction = 0·043). We emphasised that a reduction in CRC risk is associated with appropriate Se intake. However, the IL10 rs1800871 polymorphism has an impact on this reduction, with a greater effect on variant allele carriers. These findings suggest the importance of considering an individual's genetic characteristics when developing nutritional strategies for CRC prevention. [ABSTRACT FROM AUTHOR]

Background: Traditional Chinese medicine (TCM) has been found widespread application in neoplasm treatment, yielding promising therapeutic candidates. Previous studies have revealed the anti-cancer properties of Brevilin A, a naturally occurring sesquiterpene lactone derived from Centipeda minima (L.) A.Br. (C. minima), a TCM herb, specifically against lung cancer. However, the underlying mechanisms of its effects remain elusive. This study employs network pharmacology and experimental analyses to unravel the molecular mechanisms of Brevilin A in lung cancer. Methods: The Batman-TCM, Swiss Target Prediction, Pharmmapper, SuperPred, and BindingDB databases were screened to identify Brevilin A targets. Lung cancer-related targets were sourced from GEO, Genecards, OMIM, TTD, and Drugbank databases. Utilizing Cytoscape software, a protein-protein interaction (PPI) network was established. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene set enrichment analysis (GSEA), and gene-pathway correlation analysis were conducted using R software. To validate network pharmacology results, molecular docking, molecular dynamics simulations, and in vitro experiments were performed. Results: We identified 599 Brevilin A-associated targets and 3864 lung cancer-related targets, with 155 overlapping genes considered as candidate targets for Brevilin A against lung cancer. The PPI network highlighted STAT3, TNF, HIF1A, PTEN, ESR1, and MTOR as potential therapeutic targets. GO and KEGG analyses revealed 2893 enriched GO terms and 157 enriched KEGG pathways, including the PI3K-Akt signaling pathway, FoxO signaling pathway, and HIF-1 signaling pathway. GSEA demonstrated a close association between hub genes and lung cancer. Gene-pathway correlation analysis indicated significant associations between hub genes and the cellular response to hypoxia pathway. Molecular docking and dynamics simulations confirmed Brevilin A's interaction with PTEN and HIF1A, respectively. In vitro experiments demonstrated Brevilin A-induced dose- and time-dependent cell death in A549 cells. Notably, Brevilin A treatment significantly reduced HIF-1α mRNA expression while increasing PTEN mRNA levels. Conclusions: This study demonstrates that Brevilin A exerts anti-cancer effects in treating lung cancer through a multi-target and multi-pathway manner, with the HIF pathway potentially being involved. These results lay a theoretical foundation for the prospective clinical application of Brevilin A. [ABSTRACT FROM AUTHOR]

Background: Endoscopic submucosal dissection (ESD) requires high endoscopic technical skills, and trainees should develop effective training methods. In collaboration with KOTOBUKI Medical, we developed the G-Master, which is a non-animal training model that can simulate various parts of gastric ESD. We aimed to clarify the usefulness of the G-Master for inexperienced ESD trainees. Methods: We collected data from the first 5 gastric ESD cases conducted by 15 inexperienced ESD trainees at 5 participating centers between 2018 and 2022. The participants were divided into two groups: the G-Master training and non-G-Master training groups. Outcome measurements, such as procedural speed, perforation rate, self-completion rate, and en bloc resection rate, were compared between the two groups retrospectively. Results: A total of 75 gastric ESD cases were included in this study. The G-Master training group included 25 cases performed by 5 trainees, whereas the non-G-Master training group included 50 cases performed by 10 trainees. The median procedural speed for all cases was significantly faster in the G-Master training group than in the non-G-Master training group. Moreover, the procedural speed was linearly improved from the initial to the last cases in the lower location in the G-Master training group compared with the non-G-Master training group. In addition, although there was no significant difference, the G-Master training group showed lower rates of perforation and a lesser need to transition to expert operators than the non-G-Master training group. Conclusion: The G-Master could improve the ESD skills of inexperienced ESD trainees. [ABSTRACT FROM AUTHOR]

Background: Mandibular reconstruction patients often suffer abnormalities in the mandibular kinematics. In silico simulations, such as musculoskeletal modelling, can be used to predict post‐operative mandibular kinematics. It is important to validate the mandibular musculoskeletal model and analyse the factors influencing its accuracy. Objectives: To investigate the jaw opening‐closing movements after mandibular reconstruction, as predicted by the subject‐specific musculoskeletal model, and the factors influencing its accuracy. Methods: Ten mandibular reconstruction patients were enrolled in this study. Cone‐beam computed tomography images, mandibular movements, and surface electromyogram signals were recorded preoperatively. A subject‐specific mandibular musculoskeletal model was established to predict surgical outcomes using patient‐averaged muscle parameter changes as model inputs. Jaw bone geometry was replaced by surgical planning results, and the muscle insertion sites were registered based on the non‐rigid iterative closest point method. The predicted jaw kinematic data were validated based on 6‐month post‐operative measurements. Correlations between the prediction accuracy and patient characteristics (age, pathology and surgical scope) were further analysed. Results: The root mean square error (RMSE) for lower incisor displacement was 31.4%, and the error for peak magnitude of jaw opening was 4.9 mm. Age, post‐operative infection and radiotherapy influenced the prediction accuracy. The amount of masseter detachment showed little correlation with jaw opening. Conclusion: The mandibular musculoskeletal model successfully predicted short‐range jaw opening functions after mandibular reconstruction. It provides a novel surgical planning method to predict the risk of developing trismus. [ABSTRACT FROM AUTHOR]

Background Heterogeneity in ageing rates drives the need for research into lifestyle secrets of successful agers. Biological age, predicted by epigenetic clocks, has been shown to be a more reliable measure of ageing than chronological age. Dietary habits are known to affect the ageing process. However, much remains to be learnt about specific dietary habits that may directly affect the biological process of ageing. Objective To identify food groups that are directly related to biological ageing, using Copula Graphical Models. Methods We performed a preregistered analysis of 3,990 postmenopausal women from the Women's Health Initiative, based in North America. Biological age acceleration was calculated by the epigenetic clock PhenoAge using whole-blood DNA methylation. Copula Graphical Modelling, a powerful data-driven exploratory tool, was used to examine relations between food groups and biological ageing whilst adjusting for an extensive amount of confounders. Two food group–age acceleration networks were established: one based on the MyPyramid food grouping system and another based on item-level food group data. Results Intake of eggs, organ meat, sausages, cheese, legumes, starchy vegetables, added sugar and lunch meat was associated with biological age acceleration, whereas intake of peaches/nectarines/plums, poultry, nuts, discretionary oil and solid fat was associated with decelerated ageing. Conclusion We identified several associations between specific food groups and biological ageing. These findings pave the way for subsequent studies to ascertain causality and magnitude of these relationships, thereby improving the understanding of biological mechanisms underlying the interplay between food groups and biological ageing. [ABSTRACT FROM AUTHOR]

Background: Studies have reported that metabolic disturbance exhibits in patients with Alzheimer's disease (AD). Still, the presence of definitive evidence concerning the genetic effect of metabolites on AD risk remains insufficient. A systematic exploration of the genetic association between blood metabolites and AD would contribute to the identification of new targets for AD screening and prevention. Methods: We conducted an exploratory two-sample Mendelian randomization (MR) study aiming to preliminarily identify the potential metabolites involved in AD development. A genome-wide association study (GWAS) involving 7,824 participants provided information on 486 human blood metabolites. Outcome information was obtained from a large-scale GWAS meta-analysis of AD, encompassing 21,982 cases and 41,944 controls of Europeans. The primary twosample MR analysis utilized the inverse variance weighted (IVW) model while supplementary analyses used Weighted median (WM), MR Egger, Simple mode, and Weighted mode, followed by sensitivity analyses such as the heterogeneity test, horizontal pleiotropy test, and leave-one-out analysis. For the further identification of metabolites, replication and meta-analysis with FinnGen data, steiger test, linkage disequilibrium score regression, confounding analysis, and were conducted for further evaluation. Multivariable MR was performed to assess the direct effect of metabolites on AD. Besides, an extra replication analysis with EADB data was conducted for final evaluation of the most promising findings. Results: After rigorous genetic variant selection, IVW, complementary analysis, sensitivity analysis, replication and meta-analysis with the FinnGen data, five metabolites (epiandrosterone sulfate, X-12680, pyruvate, docosapentaenoate, and 1-stearoylglycerophosphocholine) were identified as being genetically associated with AD. MVMR analysis disclosed that genetically predicted these four known metabolites can directly influence AD independently of other metabolites. Only epiandrosterone sulfate and X-12680 remained suggestive significant associations with AD after replication analysis with the EADB data. Conclusion: By integrating genomics with metabonomics, this study furnishes evidence substantiating the genetic association of epiandrosterone sulfate and X-12680 with AD. These findings hold significance for the screening, prevention, and treatment strategies for AD. [ABSTRACT FROM AUTHOR]

