Circadian disturbances by altering the light-dark cycle negatively affects hematopoietic function of bone marrow in mice.

Circadian rhythms in metabolically active tissues are crucial for maintaining physical health. Circadian disturbance (CD) can cause various health issues, such as metabolic abnormalities and immune and cognitive dysfunctions. However, studies on the role of CD in immune cell development and differentiation, as well as the rhythmic expression of the core clock genes and their altered expression under CD, remain unclear. Therefore, we exposed C57bl/6j mice to repeated reversed light-dark cycles for 90 days to research the effects of CD on bone marrow (BM) hematopoietic function. We also researched the effects of CD on endogenous circadian rhythms, temporally dependent expression in peripheral blood and myeloid leukocytes, environmental homeostasis within BM, and circadian oscillations of hematopoietic-extrinsic cues. Our results confirmed that when the light and dark cycles around mice were frequently reversed, the circadian rhythmic expression of the two main circadian rhythm markers, the hypothalamic clock gene, and serum melatonin, was disturbed, indicating that the body was in a state of endogenous CD. Furthermore, CD altered the temporally dependent expression of peripheral blood and BM leukocytes and destroyed environmental homeostasis within the BM as well as circadian oscillations of hematopoietic-extrinsic cues, which may negatively affect BM hematopoiesis in mice. Collectively, these results demonstrate that circadian rhythms are vital for maintaining health and suggest that the association between CD and hematopoietic dysfunction warrants further investigation.

Lactobacillus rhamnosus GG ameliorates noise-induced cognitive deficits and systemic inflammation in rats by modulating the gut-brain axis.

Background: Environmental noise exposure is linked to neuroinflammation and imbalance of the gut microbiota. Promoting gut microbiota homeostasis may be a key factor in relieving the deleterious non-auditory effects of noise. This study aimed to investigate the effect of Lactobacillus rhamnosus GG (LGG) intervention on noise-induced cognitive deficits and systemic inflammation in rats. Methods: Learning and memory were assessed using the Morris water maze, while 16S rRNA sequencing and gas chromatography-mass spectrometry were used to analyze the gut microbiota and short-chain fatty acid (SCFA) content. Endothelial tight junction proteins and serum inflammatory mediators were assessed to explore the underlying pathological mechanisms. Results: The results indicated that Lactobacillus rhamnosus GG intervention ameliorated noise-induced memory deterioration, promoted the proliferation of beneficial bacteria, inhibited the growth of harmful bacteria, improved dysregulation of SCFA-producing bacteria, and regulated SCFA levels. Mechanistically, noise exposure led to a decrease in tight junction proteins in the gut and hippocampus and an increase in serum inflammatory mediators, which were significantly alleviated by Lactobacillus rhamnosus GG intervention. Conclusion: Taken together, Lactobacillus rhamnosus GG intervention reduced gut bacterial translocation, restored gut and blood-brain barrier functions, and improved gut bacterial balance in rats exposed to chronic noise, thereby protecting against cognitive deficits and systemic inflammation by modulating the gut-brain axis.

The efficacy and safety of Chinese herbal medicine Guizhi Fuling capsule combined with low dose mifepristone in the treatment of uterine fibroids: a systematic review and meta-analysis of 28 randomized controlled trials.

OBJECTIVE: Guizhi Fuling Capsule (GZFL), a classic traditional Chinese medicine prescription, is often recommended for the treatment of uterine fibroids (UFs). However, the efficacy and safety of GZFL in combination with low-dose mifepristone (MFP) remains controversial. MATERIALS AND METHODS: We searched eight literature databases and two clinical trial registries for randomized controlled trials (RCTs) of the efficacy and safety of GZFL combined with low-dose MFP in the treatment of UFs from database inception to April 24, 2022. Data analysis was performed using the Meta package in RStudio and RevMan 5.4. GRADE pro3.6.1 software was used for the assessment of evidence quality. RESULTS: Twenty-eight RCTs were included in this study, including a total of 2813 patients. The meta-analysis showed that compared with low-dose MFP alone, GZFL combined with low-dose MFP significantly reduced follicle stimulating hormone (p < 0.001), estradiol (p < 0.001), progesterone (p < 0.001), luteinizing hormone (p < 0.001), uterine fibroids volume (p < 0.001), uterine volume (p < 0.001), menstrual flow (p < 0.001) and increased clinical efficiency rate (p < 0.001). Meanwhile, GZFL combined with low-dose MFP did not significantly increase the incidence of adverse drug reactions compared with low-dose MFP alone (p = 0.16). The quality of the evidence for the outcomes ranged from "very low" to "moderate." CONCLUSION: This study suggests that GZFL combined with low-dose MFP is more effective and safe in the treatment of UFs, and it is a potential treatment for UFs. However, due to the poor quality of the included RCTs formulations, we recommend a rigorous, high-quality, large-sample trial to confirm our findings.

