Search

Acute lung injury (ALI) is a severe form of respiratory failure characterized by altered lung mechanics and refractory hypoxemia. Globally, the condition presents a serious threat to human health. Morin is a potential active monomer that has beneficial therapeutic effects in ALI; however, its mechanism of action remains unclear. Herein, we found significant elevation of inflammation and pyroptosis in the lung tissue of mice with lipopolysaccharide-induced ALI. Additionally, morin blocked the activation of the TLR4/TRAF6/NF-κB pathway and synergically inhibited the entry of p65 into the nucleus by downregulating the expression of Kruppel-like factor 5. Morin also inhibited caspase-1 activation and protected the GSDMD protein from cleavage. These findings are evidence that morin alleviates ALI by blocking the NF-κB pathway, reducing inflammation, and inhibiting macrophage pyroptosis.

BACKGROUND Sepsis is a major medical challenge. Magnolol is an active constituent of Houpu that improves tissue function and exerts strong anti-endotoxin and anti-inflammatory effects, but the mechanism by which it reduces intestinal inflammation in sepsis is yet unclear. AIM To assess the protective effect of magnolol on intestinal mucosal epithelial cells in sepsis and elucidate the underlying mechanisms. METHODS Enzyme-linked immunosorbent assay was used to measure tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and regulated on activation, normal T-cell expressed and secreted (RANTES) levels in serum and ileal tissue in animal studies. The histopathological changes of the ileal mucosa in different groups were observed under a microscope. Cell Counting Kit-8 and cell permeability assays were used to determine the concentration of drug-containing serum that did not affect the activity of Caco2 cells but inhibited lipopolysaccharide (LPS)-induced decrease in permeability. Immunofluorescence and Western blot assays were used to detect the levels of RANTES, inhibitor of nuclear factor kappa-B kinase β (IKKβ), phosphorylated IKKβ (p-IKKβ), inhibitor of nuclear factor kappa-B kinase α (IκBα), p65, and p-p65 proteins in different groups in vitro. RESULTS In rats treated with LPS by intravenous tail injection in the presence or absence of magnolol, magnolol inhibited the expression of proinflammatory cytokines, IL-1β, IL-6, and TNF-α in a dose-dependent manner. In addition, magnolol suppressed the production of RANTES in LPS-stimulated sepsis rats. Moreover, in vitro studies suggested that magnolol inhibited the increase of p65 nucleation, thereby markedly downregulating the production of the phosphorylated form of IKKβ in LPS-treated Caco2 cells. Specifically, magnolol inhibited the translocation of the transcription factor nuclear factor-kappa B (NF-κB) from the cytosol into the nucleus and down-regulated the expression level of the chemokine RANTES in LPS-stimulated Caco2 cells. CONCLUSION Magnolol down-regulates RANTES levels by inhibiting the LPS/NF-κB signaling pathways, thereby suppressing IL-1β, IL-6, and TNF-α expression to alleviate the mucosal barrier dysfunction in sepsis.

Functional passivators are conventionally utilized in modifying the crystallization properties of perovskites to minimize the non-radiative recombination losses in perovskite light-emitting diodes (PeLEDs). However, the weak anchor ability of some commonly adopted molecules has limited passivation ability to perovskites and even may desorb from the passivated defects in a short period of time, which bring about plenty of challenges for further development of high-performance PeLEDs. Here, a multidentate molecule, formamidine sulfinic acid (FSA), is introduced as a novel passivator to perovskites. FSA has multifunctional groups (S≐O, C≐N and NH

Energy matching between the triplet level of the exciplex hosts and phosphorescent emitters is of particular importance to achieve highly efficient exciplex-based white organic light emitting diodes (WOLEDs). Herein, we design a novel exciplex host and use it for WOLEDs by arranging rational multiple-exciplex hosts in emissive layers. The resulting two-color warm WOLED, by doping blue and orange phosphorescent emitters, shows a maximum forward-viewing power efficiency and external quantum efficiency (EQE) of 104.6 lm W−1 and 30.9%, respectively. Significantly, the EQE still remains 22.1% at 5000 cd m−2. Meanwhile, the three-color warm WOLED has a high color rendering index of over 80 with a maximum EQE of 27.0% and the EQE can remain 21.3% at 5000 cd m−2. These results indicate that rational arrangement of multiple-exciplex hosts in emissive layers is promising for the fabrication of highly efficient WOLEDs.

