Aspergillus flavus poses a serious threat to global food security and human health. Bacillus velezensis is a class of beneficial bacteria with strong antagonistic activity against A. flavus; however, the mechanism underlying this activity remains unclear. In this study, we identified a novel antifungal substance produced by B. velezensis and preliminarily elucidated its mechanism of inhibition against A. flavus. We found that prolonged cultivation of B. velezensis leads not only to the production of surfactants but also to the accumulation of organic acids with antifungal activity, particularly methylmalonic acid (MMA). Genomic analysis revealed that MMA accumulates in B. velezensis due to the absence of the methylmalonyl-CoA mutase (MUT) gene. MMA can significantly inhibit mycelium growth and aflatoxin production, disrupt hyphal cellular morphology and mitochondrial structure, and interfere with branched-chain amino acid synthesis and degradation pathways. Additionally, the tryptophan metabolic pathway was markedly disrupted following MMA treatment. Specifically, L-3-hydroxykynurenine (3-HK) was significantly enriched. Finally, we showed that both mutation of the kynurenine-3-monooxygenase (KMO) gene and treatment with a KMO inhibitor resulted in increased sensitivity to MMA. Overall, our findings show that B. velezensis can accumulate MMA, which contributes to the inhibition of A. flavus growth, and reveal that alterations in the fungal tryptophan metabolic pathway are associated with A. flavus resistance to this compound.

Theabrownin (TB), a prominent pigment in fermented dark tea, exhibits beneficial effects on adiposity reduction. Our study revealed that TB derived from Fu brick tea significantly lowered fasting blood glucose levels and insulin resistance in obese/diabetic KKAy mice. Furthermore, TB demonstrated potent anti-inflammatory effects in the liver, adipose tissue, and intestines, as well as enhancing intestinal integrity. Additionally, TB was found to inhibit hepatic gluconeogenesis and promote fatty acid oxidation. Notably, TB altered gut metabolites, particularly l-palmitoylcarnitine, which showed an elevation in serum, liver, and adipose tissue following TB intervention. l-Palmitoylcarnitine reduced gluconeogenesis in primary hepatocytes and decreased lipid deposition in both primary hepatocytes and 3T3-L1 adipocytes in vitro. However, these effects were abolished when the circadian gene Period 3 (Per3) was knocked down. Our findings suggest that l-palmitoylcarnitine may play a crucial role in improving TB-mediated glucose homeostasis and lipid metabolism by regulating Per3.

Nanoplastics (NPs) are ubiquitous environmental pollutants that have garnered considerable attention for their potential adverse health effects. In this study, male C57BL/6 J mice were orally treated with a mixture of 50-nm and 200-nm polystyrene (PS)-NPs for one week followed by measurements of their neurobehavioral performance and neuronal damage 10 months later. Notably, PS-NPs were detected in the brains of the mice by transmission electron microscopy (TEM) and a nanoscale hyperspectral microscope imaging system 10 months after the PS-NP exposure. The mice exposed to short-term PS-NPs exhibited cognitive dysfunction and anxiety-like symptoms, neuronal damage and synapse loss, and an increase in the number of M1-polarized microglia and A1-reactive astrocytes. Interestingly, the inhibition of microglial activation by minocycline significantly mitigated the PS-NP-induced synapse loss and neuron damage. In vitro studies showed that PS-NPs could be readily internalized by three types of neurovascular unit (NVU) cells, including microglia, astrocytes, and brain microvascular endothelial cells, via multiple pathways. RNA-seq analysis confirmed that microglia-mediated neuronal injury was associated with disturbances in synapse and cell death signaling pathways. Collectively, these findings suggest that short-term PS-NP exposure-induced neuroinflammation in early adulthood may not be resolved naturally but may deteriorate under the interaction of microglia and astrocytes, leading to synapse loss, neuron degeneration, and cognitive dysfunction in middle age. The results of the present study provide important insights into the potential neurological impacts of NPs and suggest that targeting microglia to suppress inflammation might be a potential intervention strategy for neurodegeneration induced by NPs.