A rapid, non-invasive method for fatigue detection based on voice information.

Fatigue results from a series of physiological and psychological changes due to continuous energy consumption. It can affect the physiological states of operators, thereby reducing their labor capacity. Fatigue can also reduce efficiency and, in serious cases, cause severe accidents. In addition, it can trigger pathological-related changes. By establishing appropriate methods to closely monitor the fatigue status of personnel and relieve the fatigue on time, operation-related injuries can be reduced. Existing fatigue detection methods mostly include subjective methods, such as fatigue scales, or those involving the use of professional instruments, which are more demanding for operators and cannot detect fatigue levels in real time. Speech contains information that can be used as acoustic biomarkers to monitor physiological and psychological statuses. In this study, we constructed a fatigue model based on the method of sleep deprivation by collecting various physiological indexes, such as P300 and glucocorticoid level in saliva, as well as fatigue questionnaires filled by 15 participants under different fatigue procedures and graded the fatigue levels accordingly. We then extracted the speech features at different instances and constructed a model to match the speech features and the degree of fatigue using a machine learning algorithm. Thus, we established a method to rapidly judge the degree of fatigue based on speech. The accuracy of the judgment based on unitary voice could reach 94%, whereas that based on long speech could reach 81%. Our fatigue detection method based on acoustic information can easily and rapidly determine the fatigue levels of the participants. This method can operate in real time and is non-invasive and efficient. Moreover, it can be combined with the advantages of information technology and big data to expand its applicability.

Around-the-Clock Noise Induces AD-like Neuropathology by Disrupting Autophagy Flux Homeostasis.

Environmental noise is a common hazard in military operations. Military service members during long operations are often exposed to around-the-clock noise and suffer massive emotional and cognitive dysfunction related to an Alzheimer's disease (AD)-like neuropathology. It is essential to clarify the mechanisms underlying the effects of around-the-clock noise exposure on the central nervous system. Here, Wistar rats were continuously exposed to white noise (95 dB during the on-duty phase [8:00-16:00] and 75 dB during the off-duty phase (16:00-8:00 the next day)) for 40 days. The levels of phosphorylated tau, amyloid-ß (Aß), and neuroinflammation in the cortex and hippocampus were assessed and autophagosome (AP) aggregation was observed by transmission electron microscopy. Dyshomeostasis of autophagic flux resulting from around-the-clock noise exposure was assessed at different stages to investigate the potential pathological mechanisms. Around-the-clock noise significantly increased Aß peptide, tau phosphorylation at Ser396 and Ser404, and neuroinflammation. Moreover, the AMPK-mTOR signaling pathway was depressed in the cortex and the hippocampus of rats exposed to around-the-clock noise. Consequently, autophagosome-lysosome fusion was deterred and resulted in AP accumulation. Our results indicate that around-the-clock noise exposure has detrimental influences on autophagic flux homeostasis and may be associated with AD-like neuropathology in the cortex and the hippocampus.

Disruption of Glutamate Release and Uptake-Related Protein Expression After Noise-Induced Synaptopathy in the Cochlea.