Introduction Severe hand, foot, and mouth disease (HFMD) may lead to serious complications, which cause child mortality during outbreaks. The aim of this study was to determine whether neutrophil-to-lymphocyte ratio (NLR) can predict death risk in severe HFMD. Methods Medical records for 664 severe HFMD patients were retrospectively examined, and NLR was calculated from blood counts. Youden's index was calculated to determine the optimal NLR cutoff. Uni- and multivariate logistic regression were used to determine death risk factors associated with severe HFMD. Results An NLR cutoff value of 2.01 and 2.50 respectively predicted mortality among all 664 severe HFMD and 137 critical HFMD. Among all 664 patients, the multivariate model identified the following as independently associated with death risk: high fever (OR 3.342, 95% CI 1.736-6.432), EV71 infection (OR 3.200, 95% CI 1.529-6.698), fasting glucose (OR 37.343, 95% CI 18.616-74.909), and NLR (>2.01) (OR 2.142, 95% CI 1.125-4.079). Among 137 critical HFMD, EV71 infection (OR 3.441, 95% CI 1.132-10.462), fasting glucose (OR 14.173, 95% CI 4.920-40.827), and NLR (>2.50) (OR 4.166, 95% CI 1.570-11.051) were associated with death risk. Conclusion In conclusion, NLR (>2.01) in severe HFMD and NLR (>2.50) in critical HFMD patients may be associated with increased death risk.

Respiratory syncytial virus (RSV) infection enhances the cell‑mediated immune responses of type 2 helper T cells and promotes the progression of allergic inflammation and asthma by producing thymic stromal lymphopoietin (TSLP), especially long isoform TSLP (lfTSLP). However, the role of short isoform TSLP (sfTSLP) in RSV infection remains to be elucidated. The present study was designed to demonstrate the role of both lfTSLP and sfTSLP, as transcription regulators, in RSV infection. The expression of lfTSLP and sfTSLP in RSV‑infected Beas‑2B cells was analyzed. Activating protein 2 (AP‑2)α was overexpressed or knocked down to detect the changes in sfTSLP and lfTSLP expression. Luciferase reporter plasmid and chromatin immunoprecipitation experiments demonstrated that AP‑2α bound to the sfTSLP promoter region. LfTSLP and sfTSLP increased while AP‑2α decreased in RSV‑infected Beas‑2B cells. In the Beas‑2B cells, AP‑2α was found to negatively regulate the activity of the sfTSLP promoter and the mRNA level of sfTSLP. AP‑2α also negatively regulated the expression of lfTSLP at both the mRNA and protein levels. The results of the chromatin immunoprecipitation assay indicated that AP‑2α bound to the core promoter region of sfTSLP. These results confirmed that the transcription factor AP‑2α can repress the expression of lfTSLP and sfTSLP in bronchial epithelial cells in RSV infection.

It has been well-acknowledged that N-methyl-D-aspartate receptors (NMDARs) in central nervous system play an important role in both physiological functions of neurons and the pathophysiological progression of various neurodegenerative diseases. Besides, the receptors have also been found to present extensively in peripheral organs, such as lungs, kidneys, heart, and pancreas. Under various pathological conditions, peripheral NMDARs are upregulated and excessively activated, initiating calcium influx and intracellular calcium overloading. Subsequently, mitochondrial dysfunction, oxidative stress, and pro-inflammatory signaling pathway activation ultimately aggravate tissue damage and organ dysfunction. In addition, excessive activation of NMDARs also directly initiates mitochondrial apoptosis in many organs. Here, we discuss pathophysiological roles of NMDARs in cardiovascular system, lungs, kidneys, and pancreas.

Xuefu Zhuyu Decoction (XFZYD), a well-known traditional Chinese medicine prescription, has been widely used to treat traumatic brain injury (TBI). However, the underlying mechanisms involved in XFZYD therapy remain unclear.We explored new therapeutic targets of XFZYD in TBI by the tsRNA-sequencing (tsRNA-seq) method.High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was used to assess the quality of XFZYD. Male Sprague-Dawley rats were randomly categorized into three groups: sham, TBI, and XFZYD. The protective effects of XFZYD were investigated in vivo by using the Morris water maze (MWM), modified neurological severity score (mNSS) tests, hematoxylin-eosin (HE) staining, and Nissl staining. tsRNA-seq was applied to analyze the expression of tsRNAs in the rat cortex. Four tsRNAs were validated by qRT-PCR. The biological function of putative tsRNAs was investigated using bioinformatics techniques. The functions of tsRNAs targeting mRNAs were verified in vitro.The mNSS and MWM indicated that XFZYD notably improved neurological deficits and cognitive function after TBI (p 0.05). HE staining and Nissl staining demonstrated that XFZYD suppressed damage and neuronal loss in the TBI rat cortex. We evaluated the dysregulated expression of 732 tsRNAs (128 tsRNAs were significantly altered in the TBI/sham group (fold change 2 and p 0.05), and 97 tsRNAs were dysregulated in the XFZYD/TBI group (fold change 2 and p 0.05)) in the TBI rat cortex. Interestingly, 41 tsRNAs were distinctly regulated by XFZYD. The qRT-PCR results of the four randomly chosen tsRNAs (tRF-54-75-Glu-TTC-2, tRF-55-75-Gln-CTG-2-M2, tRF-55-76-Val-TAC-1, tRF-64-85-Leu-AAG-1-M4) exhibited trends similar to those of the tsRNA-seq data. We certified the possible targets of tsRNAs and suggested the crosscurrent in the expression trend of the target genes. Bioinformatics analysis showed that XFZYD-related tsRNAs could contribute to regulating insulin resistance, the calcium signaling pathway, autophagy, and axon guidance.The current research implies that tsRNAs are putative therapeutic targets of XFYZD for TBI treatment. This research provides new insight into the therapeutic targets of XFZYD in treating TBI.