Background: The development of an alcohol use disorder (AUD) involves impaired behavioral control and flexibility. Behavioral inflexibility includes an inability to shift behavior in response to changes in behavioral outcomes. Low levels of ethanol drinking may promote the formation of inflexible, habitual reward seeking, but this may depend on the timing of ethanol exposure in relation to learning. The goal of this study was to determine whether a history of low‐dose ethanol exposure promoted contingency‐insensitive sucrose seeking and altered behavioral strategy selection. Methods: Male and female C57BL/6J mice were trained to perform a response (lever press) for sucrose on two different reinforcement schedules: one that is thought to promote inflexible responding (random interval) and one that maintains flexible responding (variable ratio [VR]). Following instrumental training each day, mice were exposed to saline or low‐dose ethanol (0.5 g/kg; i.p.) either proximal (1 h after) or distal (4 h after) to learning. Mice were then tested for sensitivity to changes in contingency in a contingency degradation test. Results: A history of low‐dose ethanol exposure shifted behavioral strategy selection, as measured by reward tracking behavior, but this depended on sex and reinforcement schedule history. Both male and female mice used different strategies depending on the reinforcement schedule, but only males exhibited ethanol‐induced shifts in strategy selection. A history of low‐dose ethanol exposure did not impact contingency sensitivity in males but promoted insensitivity in females specifically on the VR lever. Conclusions: Female mice show distinct behavioral effects of repeated, low‐dose ethanol exposure as compared to males, with sex differences in the use of reward tracking strategies to guide behavior. Future studies should investigate sex differences in the neural consequences of chronic low‐dose ethanol exposure that may underlie behavioral changes. [ABSTRACT FROM AUTHOR]

Background: Repeated Ovum Pick Up (OPU) could have a detrimental effect on ovarian function, reducing In Vitro Embryo Production (IVEP). The present study examined the therapeutic effect of adipose--derived Mesenchymal Stem Cells (MSCs) or its Conditioned Medium (ConM) on ovarian trauma following repeated OPU. Resolvin E1 (RvE1) and Interleukin-12 (IL-12) were investigated as biomarkers. Methods: Jersey heifers (n=8) experienced 11 OPU sessions including 5 pre-treatment and 6 treatment sessions. Heifers received intra-ovarian administration of MSCs or ConM (right ovary) and Dulbecco's Modified Phosphate Buffer Saline (DMPBS; left ovary) after OPU in sessions 5 and 8 and 2 weeks after session 11. The concentrations of RvE1 and IL-12 in follicular fluid was evaluated on sessions 1, 5, 6, 9, and 4 weeks after session 11. Following each OPU session, the IVEP parameters were recorded. Results: Intra-ovarian administration of MSCs, ConM, and DMPBS did not affect IVEP parameters (p>0.05). The concentration of IL-12 in follicular fluid increased at the last session of pre-treatment (Session 5; p<0.05) and remained elevated throughout the treatment period. There was no correlation between IL-12 and IVEP parameters (p>0.05). However, RvE1 remained relatively high during the pre-treatment and decreased toward the end of treatment period (p<0.05). This in turn was associated with decline in some IVEP parameters (p<0.05). Conclusion: Intra-ovarian administration of MSCs or ConM during repeated OPU did not enhance IVEP outcomes in Bos taurus heifers. The positive association between RvE1 and some of IVEP parameters could nominate RvE1 as a promising biomarker to predict IVEP parameters following repeated OPU. [ABSTRACT FROM AUTHOR]

Quantitative genetics models have shown that long-term selection responses depend on initial variance and mutational influx. Understanding limits of selection requires quantifying the role of mutational variance. However, correlative responses to selection on nonfocal traits can perturb the selection response on the focal trait; and generations are often confounded with selection environments so that genotype by environment (G × E) interactions are ignored. The Saclay divergent selection experiments (DSEs) on maize flowering time were used to track the fate of individual mutations combining genotyping data and phenotyping data from yearly measurements (DSEYM) and common garden experiments (DSECG) with four objectives: (1) to quantify the relative contribution of standing and mutational variance to the selection response, (2) to estimate genotypic mutation effects, (3) to study the impact of G × E interactions in the selection response, and (4) to analyze how trait correlations modulate the exploration of the phenotypic space. We validated experimentally the expected enrichment of fixed beneficial mutations with an average effect of +0.278 and +0.299 days to flowering, depending on the genetic background. Fixation of unfavorable mutations reached up to 25% of incoming mutations, a genetic load possibly due to antagonistic pleiotropy, whereby mutations fixed in the selection environment (DSEYM) turned to be unfavorable in the evaluation environment (DSECG). Global patterns of trait correlations were conserved across genetic backgrounds but exhibited temporal patterns. Traits weakly or uncorrelated with flowering time triggered stochastic exploration of the phenotypic space, owing to microenvironment-specific fixation of standing variants and pleiotropic mutational input. [ABSTRACT FROM AUTHOR]

Objective: Snail family transcriptional repressor 2 (SNAI2) is a key regulator of partial epithelial‐mesenchymal transition (p‐EMT) and is associated with tumorigenesis. Whether SNAI2 promotes oral leukoplakia (OLK) malignant transformation by modulating p‐EMT is unclear. Materials and Methods: This study utilized two clinical datasets (GSE26549 and GSE85195) from the Gene Expression Omnibus database, cytological experiments, and a 4‐nitroquinoline 1‐oxide‐induced mice model to explore the role of SNAI2 in OLK malignant transformation. Results: The clinical cohort found SNAI2, as a risk factor (HR = 2.50, 95% CI: 1.08–5.79, p = 0.033), could promote OLK malignant transformation (p = 0.012). Cytological experiments indicated that SNAI2 overexpression promoted DOK cell proliferation, invasion, migration, and increase the protein expression of p‐EMT relative signatures, whereas SNAI2 silencing has opposite effects. Furthermore, the mice model and clinical datasets demonstrated the expression of SNAI2 and p‐EMT relative signatures were increased with OLK malignant transformation. And SNAI2 was strongly correlated with p‐EMT. Besides, co‐expressed genes of SNAI2 were also enriched in p‐EMT relative biological processes and signaling pathways. Conclusions: p‐EMT plays a significant role in promoting the OLK malignant transformation. As an important regulator of p‐EMT, SNAI2 could be a target to block the OLK malignant transformation. [ABSTRACT FROM AUTHOR]

Background: Combining pulsed field ablation (PFA) with ultra‐low temperature cryoablation (ULTC) represents a novel energy source which may create more transmural cardiac lesions. We sought to assess the feasibility of lesions created by combined cryoablation and pulsed field ablation (PFCA) versus PFA alone. Methods: Ablations were performed using a custom PFA generator, ULTC console, and an ablation catheter with insertable stylets. PFA was delivered in a biphasic, bipolar train. PFCA precooled the tissue for 30 s followed by a concurrent PFA train. Benchtop testing using Schlieren imaging and microbubble volume assessment were used to compare PFA and PFCA. PFA and PFCA lesions using pre‐optimized and optimized ablation protocols were studied in 6 swine. Pre and post‐ECGs were recorded for each ablation and a gross necropsy was performed at 14 days. Results: Consistent with benchtop comparisons of heat and microbubble generation, PFA deliveries in the animals were accompanied by muscle contractions and significant microbubbles (Grade 2–3) visible on intracardiac echo while neither occurred during PFCA at higher voltage levels. Both PFA and PFCA acutely eliminated or highly attenuated (>80%) local atrial electrograms. Histology of PFA and PFCA lesions indicated depth up to 6–7 mm and nearly all lesions were transmural. Optimized PFCA produced wider cavotricuspid isthmus lesions with evidence of tissue selectivity. Conclusion: A novel technology combining PFA and ULTC into one energy source demonstrated in‐vivo feasibility for PFCA ablation. PFCA had a more favorable thermal profile and did not produce muscle contraction or microbubbles while extending lesion depth beyond cryoablation. [ABSTRACT FROM AUTHOR]

This article examines video-recorded naturally occurring human–pet interactions during which the animal's gaze is treated by the human as a turn-allocation device. Gaze exchange has been extensively studied as the social phenomenon par excellence, especially by scientific paradigms interested in defining sociality as mutual orientation. Recently, studies in ethology have shown the relevance of doing sequential analyses of gaze exchanges in animal interactions, providing important information on the "monitoring function" of gaze. Less is known about the "regulatory function" (i.e., the effect of animal gaze on the sequential organization of action) in human–animal interspecies interactions. This article aims to fill this gap, by investigating the role of domestic dogs', cats', and horses' gazes on human conversation and courses of action. Findings demonstrate a systematic format: an animal-initiated gaze followed by a verbal turn of the human participant, which evidences the turn-allocational function of the animal's gaze on human participation. Data are in French. [ABSTRACT FROM AUTHOR]

