Oil mistparticulate matter exposure induces hyperlipidemia-related inflammation via microbiota/ SCFAs/GPR43 axis inhibition and TLR4/NF-κB activation.

Metabolites produced by the human gut microbiota play an important role in fighting and intervening in inflammatory diseases. It remains unknown whether immune homeostasis is influenced by increasing concentrations of air pollutants such as oil mist particulate matters (OMPM). Herein, we report that OMPM exposure induces a hyperlipidemia-related phenotype through microbiota dysregulation-mediated downregulation of the anti-inflammatory short-chain fatty acid (SCFA)-GPR43 axis and activation of the inflammatory pathway. A rat model showed that exposure to OMPM promoted visceral and serum lipid accumulation and inflammatory cytokine upregulation. Furthermore, our research indicated a reduction in both the "healthy" microbiome and the production of SCFAs in the intestinal contents following exposure to OMPM. The SCFA receptor GPR43 was downregulated in both the ileum and white adipose tissues (WATs). The OMPM treatment mechanism was as follows: the gut barrier was compromised, leading to increased levels of lipopolysaccharide (LPS). This increase activated the Toll-like receptor 4 Nuclear Factor-κB (TLR4-NF-κB) signaling pathway in WATs, consequently fueling hyperlipidemia-related inflammation through a positive-feedback circuit. Our findings thus imply that OMPM pollution leads to hyperlipemia-related inflammation through impairing the microbiota-SCFAs-GPR43 pathway and activating the LSP-induced TLR4-NF-κB cascade; our findings also suggest that OMPM pollution is a potential threat to humanmicrobiota dysregulation and the occurrence of inflammatory diseases.

Correction: Jia et al. Exposure to Polypropylene Microplastics via Oral Ingestion Induces Colonic Apoptosis and Intestinal Barrier Damage through Oxidative Stress and Inflammation in Mice. Toxics 2023, 11, 127.

In the original publication [...].

Isopeptide Bond Bundling Superhelix for Designing Antivirals against Enveloped Viruses with Class I Fusion Proteins: A Review.

Viral infection has become one of the worst human lethal diseases. In recent years, major gains have been made in the research of peptide-based antiviral agents on account of the mechanism of viral membrane fusion, among which the peptide Enfuvirtide has been listed for the treatment of AIDS. This paper reviewed a new way to design peptide-based antiviral agents by "bundling" superhelix with isopeptide bonds to construct the active advanced structure. It can solve the problem that peptide precursor compounds derived from the natural sequence of viral envelope protein tend to aggregate and precipitate under physiological conditions and low activity and endow the peptide agents with the feature of thermal stability, protease stability and in vitro metabolic stability. This approach is also providing a new way of thinking for the research and development of broad-spectrum peptide-based antiviral agents.

Exposure to Polypropylene Microplastics via Oral Ingestion Induces Colonic Apoptosis and Intestinal Barrier Damage through Oxidative Stress and Inflammation in Mice.

Extensive environmental pollution by microplastics has increased the risk of human exposure to plastics. However, the biosafety of polypropylene microplastics (PP-MPs), especially of PP particles < 10 µm, in mammals has not been studied. Thus, here, we explored the mechanism of action and effect of exposure to small and large PP-MPs, via oral ingestion, on the mouse intestinal tract. Male C57BL/6 mice were administered PP suspensions (8 and 70 µm; 0.1, 1.0, and 10 mg/mL) for 28 days. PP-MP treatment resulted in inflammatory pathological damage, ultrastructural changes in intestinal epithelial cells, imbalance of the redox system, and inflammatory reactions in the colon. Additionally, we observed damage to the tight junctions of the colon and decreased intestinal mucus secretion and ion transporter expression. Further, the apoptotic rate of colonic cells significantly increased after PP-MP treatment. The expression of pro-inflammatory and pro-apoptosis proteins significantly increased in colon tissue, while the expression of anti-inflammatory and anti-apoptosis proteins significantly decreased. In summary, this study demonstrates that PP-MPs induce colonic apoptosis and intestinal barrier damage through oxidative stress and activation of the TLR4/NF-κB inflammatory signal pathway in mice, which provides new insights into the toxicity of MPs in mammals.

Effects of Different Concentrations of Oil Mist Particulate Matter on Pulmonary Fibrosis In Vivo and In Vitro.