Cigarette smoke (CS) is a risk factor for pulmonary fibrosis and lipopolysaccharides (LPS) are associated with human occupational lung diseases; however, their combined role in pulmonary fibrosis remains unknown. Therefore, we investigated whether CS combined with LPS induces pulmonary fibrosis in mice. C57BL/6 mice were exposed to CS or normal air for 21 or 35 days, followed by LPS or saline instillation on day 14, 21, and 28. Lung function was tested, and lung tissues were harvested for histological and molecular analyses. Compared to the control, CS and LPS groups, the CS + LPS group showed reduced body weight and survival rate, increased respiratory resistance, decreased lung compliance, marked alveolar structure destruction, and fibrotic lesion formation. Lung tissues showed a considerable increase in IL-6, TNF-α, IL-1β, α-SMA, and TGF-β levels and collagen content. Our results indicate that cigarette smoke exposure followed by LPS in mice induces pulmonary fibrosis with pathophysiology consistent with that of human pulmonary fibrosis.

Purpose Lung cancer is the most common malignant tumor in the world, and its incidence and mortality are very high. This study focuses on the mechanism of non-small cell lung cancer to find new therapeutic targets. Methods We used RT-PCR and Western blot to verify the linear relationship between E2F1 and IRF5 in normal lung tissue and lung cancer tissues. Secondly, we used overexpression and knock down E2F1 in cell lines to detect the expression of IRF5. The prime enzyme reporter plasmid verified that E2F1 binds to the core promoter region of IRF5; finally, CHIP experiments demonstrated that E2F1 binds directly to IRF5. Results We verified that E2F1 and IRF5 are decreased in patient tissues, and there is a strong linear relationship between E2F1 and IRF5. Secondly, we used overexpression of E2F1 or E2F1 siRNA transfected into HCC827 cells and found that E2F1 positively regulates the activity of the IRF5 promoter and the mRNA level of IRF5. Finally, the results of a chromatin immunoprecipitation assay demonstrated that E2F1 bound to the promoter region of IRF5 in vitro. These results suggested that the E2F1 transcription factor is the primary determinant for activating the basal transcription of the IRF5. Conclusion The transcription factor E2F1 positively regulates IRF5 in non-small cell lung cancer.

Purpose The objective of this study was to retrospectively research the clinical characteristics, pathogen distribution, prognosis of nosocomial bloodstream infection (nBSI), and the associated risk factors for nBSI. Materials and methods The clinical and microbiological data of patients with nBSI were retrospectively studied. Patients were treated at the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Hangzhou, China) between January 2013 and December 2016. Results Our study spanned a four-year period and included 704 episodes of nBSI. The incidence rate was 4.11 per 1000 admissions. Of these cases, 96.7% were monomicrobial: gram-negative bacteria (56.4%), gram-positive bacteria (33.4%), and fungal (7%). Of all the Escherichia coli isolates, 41.5% were extended-spectrum β-lactamase-producing (ESBL)-positive. Of the Klebsiella pneumoniae isolates, 50.9% were resistant to imipenem. Of the Staphylococcus aureus isolates, 42.1% were methicillin-resistant. The overall 28-day mortality rate in all patients with nBSI was 24.4%. Parenteral nutrition (PN) and sequential organ failure assessment (SOFA) scores (≥5) were closely related to the 28-day mortality rate of nBSI, while removal of venous catheters and appropriate empirical therapy were protective factors of 28-day mortality. Conclusions Gram-negative bacteria predominantly developed in nBSI. Timely removal of venous catheters (catheter retention time ≥ 7 days) and implementation of appropriate empirical therapy improved the nBSI outcomes.

