SUMOylation modification of FTO facilitates oxidative damage response of arsenic by IGF2BP3 in an m6A-dependent manner.

N6-methyladenosine (m6A) is the most common form of internal post-transcriptional methylation observed in eukaryotic mRNAs. The abnormally increased level of m6A within the cells can be catalyzed by specific demethylase fat mass and obesity-associated protein (FTO) and stay in a dynamic and reversible state. However, whether and how FTO regulates oxidative damage via m6A modification remain largely unclear. Herein, by using both in vitro and in vivo models of oxidative damage induced by arsenic, we demonstrated for the first time that exposure to arsenic caused a significant increase in SUMOylation of FTO protein, and FTO SUMOylation at lysine (K)- 216 site promoted the down-regulation of FTO expression in arsenic target organ lung, and therefore, remarkably elevating the oxidative damage via an m6A-dependent pathway by its specific m6A reader insulin-like growth factor-2 mRNA-binding protein-3 (IGF2BP3). Consequently, these findings not only reveal a novel mechanism underlying FTO-mediated oxidative damage from the perspective of m6A, but also imply that regulation of FTO SUMOylation may serve as potential approach for treatment of oxidative damage.

NBR1-mediated autophagic degradation of caspase 8 protects vascular endothelial cells against arsenite-induced apoptotic cell death.

Vascular endothelial cells play a critical role in maintaining the health of blood vessels, but dysfunction can lead to cardiovascular diseases. The impact of arsenite exposure on cardiovascular health is a significant concern due to its potential adverse effects. This study aims to explore how NBR1-mediated autophagy in vascular endothelial cells can protect against oxidative stress and apoptosis induced by arsenite. Initially, our observations revealed that arsenite exposure increased oxidative stress and triggered apoptotic cell death in human umbilical vein endothelial cells (HUVECs). However, treatment with the apoptosis inhibitor Z-VAD-FMK notably reduced arsenite-induced apoptosis. Additionally, arsenite activated the autophagy pathway and enhanced autophagic flux in HUVECs. Interestingly, inhibition of autophagy exacerbated arsenite-induced apoptotic cell death. Our findings also demonstrated the importance of autophagy receptor NBR1 in arsenite-induced cytotoxicity, as it facilitated the recruitment of caspase 8 to autophagosomes for degradation. The protective effect of NBR1 against arsenite-induced apoptosis was compromised when autophagy was inhibited using pharmacological inhibitors or through genetic knockdown of essential autophagy genes. Conversely, overexpression of NBR1 facilitated caspase 8 degradation and reduced apoptotic cell death in arsenite-treated HUVECs. In conclusion, our study highlights the vital role of NBR1-mediated autophagic degradation of caspase 8 in safeguarding vascular endothelial cells from arsenite-induced oxidative stress and apoptotic cell death. Targeting this pathway could offer a promising therapeutic approach to mitigate cardiovascular diseases associated with arsenite exposure.

Deferasirox exerts anti-epileptic effects by improving brain iron homeostasis via regulation of ITPRIP.

Epilepsy constitutes a global health concern, affecting millions of individuals and approximately one-third of patients exhibit drug resistance. Recent investigations have revealed alterations in cerebral iron content in both epilepsy patients and animal models. However, the extant literature lacks a comprehensive exploration into the ramifications of modulating iron homeostasis as an intervention in epilepsy. This study investigated the impact of deferasirox, a iron ion chelator, on epilepsy. This study unequivocally substantiated the antiepileptic efficacy of deferasirox in a kainic acid-induced epilepsy model. Furthermore, deferasirox administration mitigated seizure susceptibility in a pentylenetetrazol-induced kindling model. Conversely, the augmentation of iron levels through supplementation has emerged as a potential exacerbating factor in the precipitating onset of epilepsy. Intriguingly, our investigation revealed a hitherto unreported discovery: ITPRIP was identified as a pivotal modulator of excitatory synaptic transmission, regulating seizures in response to deferasirox treatment. In summary, our findings indicate that deferasirox exerts its antiepileptic effects through the precise targeting of ITPRIP and amelioration of cerebral iron homeostasis, suggesting that deferasirox is a promising and novel therapeutic avenue for interventions in epilepsy.

Intact lung tissue and bronchoalveolar lavage fluid are both suitable for the evaluation of murine lung microbiome in acute lung injury.

