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

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With the rapid development of nanotechnology, the risks of accidental and/or occupational exposure to zinc oxide nanoparticles (ZnONPs) are increasing. Inhalation of ZnONPs induces metal fume fever in humans and acute lung injury (ALI) in animal models. Although the intestinal microbiota is considered an important modulator of various diseases, the role and mechanism of intestinal microbiota in the pathology of ZnONP-induced ALI are unclear. Herein, we established an intratracheal instillation of a ZnONP-induced ALI mouse model and found that the inhalation of ZnONPs caused ALI along with a perturbation of intestinal flora. Antibiotic cocktail treatment-mediated depletion of intestinal microbiota aggravated ZnONP-induced ALI, and in contrast, fecal microbiota transplantation-mediated restoration of intestinal microbiota exerted the opposite effects. A decrease in short-chain fatty acids, the intestinal microbiota-derived metabolites in the plasma-in particular, acetic acid and propionic acid-occurred after exposure to ZnONPs. It is important to note that supplementation with propionic acid, but not acetic acid, ameliorated ZnONP-induced ALI. We also showed that the source of inflammatory cytokines might partially be the infiltration of macrophages. Supplementation with propionic acid was found to act on macrophages through the receptor GPR43, because knockdown of GPR43 sharply reversed the protective effects of propionic acid during the ZnONP-induced inflammatory response and oxidative stress in both primary alveolar macrophages and RAW 264.7 macrophage cell lines. Altogether, a novel gut-lung axis mechanism is revealed in which intestinal microbiota and their derived metabolite propionic acid play protective roles against ZnONP-induced ALI and suggest that fecal microbiota transplantation and supplementation with propionic acid are potential remedy strategies.

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BACKGROUND: Recent literature have indicated that the malignancy of cancer cells is modulated by hsa_circ_0000423 (named circPPP1R12A) through the way of translating protein. Herein, we investigated the role and latent mechanisms of circPPP1R12A in Non-Small Cell Lung Cancer (NSCLC). METHODS: CircPPP1R12A expression was measured by qRT-PCR. The malignancy of NSCLC was determined by CCK-8, TUNEL assay, Wound healing, Transwell and Western blotting assays. The underlying mechanisms of circPPP1R12A were confirmed by Western blotting and qRT-PCR assays. RESULTS: CircPPP1R12A expression in NSCLC tissues was higher than that of neighboring normal tissues. CircPPP1R12A showed an upregulated expression in NSCLC cells. Upregulation of circPPP1R12A could promote the cell viability of NSCLC cells and reduce the apoptosis of NSCLC cells, while it could not promote cell invasion and migration. The reduction of cell viability and apoptosis was discovered in NSCLC cells with the silencing of circPPP1R12A, but circPPP1R12A knockdown does not inhibit cell invasion and migration. There was something interesting that circPPP1R12A encoding protein circPPP1R12A-73aa was found in NSCLC cells. Mutations in circPPP1R12a-73AA might disrupt the function of circPPP1ra-73AA in A549 and H1299 cells. Next, we found that circPPP1R12A caused the increased growth of NSCLC cells by activating AKT signaling pathway. CONCLUSION: In summary, our study proved that NSCLC cell proliferation was promoted by circPPP1R12A-73aa translated from circPPP1R12A through the AKT pathway, which could throw some light on the understanding of the mechanism of NSCLC.