This study aimed to provide preliminary information about the potential adverse effects of L-Glutamate Monosodium Salt Monohydrate on maternal health and offspring development, particularly about developmental neurotoxicity and abnormal behavior in offspring after oral administration by gavage to female SD rats during the perinatal stage. The study involved administering different doses of L-glutamate monosodium salt monohydrate to four groups, including a vehicle control group. The doses were given orally via gavage from gestation day 6 (GD6) until postnatal day 21 (PND21) at levels of 6000, 3000, and 1000 mg/kg BW. The study found that parental exposure to L-Glutamate Monosodium Salt Monohydrate at a dose of 6000 mg/kg BW had adverse effects on the growth and development of the offspring. These effects included delayed physical development and reflex development. However, no effects on dams were observed. The Lowest Observed Adverse Effect Level (LOAEL) for developmental toxicity to the offspring is 6000 mg/kg BW, and the No Observed Adverse Effect Level (NOAEL) is 3000 mg/kg BW. Additionally, the NOAEL for maternal toxicity is considered to be 6000 mg/kg BW.

Short-chain chlorinated paraffins (SCCPs) are ubiquitously distributed in environmental matrices and have been detected in diverse human biospecimens. While high-dose SCCP exposure can induce liver, kidney, and thyroid toxicity, the health risks of SCCPs at environmentally relevant doses remain poorly characterized. This study systematically investigated the impacts of SCCPs at environmentally relevant doses on glucose homeostasis and insulin signaling and explored the underlying mechanisms. It was found that subacute SCCP exposure (1-50 mg/kg bw) compromised insulin and glucose tolerance, increased serum insulin levels, and impaired insulin signaling activity in mouse liver and adipose tissues. The homeostasis model assessment of insulin resistance (HOMA-IR) was increased from 2.53 in control group to 2.98, 3.22, 3.86, and 4.85 in 1, 5, 10, and 50 mg/kg bw SCCP groups, respectively. SCCP exposure triggered inflammation in these tissues, evidenced by macrophage infiltration, nuclear factor kappa B (NF-κB) activation, and upregulated Il6, Il1b, and Tnfa mRNA expression. In vitro experiments employing a hepatocyte-macrophage co-culture system revealed that SCCPs (100 μg/L) -induced insulin resistance in hepatocytes was mediated by activated macrophages. Notably, pharmacological NF-κB inhibitor (JSH-23) and cytokine neutralization (IL6 and IL1β) significantly ameliorated SCCP-induced insulin resistance in hepatocytes. These findings reveal insulin signaling as a previously unrecognized sensitive target of SCCP exposure at environmentally relevant doses and identify macrophage-mediated inflammation as a pivotal mechanism. This study only addressed the subacute effects of SCCP exposure on insulin signaling in male mice. The effects of chronic SCCP exposure on insulin signaling and potential gender differences warrant further investigation.

1-Bromopropane (1-BP), a widely used industrial solvent, has been increasingly recognized for its neurotoxic potential. Neuroinflammation has emerged as a key pathological mechanism underlying 1-BP-induced neuronal injury and cognitive impairment. Triggering receptor expressed on myeloid cells 2 (TREM2) has been implicated in various neurodegenerative and toxicant-induced neurological conditions. However, the specific contribution of TREM2 to 1-BP-induced neurotoxicity remains inadequately defined. This study aimed to elucidate the role of TREM2 in mediating neuroinflammatory responses and neuronal damage following 1-BP exposure, with a focus on its involvement in hippocampal neurodegeneration and cognitive deficits. In this investigation, a murine model of subchronic 1-BP exposure was established, and TREM2 gene knockout strategies were employed to assess its impact on microglial activation, inflammatory signaling cascades, and neuronal integrity. Behavioral assessments, immunohistochemistry, and molecular analyses were conducted to evaluate cognitive function, neuroinflammation, and cell death pathways. The results demonstrated that 1-BP exposure significantly activated microglia and upregulated the expression of both TREM2 and key components of the NOD-like receptor family pyrin domain containing 3(NLRP3) inflammasome within the hippocampus. In contrast, TREM2 deficiency markedly alleviated 1-BP-induced impairments in learning and memory, suppressed the expression of pro-inflammatory cytokines, and reduced hippocampal neuronal loss. Furthermore, knockout of TREM2 resulted in a significant decrease in the number of dying neurons, accompanied by downregulation of necroptosis-associated proteins. Collectively, these findings suggest that TREM2 plays a key role in 1-BP-related neuroinflammation and neuron damage. Targeting TREM2 could be a promising therapeutic strategy to mitigate the adverse neurological consequences of 1-BP exposure.