High-intensity noise can cause permanent hearing loss; however, short-duration medium-intensity noise only induces a temporary threshold shift (TTS) and damages synapses formed by inner hair cells (IHCs) and spiral ganglion nerves. Synaptopathy is generally thought to be caused by glutamate excitotoxicity. In this study, we investigated the expression levels of vesicle transporter protein 3 (Vglut3), responsible for the release of glutamate; glutamate/aspartate transporter protein (GLAST), responsible for the uptake of glutamate; and Na+/K+-ATPase α1 coupled with GLAST, in the process of synaptopathy in the cochlea. The results of the auditory brainstem response (ABR) and CtBP2 immunofluorescence revealed that synaptopathy was induced on day 30 after 100 dB SPL noise exposure in C57BL/6J mice. We found that GLAST and Na+/K+-ATPase α1 were co-localized in the cochlea, mainly in the stria vascularis, spiral ligament, and spiral ganglion cells. Furthermore, Vglut3, GLAST, and Na+/K+-ATPase α1 expression were disrupted after noise exposure. These results indicate that disruption of glutamate release and uptake-related protein expression may exacerbate the occurrence of synaptopathy.

Effects of noise and low-concentration carbon monoxide exposure on rat immunity.

OBJECTIVE: To evaluate the immunotoxicity and effects of noise and/or low-concentration carbon monoxide (CO) exposure on immune organs and immune functions in rats. METHODS: Male Wistar rats exposed to 98 dB(A) white noise and/or 100 ppm CO 4 h/d for 30 d were used to determine the pathological changes in the thymus and spleen, and variations in leukocyte counts, inflammatory factors, and immunoglobulin (Ig) concentrations. RESULTS: The boundaries of the cortex and medulla of the thymus were unclear following noise and combined exposure. The pathological changes in spleen after CO and combined exposure included blurred boundaries of red-pulp and white-pulp, disappearance of normal splenic nodules and neutrophil infiltration. After exposure to noise and in combination, leukocyte and lymphocyte counts decreased significantly. After exposure to low-concentration CO and in combination, serum IgM and IgG levels decreased significantly, but the levels of tumor necrosis factor-α and interferon-γ levels increased significantly. Eosinophils and IgA levels decreased significantly following exposure to noise and/or low concentration of CO, while the level of interleukin-1 increased significantly. Monocytes increased significantly only under noise or CO exposure, but not under combined exposure. CONCLUSIONS: Noise and/or low-concentration CO exposure may suppress innate and adaptive immune functions and induce inflammatory responses. Noise exposure mainly affected the innate immune function of rats, whereas low-concentration CO exposure mainly affected adaptive immune functions. Combined exposure presented higher immunotoxicity than noise or CO alone, suggesting that exposure to noise and low-concentration CO in the living and working environments can affect the immune system.

Baicalin and Geniposide Inhibit Polarization and Inflammatory Injury of OGD/R-Treated Microglia by Suppressing the 5-LOX/LTB4 Pathway.

Cerebral ischemia causes severe neurological disorders and neuronal dysfunction. Baicalin (BC), geniposide (GP), and their combination (BC/GP) have been shown to inhibit post-ischemic inflammatory injury by inhibiting the 5-LOX/CysLTs pathway. The aims of this study were to observe the inhibitory effects of BC/GP on the activation of microglial cells induced by oxygen glucose deprivation and reoxygenation (OGD/R) and to investigate whether the 5-LOX/LTB4 pathway was involved in these effects. Molecular docking showed that BC and GP exhibited considerable binding activity with LTB4 synthase LTA4H. BV-2 microglia were transfected with a 5-LOX overexpression lentiviral vector, and then OGD/R was performed. The effects of different concentrations of BC, GP, and BC/GP (6.25 µM, 12.5 µM, and 25 µM) on cell viability and apoptosis of microglia were evaluated by MTT and flow cytometry. The expression of TNF-α, IL-1ß, NF-κB, and pNF-κB also was measured by ELISA, Western blots and immunofluorescence. Western blots and qRT-PCR analysis were used to determine the levels of CD11b, CD206, and 5-LOX pathway proteins. Results showed that BC, GP, and BC/GP reduced the apoptosis caused by OGD/R in a dose-dependent manner, and cell viability was significantly increased at a concentration of 12.5 µM. OGD/R significantly increased the release of TNF-α, IL-1ß, NF-κB, pNF-κB, and CD11b. These effects were suppressed by BC, GP, and BC/GP, and the OGD/R-induced transfer of NF-κB p65 from the ctytoplasm to the nucleus was inhibited in microglia. Interestingly, the LTB4 inhibitor, U75302, exhibited the same effect. Also, BC, GP, and BC/GP significantly reduced the expression of 5-LOX pathway proteins. These results demonstrated that BC/GP inhibited OGD/R-induced polarization in BV2 microglia by regulating the 5-LOX/LTB4 signaling pathways and attenuating the inflammatory response. Our results supported the theoretical basis for additional in-depth study of the function of BC/GP and the value of determining its unique target, which might provide a new therapeutic strategy for ischemic cerebrovascular disease.