BACKGROUND: Accumulating clinical evidence suggests that lung microbiome is closely linked to the progression of pulmonary diseases; however, it is still controversial which specimen type is preferred for the evaluation of lung microbiome. METHODS AND RESULTS: To address this issue, we established a classical acute lung injury (ALI) mice model by intratracheal instillation of lipopolysaccharides (LPS). We found that the bacterial DNA obtained from the bronchoalveolar lavage fluid (BALF), intact lung tissue [Lung(i)], lung tissue after perfused [Lung(p)], and feces of one mouse were enough for 16S rRNA sequencing, except the BALF of mice treated with phosphate buffer saline (PBS), which might be due to the biomass of lung microbiome in the BALF were upregulated in the mice treated with LPS. Although the alpha diversity among the three specimens from lungs had minimal differences, Lung(p) had higher sample-to-sample variation compared with BALF and Lung(i). Consistently, PCoA analysis at phylum level indicated that BALF was similar to Lung(i), but not Lung(p), in the lungs of mice treated with LPS, suggesting that BALF and Lung(i) were suitable for the evaluation of lung microbiome in ALI. Importantly, Actinobacteria and Firmicutes were identified as the mostly changed phyla in the lungs and might be important factors involved in the gut-lung axis in ALI mice. Moreover, Actinobacteria and Proteobacteria might play indicative roles in the severity of lung injury. CONCLUSION: This study shows both Lung(i) and BALF are suitable for the evaluation of murine lung microbiome in ALI, and several bacterial phyla, such as Actinobacteria, may serve as potential biomarkers for the severity of ALI. Video Abstract.

Zinc Oxide Nanoparticles Exacerbate Epileptic Seizures by Modulating the TLR4-Autophagy Axis.

Background: Zinc oxide nanoparticles (ZnO NPs) has been widely used in various fields and has had an important impact on human public health. In addition, it inevitably damages human health, including neurological diseases. Therefore, this study explored the effect of ZnO NPs on epilepsy. Methods: The effect of ZnO NPs on epilepsy was observed by behavioral analysis. TLR4 expression and autophagy related pathways were detected by RNA-seq and Western blot. In addition, the cell types of autophagy were detected by immunofluorescence. Further, the electrophysiological changes of ZnO NPs induced autophagy were detected by whole-cell patch-clamp. Finally, the recovery experiment was carried out by TLR4 inhibitor (TAK-242). Results: We found that ZnO NPs enhanced epilepsy susceptibility and severity. Through RNA-seq analysis and Western blot, it was found that ZnO NPs affected the changes of TLR4 and autophagy related pathways. In addition, we found that ZnO NPs mainly affects autophagy of inhibitory neurons, resulting in excitation/inhibition imbalance. The autophagy and epileptic phenotypes were reversed with TAK-242. In general, ZnO NPs exacerbate epileptic seizures by modulating the TLR4-autophagy axis. Conclusion: ZnO NPs enhanced the susceptibility and severity of epilepsy. Mechanistically, ZnO NPs affected autophagy by changing the expression of TLR4. In particular, the ZnO NPs mainly affected the synaptic function of inhibitory neuron, leading to excitation/inhibition imbalances.

Distinguishing thermoelectric and photoelectric modes enables intelligent real-time detection of indoor electrical safety hazards.

Due to the prevalence of electronic devices, intelligent sensors have attracted much interest for the detecting and providing alarms with respect to indoor electrical safety. Nonetheless, how to effectively identify various indoor electrical safety hazards remains a challenge. In this study, we fabricated single-walled carbon nanotube/poly(3-hexylthiophene-2,5-diyl) (SWCNT/P3HT) composites with exceptional bifunctional thermoelectric and photoelectric responses. Through synergy of the thermo-/photoelectric effects, the composites yielded greatly enhanced output voltages compared with the use of thermoelectric effects alone. Interestingly, modes of heat transfer can be effectively distinguished using the nominal Seebeck coefficients. Based on the remarkable output voltages and deviations in the nominal Seebeck coefficients, we developed indoor intelligent sensors capable of effectively identifying and monitoring diverse indoor electrical conditions, including electrical overheating, fire, and air conditioning flow. This pioneering investigation proposes a novel avenue for designing intelligent sensors that can recognize heat transfer modes and hence effectively monitor indoor electrical safety hazards.

Semaglutide alleviates gut microbiota dysbiosis induced by a high-fat diet.