Background The hard-shelled mussel (Mytilus coruscus) is widely distributed in the temperate seas of East Asia and is an important commercial bivalve in China. Chromosome-level genome information of this species will contribute not only to the development of hard-shelled mussel genetic breeding but also to studies on larval ecology, climate change biology, marine biology, aquaculture, biofouling, and antifouling. Findings We applied a combination of Illumina sequencing, Oxford Nanopore Technologies sequencing, and high-throughput chromosome conformation capture technologies to construct a chromosome-level genome of the hard-shelled mussel, with a total length of 1.57 Gb and a median contig length of 1.49 Mb. Approximately 90.9% of the assemblies were anchored to 14 linkage groups. We assayed the genome completeness using BUSCO. In the metazoan dataset, the present assemblies have 89.4% complete, 1.9% incomplete, and 8.7% missing BUSCOs. Gene modeling enabled the annotation of 37,478 protein-coding genes and 26,917 non-coding RNA loci. Phylogenetic analysis showed that M. coruscus is the sister taxon to the clade including Modiolus philippinarum and Bathymodiolus platifrons. Conserved chromosome synteny was observed between hard-shelled mussel and king scallop, suggesting that this is shared ancestrally. Transcriptomic profiling indicated that the pathways of catecholamine biosynthesis and adrenergic signaling in cardiomyocytes might be involved in metamorphosis. Conclusions The chromosome-level assembly of the hard-shelled mussel genome will provide novel insights into mussel genome evolution and serve as a fundamental platform for studies regarding the planktonic-sessile transition, genetic diversity, and genomic breeding of this bivalve.

Massive open online course (MOOC) is a new learning model, which integrates the progress of novel educational concepts and the breakthrough of information technology. MOOC uses new web-based tools and online-environments to deliver knowledge education and lecture classes in a new paradigm. In this paper, we firstly reviewed the achievements through four stages of the construction and development of online courses of physiology in China in the past 20 years. Then, taking the physiology MOOC at Central South University of China as an example, we introduced the specific practices and experiences to construct the online physiological open course, including the online open course-based offline and online flipped classroom teaching practice. Finally, we discussed several important issues during the construction and application of online open courses, aiming to provide practical information for other universities.

Oxygen therapy is a common treatment in neonatal intensive care units, but long-term continuous hyperoxia ventilation may induce acute lung injury (ALI). Gasdermin D (GSDMD)-mediated pyroptosis participates in various diseases including ALI, but the role of GSDMD in hyperoxia-induced ALI is yet understood. Here, we showed a significant increase in GSDMD after exposure to high oxygen. To elucidate the molecular mechanisms involved in GSDMD regulation, we identified the core promoter of GSDMD, −98 ~ −12 bp relative to the transcriptional start site (TSS). The results of mutational analysis, overexpression or siRNA interference, EMSA and ChIP demonstrated that E2F4 and TFAP2A positively regulate the transcriptional activity of the GSDMD by binding to its promoter. However, only TFAP2A showed a regulatory effect on the expression of GSDMD. Moreover, TFAP2A was increased in the lung tissues of rats exposed to hyperoxia and showed a strong linear correlation with GSDMD. Our results indicated that TFAP2A positively regulates the GSDMD expression via binding to the promoter region of GSDMD.

Ferroptosis is a newly discovered non-apoptotic form of regulated cell death driven by iron-dependent lipid peroxidation. The present studies have shown that many metabolic processes and homeostasis are affected by ferroptosis. It is related to many lung diseases, including acute lung injury, chronic obstructive pulmonary disease and pulmonary fibrosis, etc. Currently, the research on ferroptosis is still in its infancy. Previous studies have confirmed that ferroptosis is regulated by a variety of genes, and the mechanism is complex, mainly involving iron homeostasis and lipid peroxidation metabolism. This review summarizes some regulation networks of metabolic processes associated with ferroptosis and discusses the roles of ferroptosis in the pathophysiological progression of many lung diseases. We expected to provide new ideas and references for the treatment of these diseases.

Bacteria of the genus Shewanella have been studied for their versatile electron-accepting abilities, particularly for extracellular electron transfer via minerals. Shewanella marisflavi ECSMB14101 was isolated from naturally formed biofilms in the East China Sea. The genome of S. marisflavi ECSMB14101 encodes 3891 genes with a total size of 4,343,492 bp in one chromosome. Its GC content is 49.89%. S. marisflavi ECSMB14101 is able to synthesize a red pigment, which may be achieved through Cytochrome c3 and electron transfer to reduce Fe(III) oxide. The genomic data presented here could provide fundamental insights to better understand the physiological characteristics of S. marisflavi, the ecological significance of red pigment synthesis, and its inductive effects on the settlement of marine invertebrate larvae.

Microbial dysbiosis in the upper digestive tract is linked to an increased risk of esophageal squamous cell carcinoma (ESCC). Overabundance of Porphyromonas gingivalis is associated with shorter survival of ESCC patients. We investigated the molecular mechanisms driving aggressive progression of ESCC by P. gingivalis. Intracellular invasion of P. gingivalis potentiated proliferation, migration, invasion, and metastasis abilities of ESCC cells via transforming growth factor-β (TGFβ)-dependent Drosophila mothers against decapentaplegic homologs (Smads)/Yes-associated protein (YAP)/Transcriptional coactivator with PDZ-binding motif (TAZ) activation. Smads/YAP/TAZ/TEA domain transcription factor1 (TEAD1) complex formation was essential to initiate downstream target gene expression, inducing an epithelial–mesenchymal transition (EMT) and stemness features. Furthermore, P. gingivalis augmented secretion and bioactivity of TGFβ through glycoprotein A repetitions predominant (GARP) up-regulation. Accordingly, disruption of either the GARP/TGFβ axis or its activated Smads/YAP/TAZ complex abrogated the tumor-promoting role of P. gingivalis. P. gingivalis signature genes based on its activated effector molecules can efficiently distinguish ESCC patients into low- and high-risk groups. Targeting P. gingivalis or its activated effectors may provide novel insights into clinical management of ESCC., Microbial dysbiosis in the upper digestive tract is linked to an increased risk of esophageal squamous cell carcinoma (ESCC); this study shows that invasion of the bacterium Porphyromonas gingivalis enhances the aggressive progression of ESCC via the TGFβ/Smad and TGFβ/YAP/TAZ pathways. Targeting P. gingivalis or its activated effectors may provide novel avenues into clinical management of ESCC.

