Manganese(I)-catalyzed nucleophilic addition of C(sp3)-H bonds to aldehydes.

The C-H bond activation catalyzed by a manganese(I) complex has achieved significant development but is limited to C(sp2)-H bonds. In this work, an efficient manganese(I)-catalyzed direct nucleophilic addition reaction of C(sp3)-H bonds to aromatic aldehydes has been developed. This is the first example of manganese(I)-catalyzed C(sp3)-H bond transformation. A manganacycle complex was isolated and proved to be the key active intermediate in the catalytic cycle.

Diethylzinc-promoted carboxylation of aryl/alkenyl boronic acids with CO2.

The carboxylation of aryl and alkenyl boronic acids with CO2 is rarely studied and only achieved using copper salts as the catalyst in the presence of a strong base. Herein, we report a diethylzinc-promoted carboxylation of aryl or alkenyl boronic acids with carbon dioxide. The reaction does not require a transition-metal catalyst, and has simple and mild conditions and a broad substrate scope.

Qi-Dong-Huo-Xue-Yin balances the immune microenvironment to protect against LPS induced acute lung injury.

COVID-19 induces acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and leads to severe immunological changes that threatens the lives of COVID-19 victims. Studies have shown that both the regulatory T cells and macrophages were deranged in COVID-19-induced ALI. Herbal drugs have long been utilized to adjust the immune microenvironment in ALI. However, the underlying mechanisms of herbal drug mediated ALI protection are largely unknown. This study aims to understand the cellular mechanism of a traditional Chinese medicine, Qi-Dong-Huo-Xue-Yin (QD), in protecting against LPS induced acute lung injury in mouse models. Our data showed that QD intrinsically promotes Foxp3 transcription via promoting acetylation of the Foxp3 promoter in CD4+ T cells and consequently facilitates CD4+CD25+Foxp3+ Tregs development. Extrinsically, QD stabilized ß-catenin in macrophages to expedite CD4+CD25+Foxp3+ Tregs development and modulated peripheral blood cytokines. Taken together, our results illustrate that QD promotes CD4+CD25+Foxp3+ Tregs development via intrinsic and extrinsic pathways and balanced cytokines within the lungs to protect against LPS induced ALI. This study suggests a potential application of QD in ALI related diseases.

Ruthenium(II)-Catalyzed Grignard-Type Nucleophilic Addition of C(sp2)-H Bonds to Unactivated Aldehydes.

The Grignard-type nucleophilic addition of C(sp2)-H bonds to aldehydes catalyzed by high-oxidation-state transition metal complexes is limited to activated aldehydes. Herein, we report the first example of Grignard-type nucleophilic addition of C(sp2)-H bonds to unactivated aldehydes catalyzed by high-oxidation-state ruthenium(II). The reaction has mild reaction conditions and good functional group tolerance. The corresponding alcohol products are obtained in good to excellent yields.

Development and validation of a risk prediction model for anxiety or depression among patients with chronic obstructive pulmonary disease between 2018 and 2020.

Anxiety and depression are important risk factors for chronic obstructive pulmonary disease (COPD). The aim of this study was to develop a prediction model to predict anxiety or depression in COPD patients. The retrospective study was conducted in COPD patients receiving stable treatment between 2018 and 2020 to develop prediction model. The variables, were readily available in clinical practice, were analysed. After data preprocessing, model training and performance evaluation were performed. Validity of the prediction model was verified in 3 comparative model training. Between 2018 and 2020, 375 eligible patients were analysed. Thirteen variables were included into the final model: gender, age, marital status, education level, long-term residence, per capita annual household income, payment method of medical expenses, direct economic costs of treating COPD in the past year, smoking, COPD progression, number of acute exacerbation of COPD in the last year, regular treatment with inhalants and family oxygen therapy. Risk score threshold in each sample in the training set was 1.414. The area under the curve value was respectively 0.763 and 0.702 in the training set and test set, which were higher than three comparative models. The simple prediction model to predict anxiety or depression in patients with COPD has been developed. Based on 13 available data in clinical indicators, the model may serve as an instrument for clinical decision-making for COPD patients who may have anxiety or depression.Key messagesThirteen variables were included into the prediction model.The AUC value was, respectively, 0.763 and 0.702 in the training set and test set, which were higher than three comparative models.The simple prediction model to predict anxiety or depression in patients with COPD has been developed.