Introduction: Proteolytic processing of amyloid protein precursor by b-site secretase enzyme (BACE1) is dependent on the cellular lipid composition and is affected by endomembrane trafficking in dementia and Alzheimer's disease (AD). Stearoyl-CoA desaturase 1 (SCD1) is responsible for the synthesis of fatty acid monounsaturation (MUFAs), whose accumulation is strongly associated with cognitive dysfunction. Methods: In this study, we analyzed the relationship between BACE1 and SCD1 in vivo and in vitro neurodegenerative models and their association in familial AD (FAD), sporadic AD (SAD), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) using microscopy, biochemical, and mass SPECT approach. Results: Our findings showed that BACE1 and SCD1 immunoreactivities were increased and colocalized in astrocytes of the hippocampus in a rat model of global cerebral ischemia (2-VO). A synergistic effect of double BACE1/SCD1 silencing on the recovery of motor and cognitive functions was obtained. This neuroprotective regulation involved the segregation of phospholipids (PLs) associated with polyunsaturated fatty acids in the hippocampus, cerebrospinal fluid, and serum. The double silencing in the sham and ischemic groups was stronger in the serum, inducing an inverse ratio between total phosphatydilcholine (PC) and lysophosphatidylcholine (LPC), representedmainly by the reduction of PC 38:4 and PC 36:4 and an increase in LPC 16:0 and LPC 18:0. Furthermore, PC 38:4 and PC:36:4 levels augmented in pathological conditions in in vitro AD models. BACE1 and SCD1 increases were confirmed in the hippocampus of FAD, SAD, and CADASIL. Conclusion: Therefore, the findings suggest a novel convergence of BACE-1 and SCD1 in neurodegeneration, related to pro-inflammatory phospholipids. [ABSTRACT FROM AUTHOR]

Background: Current evidence of the association between a single nucleotide polymorphism (SNP) in ADAMTS14 (rs4747096) and osteoarthritis (OA) is controversial. This study aimed to determine whether the ADAMTS14 SNP is closely related to OA risk. Methods: An electronic search of for the association between the rs4747096 polymorphisms and OA was performed using four online databases (updated on September 10, 2022). The association between susceptibility to OA and rs4747096 polymorphism was evaluated in four genetic models: the allele (mutation [A] vs. wild type [G]), additive (AA vs. GG and AG vs. GG), recessive (AA vs. AG + GG), and dominant (AA + AG vs. GG). This meta-analysis was performed in the R software, and effects were assessed using odds ratios (ORs) and 95% confidence intervals (CI). Results: Four studies (707 cases in the case group and 859 cases in the control group) were included. The results of the meta-analysis showed that, except in the recessive genetic model, there was a significant correlation between OA risk and the rs4747096 polymorphism using the allele (OR [95% CI] = 1.48 [1.26–1.73], P < 0.001), additive (AG vs. GG, OR [95% CI] = 2.56 [1.79–3.65], P < 0.001; AA vs. GG, OR [95% CI] = 2.81 [1.98–3.98], P < 0.001), and dominant (OR [95% CI)] = 1.72 [1.34–2.2], P < 0.001) genetic models. Conclusions: The ADAMTS14 rs4747096 polymorphism is associated with susceptibility to OA. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer is one of the most lethal human neoplasms, and its therapeutic repertoire remains limited. Advances in understanding the molecular complexity involved in the biology of the disease have paved the way for new therapeutic opportunities. AD80 is a multikinase inhibitor that inhibits S6K as well as RET, RAF, and SRC and displays antineoplastic effects in hematological and solid tumors. In the present study, we report the potential of AD80 as an antineoplastic agent for pancreatic cancer and the cellular and molecular changes induced by the drug. Significant advances in understanding the molecular complexity of the development and progression of pancreatic cancer have been made, but this disease is still considered one of the most lethal human cancers and needs new therapeutic options. In the present study, the antineoplastic effects of AD80, a multikinase inhibitor, were investigated in models of pancreatic cancer. AD80 reduced cell viability and clonogenicity and induced polyploidy in pancreatic cancer cells. At the molecular level, AD80 reduced RPS6 and histone H3 phosphorylation and induced γH2AX and PARP1 cleavage. Additionally, the drug markedly decreased AURKA phosphorylation and expression. In PANC-1 cells, AD80 strongly induced autophagic flux (consumption of LC3B and SQSTM1/p62). AD80 modulated 32 out of 84 autophagy-related genes and was associated with vacuole organization, macroautophagy, response to starvation, cellular response to nitrogen levels, and cellular response to extracellular stimulus. In 3D pancreatic cancer models, AD80 also effectively reduced growth independent of anchorage and cell viability. In summary, AD80 induces mitotic aberrations, DNA damage, autophagy, and apoptosis in pancreatic cancer cells. Our exploratory study establishes novel targets underlying the antineoplastic activity of the drug and provides insights into the development of therapeutic strategies for this disease. [ABSTRACT FROM AUTHOR]

The use of non-drug intervention for calcium deficiency has attracted attention in recent years. Although calcium carbonate is the preferred raw material for calcium supplementation, there are few reports on the mechanism of the combined action of chondroitin sulfate and calcium to alleviate osteoporosis from the perspective of gut microbiota and metabolomics. In this study, a rat model of osteoporosis was established by feeding a low-calcium diet. The intestinal microbiota abundance, fecal and plasma metabolite expression levels of rats fed a basal diet, a low-calcium diet, a low-calcium diet plus calcium carbonate, and a low-calcium diet plus chondroitin sulfate were compared. The results showed that compared with the low calcium group, the calcium content and bone mineral density of femur were significantly increased in the calcium carbonate and chondroitin sulfate groups. 16 S rRNA sequencing and metabolomics analysis showed that chondroitin sulfate intervention could reduce short-chain fatty acid synthesis of intestinal flora, slow down inflammatory response, inhibit osteoclast differentiation, promote calcium absorption and antioxidant mechanism, and alleviate osteoporosis in low-calcium feeding rats. Correlation analysis showed that the selected intestinal flora was significantly correlated with metabolites enriched in feces and plasma. This study provides scientific evidence of the potential impact of chondroitin sulfate as a dietary supplement for patients with osteoporosis. [ABSTRACT FROM AUTHOR]

Background. Asthma is a chronic inflammatory disease of the airways with recurrent attacks, which seriously affects the patients' quality of life and even threatens their lives. The disease can even threaten the lives of patients. Sijunzi decoction (SJZD), a classical Chinese medicine formula with a long history of administration, is a basic formula used for the treatment of asthma and demonstrates remarkable efficacy. However, the underlying mechanism has not been elucidated. Materials and Methods. We aimed to integrate network pharmacology and intestinal flora sequencing analysis to study the mechanism of SJZD in the treatment of allergic asthmatic mice. The active compounds of SJZD and their asthma-related targets were predicted by various databases. We performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses to identify potentially relevant pathways for target genes. Furthermore, the active compound-target and target-signaling pathway network maps were constructed by using Cytoscape 3.8.2. These results were combined with those of the intestinal flora sequencing analysis to study the influence of SJZD on airway inflammation in allergic asthmatic mice. Result. We obtained 137 active compounds from SJZD and associated them with 1445 asthma-related targets acquired from the databases. A total of 109 common targets were identified. We visualized active compound-target and target-signaling pathway network maps. The pathological analysis and inflammation score results suggested that SJZD could alleviate airway inflammation in asthmatic mice. Sequencing analysis of intestinal flora showed that SJZD could increase the relevant abundance of beneficial bacterial genus and maintain the balance of the intestinal flora. The core toll-like receptor (TLR) signaling pathway was identified based on network pharmacology analysis, and the important role TLRs play in intestinal flora and organismal immunity was also recognized. The analysis of the correlation between environmental factors and intestinal flora revealed that beneficial bacterial genera were negatively correlated with TLR2 and positively correlated with the TLR7 expression. Furthermore, they were positively correlated with IFN-γ and IL-10 levels and negatively correlated with IL-4 and IL-17 levels. Conclusion. SJZD alleviated the airway inflammation state in asthmatic mice. The findings suggest that increasing the relevant abundance of beneficial intestinal bacteria in mice with asthma, regulating intestinal flora, interfering with the level of TLR2 and TLR7 expression to adjust the secretion of inflammatory factors, and alleviating asthmatic airway inflammation may be the possible mechanism involved in the treatment of asthma by SJZD, providing a basis for further studies on SJZD. [ABSTRACT FROM AUTHOR]

