The causal relationship between genetically predicted blood metabolites and idiopathic pulmonary fibrosis: A bidirectional two-sample Mendelian randomization study.

BACKGROUND: Numerous metabolomic studies have confirmed the pivotal role of metabolic abnormalities in the development of idiopathic pulmonary fibrosis (IPF). Nevertheless, there is a lack of evidence on the causal relationship between circulating metabolites and the risk of IPF. METHODS: The potential causality between 486 blood metabolites and IPF was determined through a bidirectional two-sample Mendelian randomization (TSMR) analysis. A genome-wide association study (GWAS) involving 7,824 participants was performed to analyze metabolite data, and a GWAS meta-analysis involving 6,257 IPF cases and 947,616 control European subjects was conducted to analyze IPF data. The TSMR analysis was performed primarily with the inverse variance weighted model, supplemented by weighted mode, MR-Egger regression, and weighted median estimators. A battery of sensitivity analyses was performed, including horizontal pleiotropy assessment, heterogeneity test, Steiger test, and leave-one-out analysis. Furthermore, replication analysis and meta-analysis were conducted with another GWAS dataset of IPF containing 4,125 IPF cases and 20,464 control subjects. Mediation analyses were used to identify the mediating role of confounders in the effect of metabolites on IPF. RESULTS: There were four metabolites associated with the elevated risk of IPF, namely glucose (odds ratio [OR] = 2.49, 95% confidence interval [95%CI] = 1.13-5.49, P = 0.024), urea (OR = 6.24, 95% CI = 1.77-22.02, P = 0.004), guanosine (OR = 1.57, 95%CI = 1.07-2.30, P = 0.021), and ADpSGEGDFXAEGGGVR (OR = 1.70, 95%CI = 1.00-2.88, P = 0.0496). Of note, the effect of guanosine on IPF was found to be mediated by gastroesophageal reflux disease. Reverse Mendelian randomization analysis displayed that IPF might slightly elevate guanosine levels in the blood. CONCLUSION: Conclusively, hyperglycemia may confer a promoting effect on IPF, highlighting that attention should be paid to the relationship between diabetes and IPF, not solely to the diagnosis of diabetes. Additionally, urea, guanosine, and ADpSGEGDFXAEGGGVR also facilitate the development of IPF. This study may provide a reference for analyzing the potential mechanism of IPF and carry implications for the prevention and treatment of IPF.

Mediastinal epithelioid inflammatory myofibroblastic sarcoma with the EML4-ALK fusion: A case report and literature review.

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is an aggressive subtype of inflammatory myofibroblastic tumour which rarely affects the chest cavity. We, for the first time, report a case of mediastinal EIMS with the EML4-ALK fusion. A young woman presented to our hospital with cough, chest tightness and shortness of breath. Computed tomography (CT) showed a mixed attenuation soft-tissue mass in the right middle and upper mediastinum. Negative results were obtained from bronchoscopy forceps biopsy and endobronchial ultrasound-guided transbronchial fine needle aspiration. CT-guided percutaneous biopsy was finally performed. However, due to the rapidly progressed EIMS that compressed the trachea and right main bronchus, the patient died of respiratory failure 1 day before diagnosis. EIMS progresses rapidly, and an early diagnosis is important. For mediastinal EIMS, CT-guided percutaneous biopsy may be useful. Next-generation sequencing of blood may be instructive to EIMS patients who are intolerant to invasive biopsy.

Anticancer effect of Dihydroartemisinin via dual control of ROS-induced apoptosis and protective autophagy in prostate cancer 22Rv1 cells.