This study investigated the effects of semaglutide (Sema) on the gut microbiota of obese mice induced with high-fat diet (HFD). Male C57BL/6 J mice aged 6 weeks were enrolled and randomly distributed to four groups, which were provided with a normal control diet (NCD,NCD + Sema) and a 60% proportion of a high-fat diet (HFD,HFD + Sema), respectively. HFD was given for 10 weeks to develop an obesity model and the intervention was lasted for 18 days. The results showed semaglutide significantly reduced body weight gain, areas under the curve (AUC) of glucose tolerance test and insulin resistance test, as well as adipose tissue weight in mice. Semaglutide effectively reduced lipid deposition and lipid droplet formation in the liver of obese mice, and regulated the expression of genes related to abnormal blood glucose regulation. Additionally, semaglutide influenced the composition of gut microbiota, mitigating the microbial dysbiosis induced by a high-fat diet by impacting the diversity of the gut microbiota. After the high-fat diet intervention, certain strains such as Akkermansia, Faecalibaculum, and Allobaculum were significantly decreased, while Lachnospiraceae and Bacteroides were significantly increased. However, the application of semaglutide restored the lost flora and suppressed excessive bacterial abundance. Moreover, semaglutide increased the content of tight junction proteins and repaired the damage to intestinal barrier function caused by the high-fat diet intervention. Furthermore, correlation analysis revealed inverse relationship among Akkermansia levels and weight gain, blood glucose levels, and various obesity indicators. Correlation analysis also showed that Akkermansia level was negatively correlated with weight gain, blood glucose levels and a range of obesity indicators. This phenomenon may explain the anti-obesity effect of semaglutide, which is linked to alterations in gut microbiota, specifically an increase in the abundance of Akkermansia. In summary, our findings indicate that semaglutide has the potential to alleviate gut microbiota dysbiosis, and the gut microbiota may contribute to the obesity-related effects of this drug.

Association between Residential Greenness and Human Microbiota: Evidence from Multiple Countries.

BACKGROUND: Greenness, referring to a measurement of the density of vegetated land (e.g., gardens, parks, grasslands), has been linked with many human health outcomes. However, the evidence on greenness exposure and human microbiota remains limited, inconclusive, drawn from specific regions, and based on only modest sample size. OBJECTIVES: We aimed to study the association between greenness exposure and human microbial diversity and composition in a large sample across 34 countries and regions. METHODS: We explored associations between residential greenness and human microbial alpha-diversity, composition, and genus abundance using data from 34 countries. Greenness exposure was assessed using the normalized difference vegetation index and the enhanced vegetation index mean values in the month before sampling. We used linear regression models to estimate the association between greenness and microbial alpha-diversity and tested the effect modification of age, sex, climate zone, and pet ownership of participants. Differences in microbial composition were tested by permutational multivariate analysis of variance based on Bray-Curtis distance and differential taxa were detected using the DESeq2 R package between two greenness exposure groups split by median values of greenness. RESULTS: We found that higher greenness was significantly associated with greater richness levels in the palm and gut microbiota but decreased evenness in the gut microbiota. Pet ownership and climate zone modified some associations between greenness and alpha-diversity. Palm and gut microbial composition at the genus level also varied by greenness. Higher abundances of the genera Lactobacillus and Bifidobacterium, and lower abundances of the genera Anaerotruncus and Streptococcus, were observed in people with higher greenness levels. DISCUSSION: These findings suggest that residential greenness was associated with microbial richness and composition in the human skin and gut samples, collected across different geographic contexts. Future studies may validate the observed associations and determine whether they correspond to improvements in human health. https://doi.org/10.1289/EHP12186.

Environmental cadmium exposure facilitates mammary tumorigenesis via reprogramming gut microbiota-mediated glutamine metabolism in MMTV-Erbb2 mice.