Swertia Mussotti is used as febrifuge, analgesic and to treat calculous cholecystitis, however, the underling mechanism remains unclear. This study investigates the therapeutic effect of the active fraction named iridoid and xanthone glycoside (IXG) extracted from S. mussotii on six animal models related to calculous cholecystitis and its complications, and to explore its potential target proteins. Four main compounds including swertiamarin (STR), sweroside (SRS), gentiopicroside (GPS) and mangiferin (MGR) were identified from the IXG by UHPLC-TOF-MS. The in vivo experiments results confirmed that IXG significantly decreased the level of total bilirubin (TBIL), direct bilirubin (DBIL) and cyclooxygenase-2 (COX2) in calculous cholecystitis. IXG treatment dramatically reduced the number of twists and the time of clicking foot in 2nd phase induced by glacial acetic acid and formalin, however, no effect was showed on central pain established by hot plate test. IXG also significantly decreased the anal temperature induced by yeast and 2,4-dinitrophenol. These results indicated that IXG alleviate calculous cholecystitis and its clinical symptom. In addition, IXG suppressed the expression of Prostaglandin E2 (PGE2) in vitro. Mechanistically, COX2 was identified as the direct target of IXG in RAW264.7 cells, and downregulated the protein levels of COX2. The results confirmed that IXG ameliorates calculous cholecystitis and its clinical symptom (pain and fever) by suppressing the production of PGE2 through targeting COX2. [Display omitted] • IXG protects against the liver injury induced by calculous cholecystitis. • IXG inhibits peripheral pain induced by glacial acetic acid and formalin, respectively. • IXG inhibits inflammatory fever induced by yeast and non-inflammatory fever induced by 2,4-dinitrophenol. • IXG exerts analgesia and antipyretic effect by targeting COX2 to reduce the production of PGE2 in vitro. [ABSTRACT FROM AUTHOR]

Invigorating blood circulation to remove blood stasis is a primary strategy in TCM for treating vascular dementia (VaD). Danggui-Shaoyao San (DSS), as a traditional prescription for neuroprotective activity, has been proved to be effective in VaD treatment. However, its precise molecular mechanisms remain incompletely understood. The specific mechanism underlying the therapeutic effects of DSS on VaD was explored by employing network pharmacology as well as in vivo and in viro experiment validation. We downloaded components of DSS from the BATMAN-TCM database for target prediction. The intersection between the components of DSS and targets, PPI network, as well as GO and KEGG enrichment analysis were then performed. Subsequently, the potential mechanism of DSS predicted by network pharmacology was assessed and validated through VaD rat model induced by 2VO operation and CoCl 2 -treated PC12 cells. Briefly, the DSS extract were first quantified by HPLC. Secondly, the effect of DSS on VaD was studied using MWM test, HE staining and TUNEL assay. Finally, the molecular mechanism of DSS against VaD was validated by Western blot and RT-QPCR experiments. Through network analysis, 137 active ingredients were obtained from DSS, and 67 potential targets associated with DSS and VaD were identified. GO and KEGG analysis indicated that the action of DSS on VaD primarily involves hypoxic terms and HIF-1 pathway. In vivo validation, cognitive impairment and neuron mortality were markedly ameliorated by DSS. Additionally, DSS significantly reduced the expression of proteins related to synaptic plasticity and neuron apoptosis including PSD-95, SYP, Caspase-3 and BCL-2. Mechanistically, we confirmed DSS positively modulated the expression of HIF-1α and its downstream proteins including EPO, p-EPOR, STAT5, EPOR, and AKT1 in the hippocampus of VaD rats as well as CoCl 2 -induced PC12 cells. HIF-1 inhibitor YC-1 significantly diminished the protection of DSS on CoCl 2 -induced PC12 cell damage, with decreased HIF-1α, EPO, EPOR expression. Our results initially demonstrated DSS could exert neuroprotective effects in VaD. The pharmacological mechanism of DSS may be related to its positive regulation on HIF-1α/EPO pathway. [Display omitted] • The mechanistic effects of classic famous formula DSS in the treatment of VaD was firstly validated through network pharmacology approaches, in viro and in vivo validation. • DSS could significantly improve the cognitive impairment, hippocampal neurons injury induced by chronic hypoperfusion, and improved synaptic plasticity in VaD rats. • DSS activated hippocampal HIF-1α/EPO/EPOR signaling pathway both in VaD rats and CoCl 2 -induced PC12 cell injury models, as contributed to alleviating cognitive impairment. • HIF-1α inhibitor YC-1 significantly weakened the neuroprotective function of DSS on CoCl 2 -induced PC12 cell injury. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD), the fastest-growing neurological disorder globally, has a complex etiology. A previous study by our group identified the p.G849D variant in neurexin 2 (NRXN2), encoding the synaptic protein, NRXN2a, as a possible causal variant of PD. Therefore, we aimed to perform functional studies using proteomics in an attempt to understand the biological pathways affected by the variant. We hypothesized that this may reveal insight into the pathobiology of PD. Wild-type and mutant NRXN2a plasmids were transfected into SH-SY5Y cells. Thereafter, total protein was extracted and prepared for mass spectrometry using a Thermo Scientific Fusion mass spectrometer equipped with a Nanospray Flex ionization source. The data were then interrogated against the UniProt H. sapiens database and afterward, pathway and enrichment analyses were performed using in silico tools. Overexpression of the wild-type protein led to the enrichment of proteins involved in neurodegenerative diseases, while overexpression of the mutant protein led to the decline of proteins involved in ribosomal functioning. Thus, we concluded that the wild-type NRXN2α may be involved in pathways related to the development of neurodegenerative disorders, and that biological processes related to the ribosome, transcription, and tRNA, specifically at the synapse, could be an important mechanism in PD. Future studies targeting translation at the synapse in PD could therefore provide further information on the pathobiology of the disease. [ABSTRACT FROM AUTHOR]

Abstract: Burrowing behaviour is used to assess pain-associated behaviour in laboratory rodents. To gain insight into how models of disease-associated persistent pain and analgesics affect burrowing behaviour, we performed a systematic review and meta-analysis of studies that assessed burrowing behaviour. A systematic search in March 2020 and update in September 2020 was conducted in 4 databases. Study design characteristics and experimental data were extracted, followed by a random-effects meta-analysis. We explored the association between burrowing and monofilament-induced limb withdrawal. Dose response relationship was investigated for some analgesics. Forty-five studies were included in the meta-analysis, in which 16 model types and 14 drug classes were used. Most experiments used rat (79%) and male (72%) animals. Somatic inflammation and trauma-induced neuropathy models were associated with reduced burrowing behaviour. Analgesics (nonsteroidal anti-inflammatory drug and gabapentinoids) attenuated burrowing deficits in these models. Reporting of measures to reduce risk of bias was unclear except for randomisation which was high. There was not a correlation ( R2 = 0.1421) between burrowing and monofilament-induced limb withdrawal. Opioids, gabapentin, and naproxen showed reduced burrowing behaviour at high doses, whereas ibuprofen and celecoxib showed opposite trend. The findings indicate that burrowing could be used to assess pain-associated behaviour. We support the use of a portfolio of composite measures including spontaneous and stimulus-evoked tests. The information collected here could help in designing experiments involving burrowing assessment in models of disease-associated pain. [ABSTRACT FROM AUTHOR]

Objectives: The central nervous system disorder in systemic lupus erythematosus (SLE), called neuropsychiatric lupus (NPSLE), is one of the most severe phenotypes with various clinical symptoms, including mood disorder, psychosis and delirium as diffuse neuropsychological manifestations (dNPSLE). Although stress is one of the aggravating factors for neuropsychiatric symptoms, its role in the pathogenesis of dNPSLE remains to be elucidated. We aimed to investigate stress effects on the neuropsychiatric pathophysiology in SLE using lupus-prone mice and patients' data.Methods: Sleep disturbance stress (SDS) for 2 weeks was placed on 6-8-week-old female MRL/lpr and control mice. Behavioural phenotyping, histopathological analyses and gene and protein expression analyses were performed to assess SDS-induced neuroimmunological alterations. We also evaluated cytokines of the cerebrospinal fluid and brain regional volumes in patients with dNPSLE and patients with non-dNPSLE.Results: SDS-subjected MRL/lpr mice exhibited less anxiety-like behaviour, whereas stressed control mice showed increased anxiety. Furthermore, stress strongly activated the medial prefrontal cortex (mPFC) in SDS-subjected MRL/lpr. A transcriptome analysis of the PFC revealed the upregulation of microglial activation-related genes, including Il12b. We confirmed that stress-induced microglial activation and the upregulation of interleukin (IL) 12/23p40 proteins and increased dendritic spines in the mPFC of stressed MRL/lpr mice. IL-12/23p40 neutralisation and tyrosine kinase 2 inhibition mitigated the stress-induced neuropsychiatric phenotypes of MRL/lpr mice. We also found a higher level of cerebrospinal fluid IL-12/23p40 and more atrophy in the mPFC of patients with dNPSLE than those with non-dNPSLE.Conclusions: The microglial IL-12/23 axis in the mPFC might be associated with the pathogenesis and a promising therapeutic target for dNPSLE. [ABSTRACT FROM AUTHOR]