BACKGROUND: Dihydroartemisinin (DHA), a natural agent, exhibits potent anticancer activity. However, its biological activity on prostate cancer (PCa) 22Rv1 cells has not been previously investigated. OBJECTIVE: In this study, we demonstrate that DHA induces anticancer effects through the induction of apoptosis and autophagy. METHODS: Cell viability and proliferation rate were assessed using the CCK-8 assay and cell clone formation assay. The generation of reactive oxygen species (ROS) was detected by flow cytometry. The molecular mechanism of DHA-induced apoptosis and autophagy was examined using Western blot and RT-qPCR. The formation of autophagosomes and the changes in autophagy flux were observed using transmission electron microscopy (TEM) and confocal microscopy. The effect of DHA combined with Chloroquine (CQ) was assessed using the EdU assay and flow cytometry. The expressions of ROS/AMPK/mTOR-related proteins were detected using Western blot. The interaction between Beclin-1 and Bcl-2 was examined using Co-IP. RESULTS: DHA inhibited 22Rv1 cell proliferation and induced apoptosis. DHA exerted its anti-prostate cancer effects by increasing ROS levels. DHA promoted autophagy progression in 22Rv1 cells. Inhibition of autophagy enhanced the pro-apoptotic effect of DHA. DHA-induced autophagy initiation depended on the ROS/AMPK/mTOR pathway. After DHA treatment, the impact of Beclin-1 on Bcl-2 was weakened, and its binding with Vps34 was enhanced. CONCLUSION: DHA induces apoptosis and autophagy in 22Rv1 cells. The underlying mechanism may involve the regulation of ROS/AMPK/mTOR signaling pathways and the interaction between Beclin-1 and Bcl-2 proteins. Additionally, the combination of DHA and CQ may enhance the efficacy of DHA in inhibiting tumor cell activity.

Study on the performance efficiency, mechanism, power consumption and biochemical properties of E/Ce(IV)/PMS on the enhanced removal of RB19.

In this study, an advanced oxidation process with E/Ce(IV) synergistic PMS (E/Ce(IV)/PMS) was established for the efficient removal of Reactive Blue 19 (RB19). The catalytic oxidation performance of different coupling systems was examined and the synergistic effect of E/Ce(IV) with PMS in the system was substantiated. The oxidative removal of RB19 in E/Ce(IV)/PMS was excellent, achieving a removal efficiency of 94.47% and a reasonable power consumption (EE/O value was 3.27 kWh·m-3). The effect of pH, current density, Ce(IV) concentration, PMS concentration, initial RB19 concentration and water matrix on the removal efficiency of RB19 were explored. Additionally, quenching and EPR experiments showed that the solution contains different radicals such as SO4·-, HO∙ and 1O2, where 1O2 and SO4·- played key roles, but HO∙ just acted a weaker role. Ce ion trapping experiment confirmed that Ce(IV) was involved in the reaction process and played a major role (29.91%). RB19 was subject to three possible degradation pathways, and the intermediate products displayed well biochemical properties. To conclude, the degradation mechanism of RB19 was explored and discussed. In the presence of current, E/Ce(IV)/PMS performed a rapid Ce(IV)/Ce(III) cycle, continuously generating strong catalytic oxidation Ce(IV), The reactive radicals derived from the decomposition of PMS, in conjunction with Ce(IV) and direct electro-oxidation, efficiently destroyed the molecular structure of RB19 and showed an efficient removal rate.

A Cysteine-Reloading Process Initiating the Biosynthesis of the Bicyclic Scaffold of Dithiolopyrrolones.

Dithiolopyrrolone antibiotics are well known for their outstanding biological activities, and their biosynthesis has been studied vigorously. However, the biosynthesis mechanism of the characteristic bicyclic scaffold is still unknown after years of research. To uncover this mechanism, a multi-domain non-ribosomal peptide synthase DtpB from the biosynthetic gene cluster of thiolutin was selected as an object to study. We discovered that its adenylation domain not only recognized and adenylated cysteine, but also played an essential role in the formation of the peptide bond. Notably, an eight-membered ring compound was also discovered as an intermediate during the formation of the bicyclic structure. Based on these findings, we propose a new mechanism for the biosynthesis of the bicyclic scaffold of dithiolopyrrolones, and unveil additional functions of the adenylation domain.

Leukotriene Receptor Antagonists and Risk of Neuropsychiatric Entities: A Meta-Analysis of Observational Studies.

