Non-alcoholic fatty liver disease (NAFLD) is closely associated with type 2 diabetes mellitus, which is characterized by hepatic steatosis. Vanadium compounds have the potential to prevent hyperlipidemia. However, whether vanadium compound supplementation could rescue hepatic steatosis in NAFLD remains uncertain. We sought to investigate the molecular mechanisms by which vanadium(IV)-chlorodipicolinate (VOdipic-Cl) ameliorated hepatic steatosis in obesity. The therapeutic effect of VOdipic-Cl was evaluated using high-fat diet (HFD)-induced C57BL/6 mice and palmitic acid/oleic acid (PO)-treated L02 hepatocytes, respectively. Lipidomic analysis, RNA-sequencing (RNA-seq), Western blotting, and molecular dynamics simulation were employed to elucidate the molecular mechanism of VOdipic-Cl in regulating lipid metabolism in liver and hepatocytes. VOdipic-Cl treatment effectively reduced hepatic lipid accumulation and improved hepatic function in HFD-fed mice. Lipidomic analysis showed that the primary differential lipid metabolites were mainly associated with glycerophospholipid metabolism pathway. Transcriptomic analysis revealed that adenosine monophosphate-activated protein kinase (AMPK) signaling pathway was involved in the regulation of hepatic lipid metabolism by VOdipic-Cl treatment. Moreover, VOdipic-Cl-induced AMPK activation significantly restored hepatic mitochondrial homeostasis and reduced lipid accumulation through upregulating transcription factor peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and carnitine palmitoyltransferase 1 (CPT1) in hepatocytes, respectively. Our findings suggest that VOdipic-Cl triggers the activation of AMPK, leading to the upregulation of PGC-1α and CPT1 expression, ultimately improving mitochondrial homeostasis and decreasing lipid accumulation. Collectively, these molecular cascades contribute to the ameliorating effect of VOdipic-Cl on HFD-induced hepatic steatosis. This study also provides evidence supporting the potential utilization of VOdipic-Cl for the treatment of NAFLD.

Allergic asthma is a heterogeneous respiratory disease characterized by chronic airway inflammation and immune disorder by an intricate interplay of genetic and environmental factors. The imbalance of pulmonary macrophage polarization acts as a pivotal driver of airway inflammatory remodeling and pathological injury. Pulmonary macrophages including alveolar macrophages (AMs) and interstitial macrophages (IMs) undergo remarkable metabolic reprogramming in the microenvironment of allergic asthma. The dynamic remodeling of core metabolic pathways including glycolysis, fatty acid, and amino acid metabolism is closely associated with M1/M2 phenotypic transition and functional plasticity of macrophages. Meanwhile, metabolic enzymes, key metabolic intermediates and transcriptional regulators bidirectionally modulate macrophage polarization via epigenetic modification and signaling pathway activation. In turn, the activation and polarization of macrophages further reshape cellular metabolic patterns, forming a closed loop of metabolism-immunity interaction. This review systematically summarizes the characteristics and regulatory mechanisms of pulmonary macrophage polarization in allergic asthma, focuses on elucidating the crosstalk regulatory network between metabolic reprogramming and macrophage functional plasticity, and clarifies the roles of key metabolic pathways in airway inflammation, airway hyperresponsiveness and tissue remodeling in asthma. We also summarize that the pharmacological manipulation of macrophage glucose and lipid metabolism can effectively attenuate airway hyperresponsiveness and structural remodeling, highlighting that immunometabolic pathway serve as promising therapeutic targets for asthma intervention.

