Environmental noise stress disturbs commensal microbiota homeostasis and induces oxi-inflammmation and AD-like neuropathology through epithelial barrier disruption in the EOAD mouse model.

BACKGROUND: Both genetic factors and environmental hazards, including environmental noise stress, have been associated with gut microbiome that exacerbates Alzheimer's disease (AD) pathology. However, the role and mechanism of environmental risk factors in early-onset AD (EOAD) pathogenesis remain unclear. METHODS: The molecular pathways underlying EOAD pathophysiology following environmental noise exposure were evaluated using C57BL/6 wild-type (WT) and APP/PS1 Tg mouse models. The composition differences in intestinal microbiota were analyzed by 16S rRNA sequencing and Tax4Fun to predict the metagenome content from sequencing results. An assessment of the flora dysbiosis-triggered dyshomeostasis of oxi-inflamm-barrier and the effects of the CNS end of the gut-brain axis was conducted to explore the underlying pathological mechanisms. RESULTS: Both WT and APP/PS1 mice showed a statistically significant relationship between environmental noise and the taxonomic composition of the corresponding gut microbiome. Bacterial-encoded functional categories in noise-exposed WT and APP/PS1 mice included phospholipid and galactose metabolism, oxidative stress, and cell senescence. These alterations corresponded with imbalanced intestinal oxidation and anti-oxidation systems and low-grade systemic inflammation following noise exposure. Mechanistically, axis-series experiments demonstrated that following noise exposure, intestinal and hippocampal tight junction protein levels reduced, whereas serum levels of inflammatory mediator were elevated. Regarding APP/PS1 overexpression, noise-induced abnormalities in the gut-brain axis may contribute to aggravation of neuropathology in the presymptomatic stage of EOAD mice model. CONCLUSION: Our results demonstrate that noise exposure has deleterious effects on the homeostasis of oxi-inflamm-barrier in the microbiome-gut-brain axis. Therefore, at least in a genetic context, chronic noise may aggravate the progression of EOAD.

Effect of a beta-cypermethrin and emamectin benzoate pesticide mixture on reproductive toxicity in male mice in a greenhouse environment.

With the widespread use of pesticides, the resistance to pesticides of pests has gradually increased, caused mixed pesticides to become even more widely used for practical applications. To investigate the effects of mixed pesticides on reproductive health in an occupational greenhouse environment, the greenhouse environment and the characteristics of the actual application were constructed, and then the male mice were comprehensively exposed to a mixture of the beta-cypermethrin and emamectin benzoate environmental. Additionally, the effect of the beta-cypermethrin and emamectin benzoate mixture on the reproductive health of male mice was known. The results showed that with the prolongation of exposure duration, the activities of Glutathione Peroxidase (GSH-Px), Total Superoxide Dismutase (T-SOD), Lactate dehydrogenase (LDH) and Acid phosphatase (ACP) in the testes of mice gradually decreased and the activity of Malondialdehyde (MDA) gradually increased. It was also found that the apoptosis rate of murine testicular cells increased and that DNA damage occurred with prolonged exposure duration. Therefore, it can be inferred that exposure to a mixture of the pesticides beta-cypermethrin and emamectin benzoate in the greenhouse environment may have adverse effects on the reproductive health of male mice.

Transcriptome analysis of the hippocampus in environmental noise-exposed SAMP8 mice reveals regulatory pathways associated with Alzheimer's disease neuropathology.

BACKGROUND: Chronic noise exposure is one environmental hazard that is associated with genetic susceptibility factors that increase Alzheimer's disease (AD) pathogenesis. However, the comprehensive understanding of the link between chronic noise stress and AD is limited. Herein, we investigated the effects of chronic noise exposure on AD-like changes in senescence-accelerated mouse prone 8 (SAMP8). METHODS: A total of 30 male SAMP8 mice were randomly divided into the noise-exposed group, the control group, and aging group (positive controls), and mice in the exposure group were exposed to 98 dB SPL white noise for 30 consecutive days. Transcriptome analysis and AD-like neuropathology of hippocampus were examined by RNA sequencing and immunoblotting. Enzyme-linked immunosorbent assay and real-time PCR were used to further determine the differential gene expression and explore the underlying mechanisms of chronic noise exposure in relation to AD at the genome level. RESULTS: Chronic noise exposure led to amyloid beta accumulation and increased the hyperphosphorylation of tau at the Ser202 and Ser404 sites in young SAMP8 mice; similar observations were noted in aging SAMP8 mice. We identified 21 protein-coding transcripts that were differentially expressed: 6 were downregulated and 15 were upregulated after chronic noise exposure; 8 genes were related to AD. qPCR results indicated that the expression of Arc, Egr1, Egr2, Fos, Nauk1, and Per2 were significantly high in the noise exposure group. These outcomes mirrored the results of the RNA sequencing data. CONCLUSIONS: These findings further revealed that chronic noise exposure exacerbated aging-like impairment in the hippocampus of the SAMP8 mice and that the protein-coding transcripts discovered in the study may be key candidate regulators involved in environment-gene interactions.