Oil-mist particulate matter (OMPM) refers to oily particles with a small aerodynamic equivalent diameter in ambient air. Since the pathogenesis of pulmonary fibrosis (PF) has not been fully elucidated, this study aims to explore the potential molecular mechanisms of the adverse effects of exposure to OMPM at different concentrations in vivo and in vitro on PF. In this study, rats and cell lines were treated with different concentrations of OMPM in vivo and in vitro. Sirius Red staining analysis shows that OMPM exposure could cause pulmonary lesions and fibrosis symptoms. The expression of TGF-ß1, α-SMA, and collagen I was increased in the lung tissue of rats. The activities of MMP2 and TIMP1 were unbalanced, and increased N-Cadherin and decreased E-Cadherin upon OMPM exposure in a dose-dependent manner. In addition, OMPM exposure could activate the TGF-ß1/Smad3 and TGF-ß1/MAPK p38 signaling pathways, and the differentiation of human lung fibroblast HFL-1 cells. Therefore, OMPM exposure could induce PF by targeting the lung epithelium and fibroblasts, and activating the TGF-ß1/Smad3 and TGF-ß1/MAPK p38 signaling pathways.

Different exposure modes of PM2.5 induces bronchial asthma and fibrosis in male rats through macrophage activation and immune imbalance induced by TIPE2 methylation.

Exposure to PM2.5 can aggravate the occurrence and development of bronchial asthma and fibrosis. Here, we investigated the differences in bronchial injury caused by different exposure modes of PM2.5 (high concentration intermittent exposure and low concentration continuous exposure), and the mechanism of macrophage activation and respiratory immune imbalance induced by PM2.5, leading to bronchial asthma and airway fibrosis using animal and cell models. A "PM2.5 real-time online concentrated animal whole-body exposure system" was used to conduct PM2.5 respiratory exposure of Wistar rats for 12 weeks, which can enhance oxidative stress in rat bronchus, activate epithelial cells and macrophages, release chemokines, recruit inflammatory cells, release inflammatory factors and extracellular matrix, promote bronchial mucus hypersecretion, inhibit the expression of epithelial cytoskeletal proteins, destroy airway barrier, and induce asthma. Furthermore, PM2.5 induced M2 polarization in lung bronchial macrophages through JAK/STAT and PI3K/Akt signaling pathways, and compared with low concentration continuous exposure, high concentration intermittent exposure of PM2.5 could regulate significantly higher expression of TIPE2 protein through promoter methylation of TIPE2 DNA, thereby activating PI3K/Akt signaling pathway and more effectively inducing M2 polarization of macrophages. Additionally, activated macrophages release IL-23, and activated epithelial cells and macrophages released TGF-ß1, which promoted the differentiation of Th17 cells, triggered the Th17 dominant immune response, and activated the TGF-ß1/Smad2 signaling pathway, finally causing bronchial fibrosis. Moreover, when the total amount of PM2.5 exposure was equal, high concentration-intermittent exposure was more serious than low concentration-continuous exposure. In vitro experiments, the co-culture models of PM2.5 with BEAS-2B, WL-38 and rat primary alveolar macrophages further confirmed that PM2.5 could induce the macrophage activation through oxidative stress and TIPE2 DNA methylation, and activate the TGF-ß1/Smad2 signaling pathway, leading to the occurrence of bronchial fibrosis.

Combined multi-omics analysis reveals oil mist particulate matter-induced lung injury in rats: Pathological damage, proteomics, metabolic disturbances, and lung dysbiosis.

Oil mist particulate matter (OMPM) causes acute and chronic diseases and exacerbations. Owing to the characteristics of poor ventilation, high oil mist concentration, and a relatively closed working environment, the existence of OMPM in the cabin is inevitable, and its impact on the health of occupations on ships cannot be ignored. However, compared with several studies that summarized the health effects of OMPM from traditional sources, few studies have focused on the occupational exposure risk of OMPM from oil pollution sources in ships. In this study, we collected OMPM from oil pollution in cabins and assessed the exposure to OMPM from oil pollution and the corresponding health risks through acute exposure experiments in rats. OMPM exposure induces protein regulation in the extracellular matrix and immune responses, leading to severe inflammatory responses. The abundance and composition of the lung microbial community changed significantly. It interferes with the lung metabolite levels. However, more research is needed to fully understand the extent of health risks associated with OMPM exposure. Further research on vulnerable groups exposed to OMPM from ships is needed to inform public health interventions.