The dysbiosis gut microbiota induces the alternation of metabolism and imbalance of Th17/Treg in OSA patients.

The aim of this research was to test the hypothesis that changes in the intestinal microbiota lead to the alternation of histidine metabolism and Th17/Treg cell imbalance in obstructive sleep apnea (OSA) patients. In total, 46 subjects were enrolled in the study, with 32 subjects in the OSA group and 14 in the healthy group, according to polysomnography examinations. Basic clinical characteristics were collected for this analysis. Feces were collected from OSA patients to detect the gut microbiota using 16S rRNA sequencing. Peripheral blood was obtained to detect the Th17/Treg cell ratio by flow cytometry. The present research demonstrated that at the phylum level, OSA patients have a disproportionate Firmicutes/Bacteroidetes ratio with increased Firmicutes and decreased Bacteroidetes in the gut microbiota compared to the healthy population. A Metastats analysis also indicated that the family Rikenellaceae was prevalent in the control group but not the OSA group. In addition, the abundance of Clostridium_XlVa was reduced and the abundance of Alistipes was elevated in healthy subjects at the genus level. Furthermore, a Phylogenetic Investigation of Communities by Reconstruction of Unobserved States analysis identified the alternation of metabolic pathways in OSA patients. The current study also identified an imbalance of Th17/Treg cells in OSA patients, with OSA patients having an elevated number of Treg cells compared to the control group. We determined that the abundance of Rikenellaceae and Alistipes increased and Clostridium_XlVa decreased in patients with OSA, which may have caused an imbalance in the proportion of Th17/Treg cells.

Rhubarb Alleviates Acute Lung Injury by Modulating Gut Microbiota Dysbiosis in Mice.

Intestinal microbiota disorders can aggravate pulmonary inflammation during acute lung injury (ALI). As a traditional Chinese herb, Rhubarb can regulated the gut microbiota. Therefore, this study was conducted to test the hypothesis that rhubarb alleviates gut microbiota dysbiosis and inflammation. Feces were collected from patients with ALI to detect the gut microbiota using 16S rDNA sequencing. Subsequently, a mouse model of ALI was established using lipopolysaccharide to investigate changes in the gut microbiota, the peripheral blood was attained for detecting the Th17/Treg cell ratio and the serum level of HDAC6 and HDAC9, and the effect of rhubarb treatment on the gut microbiota and Th17/Treg ratio were also evaluated. The results indicated that both the Firmicutes phylum decreased and the Bacteroidetes phylum increased were identified in patients with ALI, which induced the alternation of histone metabolites. The mice models also showed a similar imbalance in the Firmicutes/Bacteroidetes ratio at phylum of level. Rhubarb treatment alleviated the damaged lung tissue, accelerated Alistipes, Clostridium, and Lactobacillus proliferation at the level of genus, increased the level of HDAC6 in both the mice lung tissue and serum, and markedly reduced the Treg cells and increased the Th17 cells in the spleen tissue. The study suggested that both patients and mouse models with ALI presented gut microbiota dysbiosis, and lead to a Th17/Treg cell imbalance in ALI mouse. Rhubarb promoted Alistipes, Clostridium, and Lactobacillus proliferation, increased the HDAC6 concentration, restored the Th17/Treg cell balance, and protected against ALI.