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.

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.

Exposure to copper oxide nanoparticles triggers oxidative stress and endoplasmic reticulum (ER)-stress induced toxicology and apoptosis in male rat liver and BRL-3A cell.

Copper oxide nanoparticles (Nano-CuO) toxicity has been researched widely in recent years. However, the relationship between oxidative stress and ER-stress and the possible mechanisms induced by Nano-CuO have been rarely studied. Here, the mechanism of hepatotoxicity and apoptosis through oxidative stress and ER-stress induced by Nano-CuO was investigated in vivo and in vitro. In in vivo experiments, male Wistar rats were intranasally instilled 10 µg Nano-CuO/g body weight daily for 60 days, which caused liver function impairment, oxidative stress, inflammatory response, histopathological and ultrastructural damage, ER-stress and apoptosis in liver tissue. in vitro experiments on rat hepatocytes BRL-3A cells showed that exposure to Nano-CuO for 24 h resulted in excess production of reactive oxygen species leading to decrease in mitochondria membrane potential causing cell death by inducing apoptosis. However, administration of n-acetyl cysteine decreased the apoptosis in Nano-cuo treated group. The in vivo and in vitro experiments confirmed that oxidative stress triggered ER-stress pathway, leading to the opening of apoptosis pathways of CHOP, JNK, and Caspase-12. In summary, treatment of Nano Cuo triggered oxidative stress by ROS, which in turn resulted in activation of ER stress pathways causing cell death in liver tissue and BRL-3A cells.

Safety of the Xuesaitong injection in China: results from a large-scale multicentre post-marketing surveillance study in a real-world setting.

OBJECTIVE: The safety profile of traditional Chinese medicine injections has emerged as the greatest challenge to their clinical application. The authors aimed to perform a post-marketing surveillance study in a real-world setting to evaluate the safety of the Xuesaitong (XST) injection in China. METHODS: This multi-centre, post-marketing, observational study enrolled patients who received XST injections in 42 centres in China between March 2015 and November 2017. Adverse drug reactions (ADRs) and adverse drug events (ADEs) were collected and evaluated in a post-marketing database. Logistic regression analysis was performed to analyse the risk factors for ADRs. RESULTS: A total of 30,008 consecutive patients with a mean age of 62.29 ± 14.58 years were included in this post-marketing study. The incidences of ADEs and ADRs were 0.5% and 0.33%, respectively. The most common clinical manifestations were damage to skin and appendages (47.66%). There were four new kinds of ADEs found in the present monitoring study. The majority of ADRs were type B (62.62%) and occurred within 24 h after XST injection treatment. No severe ADRs were reported in this analysis. Multivariate logistic regression analysis showed that the hospital level (OR = 0.607; 95% CI = 0.407-0.906; p = .0144), hypertension (OR = 1.979; 95% CI, 1.323-2.959; p = .0009) and solvent type (OR = 2.951; 95% CI, 1.608-5.417; p = .0005) were risk factors for ADR occurrence. CONCLUSION: XST injection is well tolerated and has a favourable safety profile for patients in a real-world setting. This post-marketing study provided further evidence of the safety of XST injections for clinical applications.

Combined exposure to formaldehyde and PM2.5: Hematopoietic toxicity and molecular mechanism in mice.