In this paper, utilizing the same recognition group dinitrophenyl and hydroxyl functional NIR fluorophore hemicyanine, directly-linked probe CyNO2 and self-immolative probe CyBNO2 were developed for evaluation of sensing PhSH. Though CyNO2 was easily synthesized and sensitive to mercapto, the probe CyBNO2 showed higher selectivity, broader linear range from 1.0 × 10−7 to 7.0 × 10−6 M with lower detection limit of 22 nM for PhSH. Moreover, CyBNO2 was successfully applied for monitoring PhSH in living cells and in vivo, indicating the great potential of self-immolative probes.

Bone marrow mesenchymal stem cells (BMSCs) have multi-lineage differentiation potential and play an important role in tissue repair. Studies have shown that BMSCs gather at the injured tissue site after granulocyte-colony stimulating factor (G-CSF) administration. In this study, we first investigated whether G-CSF could promote BMSC homing to damaged lung tissue induced by bleomycin (BLM) and then investigated whether SDF-1/CXCR4 chemotaxis might be involved in this process. Next, we further studied the potential inhibitory effect of G-CSF administration in mice with lung fibrosis induced by bleomycin. We examined both the antifibrotic effects of G-CSF in mice with bleomycin-induced pulmonary fibrosis in vivo and its effects on the proliferation, differentiation and chemotactic movement of cells in vitro. Flow cytometry, real-time PCR, transwell and Cell Counting Kit-8 (CCK-8) assays were used in this study. The results showed that both preventative and therapeutic G-CSF administration could significantly inhibit bleomycin-induced pulmonary fibrosis. G-CSF enhanced BMSC migration to lung tissues, but this effect could be alleviated by AMD3100, which blocked the SDF-1/CXCR4 axis. We also found that BMSCs could inhibit fibroblast proliferation and transdifferentiation into myofibroblasts through paracrine actions. In conclusion, G-CSF exerted antifibrotic effects in bleomycin-induced lung fibrosis, in part by promoting BMSC homing to injured lung tissues via SDF-1/CXCR4 chemotaxis.

Bronchopulmonary dysplasia (BPD) is a severe complication of preterm infants characterized by increased alveolarization and inflammation. Premature exposure to hyperoxia is believed to be a key contributor to the pathogenesis of BPD. No effective preventive or therapeutic agents have been created. Stimulator of interferon gene (STING) is associated with inflammation and apoptosis in various lung diseases. Long non-coding RNA MALAT1 has been reported to be involved in BPD. However, how MALAT1 regulates STING expression remains unknown. In this study, we assessed that STING and MALAT1 were up-regulated in the lung tissue from BPD neonates, hyperoxia-based rat models and lung epithelial cell lines. Then, using the flow cytometry and cell proliferation assay, we found that down-regulating of STING or MALAT1 inhibited the apoptosis and promoted the proliferation of hyperoxia-treated cells. Subsequently, qRT-PCR, Western blotting and dual-luciferase reporter assays showed that suppressing MALAT1 decreased the expression and promoter activity of STING. Moreover, transcription factor CREB showed its regulatory role in the transcription of STING via a chromatin immunoprecipitation. In conclusion, MALAT1 interacts with CREB to regulate STING transcription in BPD neonates. STING, CREB and MALAT1 may be promising therapeutic targets in the prevention and treatment of BPD.