Immune checkpoint inhibitor-related adverse events in lung cancer: Real-world incidence and management practices of 1905 patients in China.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are the standard treatment for advanced lung cancer, but immune-related adverse events (irAEs) remain poorly understood, especially in a real-world setting. METHODS: A multicenter observational study was conducted. Medical records of lung cancer patients treated with ICIs at 26 hospitals from January 1, 2015, to February 28, 2021, were retrieved. Types of ICIs included antiprogrammed cell death 1 or antiprogrammed cell death ligand 1 (PD-L1) monotherapy, anticytotoxic T-lymphocyte antigen-4 monotherapy, or combination therapy. RESULTS: In total, 1905 patients with advanced lung cancer were evaluated. The median age was 63 (range 28-87) years, and the male/female ratio was 3.1:1 (1442/463). The primary histological subtype was adenocarcinoma (915). A total of 26.9% (512/1905) of the patients developed 671 irAEs, and 5.8% (110/1905) developed 120 grade 3-5 irAEs. Median duration from ICI initiation to irAEs onset was 56 (range 0-1160) days. The most common irAEs were thyroid dysfunction (7.2%, 138/1905), pneumonitis (6.5%, 124/1905), and dermatological toxicities (6.0%, 115/1905). A total of 162 irAEs were treated with steroids and 11 irAEs led to death. Patients with positive PD-L1 expression (≥1%) and who received first-line ICI treatment developed more irAEs. Patients who developed irAEs had a better disease control rate (DCR, 71.3% [365/512] vs. 56.0% [780/1145]; p < 0.001). CONCLUSIONS: The incidence rate of irAEs was 26.9% in a real-world setting. IrAEs might be related to a better DCR, but clinicians should be more aware of irAE recognition and management in clinical practice.

Piperlongumine attenuates vascular remodeling in hypoxic pulmonary hypertension by regulating autophagy.

OBJECTIVE: The aim of this study was to determine the therapeutic effect of piperlongumine on hypoxic pulmonary hypertension. METHODS: A hypoxic pulmonary hypertension rat model was constructed, primary rat pulmonary artery smooth muscle cells (PASMCs) were isolated, and the proliferation of PASMCs was measured by Cell Counting Kit­8 assay. The expression of autophagic proteins microtubule-associated protein 1 light chain 3B (LC3B) and P62 were examined by western blot. Autophagic flux in PASMCs was detected by tandem mRFP-GFP-LC3 fluorescence analysis. RESULTS: Hypoxia-induced proliferation of PASMCs was significantly inhibited by piperlongumine exposure. Treatment with piperlongumine elevated LC3B II/LC3B I protein ratio and decreased the expression of P62 protein in both PASMCs and rat lung tissues. Tandem mRFP-GFP-LC3 fluorescence analysis showed that piperlongumine increased autophagic flux in PASMCs. Inhibition of autophagy using 3-methyladenine (3-MA) attenuated the inhibitory effect of piperlongumine on proliferation of PASMCs. Chronic hypoxia exposure led to a significant increase in rat right ventricle systolic pressure, right ventricular hypertrophy, wall thickness and area of pulmonary artery, and muscularization of pulmonary arterioles, which was obviously suppressed by administration of piperlongumine. 3-MA attenuated the alleviating effects of piperlongumine on pulmonary vascular remodeling. CONCLUSIONS: Piperlongumine attenuates vascular remodeling in hypoxic pulmonary hypertension by regulating autophagy. Piperlongumine treatment may serve as a promising therapy for hypoxic pulmonary hypertension.

Identification of Differentially Expressed Genes in COVID-19 and Integrated Bioinformatics Analysis of Signaling Pathways.