Cadmium (Cd) is a heavy metal that has been widely reported to be linked to the onset and progression of breast cancer (BC). However, the mechanism of Cd-induced mammary tumorigenesis remains elusive. In our study, a transgenic mouse model that spontaneously develops tumors through overexpression of wild-type Erbb2 (MMTV-Erbb2) was constructed to investigate the effects of Cd exposure on BC tumorigenesis. The results showed that oral exposure to 3.6 mg/L Cd for 23 weeks dramatically accelerated tumor appearance and growth, increased Ki67 density and enhanced focal necrosis and neovascularization in the tumor tissue of MMTV-Erbb2 mice. Notably, Cd exposure enhanced glutamine (Gln) metabolism in tumor tissue, and 6-diazo-5-oxo-l-norleucine (DON), a Gln metabolism antagonist, inhibited Cd-induced breast carcinogenesis. Then our metagenomic sequencing and mass spectrometry-based metabolomics confirmed that Cd exposure disturbed gut microbiota homeostasis, especially Helicobacter and Campylobacter abundance remodeling, which altered the gut metabolic homeostasis of Gln. Moreover, intratumoral Gln metabolism profoundly increased under Cd-elevated gut permeability. Importantly, depletion of microbiota with an antibiotic cocktail (AbX) treatment led to a significant delay in the appearance of palpable tumors, inhibition of tumor growth, decrease in tumor weight, reduction in Ki67 expression and low-grade pathology in Cd-exposed MMTV-Erbb2 mice. Also, transplantation of Cd-modulated microbiota decreased tumor latency, accelerated tumor growth, increased tumor weight, upregulated Ki67 expression and exacerbated neovascularization as well as focal necrosis in MMTV-Erbb2 mice. In summary, Cd exposure induced gut microbiota dysbiosis, elevated gut permeability and increased intratumoral Gln metabolism, leading to the promotion of mammary tumorigenesis. This study provides novel insights into environmental Cd exposure-mediated carcinogenesis.

Reproductive effects of pubertal exposure to neonicotinoid thiacloprid in immature male mice.

Thiacloprid (THIA) is a kind of neonicotinoid, a widely used insecticide class. Animal studies of adult and prenatal exposure to THIA have revealed deleterious effects on mammalian sperm fertility and embryonic development. A recent cross-sectional study linked higher THIA concentrations to delayed genitalia development stages in adolescent boys, suggesting that pubertal exposure to THIA may adversely affect reproductive development in immature males. Hence, this study aimed to investigate the effects of daily oral administration of THIA during puberty on the reproductive system of developing male mice. Young male C57 BL/6 J mice aged 21 days were administrated with THIA at concentrations of 10 (THIA-10), 50 (THIA-50) and 100 mg/kg (THIA-100) for 4 weeks by oral gavage. It is found that exposure to 100 mg/kg THIA diminished sexual behavior in immature male mice, caused a decrease in the spermatogenic cell layers and irregular arrangement of the seminiferous epithelium, and down-regulated the mRNA levels of spermatogenesis-related genes Ddx4, Scp3, Atg5, Crem, and Ki67, leading to an increase of sperm abnormality rate. In addition, THIA exposure at 50 and 100 mg/kg reduced the serum levels of testosterone and FSH, and decreased the expression levels of Star and Cyp11a1 related to testosterone biosynthesis. THIA exposure at 10 mg/kg did not produce any of the above significant changes. In conclusion, the high dose of THIA exposure impaired reproductive function in immature mice. It seems that THIA has no detrimental effects on the reproductive system of mice at low dose of 10 mg/kg.

Alterations of Gut-Derived Melatonin in Neurobehavioral Impairments Caused by Zinc Oxide Nanoparticles.

Purpose: The widespread use of zinc oxide nanoparticles (ZnONPs) has raised concerns about its potential toxicity. Melatonin is a neurohormone with tremendous anti-toxic effects. The enterochromaffin cells are an essential source of melatonin in vivo. However, studies on the effects of ZnONPs on endogenous melatonin are minimal. In the present study, we aimed to investigate the effects of ZnONPs exposure on gut-derived melatonin. Methods: In the present study, 64 adult male mice were randomly and equally divided into four groups, and each group was exposed to ZnONPs (0, 6.5, 13, 26 mg/kg/day) for 30 days. Subsequently, the neurobehavioral changes were observed. The effects of ZnONPs on the expression of melatonin-related genes arylalkylamine N-acetyltransferase (Aanat), melatonin receptor1A (Mt1/Mtnr1a), melatonin receptor1B (Mt2/Mtnr1b), and neuropeptide Y (Npy) on melatonin synthesis and secretion in duodenum, jejunum, ileum and colon during day and night were also assessed. Results: The results revealed that oral exposure to ZnONPs induced impairments of locomotor activity and anxiety-like behavior in adult mice during the day. The transcriptional analysis of brain tissues revealed that exposure to ZnONPs caused profound effects on genes and transcriptional signaling pathways associated with melatonin synthesis and metabolic processes during the day and night. We also observed that, in the duodenum, jejunum, ileum and colon sites, ZnONPs resulted in a significant reduction in the expression of the gut-derived melatonin rate-limiting enzyme Aanat, the membrane receptors Mt1 and Mt2 and Npy during the day and night. Conclusion: Taken together, this is the first study shows that oral exposure to ZnONPs interferes with melatonin synthesis and secretion in different intestinal segments of adult mice. These findings will provide novelty insights into the neurotoxic mechanisms of ZnONPs and suggest an alternative strategy for the prevention of ZnONP neurotoxicity.