Effects of dietary Bacillus amyloliquefaciens CECT 5940 supplementation on growth performance, antioxidant status, immunity, and digestive enzyme activity of broilers fed corn-wheat-soybean meal diets.

This experiment was conducted to investigate the effects of dietary supplementation with Bacillus amyloliquefaciens CECT 5940 (BA-5940) on growth performance, antioxidant capacity, immunity, and digestive enzyme activity of broiler chickens. A total of 720 one-day-old Arbor Acres male broiler chicks (average body weight, 45.87 ± 0.86 g) were randomly allocated to 5 treatments of 8 replicates with 18 chicks in each replicate. Broilers in the control group were fed a corn-wheat-soybean basal diet, the other 4 groups were fed the same basal diet supplemented with 500, 1,000, 1,500, or 2,000 mg/kg Ecobiol (1.27 × 109 CFU/g BA-5940) for 42 d, respectively. Broilers fed diets supplemented with BA-5940 showed a quadratic response (P < 0.05) of average daily gain (ADG) and feed to gain ratio (F:G) during d 22 to 42 and d 0 to 42. The glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities in serum and liver, and total antioxidant capacity (T-AOC) in liver of broilers on d 42 increased linearly (P < 0.05) with increasing levels of BA-5940, while malondialdehyde (MDA) level in serum decreased linearly (P < 0.05). Concentrations of serum immunoglobulin (Ig) A and IgM on d 21, and IgM on d 42 increased linearly (P < 0.05) as BA-5940 levels increased. Supplementation with increasing levels of BA-5940 linearly decreased serum tumor necrosis factor-α (TNF-α) levels on d 21 and 42, while increased interleukin (IL)-10 concentration (linear, P < 0.05) on d 21. Meanwhile, the levels of IL-1ß, IL-6, and TNF-α in the mucosa of jejunum and ileum were decreased (linear, P < 0.05) on d 42 as dietary supplementation of BA-5940 increased. Additionally, supplementation with BA-5940 also increased the activities of amylase (linear, P < 0.01), lipase (linear, P < 0.05) and chymotrypsin (linear, P < 0.01) in jejunal digesta, and lipase (linear, P < 0.05) in ileal digesta of broilers on d 42. To summarize, inclusion of BA-5940 in corn-wheat-soybean meal-based diet improved growth performance of broilers through improving antioxidant capacity, immunity, and digestive enzyme activity. Based on the results of this study, 1.1-1.6 × 109 CFU/kg BA-5940 is recommended for supplementation in broiler diets.

[Effect of epithelial-mesenchymal transition on cardiac fibrosis induced by oil mist particulate matter].

Objective: To investigate the effects of oil-mist particulate matter (OMPM) on cardiac tissue structure fibrosis in rats and the role of epithelial-mesenchymal transition (EMT). Methods: Six-week-old Wistar rats (half male and half female) were randomly divided into 3 groups: control group (without OMPM exposure), low-dose exposure group (50 mg/m3) and high-dose exposure group (100 mg/m3), 18 rats in each group, with 6.5 hours per day of dynamic inhalation exposure. After 42 days of continuous exposure, cardiac tissues were collected for morphological observation; Western blot was used to detect fibrosis markers collagen I and collagen III levels, epithelial marker E-cadherin levels, interstitial markers N-cadherin, fibronectin, vimentin, alpha-smooth muscle actin (α-SMA) levels, and EMT transcription factor Twist protein levels; Real-time polymerase chain reaction (RT-qPCR) was used to detect collagen I and collagen III mRNA levels. Results: After OMPM exposure, myocardial cell edema and collagen fiber deposition were increased gradually with increasing exposure dose. Western blot results showed that compared with the control group, the expression levels of collagen I, collagen III, N-Cadherin, fibronectin, vimentin, α-SMA, and Twist protein were increased significantly in the low-dose exposure group and the high-dose exposure group (P＜0.01), and protein expression levels were higher in the high-dose exposure group than those in the low-dose exposure group (P＜0.01). In contrast, E-Cadherin protein expression levels were decreased significantly, and lower in the high-dose exposure group (P＜0.01). RT-qPCR results showed that compared with the control group, collagen I and collagen III mRNA levels were increased significantly in the low-dose exposure group and the high-dose exposure group (P＜0.01), and were increased with increasing exposure dose. (P＜0.01). Conclusion: OMPM may induce cardiac fibrosis in rats by promoting EMT process.