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BACKGROUND: SARS-CoV-2 infection leads to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Both clinical data and animal experiments suggest that the renin-angiotensin system (RAS) is involved in the pathogenesis of SARS-CoV-2-induced ALI. Angiotensin-converting enzyme 2 (ACE2) is the functional receptor for SARS-CoV-2 and a crucial negative regulator of RAS. Recombinant ACE2 protein (rACE2) has been demonstrated to play protective role against SARS-CoV and avian influenza-induced ALI, and more relevant, rACE2 inhibits SARS-CoV-2 proliferation in vitro. However, whether rACE2 protects against SARS-CoV-2-induced ALI in animal models and the underlying mechanisms have yet to be elucidated. METHODS AND RESULTS: Here, we demonstrated that the SARS-CoV-2 spike receptor-binding domain (RBD) protein aggravated lipopolysaccharide (LPS)-induced ALI in mice. SARS-CoV-2 spike RBD protein directly binds and downregulated ACE2, leading to an elevation in angiotensin (Ang) II. AngII further increased the NOX1/2 through AT1R, subsequently causing oxidative stress and uncontrolled inflammation and eventually resulting in ALI/ARDS. Importantly, rACE2 remarkably reversed SARS-CoV-2 spike RBD protein-induced ALI by directly binding SARS-CoV-2 spike RBD protein, cleaving AngI or cleaving AngII. CONCLUSION: This study is the first to prove that rACE2 plays a protective role against SARS-CoV-2 spike RBD protein-aggravated LPS-induced ALI in an animal model and illustrate the mechanism by which the ACE2-AngII-AT1R-NOX1/2 axis might contribute to SARS-CoV-2-induced ALI.

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BACKGROUND: More and more evidences demonstrate that circular RNAs (circNRAs) can encode protein. As a circRNA with translation capabilities, outcomes of circß-catenin in non-small cell lung cancer (NSCLC) still need to be explored. METHOD: The research methods of circß-catenin in the article include qRT-PCR, wound healing assay, CCK-8, colony formation, and Transwell assay. Western blotting and immunofluorescence were provided to detect protein expression levels and peptide encoded by circß-catenin, respectively. RESULTS: A prominently higher circß-catenin expression was found in NSCLC tissues. Silencing of circß-catenin was able to inhibit NSCLC cell migrating, invasive, and proliferative phenotypes. Overexpression of circß-catenin could enhance the migrating, invasive, and proliferative phenotypes of NSCLC cells. Importantly, circß-catenin was found to encode a peptide in NSCLC cells. Silencing or overexpression of circß-catenin could reduce or increase ß-catenin protein expression via suppressing the degradation of ß-catenin. CONCLUSION: Circß-catenin could promote NSCLC cell malignant phenotypes via peptide-regulated ß-catenin pathway. Our study provided a new understanding for the mechanisms of NSCLC.

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Multi-label proteins can participate in carrier transportation, enzyme catalysis, hormone regulation and other life activities. Meanwhile, they play a key role in the fields of biopharmaceuticals, gene and cell therapy. This article proposes a prediction method called Mps-mvRBRL to predict the subcellular localization (SCL) of multi-label protein. Firstly, pseudo position-specific scoring matrix, dipeptide composition, position specific scoring matrix-transition probability composition, gene ontology and pseudo amino acid composition algorithms are used to obtain numerical information from different views. Based on the contribution of five individual feature extraction methods, differential evolution is used for the first time to learn the weight of single feature, and then these original features use a weighted combination method to fuse multi-view information. Secondly, the fused high-dimensional features use a weighted linear discriminant analysis framework based on binary weight form to eliminate irrelevant information. Finally, the best feature vector is input into the joint ranking support vector machine and binary relevance with robust low-rank learning classifier to predict the SCL. After applying leave-one-out cross-validation, the overall actual accuracy (OAA) and overall location accuracy (OLA) of Mps-mvRBRL on the training set of Gram-positive bacteria are both 99.81%. The OAA on the test sets of plant, virus and Gram-negative bacteria datasets are 97.24%, 98.55% and 98.20%, respectively, and the OLA are 97.16%, 97.62% and 98.28%, respectively. The results show that the model achieves good prediction performance for predicting the SCL of multi-label protein.