Risk of Environmental Chemicals on Bone Fractures Is Independent of Low Bone Mass in US Adults: Insights from 2017 to 2018 NHANES.

To assess the association of environmental chemical factors with osteopenia and/or bone fractures. All data were extracted from the National Health and Nutrition Survey (NHANES) 2017-2018 of American adults aged 20-59 years old; invalid data were excluded based on dual-energy X-ray absorptiometry. For the ultimate valid data set, multivariate logistic regression models were applied to evaluate the association of environmental chemical factors with osteopenia and bone fractures. The valid dataset was obtained from 2640 individuals, who completed a questionnaire of demographic characteristics. Urinary manganese and monomethylarsonic acid were positively associated with osteopenia in American adults, but not bone fracture. However, several environmental factors (e.g., arsenous acid, arsenocholine, dimethylarsinic acid, and 2-thioxothiazolidine-4-carboxylic acid) did not affect bone mineral density, but were significantly associated with bone fracture. Multiple environmental chemical factors significantly affect bone mass or fracture risk. However, the risk of environmental chemical factors on fractures is independent of osteopenia in US Adults. The influence of environmental chemical factors on bone quality should be considered and monitored.

Involvement of gut-brain communication in arsenite-induced neurobehavioral impairments in adult male mice.

Arsenite is a well-documented neurotoxic metalloid that widely distributes in the natural environment. However, it remains largely unclear how arsenite affects neurological function. Therefore, in this study, the healthy adult male mice were exposed to 0.5 mg/L and 5 mg/L arsenite through drinking water for 30 and 90 days, respectively. Our results showed that there was no significant alteration in the intestine and brain for 30 days exposure, but exposure to arsenite for 90 days significantly induced a reduction of locomotor activity and anxiety-like behavior, caused pathological damage and inflammatory responses in the brain and intestine. We also found that arsenite remarkably disrupted intestinal barrier integrity, decreased the levels of lysozyme and digestive enzymes. Intriguingly, chronic exposure to arsenite significantly changed the levels of gut-brain peptides. Taken together, this study provides meaningful insights that gut-brain communication may involve in the neurobehavioral impairments of arsenite.

Disruption of the lung-gut-brain axis is responsible for cortex damage induced by pulmonary exposure to zinc oxide nanoparticles.

Increasing evidence shows that gut microbiota is important for host health in response to metal nanomaterials exposure. However, the effect of gut microbiota on the cortex damage caused by pulmonary exposure to zinc oxide nanoparticles (ZnONPs) remains mainly unknown. In this study, a total of 48 adult C57BL/6J mice were intratracheally instilled with 0.6 mg/kg ZnONPs in the presence or absence of antibiotics (ABX) treatment. Besides, 24 mice were treated with or without fecal microbiota transplantation (FMT) after the intraperitoneal administration of ABX. Our results demonstrated for the first time that dysbiosis induced by ABX treatment significantly aggravated cortex damage induced by pulmonary exposure to ZnONPs. Such damage might highly occur through the induction of oxidative stress, manifested by the enhancement of antioxidative enzymes and products of lipid peroxidation. However, ferroptosis was not involved in this process. Interestingly, our data revealed that ABX treatment exacerbated the alterations of gut-brain peptides (including Sst, Sstr2, and Htr4) induced by ZnONPs in both gut and cortex tissues. Moreover, fecal microbiota transplantation (FMT) was able to alleviate cerebral cortex damage, oxidative stress, and alterations of gut-brain peptides induced by pulmonary exposure to ZnONPs. The results together indicate that pulmonary exposure to ZnONPs causes cerebral cortex damage possibly via the disruption of the lung-gut-brain axis. These findings not only propose valuable insights into the mechanism of ZnONPs neurotoxicity but also provide a potential therapeutic method against brain disorders induced by pulmonary exposure to ZnONPs. AVAILABILITY OF DATA AND MATERIALS: The datasets used and/or analyzed during the current study are available from the The corresponding author on reasonable request.