Backgrond and Objective: Crohn's disease (CD) is a chronic inflammatory bowel disease that affects a wide age range. Hence, CD patients receive a variety of drugs over their life beyond those used for CD itself. The changes to the integrity of the intestine and its drug metabolising enzymes and transporters (DMETs) can alter the oral bioavailability of drugs. However, there are other changes in systems parameters determining the fate of drugs in CD, and understanding these is essential for dose adjustment in patients with CD.Methods: The current analysis gathered all the available clinical data on the kinetics of drugs in CD (by March 2021), focusing on orally administered small molecule drugs. A meta-analysis of the systems parameters affecting oral drug pharmacokinetics was conducted. The systems information gathered on intestine, liver and blood proteins and other physiological parameters was incorporated into a physiologically based pharmacokinetic (PBPK) platform to create a virtual population of CD patients, with a view for guiding dose adjustment in the absence of clinical data in CD.Results: There were no uniform trends in the reported changes in reported oral bioavailability. The nature of the drug as well as the formulation affected the direction and magnitude of variation in kinetics in CD patients relative to healthy volunteers. Even for the same drug, the reported changes in exposure varied, possibly due to a lack of distinction between the activity states of CD. The highest alteration was seen with S-verapamil and midazolam, 8.7- and 5.3-fold greater exposure, respectively, in active CD patients relative to healthy volunteers. Only one report was available on liver DMETs in CD, and indicated reduced CYP3A4 activity. In a number of reports, mRNA expression of DMETs in the ileum and colon of CD patients was measured, focussing on P-glycoprotein (p-gp) transporter and CYP3A4 enzyme, and showed contradictory results. No data were available on protein expression in duodenum and jejunum despite their dominant role in oral drug absorption.Conclusion: There are currently inadequate dedicated clinical or quantitative proteomic studies in CD to enable predictive PBPK models with high confidence and adequate verification. The PBPK models for CD with the available systems parameters were able to capture the major physiological influencers and the gaps to be filled by future research. Quantification of DMETs in the intestine and the liver in CD is warranted, alongside well-defined clinical drug disposition studies with a number of index drugs as biomarkers of changes in DMETs in these patients, to avoid large-scale dedicated studies for every drug to determine the effects of disease on the drug's metabolism and disposition and the consequential safety and therapeutic concerns. [ABSTRACT FROM AUTHOR]

Background. Myocardial infarction (MI) is an acute and serious cardiovascular disease. Arrhythmia after MI can lead to sudden cardiac death, which seriously affects the survival outcome of patients. WenXin KeLi is a Chinese patent medicine for the treatment of arrhythmia in a clinic, which can significantly improve symptoms of palpitation and play an important role in reducing the risk of arrhythmia after MI. In this study, we aimed to explore the pharmacological mechanism of WenXin KeLi in protecting the heart. Methods. The MI model was established by ligating the left coronary artery and the ventricular fibrillation threshold (VFT) was measured by electrical stimulation. The expression of connexin43 (CX43) and autophagy-related protein were measured by Western Blot, and correlation analysis was conducted to study the relationship between cardiac autophagy, CX43, and arrhythmia in rats after MI. The effects of WenXin KeLi on arrhythmia, cardiac structure, and function in MI rats were respectively observed by electrical stimulation, cardiac gross section, Masson staining, and cardiac ultrasound. The effects of WenXin KeLi on the expression of phosphoinositide 3 kinase-protein kinase B-mammalian targets of rapamycin (PI3K-AKT-mTOR) autophagy pathway and CX43 were observed by Western Blot. Results. After 4 weeks of MI, the VFT in the model group was significantly reduced, the expression levels of yeast ATG6 homolog (Beclin1), microtubule-associated protein 1A/1B-light chain 3 (LC3II/LC3I), and p-CX43 (S368) significantly increased, the expression of sequestosome-1(P62) and CX43 significantly decreased. LC3II/LC3I and Beclin1 expression were significantly negatively correlated with the VFT, and the expression of P62 and CX43 were significantly positively correlated with the VFT. LC3II/LC3I and Beclin1 expression were negatively correlated with CX43 expression, while P62 expression was positively correlated with CX43 expression. WenXin KeLi could significantly increase the VFT, reduce the deposition of collagen fibers, and increase the index levels of the left ventricular end-diastolic anterior wall (LVEDAW), interventricular septum end-diastolic (IVSED), left ventricular end-systolic anterior wall (LVESAW), interventricular septum end-systolic (IVSES), left ventricular end-diastolic posterior wall (LVEDPW), left ventricular end-systolic posterior wall (LVESPW), left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), and reduce the index levels of the left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD), left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV). WenXin KeLi could increase the expression of CX43, P62, AKT, p-PI3K, p-AKT (308), p-AKT (473), and p-mTOR and decrease the expression of LC3II/LC3I and Beclin1. Conclusion. WenXin KeLi can activate the PI3K-AKT-mTOR signaling pathway, improve cardiac autophagy and Cx43 expression in rats after MI, reduce the risk of arrhythmia after MI, and play a cardioprotective role. [ABSTRACT FROM AUTHOR]

Calcitonin gene-related peptide (CGRP)-antagonizing drugs represent a major advance in migraine treatment. However, up to 50% of patients do not benefit from monoclonal antibodies against CGRP or its receptor. Here, we test the hypothesis that a closely related peptide, pituitary adenylate cyclase-activating peptide (PACAP-38), works independently of CGRP and thus might represent a new, alternative drug target. To understand differences in CGRP- and PACAP-mediated migraine pain, we used mouse models of provoked migraine-like pain based on multiple stimulations and subsequent measurement of tactile sensitivity response with von Frey filaments. Genetically modified mice lacking either functional CGRP receptors (Ramp1 knockout) or TRPA1 channels (Trpa1 knockout) were used together with CGRP-targeting antibodies and chemical inhibitors in wild-type mice (ntotal = 299). Ex vivo myograph studies were used to measure dilatory responses to CGRP and PACAP-38 in mouse carotid arteries. PACAP-38 provoked significant hypersensitivity and dilated the carotid arteries independently of CGRP. In contrast, glyceryl trinitrate-induced hypersensitivity is dependent on CGRP. Contrary to previous results with the migraine-inducing substances glyceryl trinitrate, cilostazol and levcromakalim, PACAP-38-induced hypersensitivity worked only partially through inhibition of ATP-sensitive potassium channels. Using multiple migraine-relevant models, these findings establish the PACAP-38 pathway as distinct from other migraine provoking pathways such as CGRP and glyceryl trinitrate. PACAP antagonism may therefore be a novel therapeutic target of particular interest in patients unresponsive to CGRP-antagonizing drugs. [ABSTRACT FROM AUTHOR]

Paradoxical sleep deprivation has been associated with impaired salivary secretion in rats. However, the mechanism that underlies this is not known. Therefore, this study assessed salivary and serum oxidative stress levels following paradoxical sleep deprivation in rats. Twenty-one male Wistar rats randomly divided into three groups of seven rats each as; Control (C); partial sleep-deprived (PSD); and total sleep-deprived (TSD) were used. Malondialdehyde (MDA) concentration, Superoxide dismutase (SOD), and catalase activities were evaluated in saliva, serum, and submandibular glands after seven days of sleep deprivation. Data were expressed as mean ± standard error of the mean and analyzed using one-way ANOVA, Tukey HSD post hoc, and Pearson's correlation tests. Serum MDA levels were significantly higher in both the TSD and PSD groups compared to the control group whereas only the TSD group showed higher submandibular MDA levels compared to the PSD group and the control group. Submandibular SOD activity was significantly lower in both the TSD and PSD groups compared to the control group. Serum catalase activity was significantly lower in the TSD group only compared to the control group. These results have demonstrated for the first time that paradoxical sleep deprivation was associated with changes in the oxidant/antioxidant defense system in the submandibular salivary glands of male Wistar rats which may contribute to impairment in salivary secretion. [ABSTRACT FROM AUTHOR]