BACKGROUND AND OBJECTIVES:The increasing prevalence of hyperuricemia in children is a global health con-cern. Plant dietary fiber may influence uric acid levels by improving gut health and lowering blood glucose and lipid levels. This study aims to examine the relationship between plant-based dietary fiber intake and hyperuricemia risk in Chinese children aged 6-17 years. METHODS AND STUDY DESIGN:This study analyzed di-etary fiber intake data from 11,423 children (aged 6-17 years) from the China Children and Lactating Wom-en Nutrition and Health Surveillance (CCLWNHS) conducted between 2016 and 2019. Plant dietary fiber intake was assessed using a food frequency questionnaire. Logistic regression was performed, adjusting for age, sex, body mass index (BMI), smoking, alcohol consumption, physical activity, and energy intake. Restricted cubic splines (RCS) and receiver operating characteristic (ROC) curves were utilized to explore nonlinear relationships and identify cut-off values for dietary fiber intake. RESULTS:Among the 11,423 children, 1,730 (15.1%) were diagnosed with hyperuricemia. The average daily fiber intake was 8.28 ± 5.90g, with cereal fiber accounting for 56.1-57.8%. A significant negative correlation was found between cereal dietary fiber intake and hyperuricemia risk (p = 0.0004). Stratified analysis indicated that overweight/obesity status modi-fied this relationship. ROC curve analysis identified optimal intake cut-off values: 8.35 g/day for boys and 11.1 g/day for girls. CONCLUSIONS:Processed and ultraprocessed foods still have a lower contribution to ener-gy and nutrient intake in Jakarta than nonprocessed foods and processed ingredients.

Biodegradable plastics (BPs) are promoted as eco-friendly alternatives to conventional plastics. However, compared to conventional microplastics (MPs), they degrade rapidly into biodegradable microplastics (BMPs), which may lead to a more significant accumulation of BMPs in the environment. This review systematically compares BMPs and MPs, summarizes current knowledge on their environmental behaviors and impacts on ecosystems and human health, and offers recommendations for future research. BMPs are detected in water, sediments, indoor dust, food, marine organisms, and human samples. Compared to MPs, BMPs are more prone to environmental transformations, such as photodegradation and biodegradation, which results in a shorter migration distance across different matrices. Like MPs, BMPs can adsorb pollutants and transport them into organisms, enhancing toxicity and health risks through the Trojan horse effect. Studies indicate that BMPs may negatively impact terrestrial and aquatic ecosystems more than MPs by disrupting nutrient cycling and inhibiting plant and animal growth. In vivo and in vitro research also shows that BMP degradation products increase bioavailability, exacerbating neurotoxicity and overall toxicity. However, findings on BMPs' environmental and health effects remain inconsistent. Further evaluation of the trade-offs between BMP risks and their biodegradability is needed to address these uncertainties.