BACKGROUND: Leukotriene receptor antagonists (LTRAs) are commonly prescribed to patients with allergic diseases. Several case reports and pharmacovigilance studies have indicated that LTRAs might increase the risk of neuropsychiatric (NP) entities. However, the results are mixed in observational studies. Thus, the association between LTRAs and NP entities remains controversial. OBJECTIVE: To quantitatively evaluate the NP risk with LTRAs based on current observational studies to provide a reference for clinical practice. METHODS: We systematically reviewed the literature in Medline, Embase, Web of Science, Cochrane Library, Scopus, and PsycINFO. A meta-analysis of observational studies that investigated the association between LTRA use and the risk of NP entities was performed. Odds ratios (OR) with 95% confidence intervals (CI) were used to measure the effect; heterogeneity was evaluated using I-squared (I2) statistics. Subgroup and sensitivity analyses were conducted to assess bias. RESULTS: Eleven articles were included in the primary analysis. No significant association was found between LTRA use and NP entities (OR: 1.08, 95% CI: 0.93-1.24, I2 = 93.7%). In patients with allergic rhinitis (AR), a mildly increased NP risk was found (OR: 1.099, 95% CI: 1.004-1.202). The association between LTRA use and NP entities was not significant in patients with asthma (OR: 1.06, 95% CI: 0.90-1.26). LTRAs increased the risk of NP entities in a single study using data from an asthma clinic (OR: 9.00, 95% CI: 1.20-69.50), but not in studies from databases (OR: 1.07, 95% CI: 0.93-1.23). CONCLUSION: At the population level, LTRAs and NP entities were unrelated. However, the association may exist in particular groups (eg, patients with AR or NP history). Subject-specific studies are required to further examine the relationship between LTRAs and NP entities and identify the underlying mechanisms.

An integrative cellular metabolomic study reveals downregulated tricarboxylic acid cycle and potential biomarkers induced by tetrabromobisphenol A in human lung A549 cells.

Tetrabromobisphenol A (TBBPA) is extensively utilized as a brominated flame retardant in numerous chemical products. As an environmental contaminant, the potential human toxicity of TBBPA has been attracting increasing attention. Nonetheless, the exact underlying mechanisms of toxicological effects caused by TBBPA remain uncertain. In this study, we investigated the potential mechanisms of TBBPA toxicity in vitro in the A549 cell line, one of the widely used type II pulmonary epithelial cell models in toxicology research. Cell viability was determined after treatment with varying concentrations of TBBPA. Liquid chromatography-mass spectrometry (LC-MS) metabolomics and metabolic flux approaches were utilized to evaluate metabolite and tricarboxylic acid (TCA) cycle oxidative flux changes. Our findings demonstrated that TBBPA significantly reduced the viability of cells and attenuated mitochondrial respiration in A549 cells. Additionally, LC-MS data showed significant reductions in TCA cycle metabolites including citrate, malate, fumarate, and alpha-ketoglutarate in 50 µM TBBPA-treated A549 cells. Metabolic flux analysis indicated reduced oxidative capacity in mitochondrial metabolism following TBBPA exposure. Moreover, diverse metabolic pathways, particularly alanine, aspartate, and glutamate metabolism and the TCA cycle, were found to be dysregulated. In total, 12 metabolites were significantly changed (p < .05) in response to 50 µM TBBPA exposure. Our results provide potential biomarkers of TBBPA toxicity in A549 cells and help elucidate the molecular mechanisms of pulmonary toxicity induced by TBBPA exposure.

Network Pharmacology and Molecular Docking Analysis on Molecular Targets and Mechanisms of Aidi Injection Treating of Nonsmall Cell Lung Cancer.

