Introduction: It has been shown that polystyrene nanoplastic (PS-NP) exposure induces toxicity in the lungs. Objectives: This study aims to provide foundational evidence to corroborate that ...ferroptosis and abnormal HIF-1α activity are the main factors contributing to pulmonary dysfunction induced by PS-NP exposure. Methods: Fifty male and female C57BL/6 mice were exposed to distilled water or 100 nm or 200 nm PS-NPs via intratracheal instillation for 7 consecutive days. Hematoxylin and eosin (H&E) and Masson trichrome staining were performed to observe the histomorphological changes in the lungs. To clarify the mechanisms of PS-NP-induced lung injury, we used 100 μg/ml, 200 μg/ml and 400 μg/ml 100 or 200 nm PS-NPs to treat the human lung bronchial epithelial cell line BEAS-2B for 24 h. RNA sequencing (RNA-seq) of BEAS-2B cells was performed following exposure. The levels of glutathione, malondialdehyde, ferrous iron (Fe2+), and reactive oxygen species (ROS) were measured. The expression levels of ferroptotic proteins were detected in BEAS-2B cells and lung tissues by Western blotting. Western blotting, immunohistochemistry, and immunofluorescence were used to evaluate the HIF-1α/HO-1 signaling pathway activity. Results: H&E staining revealed substantial perivascular lymphocytic inflammation in a bronchiolocentric pattern, and Masson trichrome staining demonstrated critical collagen deposits in the lungs after PS-NP exposure. RNA-seq revealed that the differentially expressed genes in PS-NP-exposed BEAS-2B cells were enriched in lipid metabolism and iron ion binding processes. After PS-NP exposure, the levels of malondialdehyde, Fe2+, and ROS were increased, but glutathione level was decreased. The expression levels of ferroptotic proteins were altered significantly. These results verified that PS-NP exposure led to pulmonary injury through ferroptosis. Finally, we discovered that the HIF-1α/HO-1 signaling pathway played an important role in regulating ferroptosis in the PS-NP-exposed lung injury. Conclusion: PS-NP exposure caused ferroptosis in bronchial epithelial cells by activating the HIF-1α/HO-1 signaling pathway, and eventually led to lung injury.
Tuberculous meningitis (TBM) is a devastating form of tuberculosis (TB) causing high mortality and disability. TBM arises due to immune dysregulation, but the underlying immune mechanisms are ...unclear.
We performed single-cell RNA sequencing on peripheral blood mononuclear cells (PBMCs) and cerebrospinal fluid (CSF) cells isolated from children (n=6) with TBM using 10 xGenomics platform. We used unsupervised clustering of cells and cluster visualization based on the gene expression profiles, and validated the protein and cytokines by ELISA analysis.
We revealed for the first time 33 monocyte populations across the CSF cells and PBMCs of children with TBM. Within these populations, we saw that CD4_C04 cells with Th17 and Th1 phenotypes and Macro_C01 cells with a microglia phenotype, were enriched in the CSF. Lineage tracking analysis of monocyte populations revealed myeloid cell populations, as well as subsets of CD4 and CD8 T-cell populations with distinct effector functions. Importantly, we discovered that complement-activated microglial Macro_C01 cells are associated with a neuroinflammatory response that leads to persistent meningitis. Consistently, we saw an increase in complement protein (C1Q), inflammatory markers (CRP) and inflammatory factor (TNF-α and IL-6) in CSF cells but not blood. Finally, we inferred that Macro_C01 cells recruit CD4_C04 cells through CXCL16/CXCR6.
We proposed that the microglial Macro_C01 subset activates complement and interacts with the CD4_C04 cell subset to amplify inflammatory signals, which could potentially contribute to augment inflammatory signals, resulting in hyperinflammation and an immune response elicited by
-infected tissues.