As pervasive environmental pollutants, microplastics(MPs) have been identified in marine ecosystems, food, air, and drinking water, prompting serious consideration of their probable adverse effects on public health. Emerging evidence associates MPs with respiratory risks, yet their toxic mechanisms in lung tissue remain poorly elucidated. In this investigation, C57BL/6n mice were exposed to 10 mg/kg polystyrene microplastics (PS-MPs) with varying sizes (0.2 mu m, 1 mu m) individually or combined every 2 days for 14 days. The results exhibited that PS-MPs exposure induced the size-dependent respiratory dysfunction in mice, characterized by oxidative stress and pulmonary epithelial apoptosis. In vitro experiments revealed that PS0.2 internalization of MLE-12 cells triggered apoptosis via increasing BAX-mediated cytochrome C release and caspase-3 activation. Mechanistically, PS0.2 promoted DRP1-dependent mitochondrial fission, leading to membrane potential collapse and respiratory chain impairment. The administration of Mdivi-1/si-DRP1 inhibition of DRP1 effectively attenuated mitochondrial fragmentation and apoptosis. Additionally, molecular docking analysis and coimmunoprecipitation revealed that DRP1 directly interacts with BAX to facilitate oligomerization of this pro-apoptotic protein, promoting the release of cytochrome C. These findings establish a novel DRP1-BAX signaling axis in MPs-induced pulmonary toxicity and the first molecular link between PS-MP size and mitochondrial apoptosis via DRP1-BAX oligomerization into environmental particle-related respiratory pathogenesis.

Chitinase 3-like-1 (CHI3L1) is an emerging biomarker and therapeutic target for prediction and evaluation of respiratory diseases. However, the functions and underly molecular mechanisms on the regulation of CHI3L1 in PM2.5-induced pulmonary fibrosis are unclear. In the present study, we found that increased expressions of NSUN2 and the m5C methylation of CHI3L1 mRNA in PM2.5-treated lung tissues and alveolar epithelial MLE-12 cells were observed. NSUN2 could catalyze m5C methylation of CHI3L1 at the 3'UTR, thereby promoting the transport of CHI3L1 mRNA to cytoplasm in an Aly/REF export factor (ALYREF) dependent manner. Under PM2.5 exposure, NSUN2 deficiency could counterbalance PM2.5-induced CHI3L1 m5C methylation and epithelial-mesenchymal transition (EMT) in vivo and in cells. Our research collectively offers new molecular understanding regarding the mechanisms behind pulmonary fibrosis induced by PM2.5 exposure.

The temporary explosive growth events of atmospheric fine particulate matter (PM2.5) pollution during late autumn and winter seasons still frequently occur in China. High-concentration exposure to PM2.5 aggravates lung inflammation, leading to acute lung injury (ALI). Alveolar macrophages (AMs) participate in PM2.5-induced pulmonary inflammation and injury. The polarization of AMs is dependent on metabolic reprogramming. However, the mechanism underlying the PM2.5-induced glutaminase-mediated glutaminolysis in AM polarization is still largely obscure. In this study, we found that PM2.5-treated mice exhibited pulmonary dysfunction and inflammation. The concentrations of glutamate and succinate were increased in PM2.5-treated lungs and AMs compared with the controls, whereas glutamine and alpha-ketoglutarate (alpha-KG) levels were decreased, indicating that glutaminolysis in AMs was aberrantly activated as evidenced by increased mRNA and protein levels of GLS1 after PM2.5 exposure. Moreover, we determined that the GLS1/nuclear factor kappa-B (NF-kappa B)/hypoxia-inducible factor-1 alpha (HIF-1 alpha) pathway regulated M1 polarization of AMs upon PM2.5 exposure. Inhibition of glutaminolysis by GLS1 specific inhibitor CB-839 and GLS1 siRNA significantly decreased PM2.5-induced M1 macrophage polarization and attenuated pulmonary damage. Taken together, our findings reveal a novel mechanism by which a metabolic program regulates M1 polarization of AMs and suggest that GLS1-mediated glutaminolysis is a potential therapeutic target for treating PM2.5-induced ALI.

Significant progress has been made in recent research on air pollutant exposure and respiratory diseases [...]