Coronavirus disease 2019 (COVID-19) is acutely infectious pneumonia. Currently, the specific causes and treatment targets of COVID-19 are still unclear. Herein, comprehensive bioinformatics methods were employed to analyze the hub genes in COVID-19 and tried to reveal its potential mechanisms. First of all, 34 groups of COVID-19 lung tissues and 17 other diseases' lung tissues were selected from the GSE151764 gene expression profile for research. According to the analysis of the DEGs (differentially expressed genes) in the samples using the limma software package, 84 upregulated DEGs and 46 downregulated DEGs were obtained. Later, by the Database for Annotation, Visualization, and Integrated Discovery (DAVID), they were enriched in the Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. It was found that the upregulated DEGs were enriched in the type I interferon signaling pathway, AGE-RAGE signaling pathway in diabetic complications, coronavirus disease, etc. Downregulated DEGs were in cellular response to cytokine stimulus, IL-17 signaling pathway, FoxO signaling pathway, etc. Then, based on GSEA, the enrichment of the gene set in the sample was analyzed in the GO terms, and the gene set was enriched in the positive regulation of myeloid leukocyte cytokine production involved in immune response, programmed necrotic cell death, translesion synthesis, necroptotic process, and condensed nuclear chromosome. Finally, with the help of STRING tools, the PPI (protein-protein interaction) network diagrams of DEGs were constructed. With degree ≥13 as the cutoff degree, 3 upregulated hub genes (ISG15, FN1, and HLA-G) and 4 downregulated hub genes (FOXP3, CXCR4, MMP9, and CD69) were screened out for high degree. All these findings will help us to understand the potential molecular mechanisms of COVID-19, which is also of great significance for its diagnosis and prevention.

Synergistic effects of piperlongumine and gemcitabine against KRAS mutant lung cancer.

OBJECTIVE: To determine the combined efficacy of piperlongumine and gemcitabine for treatment of KRAS mutant lung cancer. METHODS: The cell growth inhibition of piperlongumine, gemcitabine, and piperlongumine plus gemcitabine was measured by Cell Counting Kit­8 assay and the combination index was calculated. In addition, the combined effects of piperlongumine and gemcitabine on cell apoptosis, reactive oxygen species (ROS) contents, and microtubule-associated protein 1 light chain 3B (LC3B) expression were examined. RESULTS: Piperlongumine increased ROS contents and LC3B-II expression. Following the combined treatment with piperlongumine and 10 mM N-acetyl-L-cysteine (NAC), intracellular ROS and cell viability returned to normal levels, and the expression of LC3B-II decreased to the predose level. Gemcitabine also induced cell apoptosis, increased ROS contents, and LC3B-II expression. The combination of piperlongumine with gemcitabine exhibited a synergetic anticancer activity with the combination index <1. The combined application of gemcitabine and piperlongumine yielded synergistic effects on cell apoptosis, but failed to synergistically increase ROS levels and LC3B-II expression. CONCLUSION: Combination therapy with piperlongumine and gemcitabine is a promising treatment option for KRAS mutant lung cancer.

The role of obstructive sleep apnea on the prognosis of pulmonary embolism: a systemic review and meta-analysis.

PURPOSE: The relationship between obstructive sleep apnea (OSA) and pulmonary embolism (PE) has been reported by some studies but the underlying mechanism remains unclear. We aimed to systematically assess the role of OSA on the disease prognosis of PE. METHODS: We searched for studies on the relationship of OSA and the prognosis of PE published up to February 2020 among PubMed, Web of Science, EMBASE, and Cochrane Library databases. Two independent reviewers conducted the process of study search and screening, quality assessment, and data extraction. Meta-analysis was carried out using RevMan 5.3. RESULTS: A total of 9 articles were included, and the funnel plots suggested no evidence of publication bias among studies. The results showed that compared to PE patients without OSA, the PE patients with moderate-severe OSA were more likely to be high-risk type (OR = 1.96, 95% CI [1.14, 3.34]) and with higher index of disease severity (sPESI: OR = 2.29, 95% CI [1.50, 3.47]; PAOI%: MD = 13.52, 95% CI [7.2, 19.83]). The prevalence of recurrent PE was higher in PE patients with OSA than those without OSA (RR = 3.87, 95% CI [1.65, 9.07]). However, there was no significant difference in right ventricle to left ventricle short-axis diameter (MD = 0.08, 95% CI [- 0.06, 0.21]), length of hospital stay (MD = 1.03, 95% CI [- 1.11, 3.17]), or prevalence of deep vein thrombosis (OR = 0.87, 95% CI [0.48, 1.57]). Sensitivity and subgroup analysis showed that the pooled outcomes were stable. CONCLUSION: OSA, especially moderate-severe OSA, was a risk factor for high-risk PE and recurrent PE. However, the current evidence showed that the length of hospital stay is not influenced by OSA.