Inhibition of cGAS ameliorates acute lung injury triggered by zinc oxide nanoparticles.

PURPOSE: Zinc oxide nanoparticles (ZnONPs) have been widely used in various industrial and biomedical fields. Occupational or accidental inhalation exposure to ZnONPs might lead to acute lung injury (ALI). Cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) are critical for the initiation and expansion of inflammation and contribute to tissue injury; however, the role and mechanism of the cGAS-STING pathway in ALI-induced by ZnONPs are unclear. METHODS: Male C57BL/6 J mice were intratracheally injected with ZnONPs (0.6 mg/kg) or mock. The mice were euthanized and the degree of lung injury was determined 3 days after the instillation of ZnONPs. The BEAS-2B cell line was used as a cell model to investigate the cytotoxicity of ZnONPs in vitro. RESULTS: We found that ZnONPs inhalation induced ALI in mice, manifested by exacerbated lung pathological changes, mitochondrial damage, oxidative stress and inflammation. Interestingly, cGAS and STING were activated in the lung tissues of the mice and BEAS-2B lung epithelial cells treated with ZnONPs. More importantly, we illustrated that the cGAS inhibitor RU.521 inhibited the activation of the cGAS-STING pathway, further decreased oxidative stress and inflammation, and led to ameliorated lung injury in mice treated with ZnONPs. CONCLUSION: This study demonstrated that ZnONPs trigger the activation of the cGAS-STING pathway, which plays an important role in ZnONPs-induced ALI. Inhibition of cGAS with RU.521 mitigates the oxidative stress induced by ZnONPs, suggesting that targeting the cGAS-STING pathway may be a feasible strategy to ameliorate the pulmonary injury caused by nanoparticles.

Heterozygous disruption of beclin 1 alleviates neurotoxicity induced by sub-chronic exposure of arsenite in mice.

Arsenite is a well-documented neurotoxicant that widely exists in the environment. However, the detailed mechanisms of arsenite neurotoxicity are not fully clarified. Autophagy has been reported to be involved in many neurological problems induced by arsenite. Since beclin 1 is an essential mediator of autophagy, we herein used both adult wild-type (beclin 1+/+) and heterozygous disruption of beclin 1 (beclin 1+/-) mice for chronic administration of 50 mg/L arsenite via drinking water for 3 months. Our results demonstrated that exposure of arsenite caused the working memory deficit, anxiety-like behavior and motor coordination disorder in beclin 1+/+ mice, accompanied with pathological changes in morphology and electrophysiology in the cortical tissues. This treatment of arsenite significantly reduced the number of neuronal cells and induced microglia activation and synaptic transmission disorders in the wild-type mice as compared with vehicle controls. Intriguingly, by using beclin 1+/- mice, we found that heterozygous disruption of beclin 1 profoundly attenuated these neurotoxic effects induced by arsenite, mainly manifested by improvements in the neurobehavioral impairments, abnormal electrophysiologic alterations as well as dysregulation of synaptic transmission. These findings together indicate that regulation of autophagy via beclin 1 would be a potential strategy for treatment against arsenite neurotoxicity.

Exposure to di (2-ethylhexyl) phthalate causes locomotor increase and anxiety-like behavior via induction of oxidative stress in brain.

Di (2-ethylhexyl) phthalate (DEHP) is one of the most prevalent xenoestrogen endocrine disruptor in daily life. A growing number of studies showed that DEHP could exhibit long-term adverse health effects on the human body, particularly in the liver, kidneys, heart and reproductive systems. However, the impact of oral intake of DEHP on the nervous system is extremely limited. In the present study, the adult C57BL/6J male mice were intragastrically administered with two dosages of DEHP for 35 days. The behavioral parameters were assessed using the elevated plus maze and open-field test. The mRNA expression levels of neuropeptides and the oxidative stress-associated proteins were detected by qPCR and western blot seperately. The histopathologic alterations of the brain were observed by H&E and Nissl staining. The results demonstrated that DEHP exposure could result in neurobehavioral impairments such as locomotor increase and anxiety-like behavior. Furthermore, pathological damages were clearly observed in the cerebral cortex and hippocampus, accompanied by a decrease in neuropeptides and an increase in oxidative stress, which were all positively correlated with the dose of DEHP. Together, these findings provide valuable clues into the DEHP-induced neurotoxicity.