Emerging evidence has demonstrated the association between microplastics (MPs) with a diameter of <5 mm and the risk of intestinal diseases. However, the molecular mechanisms contributing to MP-induced intestinal barrier dysfunction have not been fully appreciated. In this study, C57BL/6 J mice were exposed to polystyrene microplastics (PS-MPs, 0.2, 1 or 5 μm) at 1 mg/kg body weight daily by oral gavage for 28 days. We found that PS-MPs exposure induced oxidative stress and inflammatory cell infiltration in mice colon, leading to an increased expression of pro-inflammatory cytokine. Moreover, there were an increase in intestinal permeability and decrease in mucus secretion, accompanied by downregulation of tight junction (TJ)-related zonula occluden-1 (ZO-1), occluding (OCLN) and claudin-1 (CLDN-1) in mice colon. Especially, 5 μm PS-MPs (PS5)-induced intestinal epithelial TJ barrier damage was more severe than 0.2 μm PS-MPs (PS0.2) and 1 μm PS-MPs (PS1). In vitro experiments indicated that PS5-induced oxidative stress upregulated the expression of nuclear factor kappa B (NF-κB), nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome, and myosin light chain kinase (MLCK). Meanwhile, pre-treatment with the antioxidant NAC, NLRP3 inhibitor MCC950 and MLCK inhibitor ML-7 considerably reduced PS5-triggered reactive oxygen species (ROS) production and inflammatory response, inhibited the activation of the NF-κB/NLRP3/MLCK pathway, and upregulated ZO-1, OCLN and CLDN-1 expression in Caco-2 cells. Taken together, our study demonstrated that PS-MPs cause intestinal barrier dysfunction through the ROS-dependent NF-κB/NLRP3/IL-1β/MLCK pathway.

Emerging evidence has demonstrated the association between microplastics (MPs) with a diameter of <5 mm and the risk of intestinal diseases. However, the molecular mechanisms contributing to MP-induced intestinal barrier dysfunction have not been fully appreciated. In this study, C57BL/6 J mice were exposed to polystyrene microplastics (PS-MPs, 0.2, 1 or 5 mu m) at 1 mg/kg body weight daily by oral gavage for 28 days. We found that PS-MPs exposure induced oxidative stress and inflammatory cell infiltration in mice colon, leading to an increased expression of pro-inflammatory cytokine. Moreover, there were an increase in intestinal permeability and decrease in mucus secretion, accompanied by downregulation of tight junction (TJ)-related zonula occluden1 (ZO-1), occluding (OCLN) and claudin-1 (CLDN-1) in mice colon. Especially, 5 mu m PS-MPs (PS5)-induced intestinal epithelial TJ barrier damage was more severe than 0.2 mu m PS-MPs (PS0.2) and 1 mu m PS-MPs (PS1). In vitro experiments indicated that PS5-induced oxidative stress upregulated the expression of nuclear factor kappa B (NF-kappa B), nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome, and myosin light chain kinase (MLCK). Meanwhile, pre-treatment with the antioxidant NAC, NLRP3 inhibitor MCC950 and MLCK inhibitor ML-7 considerably reduced PS5-triggered reactive oxygen species (ROS) production and inflammatory response, inhibited the activation of the NF-kappa B/NLRP3/MLCK pathway, and upregulated ZO-1, OCLN and CLDN-1 expression in Caco-2 cells. Taken together, our study demonstrated that PS-MPs cause intestinal barrier dysfunction through the ROS-dependent NF-kappa B/NLRP3/IL-1 beta/MLCK pathway.

Airborne fine particulate matter (PM2.5) can cause pulmonary inflammation and even fibrosis, however, the underlying molecular mechanisms of the pathogenesis of PM2.5 exposure have not been fully appreciated. In the present study, we explored the dynamics of glycolysis and modification of histone lactylation in macrophages induced by PM2.5-exposure in both in vivo and in vitro models. Male C57BL/6 J mice were anesthetized and administrated with PM2.5 by intratracheal instillation once every other day for 4 weeks. Mouse RAW264.7 macrophages and alveolar epithelial MLE-12 cells were treated with PM2.5 for 24 h. We found that PM2.5 significantly increased lactate dehydrogenase (LDH) activities and lactate contents, and up-regulated the mRNA expression of key glycolytic enzymes in the lungs and bronchoalveolar lavage fluids of mice. Moreover, PM2.5 increased the levels of histone lactylation in both PM2.5-exposed lungs and RAW264.7 cells. The pro-fibrotic cytokines secreted from PM2.5-treated RAW264.7 cells triggered epithelial-mesenchymal transition (EMT) in MLE-12 cells through activating transforming growth factor-β (TGF-β)/Smad2/3 and VEGFA/ERK pathways. In contrast, LDHA inhibitor (GNE-140) pretreatment effectively alleviated PM2.5-induced pulmonary inflammation and fibrosis via inhibiting glycolysis and subsequent modification of histone lactylation in mice. Thus, our findings suggest that PM2.5-induced glycolysis and subsequent modification of histone lactylation play critical role in the PM2.5-associated pulmonary fibrosis.