A healthy alveolar epithelium is critical to the gas exchange function of the lungs. As the major cell type of alveolar epithelium, alveolar type 2 (AT2) cells play a critical role in maintaining ...pulmonary homeostasis by serving as alveolar progenitors during lung injury, inflammation, and repair. Dysregulation of AT2 cells may lead to the development of acute and chronic lung diseases and cancer. The lack of clinically relevant AT2 cell models hampers our ability to understand pulmonary diseases. Here, we sought to establish reversibly immortalized mouse pulmonary alveolar type 2 cells (imPAC2) and investigate their potential in forming alveolar organoids to model pulmonary diseases. Primary mouse pulmonary alveolar cells (mPACs) were isolated and immortalized with a retroviral expression of SV40 Large T antigen (LTA). Cell proliferation and survival was assessed by crystal violet staining and WST-1 assays. Marker gene expression was assessed by qPCR, Western blotting, and/or immunostaining. Alveolar organoids were generated by using matrigel. Ad-TGF-beta1 was used to transiently express TGF-beta1. Stable silencing beta-catenin or overexpression of mutant KRAS and TP53 was accomplished by using retroviral vectors. Subcutaneous cell implantations were carried out in athymic nude mice. The retrieved tissue masses were subjected to H & E histologic evaluation. We immortalized primary mPACs with SV40 LTA to yield the imPACs that were non-tumorigenic and maintained long-term proliferative activity that was reversible by FLP-mediated removal of SV40 LTA. The EpCAM.sup.+ AT2-enriched subpopulation (i.e., imPAC2) was sorted out from the imPACs, and was shown to express AT2 markers and form alveolar organoids. Functionally, silencing beta-catenin decreased the expression of AT2 markers in imPAC2 cells, while TGF-beta1 induced fibrosis-like response by regulating the expression of epithelial-mesenchymal transition markers in the imPAC2 cells. Lastly, concurrent expression of oncogenic KRAS and mutant TP53 rendered the imPAC2 cells a tumor-like phenotype and activated lung cancer-associated pathways. Collectively, our results suggest that the imPAC2 cells may faithfully represent AT2 populations that can be further explored to model pulmonary diseases.
The Brg1 (Brahma-related gene 1) is an important chromatin remodeling factor protein. The Brg1 protein can promote the transcriptional activation or inhibit target genes through regulating ATP ...hydrolysis which rearranges the nucleosomes position and the histone DNA interaction. In this study, we explored the role of Brg1 in house dust mite (HDM) stimulated airway inflammation.
The wild-type C57BL/6 mice (wild-type, WT) and alveolar epithelial cells specifically knockout Brg1 mice (Brg1fl/fl) were selected as the experimental subjects. HDM was used to stimulate human bronchial epithelial cells (16HBE) to construct an model of airway inflammation in vitro. The asthma group was established with HDM, and the control group was treated with normal saline. Wright's staining for the detection of differential counts of inflammatory cells in bronchoalveolar lavage fluid (BALF). Invasive lung function was used to assess the airway compliance. Hematoxylin and eosin (HE) staining and periodic acid-schiff (PAS) staining were used to detect mucus secretion. Immunohistochemistry was used to measure mucin glycoprotein 5AC (MUC5AC) protein expression in airway epithelium. Western blotting was used to detect the MUC5AC and JAK1/2-STAT6 proteins in mouse lung tissues and 16HBE cells. Co-immunoprecipitation (Co-IP) and Chromatin Immunoprecipitation (CHIP) were used to detect whether Brg1 could regulate the JAK1/2-STAT6 signaling pathway.
The airway inflammation, pulmonary ventilation resistance, airway mucus secretion, MUC5AC and IL-13 in BALF and MUC5AC protein expression in lung tissue of Brg1 knockout mice stimulated by HDM were lower than those of wild-type mice. The expression of MUC5AC protein in HDM stimulated Brg1 knockdown 16HBE cells was significantly lower than that in the control group. In vivo and in vitro, it was found that the activation of JAK1/2-STAT6 signal pathway in mouse lung tissue or 16HBE cells was inhibited after knockdown of Brg1 gene. The Co-IP and CHIP results showed that Brg1 could bind to the JAK1/2 promoter region and regulate the expression of JAK1/2 gene.
The Brg1 may promote the secretion of airway mucus stimulated by HDM through regulating the JAK1/2-STAT6 pathway. Knockdown of Brg1 reduced mucus secretion in HDM stimulated airway inflammation.