Acute lung injury (ALI) is characterized by inflammatory cell infiltration, macrophage activation, and excessive pro-inflammatory cytokine production. Bleomycin (BLM) is widely used to induce acute lung injury (ALI) and fibrosis in murine models. Intratracheally administration of BLM leads to the early stage of inflammatory response and the late stage of collagen deposition. Omentin-1 exerts an anti-inflammatory role in reducing tumor necrosis factor α (TNF-α)-induced cyclooxygenase-2 expression in endothelial cells and attenuating lipopolysaccharide (LPS)-induced ALI. However, the role of omentin-1 in BLM-induced ALI remains unclear. The aim of this study is to examine the effects of omentin-1 on BLM-induced ALI. We found that omentin-1 was decreased in lungs of BLM-induced ALI mice. Omentin-1 overexpression mediated by adenovirus alleviated lung injury and maintained the integrity of the alveolar septa. Omentin-1 overexpression also remarkably decreased the aggregation of neutrophil and macrophages activation, the expression of monocyte chemotactic protein 1 (MCP-1), and down-regulated expression of interleukin 1β (IL-1β) in lungs of BLM-induced ALI mice. Furthermore, we observed that omentin-1 reduced oxidative stress and suppressed the activation of NF-κB pathway in BLM-induced ALI and LPS-induced macrophages activation. Together, our findings indicated that omentin-1 protected mice from BLM-induced ALI may through reducing inflammatory cells recruitment and macrophages activation via alleviation of oxidative stress and NF-κB pathway. Thus, therapeutic strategies aiming to restore omentin-1 levels may be valuable for the prevention of BLM-induced ALI.

Ferroptosis is a newly discovered type of regulated cell death, characterized by the iron-dependent accumulation of lipid reactive oxygen species, which has been implicated in numerous human diseases. However, its role in pulmonary fibrosis, a fatal lung disease with unknown etiology, is largely unknown. Here, we investigated the role of ferroptosis in pulmonary fibrosis. We found a large amount of iron deposition in the lung tissue of patients with pulmonary fibrosis. We observed ferroptosis in alveolar type II (ATII) cells, fibrotic lung tissues of BLM-induced pulmonary fibrosis mice. BLM-induced increase in iron level was accompanied by pathological changes, collagen deposition, and ferroptosis in ATII cells, indicating iron deposition-induced ferroptosis, which promoted the development of pulmonary fibrosis. Moreover, deferoxamine (DFO) completely prevented the pro-fibrosis effects of BLM by reducing iron deposition and ferroptosis in ATII cells. Genes associated with intracellular iron metabolism and homeostasis, such as transferrin receptor 1, divalent metal transporter 1, and ferroportin-1, and showed abnormal expression levels in animal tissues and lung epithelial MLE-12 cells, which responded to BLM stimulation. Overall, we demonstrated that BLM-induced iron deposition in MLE-12 cells is prone to both mitochondrial dysfunction and ferroptosis and that DFO reverses this phenotype. In the future, understanding the role of ferroptosis may shed new light on the etiology of pulmonary fibrosis. Ferroptosis inhibitors or genetic engineering of ferroptosis-related genes might offer potential targets to treat pulmonary fibrosis.

Three isostructural heterometallic metal-organic frameworks (MOFs) {[Ln2Ni(OAc)5(HL)(L)]·solvent molecules}n (H2L = 2-hydroxyimino-N-[1-(2-pyrazinyl)ethylidene]-propanohydrazone, Ln = Dy for 1, Tb for 2 and Gd for 3) were solvothermally synthesized by varying rare-earth metal ions with different electron configurations. Their crystal structures, gas adsorption and magnetic behaviors were fully investigated. The three isomorphous MOFs exhibit three-dimensional microporous frameworks with two different orientated dodecane metallic {NiIILnIII(HL)}6 metallomacrocycles alternately connected by {LnIII(L)} connectors, in which an empty one-dimensional channel decorated by the basic hydrazone interior is generated. Due to their LnIII-independent microporous nature, the activated sample of 1 as a representative example has a significant CO2 uptake up to 42.2 cm3 g-1 and an unusually high CO2/N2 and CO2/CH4 adsorption selectivity of up to 98.8 and 16.8 at 298 K and 100 kPa. Magnetically, apparent antiferromagnetic interactions for both 1 and 2 as well as ferromagnetic coupling for 3 are respectively observed at low temperature resulting from the competition of magnetic anisotropy and intermetallic ferromagnetic superexchange. Additionally, 1 with highly anisotropic DyIII spin shows slow magnetization relaxation under zero dc field, whereas 3 possessing isotropic GdIII ions displays a significant cryogenic magnetocaloric effect with a maximum entropy change of 26.6 J kg-1 K-1 at 3.0 K and 70 kOe. These interesting results can provide valuable information on gas separation-based multifunctional 3d-4f MOF materials.