The increasing incidence of multidrug-resistant (MDR) Salmonella enterica serovar Typhimurium (S. Tm), known for causing invasive enteric infections, presents a significant public health challenge. Given the diminishing efficacy of existing antibiotics, it is imperative to explore novel alternatives for the treatment of MDR S. Tm infections. Here, we identified esculetin (EST), a natural coumarin abundant in dietary foods and herbs, as a compound exhibiting broad-spectrum antibacterial properties against a range of MDR bacteria. Our findings demonstrate that EST effectively inhibited the proliferation and expansion of MDR S. Tm in both in vitro experiments and animal models. Specifically, EST significantly downregulated the type 3 secretion system-1 (T3SS-1) virulence expression of MDR S. Tm, thereby preventing its invasion into intestinal epithelial cells. In S. Tm-infected mice, we observed cecal injury characterized by the upregulation of inflammatory cytokines, a reduction in goblet cell numbers, a decreased expression of tight junction proteins, and microbial dysbiosis. Conversely, EST treatment ameliorated these pathological changes induced by S. Tm infection and reduced oxidative stress by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, thereby improving intestinal barrier function. These results suggest that dietary coumarins or a targeted plant-based diet may offer a promising strategy to counteract MDR bacteria-induced enteric diseases.

The microbial colonization on ancient murals attracts more and more attention since the threaten by microorganisms was first reported in Lascaux, Spain. However, the biodeterioration or biodegradation of mural paintings resulted by microorganisms is not clear yet. Especially the biological function of microbial communities in different conditions remained largely unaddressed. The two mausoleums of the Southern Tang Dynasty are the largest group of emperor mausoleums during the Five Dynasties and Ten Kingdoms period in China, which are of great significance to the study of the architecture, imperial mausoleum systems and art in the Tang and Song Dynasties. To make clear the species composition and metabolic functions of different microbial communities (MID and BK), we analyzed the samples from the wall paintings in one of the two mausoleums of the Southern Tang Dynasty with metagenomics method. The result showed totally 55 phyla and 1729 genera were detected in the mural paintings. The two microbial community structure were similar with the dominance of Proteobacteria, Actinobacteria and Cyanobacteria. However, the species abundance presented a significant difference between two communities at genus level --- MID is Lysobacter, Luteimonas are predominant in MID while Sphingomonas and Streptomyces are popular in BK, which is partially attributed to the different substrate materials of murals. As a result, the two communities presented the different metabolic patterns that MID community was mainly participated in the formation of biofilm as well as the degradation of exogenous pollutants while the BK was predominantly related to the photosynthesis process and biosynthesis of secondary metabolites. Taken together, these findings indicated the effect of environmental factor on the taxonomic composition and functional diversity of the microbial populations. The installation of artificial lighting needs to be considered carefully in the future protection of cultural relics.

Short-term high-concentration exposure to airborne fine particulate matter (PM2.5) is strongly associated with the risk of acute lung injury (ALI). It has been recently reported that exosomes (Exos) involve in the progression of respiratory diseases. However, the molecular mechanisms by which exosome-mediated intercellular signaling exacerbate PM2.5-induced ALI remains largely unaddressed. In the present study, we firstly investigated the effect of macrophage-derived exosomal tumor necrosis factor α (TNF-α) on pulmonary surfactant proteins (SPs) expression in epithelial MLE-12 cells after PM2.5 exposure. The higher levels of exosomes in the bronchoalveolar lavage fluid (BALF) of PM2.5-induced ALI mice were found. BALF-exosomes significantly up-regulated SPs expression in MLE-12 cells. Moreover, we found that remarkably high expression of TNF-α in exosomes secreted by PM2.5-treated RAW264.7 cells. Exosomal TNF-α promoted thyroid transcription factor-1 (TTF-1) activation and SPs expression in MLE-12 cells. Furthermore, intratracheal instillation of macrophage-derived TNF-α-containing exosomes increased epithelial cell SPs expression in the lungs of mice. Taken together, these results suggest that macrophages-secreted exosomal TNF-α can trigger epithelial cell SPs expression, which provides new insight and potential target in the mechanism of epithelial cell dysfunction in PM2.5-induced ALI.