Dan'e fukang decoction (DFD) is a traditional Chinese medicine formula. DFD obtains 10 herbs, including Salvia yunnanensis C.H.Wright (Zidanshen), Curcuma zedoaria (Christm.) Roscoe (Ezhu), Angelica sinensis (Oliv.) Diels (Danggui), Cyperus rotundus L. (Xiangfuzi) , Corydalis yanhusuo (Y.H.Chou & Chun C. Hsu) W.T.Wang ex Z.Y.Su & C.Y.Wu , Bupleurum marginatum Wall. ex DC. (Yanhusuo) , Sparganium stoloniferum (Buch.-Ham. ex Graebn.) Buch.-Ham. ex Juz. (Sanleng) , Panax notoginseng (Burkill) F.H.Chen (Sanqi) , Paeonia lactiflora Pall. (Shaoyao) and Glycyrrhiza uralensis Fisch. (Gancao). DFD is now clinically used for the treatment of menstrual irregularities, dysmenorrhea and menstrual discomfort caused by blood stasis and easing of endometriosis. Based on this, it is reasonable to presume that DFD may be effective in treating incomplete abortion and reducing postpartum bleeding, but no specific studies have been reported so far. To investigate the efficacy of Dan'e fukang decoction (DFD) in reducing prolonged vaginal bleeding followed by mifepristone induced incomplete abortion and explore the mechanisms of action of DFD in treating incomplete abortion. An incomplete abortion model of rat was established by single intragastrically administered 8.5 mg/kg mifepristone on the 7th day of pregnancy. From the 8th day of pregnancy, the abortive rats were administered solvent, a positive control drug, or different doses of DFD, respectively for seven consecutive days. The efficacy of DFD was assessed by measuring the vaginal bleeding volume of the rats. Four coagulation parameters and platelet counts were measured. Hematoxylin and eosin (HE) staining was performed to evaluate pathological changes in the uterine embryos. Serum levels of progesterone and estrogen were measured using ELISA. Network pharmacology and transcriptomics were used to predict potential targets and pathways for DFD to reduce hemorrhage. The levels of mRNA related to cell adhesion molecules (CAMs) were detected by RT-qPCR. The levels of progesterone and estrogen receptors and the proteins associated with CAMs pathway in uterine tissues were detected by Western Blot. DFD significantly reduced the volume of vaginal bleeding of the abortive rats and significantly downgraded the pathological scores of uterine embryos. DFD significantly increased serum levels of E2, and had no impact on serum levels of P4 and the protein expression of ER and PR in the uteri of the abortive rats. Pathways in cancer, lipid, focal adhesion and immune-related signaling were predicted to be influenced by DFD via the analysis of network pharmacology. The CAMs signaling was found the most critical pathway regulated by both mifepristone and DFD via RNA-seq assay, followed by axon guidance, basal cell carcinoma, hippo signaling pathway and neuroactive ligand-receptor interaction. Combining the two analytical methods, ICAM-1 was predicted likely the key targeted gene by DFD. Finally, DFD was validated to decrease the protein expression of ICAM-1, ITGB2, ITGB7 and RASSF5 in the uterine tissues, which correlated to suppress the CAMs signaling pathway. DFD significantly reduced hemorrhage. DFD significantly increased the serum levels of E2 and inhibited CAMs signaling pathway, which was likely to be involved in the mechanism of action of DFD facilitating residual uterine embryo expulsion in the rat model of incomplete abortion. [Display omitted] • DFD reduced hemorrhage in a rat model of induced incomplete abortion. • DFD facilitated the expulsion of residual embryos. • DFD upregulated serum levels of E2. • DFD suppressed cell adhesion molecules (CAMs) signaling pathway. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a chronic inflammatory bowel condition that is frequently related with Spleen-Kidney Yang Deficiency Syndrome (SKYD) in Chinese medicine. Fuzi Lizhong Pill (FLZP), a traditional medicine for SKYD, has been utilized in China for generations, although the exact mechanism by which it treats UC is unknown. The goal of this study is to further understand FLZP's therapeutic mechanism in SKYD-associated UC. To investigate the impact of FLZP on SKYD-associated UC, we used a comprehensive method that included serum metabolomics and gut microbiota profiling. The chemical composition of FLZP was determined using mass spectrometry. UC rats with SKYD were induced and treated with FLZP. Serum metabolomics and 16S rRNA microbial community analysis were used to evaluate FLZP's effects on endogenous metabolites and gut microbiota, respectively. Correlation analysis investigated the association between metabolites and intestinal flora. A metabolic pathway analysis was undertaken to discover putative FLZP action mechanisms. FLZP contains 109 components, including liquiritin (584.8176 μg/g), benzoylaconine (16.3087 μg/g), benzoylhypaconine (31.9583), and hypaconitine (8.1160 μg/g). FLZP predominantly regulated seven metabolites and eight metabolic pathways involved in amino acid and nucleotide metabolism, with an emphasis on energy metabolism and gastrointestinal digestion. FLZP also influenced intestinal flora variety, increasing probiotic abundance while decreasing pathogenic bacteria prevalence. An integrated investigation identified associations between changes in certain gut flora and energy metabolism, specifically the tricarboxylic acid (TCA) cycle. FLZP successfully cures UC in SKYD rats by regulating amino acid and energy metabolism. Its positive effects may include altering microbiota composition and metabolite profiles in UC rats with SKYD. These findings shed light on FLZP's mode of action and its implications for UC management. [Display omitted] • FLZP primarily regulates metabolic pathways related to amino acid and nucleotide metabolism. • FLZP may treat UC rats in SKYD by modulating the species richness and diversity of intestinal flora. • Some gut bacteria changes in UC rats with SKYD link to TCA cycle energy metabolism. • FLZP's relief of UC in SKYD rats may involve microbiota and metabolite changes. [ABSTRACT FROM AUTHOR]

Palmatine is a main bioactive alkaloid of Cortex Phellodendri, which has been commonly prescribed for the treatment of hyperuricemia (HUA) in China. The metabolites of palmatine were crucial to its prominent biological activity. 9-Hydroxy-8-oxypalmatine (9-OPAL) is a novel liver-mediated secondary oxymetabolite of palmatine. The current study was to assess the efficacy of 9-OPAL, a novel liver-mediated secondary oxymetabolite of palmatine derived from Cortex Phellodendri, in experimental HUA mouse model and further explore its underlying mechanism. An in vitro metabolic experiment with oxypalmatine was carried out using liver samples. We separated and identified a novel liver metabolite, and investigated its anti-HUA effect in mice. HUA mice were induced by potassium oxonate and hypoxanthine daily for one week. After 1 h of modeling, mice were orally administered with different doses of 9-OPAL (5, 10 and 20 mg/kg). The pathological changes of the kidneys were evaluated using hematoxylin-eosin staining (H&E). The acute toxicity of 9-OPAL was assessed. The effects of 9-OPAL on serum levels of uric acid (UA), adenosine deaminase (ADA), xanthine oxidase (XOD), creatinine (CRE), blood urea nitrogen (BUN) and inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA) or biochemical method. Furthermore, Western blot, quantitative real-time PCR (qRT-PCR) and molecular docking were used to investigate the effect of 9-OPAL on the expression of renal urate transporters and NLRP3 signaling pathway in HUA mice. 9-OPAL had been discovered to be a novel liver-mediated oxymetabolite of palmatine for the first time. Treatment with 9-OPAL significantly reduced the UA, CRE as well as BUN levels, and also effectively attenuated abnormal renal histopathological deterioration with favorable safety profile. Besides, 9-OPAL significantly decreased the serum and hepatic activities of XOD and ADA, dramatically inhibited the up-regulation of UA transporter protein 1 (URAT1) and glucose transporter protein 9 (GLUT9), and reversed the down-regulation of organic anion transporter protein 1 (OAT1). Additionally, 9-OPAL effectively mitigated the renal inflammatory markers (TNF-α, IL-1β, IL-6 and IL-18), and downregulated the transcriptional and translational expressions of renal Nod-like receptor family pyrin domain containing 3 (NLRP3), caspase-1, apoptosis-associated speck-like (ASC) and IL-1β in HUA mice. Molecular docking results revealed 9-OPAL bound firmly with XOD, OAT1, GLUT9, URAT1, NLRP3, caspase-1, ASC and IL-1β. 9-OPAL was found to be a novel liver-mediated secondary metabolite of palmatine with favorable safety profile. 9-OPAL had eminent anti-hyperuricemic and renal-protective effects, and the mechanisms might be intimately associated with repressing XOD activities, modulating renal urate transporter expression and suppressing the NLRP3 inflammasome activation. Our investigation might also provide further experimental evidence for the traditional application of Cortex Phellodendri in the treatment of HUA. [Display omitted] [ABSTRACT FROM AUTHOR]

Purpose: To test the antibacterial effects of different toothpastes with the slurry method of toothpaste application in an in vitro oral biofilm model including relevant periodontal pathogens.Materials and Methods: Four commercially available toothpastes, two containing sodium fluoride (NaF) at different concentrations (1450 and 2500 ppm), two NaF with either triclosan or stannous fluoride, and a control phosphate-buffered saline (PBS) were used. Multispecies biofilms containing 6 species of oral bacteria were grown on hydroxyapatite disks for 72 h and then exposed for 2 min to the toothpaste slurries or phosphate buffer saline (PBS) by immersion, under continuous agitation at 37°C. Biofilms were then analysed by means of real-time polymerase chain reaction (PCR), combined with propidium monoazide (PMA). Statistical evaluation was performed using ANOVA and Student's t-test, with Bonferroni correction for multiple comparisons.Results: The toothpastes containing NaF and stannous fluoride demonstrated superior antimicrobial activity for A. actinomycetencomitans, P. gingivalis and F. nucleatum when compared to those containing NaF and triclosan, 1450 ppm NaF or 2500 ppm NaF in this multispecies biofilm model.Conclusion: The proposed model for the evaluation of toothpastes in the form of slurries detected significant differences in the antimicrobial effects among the tested NaF-containing toothpastes, with the stannous fluoride-based formulation achieving better results than the other formulations. The use of toothpaste as slurries and real-time PCR with PMA is an adequate method for comparing the in vitro antimicrobial effect of different toothpastes. [ABSTRACT FROM AUTHOR]