N,N-dimethylformamide (DMF) is a widely utilized chemical solvent with various industrial applications. Previous studies have indicated that the liver is the most susceptible target to DMF exposure, whereas the underlying mechanisms remain to be elucidated. This study aimed to investigate the role of NLRP3 inflammasome in DMF-induced liver injury in mice by using two NLRP3 inflammasome inhibitors, Nlrp3−/− mice, Nfe2l2−/− mice, and a macrophage-depleting agent. RNA sequencing revealed that endoplasmic reticulum (ER) stress and NLRP3 inflammasome-associated pathways were activated in the mouse liver after acute DMF exposure, which was validated by Western blotting. Interestingly, DMF-induced liver injury was effectively suppressed by two inflammasome inhibitors, MCC950 and Dapansutrile. In addition, knockout of Nlrp3 markedly attenuated DMF-induced liver injury without affecting the metabolism of DMF. Furthermore, silencing Nfe2l2 aggravated the liver injury and the NLRP3 inflammasome activation in mouse liver. Finally, the depletion of hepatic macrophages by clodronate liposomes significantly reduced the liver damage caused by DMF. These results suggest that NLRP3 inflammasome activation is the upstream molecular event in the development of acute liver injury induced by DMF.

Di(2-ethylhexyl) phthalate (DEHP) is a widely used plastic additive with persistent characteristics in the environment. This study was designed to investigate the detrimental effects of chronic DEHP exposure at environmental-relevant doses on bone metabolism and the underlying mechanisms. It was found that exposure to 25 μg/kg bw and 50 μg/kg bw DEHP for 29 weeks led to a reduction of whole-body bone mineral density (BMD), femur microstructure damage, decreased femur new bone formation, and increased femur bone marrow adipogenesis in C57BL/6 female mice, which was not observed in mice exposed to 5000 μg/kg bw DEHP. Further in vitro study showed that DEHP treatment robustly promoted adipogenic differentiation and suppressed osteogenic differentiation of the bone marrow mesenchymal stem cells (BMSCs). Mechanistically, DEHP exposure resulted in elevated expressions of DYRK1B, CDK5, PPARγ, and p-PPARγSer273 in both bone tissue and BMSCs. Interestingly, co-IP analysis showed potential interactions among DYRK1B, PPARγ, and CDK5. Lastly, antagonists of DYRK1B and CDK5 effectively alleviated the BMSCs differentiation disturbance induced by DEHP. These results suggest that DEHP may disturb the BMSCs differentiation by upregulating the PPARγ signaling which may be associated with the activation of DYRK1B and CDK5.

PM2.5-bound metal contaminants are associated with multiple chronic diseases in human. At global level, the contamination status has not been well controlled yet. Here we report findings from a long-term air pollution surveillance in Jinan city of Shandong, China. During 2014-2022, the dynamics and trends of PM2.5-bound heavy metal contaminants were monitored in an industrial area and a downtown area. The surveillance targets included: antimony (Sb), aluminum (Al), arsenic (As), beryllium (Be), cadmium (Cd), chromium (Cr), mercury (Hg), lead (Pb), manganese (Mn), nickel (Ni), selenium (Se). The human exposure and health risks were calculated and we found that the health risks of most contaminants showed peak values in autumn and winter. But Al, Mn, Hg and Be were found to result in highest health risk in spring or summer in the downtown area. In the industrial area we identified 100% alarming health index >1 (ranged from 1.12 to 3.35) in autumn and winter. In winter the total non-carcinogenic HI was all above 1 (peak value 2.21). Mn and As together posed >85% non-carcinogenic risk. As and Cd were ranked as major drivers of carcinogenic risks (5.84 x 10(-6 )and 2.78 x 10(-6)). Pd and Cd both showed non-negligible environmental levels but risk assessment model for their air-exposure associated non-carcinogenic risks are not yet available. This study updates air pollution data and status for air pollution status in China. This study provides valuable 9 year long-term reference to experimental and field studies in the related fields.