Melatonin is an indoleamine hormone secreted by the pineal gland. It has antioxidation and anti-apoptosis effects and a clear protective effect against cardiovascular diseases. Our previous studies demonstrated that embryonic exposure to sodium arsenite (NaAsO2) can lead to an abnormal cardiac development. The aim of this study was to determine whether melatonin could protect against NaAsO2-induced generation of reactive oxygen species (ROS), oxidative stress, apoptosis, and abnormal cardiac development in a zebrafish (Danio rerio) model. We found that melatonin decreased NaAsO2-induced zebrafish embryonic heart malformations and abnormal heart rates at a melatonin concentration as low as 10−9 mol/L. The NaAsO2-induced oxidative stress was counteracted by melatonin supplementation. Melatonin blunted the NaAsO2-induced overproduction of ROS, the upregulation of oxidative stress-related genes (sod2, cat, gpx, nrf2, ho-1), and the production of antioxidant enzymes (Total SOD, SOD1, SOD2, CAT). Melatonin attenuated the NaAsO2-induced oxidative damage, DNA damage, and apoptosis, based on malonaldehyde and 8-OHdG levels and apoptosis-related gene expression (caspase-3, bax, bcl-2), respectively. Melatonin also maintained the control levels of heart development-related genes (nkx2.5, sox9b) affected by NaAsO2. In conclusion, melatonin protected against NaAsO2-induced heart malformations by inhibiting the oxidative stress and apoptosis in zebrafish.

Background Airborne fine particulate matter with aerodynamic diameter ≤ 2.5 μm (PM 2.5 ) pollution is associated with the prevalence of respiratory diseases, including asthma, bronchitis and chronic obstructive pulmonary disease. In patients with those diseases, circulating asymmetric dimethylarginine (ADMA) levels are increased, which contributes to airway nitric oxide deficiency, oxidative stress and inflammation. Overexpression of dimethylarginine dimethylaminohydrolase 1 (DDAH1), an enzyme degrading ADMA, exerts protective effects in animal models. However, the impact of DDAH1/ADMA on PM 2.5 -induced lung injury has not been investigated. Methods Ddah1 −/− and DDAH1-transgenic mice, as well as their respective wild-type (WT) littermates, were exposed to either filtered air or airborne PM 2.5 (mean daily concentration ~ 50 µg/m 3 ) for 6 months through a whole-body exposure system. Mice were also acutely exposed to 10 mg/kg PM 2.5 and/or exogenous ADMA (2 mg/kg) via intratracheal instillation every other day for 2 weeks. Inflammatory response, oxidative stress and related gene expressions in the lungs were examined. In addition, RAW264.7 cells were exposed to PM 2.5 and/or ADMA and the changes in intracellular oxidative stress and inflammatory response were determined. Results Ddah1 −/− mice developed more severe lung injury than WT mice after long-term PM 2.5 exposure, which was associated with greater induction of pulmonary oxidative stress and inflammation. In the lungs of PM 2.5 -exposed mice, Ddah1 deficiency increased protein expression of p-p65, iNOS and Bax, and decreased protein expression of Bcl-2, SOD1 and peroxiredoxin 4. Conversely, DDAH1 overexpression significantly alleviated lung injury, attenuated pulmonary oxidative stress and inflammation, and exerted opposite effects on those proteins in PM 2.5 -exposed mice. In addition, exogenous ADMA administration could mimic the effect of Ddah1 deficiency on PM 2.5 -induced lung injury, oxidative stress and inflammation. In PM 2.5 -exposed macrophages, ADMA aggravated the inflammatory response and oxidative stress in an iNOS-dependent manner. Conclusion Our data revealed that DDAH1 has a marked protective effect on long-term PM 2.5 exposure-induced lung injury.