Calcium oxalate crystals play a key role in the development and recurrence of kidney stones (also known as urolithiasis); thus, inhibiting the formation of these crystals is a central focus of urolithiasis prevention and treatment. Previously, we reported the noteworthy in vitro inhibitory effects of Aspidopterys obcordata fructo oligosaccharide (AOFOS), an active polysaccharide of the traditional Dai medicine Aspidopterys obcordata Hemsl. (commonly known as Hei Gai Guan), on the growth of calcium oxalate crystals. To investigated the effectiveness and mechanism of AOFOS in treating kidney stones. A kidney stones rats model was developed, followed by examining AOFOS transport dynamics and effectiveness in live rats. Additionally, a correlation between the polysaccharide and calcium oxalate crystals was studied by combining crystallization experiments with density functional theory calculations. The results showed that the polysaccharide was transported to the urinary system. Furthermore, their accumulation was inhibited by controlling their crystallization and modulating calcium ion and oxalate properties in the urine. Consequently, this approach helped effectively prevent kidney stone formation in the rats. The present study emphasized the role of the polysaccharide AOFOS in modulating crystal properties and controlling crystal growth, providing valuable insights into their potential therapeutic use in managing kidney stone formation. [Display omitted] • The Aspidopterys obcordata (Hei Gai Guan) has long been utilized in the treatment of Urolithiasis. • Inulin-type AOFOS extracted from Aspidopterys obcordata has shown inhibitory effects on kidney stones in rat models. • AOFOS plays a vital role in preventing Urolithiasis by regulating the crystallization of Calcium Oxalate in urine. [ABSTRACT FROM AUTHOR]

Background: Modulation of serotonergic signaling by treatment with selective serotonin reuptake inhibitors (SSRIs) has been suggested to mitigate amyloid-β (Aβ) pathology in Alzheimer's disease, in addition to exerting an anti-depressant action.Objective: To investigate the efficacy of chronic treatment with the SSRI paroxetine, in mitigating Aβ pathology and Aβ plaque-induced microgliosis in the hippocampus of 18-month-old APPswe/PS1ΔE9 mice.Methods: Plaque-bearing APPswe/PS1ΔE9 and wildtype mice were treated with paroxetine per os at a dose of 5 mg/kg/day, from 9 to 18 months of age. The per os treatment was monitored by recording of the body weights and serum paroxetine concentrations, and by assessment of the serotonin transporter occupancy by [3H]DASB-binding in wildtype mice. Additionally, 5,7-dihydroxytryptamine was administered to 9-month-old APPswe/PS1ΔE9 mice, to examine the effect of serotonin depletion on Aβ pathology. Aβ pathology was evaluated by Aβ plaque load estimation and the Aβ42/Aβ40 ratio by ELISA.Results: Paroxetine treatment led to > 80% serotonin transporter occupancy. The treatment increased the body weight of wildtype mice, but not of APPswe/PS1ΔE9 mice. The treatment had no effect on the Aβ plaque load (p = 0.39), the number and size of plaques, or the Aβ plaque-induced increases in microglial numbers in the dentate gyrus. Three months of serotonin depletion did not significantly impact the Aβ plaque load or Aβ42/Aβ40 ratio in APPswe/PS1ΔE9 mice at 12 months.Conclusion: Our results show that chronic treatment with the SSRI paroxetine does not mitigate Aβ pathology and Aβ plaque-induced microgliosis in the hippocampus of APPswe/PS1ΔE9 mice. [ABSTRACT FROM AUTHOR]

Background: Tau hyperphosphorylation at several sites, including those close to its microtubule domain (MD), is considered a key pathogenic event in the development of tauopathies. Nevertheless, we recently demonstrated that at the very early disease stage, tau phosphorylation (pTau) at MD sites promotes neuroprotection by preventing seizure-like activity.Objective: To further support the notion that very early pTau is not detrimental, the present work evaluated the young rTg4510 mouse model of tauopathy as a case study. Thus, in mice at one month of age (PN30-35), we studied the increase of pTau within the hippocampal area as well as hippocampal and locomotor function.Methods: We used immunohistochemistry, T-maze, nesting test, novel object recognition test, open field arena, and electrophysiology.Results: Our results showed that the very young rTg4510 mouse model has no detectable changes in hippocampal dependent tasks, such as spontaneous alternation and nesting, or in locomotor activity. However, at this very early stage the hippocampal neurons from PN30-35 rTg4510 mice accumulate pTau protein and exhibit changes in hippocampal oscillatory activity. Moreover, we found a significant reduction in the somatic area of pTau positive pyramidal and granule neurons in the young rTg4510 mice. Despite this, improved memory and increased number of dendrites per cell in granule neurons was found.Conclusion: Altogether, this study provides new insights into the early pathogenesis of tauopathies and provides further evidence that pTau remodels hippocampal function and morphology. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is characterized by a high etiological and clinical heterogeneity, which has obscured the diagnostic and treatment efficacy, as well as limited the development of potential drugs. Sex differences are among the risk factors that contribute to the variability of disease manifestation. Unlike men, women are at greater risk of developing AD and suffer from higher cognitive deterioration, together with important changes in pathological features. Alterations in glucose metabolism are emerging as a key player in the pathogenesis of AD, which appear even decades before the presence of clinical symptoms.Objective: We aimed to study whether AD-related sex differences influence glucose metabolism.Methods: We used male and female APPswe/PS1dE9 (APP/PS1) transgenic mice of different ages to examine glucose metabolism effects on AD development.Results: Our analysis suggests an age-dependent decline of metabolic responses, cognitive functions, and brain energy homeostasis, together with an increase of Aβ levels in both males and females APP/PS1 mice. The administration of Andrographolide (Andro), an anti-inflammatory and anti-diabetic compound, was able to restore several metabolic disturbances, including the glycolytic and the pentose phosphate pathway fluxes, ATP levels, AMPKα activity, and Glut3 expression in 8-month-old mice, independent of the sex, while rescuing these abnormalities only in older females. Similarly, Andro also prevented Aβ accumulation and cognitive decline in all but old males.Conclusion: Our study provides insight into the heterogeneity of the disease and supports the use of Andro as a potential drug to promote personalized medicine in AD. [ABSTRACT FROM AUTHOR]

Antibiotics underpin modern medicine and are critical for pandemic preparedness. Push funding has revitalized the preclinical antimicrobial resistance (AMR) pipeline and government funding via CARB-X and BARDA, as well as private sector–led investment via the AMR Action Fund, will help several new antibiotics obtain regulatory approval. Nevertheless, revenues generated by new antibiotics are not considered sufficiently profitable by commercial developers to address unmet need. The question remains: Who could viably fund development and secure global equitable access for new antibiotics? Public health need should be the primary driver for antibiotic development. Improved prioritization and government oversight by funders who allocate public resources are a needed first step. In this framework, nonprofit research and development organizations, with support from public funders, and unconstrained by commercial profitability requirements are well positioned to work with public and private actors to viably provide new antibiotics to all in need. [ABSTRACT FROM AUTHOR]

Abstract: Many analgesics inadequately address the psychiatric comorbidities of chronic and persistent pain, but there is no standard preclinical model of pain-altered behavior to support the development of new therapies. To explore this conflicting and inconclusive literature, we conducted a focused systematic review and meta-analysis on the effect of complete Freund adjuvant-induced (CFA) rodent hind paw inflammation on multiple classical indicators of exploratory behavior, stress coping, and naturalistic behavior. Our primary objective was to define CFA's effect on assays including, but not limited to, the elevated plus maze and forced swim test. Our secondary objective was to discover how variables such as species and strain may influence outcomes in such assays. We searched Ovid MEDLINE, Embase, Scopus, and Web of Science in April and October 2020 for studies with adult rodents injected with CFA into the hind paw and subsequently tested for aspects of "anxiety-like" or "depressive-like" behaviors. Forty-four studies evaluated performance in the elevated plus or zero maze, open field test, light-dark box, place escape and avoidance paradigm, forced swim test, tail suspension test, sucrose preference test, wheel running, and burrowing assay. Complete Freund adjuvant modestly but significantly decreased exploratory behavior, significantly increased passive stress coping in the tail suspension test but not the forced swim test, and significantly decreased preference for sucrose and naturally rewarding activity. Subgroup analyses revealed significant differences between species and animal sourcing. Based on the evidence provided here, we conclude future studies should focus on CFA's effect on natural rewards and naturalistic behaviors. [ABSTRACT FROM AUTHOR]

Background: Pneumoconiosis patients exhibit significantly more anxiety and depression than healthy individuals. However, the mechanism of coal dust-induced anxiety and depression remains unclear.Methods: A pneumoconiosis mouse model with anxiety- and depression-like behaviors were established after 28 days of exposure to coal dust. Vitamin D3 treatment (1200 IU/kg/week) was administered intraperitoneally for 3 months starting from the first coal exposure. Tail suspension test (TST), open field test (OFT), and elevated plus-maze (EPM) test were used to assess anxiety- and depression-like behaviors. Theserum concentration of 25(OH)D3 and fibrillary acid protein (GFAP) expression were determined. In addition, the morphology and distribution of GFAP and neurogenic differentiation factor1 expression (NeuroD1) in different cerebral hippocampus were observed.Results: In coal dust-exposed mice, immobility time decreased in OFT and increased in TST,and the frequency of entering the open arm decreased in the EPM compared with the control mice. Coal dust increased hippocampal GFAP expression and astrocyte activation and reduced neurogenic differentiation factor1 expression (NeuroD1). In addition, Vitamin D3 significantly alleviated anxiety- and depressive-like behaviors in TST and EPM test, decreased GFAP expression level, modified hippocampal astrocyte activation pattern, and advanced brain-derived neurotrophic factor (BDNF) distribution and expression in CA1 and CA3 of the hippocampus.Conclusions: Taken together, our results suggest that, by inhibiting the over-activation of astrocytes and increasing BDNF and neuron protection, vitamin D treatment ameliorates coal-dust-induced depressive and anxiety-like behavior, which is the first evidence that vitamin D may be a new approach for treating mood disorders caused by particulate matter. [ABSTRACT FROM AUTHOR]