Neurodegenerative diseases are a group of diseases characterized by the progressive loss of neurons, including Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis. These diseases have a high incidence and mortality rate globally, placing a heavy burden on patients and their families. The pathogenesis of neurodegenerative diseases is complex, and there are no effective treatments at present. Cyclin-dependent kinase 5 is a proline-directed serine/threonine protein kinase that is closely related to the development and function of the nervous system. Under physiological conditions, it is involved in regulating the process of neuronal proliferation, differentiation, migration, and synaptic plasticity. Moreover, there is increasing evidence that cyclin-dependent kinase 5 also plays an important role in the pathogenesis of neurodegenerative diseases. In this review, we address the biological characteristics of cyclin-dependent kinase 5 and its role in neurodegenerative diseases. In particular, this review highlights the underlying mechanistic linkages between cyclin-dependent kinase 5 and mitochondrial dysfunction, oxidative stress and neuroinflammation in the context of neurodegeneration. Finally, we also summarize the currently available cyclin-dependent kinase 5 inhibitors and their prospects for the treatment of neurodegenerative diseases. Taken together, a better understanding of the molecular mechanisms of cyclin-dependent kinase 5 involved in neurodegenerative diseases can lead to the development of new strategies for the prevention and treatment of these devastating diseases.

In recent years, accumulating evidence supports that occupational exposure to solvents is associated with an increased incidence of Parkinson's disease (PD) among workers. The neurotoxic effects of 1-bromopropane (1-BP), a widely used new-type solvent, are well-established, yet data on its relationship with the etiology of PD remain limited. Simultaneously, high-fat consumption in modern society is recognized as a significant risk factor for PD. However, whether there is a synergistic effect between a high-fat diet and 1-BP exposure remains unclear. In this study, adult C57BL/6 mice were fed either a chow or a high-fat diet for 18 weeks prior to 12-week 1-BP treatment. Subsequent neurobehavioral and neuropathological examinations were conducted to assess the effects of 1-BP exposure on parkinsonian pathology. The results demonstrated that 1-BP exposure produced obvious neurobehavioral abnormalities and dopaminergic degeneration in the nigral region of mice. Importantly, a high-fat diet further exacerbated the impact of 1-BP on motor and cognitive abnormalities in mice. Mechanistic investigation revealed that mitochondrial damage and mtDNA release induced by 1-BP and high-fat diet activate NLRP3 and cGAS-STING pathway- mediated neuroinflammatory response, and ultimately lead to necroptosis of dopaminergic neurons. In summary, our study unveils a potential link between chronic 1-BP exposure and PD-like pathology with motor and no-motor defects in experimental animals, and long-term high-fat diet can further promote 1-BP neurotoxicity, which underscores the pivotal role of environmental factors in the etiology of PD.

Deoxynivalenol (DON) can induce endoplasmic reticulum (ER) stress, mitochondrial ROS burst, and macrophage polarization. Here, we investigated the mechanism linking the above three aspects with the dose range relevant to low-level exposure in children. At 0.5 μg/kg bw/day, we found remarkable liver and gut inflammatory responses after 6-week exposure in mice age comparable to humans 7-12 years old. Through antioxidant intervention, we found that ROS played a driver role in macrophage polarization and inflammatory responses induced by DON in the liver and gut. Further bioinformatics analysis uncovered that ER stress-associated protein MAPK7 (ERK5) may bind with AhR to initiate a mitochondrial ROS burst and macrophage M1 polarization. The downstream cellular events of MAPK7-AhR interaction may be mediated by the AhR/STAT3/p-STAT(Ser727) pathway. This mechanism was further supported by DON toxicity mitigation using cyanidin-3-glucoside (C-3-G), which docks to MAPK7 oligomerization region 200-400 aa and disrupts MAPK7-AhR interaction. Overall, our study provides novel evidence and mechanism for DON-induced inflammatory responses in the liver and gut system. Our findings call attention to the health risks associated with low-level DON exposure in the prepuberty children population.