Background: Aidi injection (ADI) is a compound preparation injection of Chinese herbs used to treat patients of nonsmall cell lung cancer (NSCLC) in China. This study aimed to reveal the mechanism of ADI in the treatment of NSCLC by using network pharmacology and molecular docking. Methods: The related targets of ADI and NSCLC were obtained from multiple databases. The network diagram of disease-drug-components-targets (DDCT) and protein-protein interaction (PPI) was constructed to screen key targets. Then, the key targets and main signaling pathways were screened by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Next, in order to validate the results of network pharmacology, expression analysis and survival analysis of key genes were performed. Finally, we carried out the technology of molecular docking to further validate the accuracy of the above results. Results: A total of 207 targets of ADI and 5282 targets of NSCLC were obtained finally. Through the construction of DDCT and PPI network diagrams, 28 key targets were finally obtained. The results of the KEGG enrichment analysis indicated that multiple signaling pathways were associated with NSCLC, which included the MAPK signaling pathway, the IL-17 signaling pathway, and the PI3K/AKT signaling pathway. The key genes in the signaling pathway mainly include TP53, CASP3, MMP9, AKT1, PTGS2, and MAPK1. The results of differently expressed analysis of key genes showed that TP53, CASP3, MMP9, AKT1, PTGS2, and MAPK1 had statistical differences in lung squamous cell carcinoma (LUSC) compared with normal tissue (p < 0.001). In lung adenocarcinoma (LUAD), the expression of TP53, CASP3, MMP9, AKT1, and PTGS2 had statistical differences compared with normal tissue (p < 0.001), while the expression of MAPK1 had no statistical difference (p > 0.05). The results of survival analysis of key genes showed that AKT1, MAPK1, CASP3, MMP9, TP53, and PTGS2 had statistical differences in the OS or RFS of NSCLC patients (p < 0.05). In addition, the results of molecular docking indicated that the key genes and the main components have good docking activity. Conclusions: This study revealed the potential mechanism of ADI in the treatment of NSCLC with multipathways and multitargets and provided a scientific basis for the in-depth study of ADI in the treatment of NSCLC.

Dietary Salt Disrupts Tricarboxylic Acid Cycle and Induces Tau Hyperphosphorylation and Synapse Dysfunction during Aging.

Dietary salt causes synaptic deficits and tau hyperphosphorylation, which are detrimental to cognitive function. However, the specific effects of a high-salt diet on synapse and tau protein remain poorly understood. In this study, aged (15-month-old) C57BL/6 mice received a normal (0.5% NaCl) or high-salt (8% NaCl) diet for 3 months, and N2a cells were treated with normal culture medium or a NaCl medium (40 mM). Spatial learning and memory abilities were tested using the Morris water maze. The levels of metabolites and related enzymes in the tricarboxylic acid (TCA) cycle were confirmed using liquid chromatography-tandem mass spectrometry, western blotting, and immunofluorescence. We also investigated synapse morphology and the phosphorylation of tau protein. Under the high-salt diet, mice displayed impaired learning and memory compared to mice fed the normal diet. Furthermore, excessive salt intake disturbed the TCA cycle in both animals and cells compared to the respective normal controls. High dietary salt reduced postsynaptic density protein 95 (PSD95) and brain-derived neurotrophic factor (BDNF) expression, impaired neurons, and caused synaptic loss in the mice. We also detected tau hyperphosphorylation at different sites (Thr205, Thr231, and Thr181) without increasing total tau levels in response to high salt treatment, both in vivo and in vitro. We concluded that elevated salt intake impairs the TCA cycle and induces tau hyperphosphorylation and synapse dysfunction during aging, which ultimately results in cognitive impairment.

Clinical Study on Anesthesia with Remifentanil and Propofol in Patients with High Hemodynamics.

Objective: To study the effect of remifentanil and propofol as an anesthesia regimen in patients with high hemodynamics. Methods: From January 2019 to October 2020, 200 patients with high hemodynamics undergoing surgery at the First Affiliated Hospital of Nanchang University in China were selected as study participants, including 100 patients anesthetized with remifentanil and propofol (research group), and 100 patients anesthetized with fentanyl and propofol (control group). Vital signs, hemodynamic changes and recovery time after anesthesia were compared in the 2 groups and any adverse events while under anesthesia were recorded. Results: Both groups had significant fluctuations in vital signs and hemodynamics during anesthesia (P > .05), but the research group showed smaller changes with more stable vital signs and hemodynamics (P < .05). In addition, postoperative recovery time from anesthesia was shorter and the incidence of adverse events was lower in the research group than in the control group (P < .05). Conclusion: Remifentanil-propofol anesthesia is simple, convenient, safe and reliable in patients with high hemodynamics, and can integrate narcotic drugs with blood pressure control.