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PURPOSE: Zinc oxide nanoparticles (ZnONPs) are one of the most important nanomaterials that are widely used in the food, cosmetic and medical industries. Humans are often exposed to ZnONPs via inhalation, and they may reach the brain where neurotoxic effects could occur via systemic distribution. However, the mechanisms underlying how ZnONPs produce neurotoxic effects in the brain remain unclear. In this study, we aimed to investigate the novel mechanism involved in ZnONPs-induced neurotoxicity. METHODS AND RESULTS: We demonstrated for the first time that pulmonary exposure to ZnONPs by intratracheal instillation could trigger ferroptosis, a new form of cell death, in the neuronal cells of mouse cerebral cortex. A similar phenomenon was also observed in cultured neuron-like PC-12 cell line. By using a specific inhibitor of ferroptosis ferrostatin-1 (Fer-1), our results showed that inhibition of ferroptosis by Fer-1 could significantly alleviate the ZnONPs-induced neuronal cell death both in vivo and in vitro. Mechanistic investigation revealed that ZnONPs selectively activated the JNK pathway and thus resulted in the ferroptotic phenotypes, JNK inhibitor SP600125 could reverse lipid peroxidation upregulation and ferroptotic cell death induced by ZnONPs in PC-12 cells. CONCLUSION: Taken together, this study not only demonstrates that pulmonary exposure of ZnONPs can induce JNK-involved ferroptotic cell death in mouse cortex and PC-12 cells, but also provides a clue that inhibition of ferroptosis by specific agents or drugs may serve as a feasible approach for reducing the untreatable neurotoxicity induced by ZnONPs.

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The aim of this study is to explore the potential association between cystatin C (Cys-c) and coronary heart disease (CHD) in hypertensive patients.In this study, circulating levels of Cys-c in 62 essential hypertension (EH) patients, 147 hypertension with coronary heart disease (EH + CHD) patients, and 60 healthy volunteers were investigated using immunoturbidimetry. Then, we analyzed the correlations between Cys-C and other clinical parameters.Serum Cys-C level was significantly higher in the EH and EH + CHD groups than in the control group, and higher in the EH + CHD group than in the EH group. Receiver operating characteristic curve (ROC) analysis showed that the diagnostic value of Cys-C for patients with hypertension combined CHD was 0.871(95% CI: 0.818-0.913). Serum Cys-C level was significantly higher in the double-vessel disease group and multi-vessel disease group than in the single-vessel disease group, and higher in the multi-vessel disease group than in the double-vessel disease group. Urinary albumin and CRP correlated positively with Cys-C, and HDL correlated negatively with Cys-C. Cys-C was an independent risk factor for CHD in hypertensive patients.Our results suggested that circulating Cys-C levels was up-regulated in patients with hypertension and CHD, and had correlation with the severity of coronary artery disease. As one of the important risk factors for CHD, Cys-C can predict the occurrence of CHD in patients with hypertension.

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We present a facile strategy for the fabrication of mechanically tough and self-recoverable nanocomposite hydrogels reinforced by surface-modified cellulose nanocrystals. Polyacrylamide grafted cellulose nanocrystal (CNC-g-PAM) was first synthesized by ceric salt initiated surface graft polymerization of acrylamide onto CNC, then incorporated into chemically crosslinked poly(acrylic acid) (PAA) networks to obtain dual-crosslinked CNC-g-PAM/PAA nanocomposite hydrogels. CNC-g-PAM acted as both interfacial compatible nanofillers and physical crosslinkers through reversible hydrogen bonds between PAA and PAM on the surface of CNC. FTIR analysis confirmed the formation of above hydrogen bonds. Scanning electron microscopy observations revealed good interfacial compatibility between CNC and PAA matrix. The nanocomposite hydrogels exhibited decreasing swelling ratio with increasing CNC-g-PAM content. Uniaxial tensile tests and tensile loading-unloading tests showed that elastic modulus, breaking strength and elongation at break of the nanocomposite hydrogels were significantly increased compared to PAA hydrogel, and that the nanocomposite hydrogels exhibited good self-recovery ability after large deformation.