Background: A Western diet (WD) is associated with increased inflammation in the large intestine, which is often ascribed to the high dietary fat content. Intestinal inflammation in rodents can be induced by oral administration of dextran sodium sulfate (DSS). However, most studies investigating effects of WD and DSS have not used appropriate low-fat diets (LFDs) as control.Objectives: To compare the effects of a WD with those of an LFD on colon health in a DSS-induced low-grade colonic inflammation mouse model.Methods: Six-week-old male C57BL/6JRj mice were fed an LFD (fat = 10.3% energy, n = 24) or a WD (fat = 41.2% energy, n = 24) for 15 wk [Experiment 1 (Exp.1)]. Half the mice on each diet (n = 12) then received 1% DSS in water for 6 d with the remainder (n = 12 in each diet) administered water. Disease activity, proinflammatory genes, inflammatory biomarkers, and fecal microbiota (16S rRNA) were assessed (Exp.1). Follow-up experiments (Exp.2 and Exp.3) were performed to investigate whether fat source (milk or lard; Exp.2) affected outcomes and whether a shift from LFD to WD 1 d prior to 1% DSS exposure caused an immediate effect on DSS-induced inflammation (Exp.3).Results: In Exp.1, 1% DSS treatment significantly increased disease score in the LFD group compared with the WD group (2.7 compared with 0.8; P < 0.001). Higher concentrations of fecal lipocalin (11-fold; P < 0.001), proinflammatory gene expression (≤82-fold), and Proteobacteria were observed in LFD-fed mice compared with the WD group. The 2 fat sources in WDs (Exp.2) revealed the same low inflammation in WD+DSS mice compared with LFD+DSS mice. Finally, the switch from LFD to WD just before DSS exposure resulted in reduced colonic inflammation (Exp.3).Conclusions: Herein, WDs (with milk or lard) protected mice against DSS-induced colonic inflammation compared with LFD-fed mice. Whether fat intake induces protective mechanisms against DSS-mediated inflammation or inhibits establishment of the DSS-induced colitis model is unclear. [ABSTRACT FROM AUTHOR]

Background: Defining cellular mechanisms that drive Alzheimer's disease (AD) pathogenesis and progression will be aided by studies defining how gene expression patterns change during pre-symptomatic AD and ensuing periods of declining cognition. Previous studies have emphasized changes in transcriptome, but not translatome regulation, leaving the ultimate results of gene expression alterations relatively unexplored in the context of AD.Objective: To identify genes whose expression might be regulated at the transcriptome and translatome levels in AD, we analyzed gene expression in cerebral cortex of two AD model mouse strains, CVN (APPSwDI;NOS2 -/- ) and Tg2576 (APPSw), and their companion wild type (WT) strains at 6 months of age by tandem RNA-Seq and Ribo-Seq (ribosome profiling).Methods: Identical starting pools of bulk RNA were used for RNA-Seq and Ribo-Seq. Differential gene expression analysis was performed at the transcriptome, translatome, and translational efficiency levels. Regulated genes were functionally evaluated by gene ontology tools.Results: Compared to WT mice, AD model mice had similar levels of transcriptome regulation, but differences in translatome regulation. A microglial signature associated with early stages of Aβ accumulation was upregulated at both levels in CVN mice. Although the two mice strains did not share many regulated genes, they showed common regulated pathways related to AβPP metabolism associated with neurotoxicity and neuroprotection.Conclusion: This work represents the first genome-wide study of brain translatome regulation in animal models of AD and provides evidence of a tight and early translatome regulation of gene expression controlling the balance between neuroprotective and neurodegenerative processes in brain. [ABSTRACT FROM AUTHOR]

Background: Dendrobium nobile Lindl. alkaloids (DNLA) are effective in ameliorating cognitive deficit in SAMP8, AβPP/PS1, and LPS-induced AD animal models, and prevented Aβ-induced synaptic degeneration in cultured hippocampal neurons. However, the underlying mechanisms remain unexplored.Objective: This study investigated the protective effects of DNLA on synaptic damage in an Aβ25-35-induced rat AD model, in primary cortical neuron cultures, and in PC12 cells transfected with human AβPP695, focusing on the Wnt/β-catenin pathway.Methods: Sprague-Dawley rats received a single Aβ25-35 injection (10μg) into the bilateral hippocampi. DNLA (40 and 80 mg/kg/d) was intragastrically administrated 7 days prior to Aβ injection and continued for 28 days. The spatial learning and memory, synaptic morphology, synapse-related proteins, and Wnt signaling components GSK3β and β-catenin phosphorylation were evaluated. Rat primary cortical neuron cultures and AβPP695-PC12 cells were used to evaluate axonal mitochondria distribution, reactive oxygen species production, amyloidogenesis, and Wnt pathway in the protection.Results: DNLA ameliorated Aβ-induced cognitive impairment, increased the number of synapses, elevated the postsynaptic density thickness and expression of synapsin and PSD95 in the hippocampus, and suppressed Aβ-mediated GSK3β activity and the β-catenin phosphorylation. In primary neurons and AβPP695-PC12 cells, DNLA restored Aβ25-35 induced mitochondrial dysfunction and inhibited reactive oxygen species production and amyloidogenesis. Furthermore, the Wnt/β-catenin pathway inhibitor Dkk-1 blocked the effect of DNLA on the expression of Aβ1-42 and PSD95.Conclusion: DNLA rescued Aβ-mediated synaptic and mitochondrial injury and inhibited amyloidogenesis in vivo and in vitro, probably through the activation of Wnt/β-catenin signaling pathway to protect synaptic integrity. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a debilitating disorder involving the loss of plasticity and cholinergic neurons in the cortex. Pharmaceutical treatments are limited in their efficacy, but brain stimulation is emerging as a treatment for diseases of cognition. More research is needed to determine the biochemical mechanisms and treatment efficacy of this technique.Objective: We aimed to determine if forebrain repetitive transcranial magnetic stimulation can improve cortical BDNF gene expression and cholinergic signaling in the 3xTgAD mouse model of AD.Methods: Both B6 wild type mice and 3xTgAD mice aged 12 months were given daily treatment sessions for 14 days or twice weekly for 6 weeks. Following treatment, brain tissue was extracted for immunological stains for plaque load, as well as biochemical analysis for BDNF gene expression and cholinergic signaling via acetylcholinesterase and choline acetyltransferase ELISA assays.Results: For the 3xTgAD mice, both 14 days and 6 weeks treatment regimens resulted in an increase in BDNF gene expression relative to sham treatment, with a larger increase in the 6-week group. Acetylcholinesterase activity also increased for both treatments in 3xTgAD mice. The B6 mice only had an increase in BDNF gene expression for the 6-week group.Conclusion: Brain stimulation is a possible non-invasive and nonpharmaceutical treatment option for AD as it improves both plasticity markers and cholinergic signaling in an AD mouse model. [ABSTRACT FROM AUTHOR]

Background: Prehospital cardiopulmonary resuscitation has commonly been considered ineffective in traumatic cardiopulmonary arrest because traditional chest compressions do not produce substantial cardiac output. However, recent evidence suggests that chest compressions located over the left ventricle (LV) produce greater hemodynamics when compared to traditional compressions. We hypothesized that chest compressions located directly over the LV would result in an increase in return of spontaneous circulation (ROSC) and hemodynamic variables, when compared to traditional chest compressions, in a swine model of traumatic pulseless electrical activity (PEA).Methods: Transthoracic echocardiography was used to mark the location of the aortic root (traditional compressions) and the center of the LV on animals (n = 34) that were randomized to receive chest compressions in one of the two locations. Animals were hemorrhaged to mean arterial pressure <20 to simulate traumatic PEA. After 5 minutes of PEA, basic life support (BLS) with mechanical cardiopulmonary resuscitation was initiated and performed for 10 minutes followed by advanced life support for an additional 10 minutes. Hemodynamic variables were averaged over the final 2 minutes of BLS and advanced life support periods.Results: Six of the LV group (35%) achieved ROSC compared to eight of the traditional group (47%) (P = .73). There was an increase in aortic systolic blood pressure (P < .01), right atrial systolic blood pressure (P < .01), and right atrial diastolic blood pressure (P = .02) at the end of BLS in the LV group compared to the traditional group.Conclusions: In our swine model of traumatic PEA, chest compressions performed directly over the LV improved blood pressures during BLS but not ROSC. [ABSTRACT FROM AUTHOR]