FeS redox power motor for PDS continuous generation of active radicals on efficient degradation and removal of diclofenac: Role of ultrasonic.

Diclofenac (DCF), as a typical representative of PPCPs, has potential ecotoxicity to the water environment. In this study, ultrasound (US) enhanced ferrous sulfide (FeS)-activated persulfate (PDS) technology (US/FeS/PDS) was used to degrade DCF. By comparing the degradation effects of US, US/PDS, FeS/PDS and US/FeS/PDS systems on DCF, this study confirmed the synergy and strengthening effects of US. The influences of single-factor experimental conditions on the US/FeS/PDS system were investigated and optimized. The FeS catalysts before and after the reaction were characterized and analyzed by X-ray diffractometer (XRD) and X-ray photoelectron spectroscopy (XPS). The heterogeneous reaction proceeded on the surface of FeS, and a small part of FeS2 was formed on FeS surface. During the reaction, the proportion of S2- on the catalyst surface decreased from 51% to 44%. Correspondingly, the proportion of Sx2- increased from 21% to 26%. It indicated that S2- was oxidized into Sx2- in the reaction, and the loss electrons of S2- caused the reduction of Fe3+ to Fe2+on the FeS surface, which promoted the cycle between Fe2+ and Fe3+ in turn. Furthermore, SO4- and ‧OH were the main active free radicals, of which the contribution rate of ‧OH was about 34.4%, while that of SO4- was approximately 52.2%. In US/FeS/PDS, the introduction of US could promote the dissolution of iron on the FeS surface. US contributed to the formation of a redox power motor between S2-Sx2- and Fe2+-Fe3+, which continuously decomposed PDS to generate sufficient active SO4- and ‧OH radicals, thereby efficiently and continuously degrading DCF. Finally, the related mechanism of DCF degradation by US/FeS/PDS was summarized. Overall, US/FeS/PDS can not only efficiently degrade and remove DCF, but also has potential application value in organic pollution removal and wastewater purification.

Taping into the super power and magic appeal of ultrasound coupled with EDTA on degradation of 2,4,6-TCP by Fe0 based advanced oxidation processes.

Chlorophenol is a widely used organic compound, and the environmental and health problems caused by it have being worsened in recent years. This study used 2,4,6-trichlorophenol (2,4,6-TCP) as the target pollutant, and employed ultrasound (US) enhanced zero-valent iron (Fe0)/EDTA/air system (FEA), namely US/FEA, to remove 2,4,6-TCP. The influence of single factor experimental conditions such as EDTA concentration, Fe0 dosage, US power, pH and pollutant concentration on the removal efficiency of 2,4,6-TCP was investigated, and the optimal reaction conditions were determined. The mechanism of reactive oxygen species (ROS) produced by US/FEA was explored. The degradation process and removal mechanism of 2,4,6-TCP in the US/FEA were discussed through the determination and analysis of intermediate products. The results showed that US could continuously activate and renew the Fe0 surface, accelerate its oxidation and corrosion process, and then continuously and stably produce sufficient amounts of Fe2+ and Fe3+. Ultrasonic cavitation effect could reduce the difficulty of O2 activation reaction, and promote the production of sufficient H2O2. The addition of EDTA made the system have a wide range of pH applications, and its performance under neutral and alkaline conditions was also superior. The ROS of US/FEA included ·OH, O2·- and Fe(IV), where Fe(IV) was the main contributor to the removal of 2,4,6-TCP. In addition, the degradation of 2,4,6-TCP had two processes including dechlorination and benzene ring opening. First, 2,4,6-TCP was dechlorinated and degraded into phenol. And then, phenol was degraded into small molecular acids by ring-opening, and finally it was mineralized into CO2 and H2O completely. US/FEA is a promising technology for high-efficiency degradation of organic matter and deep environmental purification.

Role of mitophagy in the hallmarks of aging.