Intrauterine growth retardation (IUGR) is closely related to the later development of type 2 diabetes in adulthood. Excessive activation of N-methly-D-aspartate receptors (NMDARs) causes excitatory neurotoxicity, resulting in neuronal injury or death. Inhibition of NMDARs enhances the glucose-stimulated insulin secretion and survival of islet cells in type 2 diabetic mouse and human islets. Here, we examined whether antenatal blockade of NMDARs by Memantine could decrease the risk of diabetes induced by a high-fat (HF) diet at adulthood in IUGR rats. Pregnant SD rats were assigned to four groups: control, IUGR, Memantine, and Memantine + IUGR. The pregnant rats were exposed to hypoxic conditions (FiO2 = 0.105) for 8 h/day (IUGR group) or given a daily Memantine injection (5 mg/kg, i.p.) before hypoxia exposure from embryonic day (E) 14.5 to E 20.5 (Memantine + IUGR). The offspring were fed an HF diet with 60% of the calories from age 4 to 12 weeks. We found that NMDAR mRNAs were expressed in the fetal rat pancreas. An HF diet resulted in a high rate of diabetes at adulthood in the IUGR group. Antenatal Memantine treatment decreased the risk of diabetes at adulthood of rats with IUGR, which was associated with rescued glucose tolerance, increased insulin release, improved the insulin sensitivity, and increased expression of genes related to beta-cell function in the pancreas. Together, our results suggest that antenatal blockade of NMDARs by Memantine in pregnant rats improves fetal development and reduces the susceptibility to diabetes at adulthood in offspring.

ATP-binding cassette transporter A1 (ABCA1) is an essential regulator of intracellular cholesterol efflux. Secreted cholesterol binds to lipid-free apolipoprotein A-I (apoA-I) in peripheral blood to constitute high-density lipoprotein cholesterol (HDL) complexes. ABCA1 protein on the surface of macrophages acts as a crucial controller in preventing cholesterol accumulation. Importantly, ABCA1 is unstable and easily degraded via a series of biochemical activities, including but not limited to calpain-mediated and ubiquitin-proteasome system-mediated processes. How accelerated ABCA1 degradation impacts disordered lipid metabolism in macrophages and foam cell formation is unclear. N-methyl d -aspartate receptors (NMDARs) are ionotropic glutamate receptors with high calcium permeability. Calcium influx via NMDARs activates downstream signaling pathways. Over-activation of NMDARs stimulated by NMDA contributes to dysfunctional lipid metabolism in macrophages and foam cell formation via promotion of calpain-mediated ABCA1 proteolysis. However, increased NMDAR activity does not affect liver X receptor expression or ABCA1 mRNA levels. Following NMDA receptor silencing or calpain inhibition, NMDA treatment did not reduce ABCA1 protein levels, nor caused lipid accumulation in macrophages. In addition, NMDAR over-activation activates NF-κB signaling to promote IL-1β and IL-6 macrophage marker expression. However, NMDAR silencing and calpain inhibition reduce inflammatory macrophage responses. In summary, our study suggests that NMDAR activation reduces surface ABCA1 protein, promotes lipid accumulation, and induces the production and secretion of many inflammatory mediators in macrophages, possibly through enhanced calpain-mediated ABCA1 protein degradation. Thus, the NMDAR receptor may be a novel pharmacologic target for atherosclerosis therapy.

Hemicyanine dyes including hemi-indocyanine and hemi-benzindocyanine have been attracted considerable attentions to develop near infrared probes for in vivo fluorescence imaging. However, hemi-benzothiazolecyanine dye (MTR) is rarely reported for detection analytes. In this work, to extend the sensing applications of MTR, we present an optimized route for facile preparation of the dye. And as a proof-of-concept, a self-immolative NIR probe MTR-HH based on hemi-benzothiazolecyanine dye was designed and synthesized for H2O2. The probe exhibited a 284-fold fluorescent enhancement to H2O2 with a detection limit of 0.32 μM over other biospecies. Moreover, MTR-HH was successfully applied for visualizing endogenous H2O2 in living cells and mice.

Selenocysteine (Sec, pKa 5.8) is genetically encoded 21st amino acid into the active site of selenoproteins, which have broad functions relevant to various diseases, tissues or organs and subcellular organelles. However, many selenoproteins involved cellular functions still remains unclear. In addition, since biothiols such as glutathione (GSH, pKa 8.3), possessing similar chemical properties with Sec, commonly exist in living systems at high levels. Thus, it is of great importance and high challenge to identify novel probes for selectively monitoring Sec over biothiols. In this paper, we proposed a smart strategy which allowed us to develop a lysosome targetable probe for specifically sensing Sec. By restricting weak acidic microenvironment, the probe shows a specific detection for Sec with 85-fold fluorescence enhancement owing to the remaining high activity of Sec at pH 5.0. Moreover, being low cytotoxicity to the cells verified by MTS assay, the probe was then successfully applied for imaging exogenous and endogenous Sec in lysosomes, indicating its potential for the biological investigation of Sec in subcellular organelles.