Antibiotics administration alleviates the high fat diet-induced obesity through altering the lipid metabolism in young mice.

Currently, there is a global trend of rapid increase in obesity, especially among adolescents. The antibiotics cocktails (ABX) therapy is commonly used as an adjunctive treatment for gut microbiota related diseases, including obesity. However, the effects of broad-spectrum antibiotics alone on young obese hosts have rarely been reported. In the present study, the 3-week-old C57BL/6J male mice fed a high-fat diet (HFD) were intragastric administration with ampicillin, vancomycin, metronidazole or neomycin for 30 days. The lipid metabolites in plasma were assessed by biochemical assay kits, and genes related to lipid metabolite in the white adipose were assessed by qPCR. To further analyze the underlying mechanisms, the expression of genes related to lipid metabolism, inflammatory reactions and oxidative stress in the liver were determined by qPCR assay. In addition, the expression of oxidative damage-associated proteins in the liver were detected by western blot. The results showed that oral antibiotics exposure could reduce body weight and fat index in HFD-fed mice, concurrent with the increase of white adipose lipolysis genes and the decrease of hepatic lipogenic genes. Furthermore, antibiotics treatment could clearly reverse the HFD-induced elevation of oxidative damage-related proteins in the liver. Together, these findings will provide valuable clues into the effects of antibiotics on obesity.

Analysis of m6A modification regulators in the substantia nigra and striatum of MPTP-induced Parkinson's disease mice.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders of aging that impairs predominately dopaminergic neurons. N6-methyladenosine (m6A) is the most prevalent form of internal RNA modification in eukaryotes and it plays an essential role in normal brain development and neurodegenerative diseases. The m6A status is dynamically modulated by diverse types of genes called "writers", "erasers" and "readers". However, whether these m6A regulators are perturbed in PD remains poorly understood. To clarify this point, we established a PD mouse model using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The motor as well as learning and memory ability of mice were evaluated through and rotarod and Y maze spontaneous alternation tests. Morphological characteristics of tyrosine hydroxylase (TH)-positive cells were visualized using immunohistochemistry, while expressions of alpha-synuclein (α-syn) and TH were determined by using western blot. Furthermore, the expressions of the m6A regulators in the substantia nigra and striatum were evaluated by using qRT-PCR and western blot. As a result, the MPTP-induced PD mice suffered from learning and memory as well as motor defects. Additionally, there were significant TH+ neuron losses in the substantia nigra and striatum of MPTP-injected mice. In the PD mice, proteins including ALKBH5, IGF2BP2 were up-regulated in the substantia nigra, while YTHDF1 and FMR1 was down-regulated. For the striatum, FMR1 and CBLL1 were up-regulated, while IGF2BP3, METTL3 and RBM15 were down-regulated. The expression of genes at the mRNA level were partially in accordance with the protein changes. These findings indicate the m6A regulators may participate in PD pathogenesis.

Asparagus cochinchinensis alleviates disturbances of lipid metabolism and gut microbiota in high-fat diet-induced obesity mice.

Asparagus cochinchinensis is a valuable traditional Chinese medicine that has anti-inflammatory ability and effectively regulates the dysbiosis within the body. Obesity is usually characterized by chronic low-grade inflammation with aberrant gut microbiota. However, the role of Asparagus cochinchinensis against obesity remains unknown. Therefore, a high-fat diet (HFD)-induced obese mouse model with or without aqueous extract from Asparagus cochinchinensis root (ACE) treatment was established herein to determine whether ACE alleviated obesity and its involved mechanisms. Our results showed that ACE administration significantly decreased the weight gain and relieved dyslipidemia induced by HFD Treatment of ACE also improved glucose tolerance and insulin resistance in obese animal model, and remarkably decreased inflammation and lipogenesis in the liver and adipose. Moreover, administration of ACE significantly reshaped the gut microbiota of obese mice. These findings together suggest that ACE has beneficial effect against HFD-induced obesity and will provide valuable insights for the therapeutic potential of ACE against obesity and may aid in strategy-making for weight loss.