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.

Toxic effects of the food additives titanium dioxide and silica on the murine intestinal tract: Mechanisms related to intestinal barrier dysfunction involved by gut microbiota.

This study aimed to compare the effects of three food-grade particles (micro-TiO2, nano-TiO2, and nano-SiO2) on the murine intestinal tract and to investigate their potential mechanisms of action. A 28-day oral exposure murine model was established. Samples of blood, intestinal tissues and colon contents were collected for detection. The results showed that all three particles could cause inflammatory damage to the intestine, with nano-TiO2 showing the strongest effects. Exposure also led to changes in gut microbiota, especially mucus-associated bacteria. Our results suggest that the toxic effects on the intestine were due to reduced intestinal mucus barrier function and an increase in metabolite lipopolysaccharides which activated the expression of inflammatory factors downstream. In mice exposed to nano-TiO2, the intestinal PKC/TLR4/NF-κB signalling pathway was activated. These findings will raise awareness of toxicities associated with the use of food-grade TiO2 and SiO2.

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.

Identification of apoptosis-associated protein factors distinctly expressed in cigarette smoke condensate-exposed airway bronchial epithelial cells.

Smoking is associated with an increased risk of respiratory diseases, including lung cancer and asthma. However, the mechanisms or diagnostic markers for smoking-related diseases remain largely unknown. Here we investigated the role of cigarette smoke condensate (CSC) in the regulation of human bronchial epithelial cell (BEAS-2B) behavior. We found that exposure to CSC significantly inhibited BEAS-2B cell viability, impaired cell morphology, induced cell apoptosis, triggered oxidative damage, and promoted inflammatory response, which suggests a deleterious effect of CSC on bronchial epithelial cells. In addition, CSC markedly altered the expression of apoptosis-associated protein factors, including p21, soluble tumor necrosis factor receptor 1, and Fas ligand. In sum, our study identified a panel of novel protein factors that may mediate the actions of CSC on bronchial epithelial cells and have a predictive value for the development and progression of smoking-related diseases, thus providing insights into the development of potential diagnostic and therapeutic strategies against these diseases.

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.

Precisely Designed Isopeptide Bridge-Crosslinking Endows Artificial Hydrolases with High Stability and Catalytic Activity under Extreme Denaturing Conditions.

Enzymes normally lose their activities under extreme conditions due to the dissociation of their active tertiary structure. If an enzyme could maintain its catalytic activity under non-physiological or denaturing conditions, it might be used in more applications in the pharmaceutical and chemical industries. Recently, we reported a coiled-coil six-helical bundle (6HB) structure as a scaffold for designing artificial hydrolytic enzymes. Here, intermolecular isopeptide bonds were incorporated to enhance the stability and activity of such biomolecules under denaturing conditions. These isopeptide bridge-tethered 6HB enzymes showed exceptional stability against unfolding and retained or even had increased catalytic activity for a model hydrolysis reaction under thermal and chemical denaturing conditions. Thus, isopeptide bond-tethering represents an efficient route to construct ultrastable artificial hydrolases, with promising potential to maintain biocatalysis under extreme conditions.

Site-specific Isopeptide Bridge Tethering of Chimeric gp41 N-terminal Heptad Repeat Helical Trimers for the Treatment of HIV-1 Infection.

Peptides derived from the N-terminal heptad repeat (NHR) of HIV-1 gp41 can be potent inhibitors against viral entry when presented in a nonaggregating trimeric coiled-coil conformation via the introduction of exogenous trimerization motifs and intermolecular disulfide bonds. We recently discovered that crosslinking isopeptide bridges within the de novo helical trimers added exceptional resistance to unfolding. Herein, we attempted to optimize (CCIZN17)3, a representative disulfide bond-stabilized chimeric NHR-trimer, by incorporating site-specific interhelical isopeptide bonds as the redox-sensitive disulfide surrogate. In this process, we systematically examined the effect of isopeptide bond position and molecular sizes of auxiliary trimeric coiled-coil motif and NHR fragments on the antiviral potency of these NHR-trimers. Pleasingly, (IZ14N24N)3 possessed promising inhibitory activity against HIV-1 infection and markedly increased proteolytic stability relative to its disulfide-tethered counterpart, suggesting good potential for further development as an effective antiviral agent for treatment of HIV-1 infection.