Three isostructural heterometallic metal-organic frameworks (MOFs) {[Ln

In this paper, by utilizing the rainbow functions that were proposed by Amelino-Camelia \emph{et al}., the information flux of rainbow Schwarzschild black hole and the sparsity of Hawking radiation in rainbow gravity are explored. The results show that the rainbow gravity has a very significant effect on the information flux. When the mass of rainbow Schwarzschild black hole approaches to the order of Planck scale, the Bekenstein entropy loss per emitted quanta in terms of the mass of Schwarzschild black hole reduces to zero. Furthermore, we also find the sparsity of Hawking radiation in rainbow gravity is no longer a constant; instead, it monotonically decreases as the mass of black hole decrease. At the final stages of evaporation, the modified sparsity becomes infinity, which indicates the effect of quantum gravity stops Hawking radiation and leads to remnant., 8 pages, 4 figures, added references, corrected typos

An enhanced chronic inflammatory response in the airways has been regarded as a critical characteristic of chronic obstructive pulmonary disease (COPD). Memantine, an N-methyl- d -aspartate (NMDA) receptors antagonist, has been reported to alleviate lung inflammation. In this study, we investigated the effect and mechanism of memantine on the COPD model induced by cigarette smoke (CS) combined with LPS. Mice and RAW264.7 cells were treated with LPS in the presence or absence of CS. We performed H&E staining to analysis the lung histopathological characteristics. Cytokines (IL-6, TNF-α, and IFN-γ) levels in bronchoalveolar lavage fluid (BALF), lung tissue homogenates and RAW264.7 cell culture medium were determined. Glutamate levels in plasma and culture medium of RAW264.7 were determined. The intracellular Ca2+ flux in RAW264.7 cells was measured by fluo-3 AM staining. The protein levels of NR-1, xCT, ERK1/2, and AKT signaling in the lung tissue and cells were investigated. The result showed that CS and LPS stimulation caused inflammation response, a significant increase in the release of cytokines, including TNF-α, IL-6, and IFN-γ, the elevated release of glutamate and protein levels of NR-1 and xCT, increased Ca2+ influx, and the activation of the ERK1/2 pathway in vitro and in vivo. The above effects of CS and LPS stimulation could be significantly attenuated by memantine treatment. In conclusion, memantine can effectively ameliorate pulmonary inflammation in CS + LPS-induced COPD in mice via reducing NR-1 and xCT expression, glutamate release, Ca2+ influx, and the phosphorylation of Erk1/2. We provided a possible mechanism by which memantine ameliorates COPD in mice.

Endogenous glutamate (Glu) release and N-methyl-d-aspartate (NMDA) receptor (NMDAR) activation are associated with lung injury in different animal models. However, the underlying mechanism is unclear. Bone marrow-derived mesenchymal stem cells (BM-MSCs), which show potential use for immunomodulation and tissue protection, play a protective role in pulmonary fibrosis (PF) process. Here, we found the increased Glu release from the BM cells of bleomycin (BLM)-induced PF mice in vivo. BLM stimulation also increased the extracellular Glu in BM-MSCs via the antiporter system xc− in vitro. The gene expression of each subunit of NMDAR was detected in BM-MSCs. NMDAR activation inhibited the proliferation, migration, and paracrine function of BM-MSCs in vitro. BM-MSCs were derived from male C57BL/6 mice, transfected with lentiviral vectors carrying the enhanced green fluorescence protein gene, pretreated with NMDA, and transplanted into the female recipient mice that were intratracheally injected with BLM to induce PF. Transplantation of NMDA-pretreated BM-MSCs significantly aggravated PF as compared with that in the normal BM-MSCs transplantation group. The sex determination gene Y chromosome and green fluorescence protein genes of BM-MSCs were detected to observe BM-MSCs homing in the fibrotic lungs. Moreover, NMDAR activation inhibited BM-MSC migration by downregulating the stromal cell-derived factor-1/C-X-C chemokine receptor type 4 signaling axis. NMDAR activation aggravated the transforming growth factor-β1-induced extracellular matrix production in alveolar epithelial cells and fibroblasts through the paracrine effects of BM-MSCs. In summary, these findings suggested that NMDAR activation-mediated Glu excitotoxicity induced by BLM in BM-MSCs abolished the therapeutic effects of normal BM-MSCs transplantation on BLM-induced PF.

A novel pathway for the synthesis of pyridine and 3-picoline was developed in this work. The method involved the condensation of gas-phase acrolein diethyl acetal and ammonia over the ZnO/HZSM-5 catalyst in a fixed-bed reactor. The problem of polymerization in existing process was effectively solved. The ZnO/HZSM-5 catalyst was proved to be the most promising catalyst relative to the ZnO/Al2O3 and ZnO/HY ones. The reaction conditions and preparation conditions of the ZnO/HZSM-5 catalyst had great influences on the total yield of pyridine and 3-picoline. Characterization of ZnO/HZSM-5 had been done using X-ray diffraction (XRD), N2 adsorption–desorption isotherms, ammonia temperature programmed desorption (NH3-TPD) and X-ray photoelectron spectroscopy (XPS) techniques. The characterized results revealed change of the pore structure and acidity of the catalyst upon ZnO introduction. The superior specific activity of ZnO/HZSM-5 was attributed to enhancing the various processes such as dehydrogenation in the addressed reaction. The raw materials from biological sources are possible for the synthesis of pyridine and 3-picoline in industry.