Non-alcoholic fatty liver disease (NAFLD) is increasingly prevalent and represents a growing challenge in terms of prevention and treatment. The aim of this study is to investigate the protective effects and the underlying mechanisms of vanadium(IV)-chlorodipicolinate ([VIVO(dipic-Cl)(H2O)2, VOdipic-Cl]) in a mouse model of NAFLD induced by a high-fat diet (HFD). VOdipic-Cl (10 mg/kg/day body weight) treatment for 4 weeks significantly controlled body weight gain, and effectively reduced the increase in serum and hepatic triglyceride (TG) and total cholesterol (TC) levels, mitigated pathological injury, decreased malondialdehyde (MDA) level, and inhibited endoplasmic reticulum (ER) stress and inflammatory response in the livers of C57BL/6 obese mice. Moreover, RNA-sequencing analysis revealed distinct transcriptional profiles with differentially expressed genes (DEGs) in livers. We found that VOdipic-Cl effectively down-regulated genes related to lipid synthesis and up-regulated genes related to fatty acid transport and lipolysis, and down-regulated the expression of genes related to ER stress and immune response in the livers of obese mice. In conclusion, VOdipic-Cl effectively prevented hepatic steatosis by controlling body weight, mitigating oxidative stress, and regulating the expression of genes related to lipid metabolism, ER stress and immune response, which provides new insights into the molecular mechanism of the protective effect of VOdipic-Cl against hepatic steatosis.

Numerous epidemiological and experimental studies have demonstrated that the exposure to fine particulate matter (aerodynamic diameter <2.5 μm, PM2.5) was closely associated with cardiovascular morbidity and mortality. Our previous studies revealed that PM2.5 exposure induced cardiac dysfunction and fibrosis. However, the corresponding underlying mechanism remains largely unaddressed. Here, PM2.5-induced cardiotoxicity is presented to directly promote collagen deposition in cardiomyocytes through the transforming growth factor-β (TGF-β)-containing small extracellular vesicles (sEV). The sEV transition may play an important role in PM2.5-induced cardiac fibrosis. Firstly, long-term PM2.5 exposure can directly induce cardiac fibrosis and increase the level of serum sEV. Secondly, PM2.5 can directly activate macrophages and increase the release of tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and TGF-β-containing sEV. Thirdly, TGF-β-containing sEV increases the expression of α-smooth muscle actin (α-SMA), collagen I, and collagen III in mouse cardiac muscle HL-1 cells. Finally, TGF-β-containing sEV released from PM2.5-treated macrophages can increase collagen through the activation of the TGF-β-Smad2/3 signaling pathway in HL-1 cells from which some fibroblasts involved in cardiac fibrosis are thought to originate. These findings suggest that TGF-β-containing sEV from PM2.5-activated macrophages play a critical role in the process of increasing cardiac collagen content via activating the TGF-β-Smad2/3 signaling pathway.

Human tuberous sclerosis (TSC) is mainly caused by genetic mutations of tuberous TSC1or TSC2. Recent studies found that TSC1 deficiency promoted classical M1 macrophage polarization. However, whether TSC1 regulates other inflammatory cytokine expression in lipopolysaccharidem (LPS)-stimulated macrophages is unknown. Herein, we studied the cytokine expression profile of wild-type (WT) and TSC1-deleted macrophages after LPS stimulation in vitro and the pathogenesis of dextran sodium sulfate (DSS)-induced colitis in mice with myeloid-specific TSC1 deletion (TSC1cKO mice). We found that TSC1-deficient macrophages exhibited the enhanced secretion of interleukin-17A (IL-17A), IL-17F, and interferon-gamma (IFN-γ) in response to LPS stimulation in vitro. This is in contrast to LPS-stimulated WT macrophages, which usually do not. Importantly, TSC1cKO mice exhibited exacerbated DSS-induced acute colitis with severer symptoms. MTOR deletion or rapamycin treatment significantly reversed the enhanced expressions of IL-17A, IL-17F, and IFN-γ in LPS-stimulated TSC1-deficient macrophages in vitro and rescued the enhanced DSS-induced colitis in TSC1cKO mice, indicating that TSC1 deficiency increased these cytokine productions in an mTOR-dependent manner. RNA-sequencing and molecular studies indicated that TSC1 deficiency enhanced the aerobic glycolysis process and the activities of mTOR-STAT3-RORγT pathway in LPS-stimulated macrophages. Inhibition of aerobic glycolysis, STAT3, or RORγT reversed IL-17 and IFN-γ expression in LPS-treated TSC1-deficient macrophages. Thus, TSC1 is essential for macrophages to shut down IL-17A, IL-17F, and IFN-γ expression during LPS stimulation by suppressing the aerobic glycolysis process and mTOR-STAT3, RORγT, and T-bet pathways. The present study uncovered the key role of TSC1 in shutting down IL-17A, IL-17F, and IFN-γ expressions in LPS-treated macrophages.