•Brg1 promotes mucus secretion in HDM stimulated airway inflammation.•Knockdown of Brg1 reduces MUC5AC and IL-13 secretion in HDM stimulated airway inflammation.•Knockdown of Brg1 can inhibit the activation of JAK1/2-STAT6 signaling pathway and reduce HDM-induced mucus hypersecretion.•Brg1 gene can regulate JAK1/2-STAT6 signaling pathway by binding to the promoter region of JAK gene.
Panax notoginseng saponin R1(PNS-R1), derived from Panax notoginseng roots, promotes wound repair, whereas glucocorticoids can inhibit the repair of airway epithelial damage in asthma.
This study ...investigated whether PNS-R1 counteracts the inhibitory effects of glucocorticoids on the repair of airway epithelial damage in asthma.
In vivo, female C57BL/6 mice were sensitized, challenged with house dust mites (HDM), and treated with dexamethasone, PNS-R1, and/or adenovirus GRβ-shRNA. Airway epithelium damage was examined using pathological sections of the trachea and bronchi, markers of airway inflammation, epithelial cells in bronchoalveolar lavage fluid, and expression of the E-cadherin protein. In vitro, we treated 16HBE cells with dexamethasone, PNS-R1, and/or GRβ-siRNA and detected cell proliferation and migration. The expression of GRβ and key components of MKP-1 and Erk1/2 were detected by western blotting.
In vivo, PNS-R1 reduced airway inflammation, hyperresponsiveness, and mucus hypersecretion; the combination of PNS-R1 and dexamethasone promoted airway epithelial integrity and reduced cell detachment. In vitro, PNS-R1 alleviated the inhibition of bronchial epithelial cell growth, migration, and proliferation by dexamethasone; PNS-R1 promoted GRβ expression, inhibited MKP-1 protein expression, and activated MAPK signaling, thereby promoting airway epithelial cell proliferation and repair.
Panax notoginseng saponin R1 alleviated the inhibitory effect of dexamethasone on the repair of airway epithelial damage in asthmatic mice, likely by promoting the proliferation of airway epithelial cells by stimulating GRβ expression and activating the MAPK pathway.
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•The specific mechanisms of PS-NP-induced pulmonary injury are unclear.•A mouse model of lung injury is created based on the real-world NP exposure in human.•PS-NP exposure induces ...ferroptosis in lung tissues and bronchial epithelial cells.•HIF-1α inhibition rescues PS-NP-induced ferroptosis in bronchial epithelial cells.•PS-NP exposure induces ferroptosis via the HIF-1α/HO-1signaling pathway in lungs.
It has been shown that polystyrenenanoplastic (PS-NP) exposure induces toxicity in the lungs.
This study aims to provide foundational evidence to corroborate that ferroptosis and abnormal HIF-1α activity are the main factors contributing to pulmonary dysfunction induced by PS-NP exposure.
Fifty male and female C57BL/6 mice were exposed to distilled water or 100 nm or 200 nm PS-NPs via intratracheal instillation for 7 consecutive days. Hematoxylin and eosin (H&E) and Masson trichrome staining were performed to observe the histomorphological changes in the lungs. To clarify the mechanisms of PS-NP-induced lung injury, we used 100 μg/ml, 200 μg/ml and 400 μg/ml 100 or 200 nm PS-NPs to treat the human lung bronchial epithelial cell line BEAS-2B for 24 h. RNA sequencing (RNA-seq) of BEAS-2B cells was performed following exposure. The levels of glutathione, malondialdehyde, ferrous iron (Fe2+), and reactive oxygen species (ROS) were measured. The expression levels of ferroptotic proteins were detected in BEAS-2B cells and lung tissues by Western blotting. Western blotting, immunohistochemistry, and immunofluorescence were used to evaluate the HIF-1α/HO-1 signaling pathway activity.
H&E staining revealed substantial perivascular lymphocytic inflammation in a bronchiolocentric pattern, and Masson trichrome staining demonstrated critical collagen deposits in the lungs after PS-NP exposure. RNA-seq revealed that the differentially expressed genes in PS-NP-exposed BEAS-2B cells were enriched in lipid metabolism and iron ion binding processes. After PS-NP exposure, the levels of malondialdehyde, Fe2+, and ROS were increased, but glutathione level was decreased. The expression levels of ferroptotic proteins were altered significantly. These results verified that PS-NP exposure led to pulmonary injury through ferroptosis. Finally, we discovered that the HIF-1α/HO-1 signaling pathway played an important role in regulating ferroptosis in the PS-NP-exposed lung injury.