Proteomes analysis reveals the involvement of autophagy in AD-like neuropathology induced by noise exposure and ApoE4.

BACKGROUND: Noise is one of the most important environmental health hazards for humans. Environmental noise or apolipoprotein ε4 (ApoE4) can cause typical Alzheimer's disease (AD)-like pathological changes, which is characterized by progressive cognitive decline and neurodegenerative lesions. Gene-environment interactions may accelerate cognitive decline and increase AD risk. However, there is limited experimental evidence regarding the underlying mechanisms of noise-ApoE4 interactions and AD, which may be closely related to AD development. METHODS: In this study, we investigated the combined effects of chronic noise exposure and the ApoE4 gene activation on hippocampus by using proteomics and differentially expressed proteins were found through performed gene ontology function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. In addition, we assessed the changes in adult hippocampal neurogenesis and potential underlying mechanism for AD-like neuropathology. RESULTS: Relative to control rats, combined exposure of noise and ApoE4 synergistically increased the characteristic pathological amyloid ß-protein of AD-like neuropathology changes in hippocampus. The research identifies a total of 4147 proteins and 15 differentially expressed proteins in hippocampus. Furthermore, comparison of several of the diverse key pathways studied (e.g., PI3K/AKT, insulin, calpain-CDK5, and mammalian target of rapamycin (mTOR) signaling pathways) help to articulate the different mechanisms involved in combined effects of noise and ApoE4 on AD-like pathology. We verified four selected proteins, namely, eukaryotic translation elongation factor 1 epsilon 1, glycine amidinotransferase, nucleoredoxin, and tuberous sclerosis 1 proteins. Validation data shows significant effects of chronic noise and ApoE4 on the expression of four selected proteins, eukaryotic translation elongation factor 1 epsilon 1, glycine amidinotransferase, nucleoredoxin, and tuberous sclerosis 1 proteins, and mTOR and autophagy-related proteins, which share significant interaction effect of chronic noise and ApoE4. CONCLUSION: Gene-environment interactions between chronic noise and ApoE4 activate the mTOR signaling, decrease autophagy, and facilitate AD-like changes in the hippocampus. Thus, our findings may help elucidate the role of gene-environment interactions in AD development.

Enhancing the diagnostic accuracy of colorectal cancer through the integration of serum tumor markers and hematological indicators with machine learning algorithms.

BACKGROUND: Colorectal cancer has a high incidence and mortality rate due to a low rate of early diagnosis. Therefore, efficient diagnostic methods are urgently needed. PURPOSE: This study assesses the diagnostic effectiveness of Carbohydrate Antigen 19-9 (CA19-9), Carcinoembryonic Antigen (CEA), Alpha-fetoprotein (AFP), and Cancer Antigen 125 (CA125) serum tumor markers for colorectal cancer (CRC) and investigates a machine learning-based diagnostic model incorporating these markers with blood biochemical indices for improved CRC detection. METHOD: Between January 2019 and December 2021, data from 800 CRC patients and 697 controls were collected; 52 patients and 63 controls attending the same hospital in 2022 were collected as an external validation set. Markers' effectiveness was analyzed individually and collectively, using metrics like ROC curve AUC and F1 score. Variables chosen through backward regression, including demographics and blood tests, were tested on six machine learning models using these metrics. RESULT: In the case group, the levels of CEA, CA199, and CA125 were found to be higher than those in the control group. Combining these with a fourth serum marker significantly improved predictive efficacy over using any single marker alone, achieving an Area Under the Curve (AUC) value of 0.801. Using stepwise regression (backward), 17 variables were meticulously selected for evaluation in six machine learning models. Among these models, the Gradient Boosting Machine (GBM) emerged as the top performer in the training set, test set, and external validation set, boasting an AUC value of over 0.9, indicating its superior predictive power. CONCLUSION: Machine learning models integrating tumor markers and blood indices offer superior CRC diagnostic accuracy, potentially enhancing clinical practice.