Aflatoxin B1 (AFB1) is a major mycotoxin contaminant showing in the environment and foods. In this study, the molecular initiating events (MIEs) of AFB1-induced steatohepatitis were explored in mice and human cell model. We observed dose -dependent steatohepatitis in the AFB1-treated mice, including triglyceride accumulation, fibrotic collagen secretion, enrichment of CD11b + and F4/80+ macrophages/Kupffer cells, cell death, lymphocytes clusters and remarkable atrophy areas. The gut barrier and gut-microbiota were also severely damaged after the AFB1 treatment and pre -conditioned colitis in the experimental mice aggravated the steatohepatitis phenotypes. We found that macrophages cells can be pro -inflammatorily activated to M1 -like phenotype by AFB1 through an AHR/TLR4/p-STAT3 (Ser727)-mediated mitochondrial oxidative stress. The phenotypes can be rescued by AHR inhibitors in the mice model and human cell model. We further showed that this signaling axis is based on the cross -talk interaction between AHR and TLR4. Gene knock -up experiment found that the signaling is dependent on AFB1 ligand-binding with AHR, but not protein expressions of TLR4. The signaling elevated NLRP3 and two immune metabolic enzymes ICAM-1 and IDO that are associated with macrophage polarization. Results from intervention experiments with natural anti -oxidant and AHR inhibitor CH223191 suggest that the macrophage polarization may rely on AHR and ROS. Our study provides novel and critical references to the food safety and public health regulation of AFB1.

The application of different types of pesticides can result in the coexistence of multiple pesticide residues in our food and the environment. This can have detrimental effects on the health of offspring across generations when parents are exposed to these pesticides. Therefore, it is imperative to understand the long-term effects that can be inherited by future generations when assessing the risks associated with pesticides. To study the genotoxic effects of commonly used pesticides, prochloraz (PRO) and chlorpyrifos (CHL), and assess whether their combined exposures have a different toxic effect, we modeled the transgenerational effects of parental (F0-generation) and/or offspring (F1-generation) exposures on zebrafish embryos in the F1-generation. Following the exposures, we proceeded to assess the impacts of these exposures on a range of biological processes in F1-generation zebrafish. Our results revealed that exposure to PRO and CHL altered multiple biological processes, such as inflammation, apoptosis, oxidative stress, and thyroid hormone synthesis, and detoxification system, providing molecular targets for subsequent studies on toxicity mechanisms. Notably, our study also found that the biological processes of F1-generation zebrafish embryos were altered even though they were not exposed to any pesticide when F0-generation zebrafish were exposed to PRO or CHL, suggesting potential genotoxicity. In conclusion, we provided in-vivo evidence that parental exposure to PRO and/or CHL can induce genotoxicity in the offspring. Moreover, we observed that the toxic effects resulting from the combined exposure were interactive, suggesting a potential synergistic impact on the offspring.

Mitochondrial dysfunction is a key pathological event in the acute liver injury following the overdose of acetaminophen (APAP). Calpain is the calcium-dependent protease, recent studies demonstrate that it is involved in the impairment of mitochondrial dynamics. The mitochondrial unfolded protein response (UPRmt) is commonly activated in the context of mitochondrial damage following pathological insults and contributes to the maintenance of the mitochondrial quality control through regulating a wide range of gene expression. More importantly, it is reported that abnormal aggregation of TDP-43 in mitochondria induced the activation of UPRmt. However, whether it is involved in APAP induced-hepatotoxicity remains unclear. In the present study, C57/BL6 mice were given 300 mg/kg APAP to establish a time-course model of acute liver injury. Furthermore, Calpeptin, the specific inhibiter of calpains, was used to conduct the intervention experiment. Our results showed, APAP exposure produced severe liver injury. Moreover, TDP-43 was obviously accumulated within mitochondria whereas mitochondrial protease LonP1 was significantly decreased. However, these changes exhibited significant recovery at 48 h. By contrast, the mitochondrial protease ClpP and chaperone mtHSP70 and HSP60 were consistently increased, which supported the UPRmt was activated to promote protein homeostasis. Further investigation revealed that calpain-mediated cleavage of TDP-43 could promote the accumulation of TDP-43 in mitochondria compartment, thereby facilitating the activation of UPRmt. Additionally, Calpeptin pretreatment not only protected against APAP-induced liver injury, but also suppressed the formation of TDP-43 aggregates and the activation of UPRmt. Taken together, our findings indicated that in APAP-induced acute liver injury, calpain-mediated cleavage of TDP43 caused its aberrant aggregation on the mitochondria. As a stress-protective response, the induction of UPRmt contributed to the recovery of mitochondrial function.