PM2.5 and formaldehyde (FA) are major outdoor and indoor air pollutants in China, respectively, and both are known to be harmful to human health and to be carcinogenic. Of all the known chronic health effects, leukaemia is one of the most serious health risks associated with these two pollutants. To explore the influence and underlying mechanisms of exposure to formaldehyde and PM2.5 on hematopoietic toxicity, we systematically studied the toxicity induced in hematopoietic organs: bone marrow (BM); spleen; and myeloid progenitor cells (MPCs). Male Balb/c mice were exposed to: PM2.5 (20, 160 µg/kg·d) at a dose of 40 µL per mouse or formaldehyde (0.5, 3.0 mg/m3) for 8 h per day for 2 weeks or co-exposed to formaldehyde and PM2.5 (20 µg/kg·d PM2.5 + 0.5 mg/m3 FA, 20 µg/kg·d PM2.5 + 3 mg/m3 FA, 160 µg/kg·d PM2.5 + 0.5 mg/m3 FA, 160 µg/kg·d PM2.5 + 3 mg/m3 FA) for 2 weeks. Similar toxic effects were found in the formaldehyde-only and PM2.5-only groups, including significant decrease of blood cells and MPCs, along with decreased expression of hematopoietic growth factors. In addition, individual exposure of formaldehyde or PM2.5 increased oxidative stress, DNA damage and immune system disorder by destroying the balance of Th1/Th2, and Treg/Th17. DNA repair was markedly inhibited by deregulating the mammalian target of rapamycin (mTOR) pathway. Combined exposure to PM2.5 and formaldehyde led to more severe effects. Administration of Vitamin E (VE) was shown to attenuate these effects. In conclusion, our findings suggested that PM2.5 and formaldehyde may induce hematopoietic toxicity by reducing the expression of hematopoietic growth factors, increasing oxidative stress and DNA damage, activating the 'immune imbalance' pathway and suppressing the DNA-repair related mTOR pathway. The hematopoietic toxicity induced by combined exposure of PM2.5 and formaldehyde might provide further insights into the increased incidence of hematological diseases, including human myeloid leukaemia.

Neurotoxicity of aluminum oxide nanoparticles and their mechanistic role in dopaminergic neuron injury involving p53-related pathways.

The central nervous system is a potential target for Al2O3 nanoparticles (Nano-Al2O3). Here, we investigated the effects of intranasal instillation of Nano-Al2O3 on the distribution and damage in crucial functional sub-brain regions of rats. In vivo results show that Nano-Al2O3 was translocated into the brain via the olfactory nerve pathway. Nano-Al2O3 accumulated in the hippocampus, olfactory bulb, cerebral cortex, and striatum, causing ultrastructural changes, oxidative damage, inflammatory responses, and histopathological damage in sub-brain regions. As indicated by in vitro studies, cell viability decreased with the addition of Nano-Al2O3, which increased the levels of lactate dehydrogenase and oxidative stress. Nano-Al2O3 also impaired mitochondrial function, disturbed the cell cycle and induced apoptosis. In addition, Nano-Al2O3 decreased the expression of cyclin D1, bcl-2, Mdm2, and phospho-Rb and increased the expression of p53, p21, Bax, and Rb. Therefore, oxidative stress, mitochondrial dysfunction, and p53-related pathways might be important in the process of dopaminergic neurotoxicity induced by Nano-Al2O3. The current study establishes a striatum damage model and identifies molecular biomarkers of dopaminergic neuron damage induced by Nano-Al2O3. In brief, our study demonstrates that Nano-Al2O3 exposure can be a risk factor for neurodegenerative diseases and may negatively impact the hippocampus, striatum, and dopaminergic neurons.

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.

Neurotoxicity and biomarkers of zinc oxide nanoparticles in main functional brain regions and dopaminergic neurons.