APP/PS1 Gene-Environment Noise Interaction Aggravates AD-like Neuropathology in Hippocampus Via Activation of the VDAC1 Positive Feedback Loop.

BACKGROUND: Environmental risk factors, including environmental noise stress, and genetic factors, have been associated with the occurrence and development of Alzheimer's disease (AD). However, the exact role and mechanism of AD-like pathology induced by environment-gene interactions between environmental noise and APP/PS1 gene remain elusive. METHODS: Herein, we investigated the impact of chronic noise exposure on AD-like neuropathology in APP/PS1 transgenic mice. The Morris water maze (MWM) task was conducted to evaluate AD-like changes. The hippocampal phosphorylated Tau, amyloid-ß (Aß), and neuroinflammation were assessed. We also assessed changes in positive feedback loop signaling of the voltage-dependent anion channel 1 (VDAC1) to explore the potential underlying mechanism linking AD-like neuropathology to noise-APP/PS1 interactions. RESULTS: Long-term noise exposure significantly increased the escape latency and the number of platform crossings in the MWM task. The Aß overproduction was induced in the hippocampus of APP/PS1 mice, along with the increase of Tau phosphorylation at Ser396 and Thr231 and the increase of the microglia and astrocytes markers expression. Moreover, the VDAC1-AKT (protein kinase B)-GSK3ß (glycogen synthase kinase 3 beta)-VDAC1 signaling pathway was abnormally activated in the hippocampus of APP/PS1 mice after noise exposure. CONCLUSION: Chronic noise exposure and APP/PS1 overexpression may synergistically exacerbate cognitive impairment and neuropathological changes that occur in AD. This interaction may be mediated by the positive feedback loop of the VDAC1-AKT-GSK3ß-VDAC1 signaling pathway.

An alternative choice of lidocaine-loaded liposomes: lidocaine-loaded lipid-polymer hybrid nanoparticles for local anesthetic therapy.

PURPOSE: The skin permeation enhancement of local anesthetics by newer innovative nanotechnologies has been an appealing field recently. However, which nanocarrier is better for drug loading and has better stability? Therefore, the aim of our study was to compare two kinds of nanocarriers: liposomes and lipid-polymer hybrid nanoparticles (LPNs) for lidocaine (LA) delivery. METHODS: LA-loaded liposomes (LA-LPs) and LPNs (LA-LPNs) were prepared. Two kinds of nanocarriers were characterized in terms of particle size, zeta potential, drug encapsulation efficiency (EE), drug release, and stability. Their in vitro skin permeation was studied using a Franz diffusion cell mounted with depilated mouse skin in vitro. In vivo local anesthetic effects of LA containing formulations were evaluated by tail flick latency (TFL) test using a tail-flick measuring device. RESULTS: Compared with LA-LPs, LA-LPNs showed significantly better in vitro skin permeation ability and in vivo local anesthetic effects. CONCLUSION: The results demonstrated that LPNs could improve the efficacy of drugs to higher levels than LPs and free drugs, thus could serve as an effective drug system for LA loading for local anesthetic therapy.

Local anesthetic lidocaine delivery system: chitosan and hyaluronic acid-modified layer-by-layer lipid nanoparticles.

CONTEXT: Transdermal local anesthesia is one of the most applied strategies to avoid systemic adverse effects; there is an appealing need for a prolonged local anesthetic that would provide better bioavailability and longer pain relief with a single administration. OBJECTIVE: Layer-by-layer (LBL) technique was used in this study to explore a nanosized drug delivery system for local anesthetic therapy. MATERIALS AND METHODS: LBL-coated lidocaine-loaded nanostructured lipid nanoparticles (LBL-LA/NLCs) were prepared and characterized in terms of particle size (PS), zeta potential, drug encapsulation efficiency (EE), in vitro skin permeation and in vivo local anesthetic studies. RESULTS: Evaluation of the in vitro skin permeation and in vivo anesthesia effect illustrated that LBL-LA/NLCs can enhance and prolong the anesthetic effect of LA. DISCUSSION AND CONCLUSION: LBL-LA/NLCs could function as a promising drug delivery strategy for overcoming the barrier function of the skin and could deliver anesthetic through the skin with sustained release behavior for local anesthetic therapy.