There is evidence of an association between exposure to ambient fine particulate matter (PM2.5) and female ovarian dysfunction in adults. However, it is not fully clear whether maternal exposure to PM2.5 negatively affects the ovarian function in offspring. The size of primordial follicle pool, definitely assembled during fetal life, determines ovarian reserve and ovarian function. In this study, female C57BL/6 mice were exposed to either ambient PM2.5 (mean daily concentration 49 µg/m3) or filtered air through a whole-body exposure system for 4 weeks before mating, and remained exposed until postpartum. We found that maternal exposure to PM2.5 reduces the initial size of primordial follicle pool and impairs its development in offspring mice. The number of primordial follicles and total follicles was decreased in PM2.5-exposed offspring mice on postnatal day 3 (PND3) and postnatal day 7 (PND7). Maternal PM2.5 exposure promoted the activation of primordial follicles and upregulated the level of p-AKT in offspring mice, accelerating the depletion of primordial follicle pool. While LY294002, a specific inhibitor of PI3K, reversed the overactivation of primordial follicles induced by PM2.5. Besides, maternal PM2.5 exposure induced follicular atresia and granulosa cell apoptosis, increased the accumulation of lipid peroxidation products 4-HNE, and elevated the expression of oxidative stress-related genes and p-p65, p-IκBα in offspring mice. While N-acetylcysteine (NAC) pretreatment abolished the increases of apoptosis, reactive oxygen species (ROS), p-p65 and p-IκBα levels in ovarian granulosa COV434 cells induced by PM2.5 exposure. These findings reveal that maternal exposure to PM2.5 decreases the initial size of primordial follicle pool, and impairs ovarian follicular development in offspring mice. Our data suggest that this involves the activation of the PI3K/AKT/FoxO3a pathway and the ROS-dependent NF-κB pathway. Our study implicates a link between maternal PM2.5 exposure and ovarian reserve in offspring, and improves our understanding of the effects of PM2.5 on reproductive health.

In this study, we propose a self-consistent numerical framework for modeling planar Direct Current (DC) magnetron sputtering for a single alloy target. Unlike other reported numerical methods in literature which need experimental data of racetrack and discharge current to calculate the argon ion flux on target, the present self-consistent model obtains that necessary information from discharge simulation without doing experiment. Furthermore, the model also shows the advantage of more accurate calculation of total knocked out target atoms due to take into consideration of spatial argon ion flux and energy distribution on the target. In the model, we account for electromagnetics, fluid dynamics, discharge chemistry and thermal transport across multiple length scales. Specifically, we employ Lattice Boltzmann Method (LBM) for transport phenomena, Finite Elements Method (FEM) for magnetron discharge transport, and binary collision approximation Monte-Carlo method for sputtering and atomic deposition. Our modeling framework could predict the composition, uniformity, and deposition flux of deposited thin film alloys. Furthermore, the simulation also provides the information of plasma in the chamber such as electron, ion densities, argon ion energy and argon ion flux bombarding on the target. Through parametric analyses, we found that a reduction in substrate radius and substrate-target distance can lead to improved deposition efficiency and film uniformity, and that magnetic fields can significantly affect the substrate deposition flux and film uniformity. Substrate composition is found to scale with both chamber pressure and inverse chamber temperature, although the effect of chamber temperature is considerably marginal under low pressure conditions. Our work provides useful insights to operational heuristics involved in magnetron sputtering and other physical chemical processes.