Aging, subjected to scientific scrutiny, is extensively defined as a time-dependent decline in functions that involves the majority of organisms. The time-dependent accretion of cellular lesions is generally a universal trigger of aging, while mitochondrial dysfunction is a sign of aging. Dysfunctional mitochondria are identified and removed by mitophagy, a selective form of macroautophagy. Increased mitochondrial damage resulting from reduced biogenesis and clearance may promote the aging process. The primary purpose of this paper is to illustrate in detail the effects of mitophagy on aging and emphasize the associations between mitophagy and other signs of aging, including dietary restriction, telomere shortening, epigenetic alterations, and protein imbalance. The evidence regarding the effects of these elements on aging is still limited. And although the understanding of relationship between mitophagy and aging has been long-awaited, to analyze details of such a relationship remains the main challenge in aging studies.

LC-MS Based Metabolomics Study of the Effects of EGCG on A549 Cells.

(-)-Epigallocatechin-3-gallate (EGCG) is the main bioactive catechin in green tea. The antitumor activity of EGCG has been confirmed in various types of cancer, including lung cancer. However, the precise underlying mechanisms are still largely unclear. In the present study, we investigated the metabolite changes in A549 cells induced by EGCG in vitro utilizing liquid chromatography-mass spectrometry (LC-MS)-based metabolomics. The result revealed 33 differentially expressed metabolites between untreated and 80 µM EGCG-treated A549 cells. The altered metabolites were involved in the metabolism of glucose, amino acid, nucleotide, glutathione, and vitamin. Two markedly altered pathways, including glycine, serine and threonine metabolism and alanine, aspartate and glutamate metabolism, were identified by MetaboAnalyst 5.0 metabolic pathway analysis. These results may provide potential clues for the intramolecular mechanisms of EGCG's effect on A549 cells. Our study may contribute to future molecular mechanistic studies of EGCG and the therapeutic application of EGCG in cancer management.

Idiopathic pulmonary fibrosis and diabetes mellitus: a meta-analysis and systematic review.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic diffuse interstitial lung disease, of which the etiology has been poorly understood. Several studies have focused on the relationship between IPF and diabetes mellitus (DM) in the past years but have failed to reach a consensus. This meta-analysis aimed to examine the association between diabetes to IPF. METHODS: We accumulated studies investigating the association between DM and IPF from databases including Medline, Cochrane Library, Embase, Web of Science, and China National Knowledge Infrastructure. RevMan 5.3 and the Newcastle-Ottawa Scale (NOS) were utilized to analyze the data and assess the quality of the included studies. The value of odds ratio (OR) with 95% confidence interval (CI) was used as the measure to estimate the risk of DM in IPF. Heterogeneity was assessed by I2 statistics. We also performed subgroup analysis, meta-regression, and Egger's test for bias analysis. RESULTS: Nine case-control studies with 5096 IPF patients and 19,095 control subjects were included in the present meta-analysis, which indicated a positive correlation between DM and IPF (OR 1.65, 95% CI 1.30-2.10; P < 0.0001). Meta-regression and subgroup analysis negated the influence of covariates like cigarette smoking, age and gender, but the heterogeneity existed and could not be fully explained. CONCLUSION: IPF and DM may be associated, but the causal relationship remains indeterminate till now. Further rigorously designed studies are required to confirm the present findings and investigate the possible mechanisms behind the effect of DM on IPF.

Metastable helium Faraday filter for helium lidar to measure the density of the thermosphere.

We demonstrate a metastable helium Faraday optical filter operating on the 23S1 - 23P1 and 23S1 - 23P2 transition at 1083 nm by using a 3 cm long helium cell. The influence of the magnetic field and gas pressure of the helium cell on the filter characteristics is experimental studied. When the magnetic field is 230 Gs and the gas pressure of helium cell is about 110 Pa, the peak transmission corresponding to the two energy level transitions is about 32% and 57%, respectively. The equivalent noise bandwidth (ENBW) under this working condition is about 1.9 GHz. The metastable helium Faraday filter can be used to improve the optical inefficiency of a helium resonance fluorescence lidar to achieve the metastable helium density detection at 200-1000 km thermosphere.