PS-NP exposure caused ferroptosis in bronchial epithelial cells by activating the HIF-1α/HO-1 signaling pathway, and eventually led to lung injury.
There is a growing interest in using natural medicines to treat stroke as the leading cause of disability worldwide. Especially plant-derived natural medicines have multiple beneficial effects, ...including antioxidative, anti-inflammatory, antiapoptotic, suggesting their potential for stroke treatment. However, failure in clinical translation has created a substantial challenge for their use as stroke treatment. This review summarises the status of using natural medicinal formulations in stroke treatment, as well as the challenges. Although natural medicines have excellent prospects for ischaemic stroke treatment, several concerns need to be addressed for translating the success in animal research to humans. Specifically, there should be more considerations for investigating the precise mechanisms of natural medicines mediating the neuroprotective effects on stroke. Moreover, to further improve the prospects of clinical translation, further studies should be performed in aged animals rather than young adult animals.
Natural rubber is one of most famous self‐reinforced rubbers thanks to the phenomenon of strain‐induced crystallization. It is usually used in a vulcanized form to enhance the mechanical strength but ...this results in recycling issues. Herein a thermoplastic analogue of vulcanized natural rubber is obtained as a structural mimic. Terminally functionalized polyisoprene rubber B‐4A‐PIP was prepared by using tetra‐analine as physical crosslinking units. The strong binding of tetra‐analine groups gave B‐4A‐PIP a high tensile strength (15 MPa) and breaking strain of 890 %, which is much higher than those of undecorated copolymer B‐OH‐PIP. B‐4A‐PIP has a similar onset strain of crystallization and crystallization index to vulcanized natural rubber. Randomly functionalized polyisoprene R‐4A‐PIP showed a much lower mechanical strength and SIC properties although R‐4A‐PIP and B‐4A‐PIP possessed similar molecular weights and amounts of tetra‐analine groups.
Terminal functionalization: Tetrapeptide grafting polyisoprenes were prepared with different sequences of polar groups. The terminal polar block promoted the toughness and stain‐induced crystallization behavior of thermoplastic polyisoprene; these properties were comparable to vulcanized natural rubber.
•Fractional-order models are more accurate than integer-order models in reflecting some properties of objects when studying practical problems.•This paper analyses the relationship between enterprise ...management and financial performance, mathematically models its relationship.•We constructs fractional differential equations, and tests it through empirical research.•The influence of the characteristics of management age, international experience, team size etc. on the financial performance of the company.
With the development of science and technology, people also find that fractional-order models are more accurate than integer-order models in describing some phenomena and reflecting some properties of objects when studying practical problems. Since the fractional derivative is a quasi-differential operator, its memory-preserving non-locality, while beautifully portraying the real problem, also brings considerable difficulties to theoretical analysis and numerical calculation. This paper analyses the relationship between enterprise management and financial performance, analyses the mean and heterogeneity of the characteristics of enterprise management team, mathematically models its relationship, constructs fractional differential equations, and tests it through empirical research. The influence of the characteristics of enterprise management age, international experience, education level, team size and government background on the financial performance of the company.
Supramolecular interactions such as hydrogen bonds have seldomly considered to be strong enough to maintain dimensional stability of elastomers. Herein, the interplay between spacer length and ...oligopeptide binding have been used to harvest a strong and stable polyisoprene elastomer comparable to vulcanized counterpart. It is found that along the increase of spacer length from 3 to 5 and 7, the mechanical strength and thermostabilities of elastomers increased remarkably with the maintenance of high extensibility. The high apparent activation energies and obviously reduced relaxation rate could account for the observed phenomenon. This case indicates that the architecture control of polymer could coordinate with supramolecular interactions and broaden their applications.
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•A series of tetrapeptide-decorated polyisoprenes with different spacer lengths were prepared.•The sample with longer spacer length showed superior mechanical properties and dimensional stability.•4A-7-PIP with seven -CH2 spacer exhibits a stress of 18.3 MPa at 870% strain and excellent creep-resistant property.
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