Manufactured zinc oxide nanoparticles (Nano-ZnO) are being used increasingly in many fields owing to their excellent physicochemical properties. Consequently, biosecurity has become a growing concern for human health and the environment. In the present study, Nano-ZnO neurotoxicity was investigated in vivo and in vitro. In vivo results showed that Nano-ZnO particles delivered through intranasal instillation were translocated to the brain, specifically deposited in the olfactory bulb, hippocampus, striatum, and cerebral cortex, and caused ultrastructural changes, oxidative damage, inflammatory responses, and histopathological damages there, which may be important for inducing Nano-ZnO neurotoxicity. Further in vitro studies on PC12 cell line illustrated that exposure to Nano-ZnO for 6 h affected cell morphology, decreased cell viability, increased lactate dehydrogenase and oxidative stress activity levels, impaired mitochondrial function, and disturbed the cell cycle. In addition, Nano-ZnO could destroy neuronal structure by affecting cytoskeleton proteins (tubulin-α, tubulin-ß and NF-H), resulting in the interruption of connection between nerve cells, which lead to nervous system function damage. Meanwhile, Nano-ZnO could induce neuronal repair and regeneration disorders by affecting the growth-related protein GAP-43 and delayed neurotoxicity by affecting the calcium/calcium-regulated kinase (CAMK2A/CAMK2B protein) signaling pathway.

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.

Tris (1,3-dichloro-2-propyl) phosphate induces toxicity by stimulating CaMK2 in PC12 cells.

Tris (1,3-dichloro-2-propyl) phosphate (TDCIPP) is one of the widely used organophosphorus flame retardants (OPFRs), which are regarded as suitable substitutes for brominated flame retardants (BFRs). Previously, we have validated the toxicity of TDCIPP in PC12 cells owing to the induced alterations in GAP43, NF-H, CaMK2a/2b, and tubulin α/ß proteins; however, limited information is currently available on the toxicity and mechanism of TDCIPP. In the present study, cytotoxicity effects were evaluated by exposing PC12 cells to different concentrations of TDCIPP (0-50 µM) for 4 days. To explore the possible mechanisms through which cytotoxicity is induced, changes in intracellular [Ca2+ ]i levels and the activation of calmodulin dependent protein kinase 2 (CaMK2), c-Jun N-terminal kinase (JNK), extracellular regulated protein kinases (ERK1/2), and p38 mitogen-activated protein kinases (MAPK) pathways were evaluated. Furthermore, PC12 cells were pretreated with CaMK2 inhibitor KN93 to investigate the relationship between TDCIPP-induced phosphorylation of CaMK2 and activation of JNK, ERK1/2, and p38 MAPK pathways. Our results indicate that TDCIPP-induced toxicity might be associated with the overload of [Ca2+ ]i levels, increased phosphorylation of CaMK2, and activation of the JNK, ERK1/2, and p38 MAPK pathways, the lattermost of which was further demonstrated to be partially elicited by the CaMK2 phosphorylation.

Effects of tris(1,3-dichloro-2-propyl)phosphate on pathomorphology and gene/protein expression related to thyroid disruption in rats.

Previous studies demonstrated that tris(1,3-dichloro-2-propyl)phosphate (TDCIPP) caused adverse effects on thyroid hormone (TH) imbalance in aquatic and avian organisms. This study focused on the effects of TDCIPP on thyroid function and hormone homeostasis in mammals. Pubertal female Sprague-Dawley rats were orally administered 50, 100, or 250 mg per kg per d of TDCIPP from postnatal day (PND) 22 to PND42 for 21 days. The serum triiodothyronine (T3) levels increased significantly at 250 mg per kg per d of TDCIPP. There were no significant differences in the body weight, serum thyroxine (T4) and free thyroxine (FT4) levels between the control and TDCIPP treated groups. There were significant dose-dependent increases in the mRNA and protein expression levels of genes related to drug metabolism (cytochrome-p450-3A1, CYP3A1) and TH clearance (udp-glucuronosyltransferase-1A6, UGT1A6) in the liver. Treatment with TDCIPP increased hepatic type 1 deiodinase (DIO1) mRNA at 250 mg per kg per d but down-regulated hepatic TH receptor beta (TRß) mRNA expression. In addition, TDCIPP exposure induced slight thyroid follicular hyperplasia, and several genes involved in TH biosynthesis (NIS, TPO, Tg) were altered at 100 and 250 mg per kg per d of TDCIPP. Nevertheless, serum thyroid stimulating hormone (TSH) levels and the receptor (TSHr) mRNA significantly decreased at only the low dose group. Based on these results, we certified that TDCIPP disturbs the normal bioprocess on TH synthesis, biotransformation or clearance, and hepatic detoxification of pubertal female SD rats, causing thyroid function disorder.