Diagnostic value of pentraxin 3 in respiratory tract infections: A meta-analysis.

BACKGROUND: Pentraxin 3 is an acute inflammatory protein of the long pentraxin subfamily. A meta-analysis was performed to assess diagnostic accuracy of pentraxin 3 for respiratory tract infections. METHODS: We identify studies examining diagnostic value of pentraxin 3 for respiratory tract infections by searching Pubmed, Web of Knowledge, and Cochrane Library. The sensitivity, specificity, negative likelihood ratio (LR), positive LR, and diagnostic odds ratio were pooled. The area under the summary receiver operator characteristic (SROC) curve and Q point value (Q*) were calculated. RESULTS: A total of 8 studies with 961 individuals were eligible for this meta-analysis. The pooled sensitivity of pentraxin 3 in diagnosis of respiratory tract infections was 0.78, the pooled specificity was 0.73, the area under the SROC curve was 0.84, and the Q* was 0.77. The area under the SROC curve of serum and bronchoalveolar lavage fluid (BALF) pentraxin 3 was 0.85 and 0.89, respectively. Meta-regression analysis revealed that cutoff value was the source of heterogeneity among the included studies. The Deek funnel plot test suggested no evidence of publication bias. Subgroup analyses showed that the area under the SROC curve of pentraxin 3 in diagnosis of ventilator-associated pneumonia (VAP) was 0.89. CONCLUSION: Pentraxin 3 has a moderate accuracy for diagnosing respiratory tract infections and VAP. The overall diagnostic value of BALF level of pentraxin 3 is superior to its serum concentration.

Differentially Expressed Gene Screening, Biological Function Enrichment, and Correlation with Prognosis in Non-Small Cell Lung Cancer.

BACKGROUND The aim of this study was to explore the differently expressed genes and pathways in non-small cell lung cancer (NSCLC) and their correlation with the prognosis. MATERIAL AND METHODS Gene expression data series of GSE19804, GSE101929, and GSE33532 were downloaded from the Gene Expression Ominibus (GEO) database. The overlaping differently expressed genes (DEGs) were identified form the above 3 data series. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEEG) were used to analyze the biological functions and signal pathways of DEGs. The protein-protein interaction (PPI) was analyzed thorough Search Tool for the Retrieval of Interacting Gens (STRING). The relationship between the expression of hub genes and the prognosis of patients was analyzed by Kaplan-Meier Plotter online software. RESULTS Twenty-nine DEGs were identified, with 22 upregulated genes and 7 downregulated genes. The enriched biological processes were mainly related to diet-induced thermogenesis and actin filament binding. The KEGG pathways were enriched in calcium signaling, regulation of lipolysis in adipocytes, and PPAR signaling. Two downregulated genes (MMP1 and SPP1) were identified as hub genes by Cytohubba. Twenty-two dysregulated genes were correlated with patient prognosis. CONCLUSIONS Differentially expressed genes are common in NSCLC patients and can be used as biomarkers for patient prognosis.

ERp29 downregulation enhances lung adenocarcinoma cell chemosensitivity to gemcitabine by upregulating HSP27 phosphorylation.

The aim of the current study was to assess the underlying mechanism of endoplasmic reticulum protein 29 (ERp29) in lung adenocarcinoma chemosensitivity to gemcitabine. Western blot analysis was performed to detect ERp29 expression following lung adenocarcinoma cell treatment with gemcitabine. The effects of gemcitabine in combination with ERp29 siRNA on cell apoptosis, cell cycle and heat shock protein 27 (HSP27) expression were assessed. The results demonstrated that ERp29 expression was increased on exposure to gemcitabine. The apoptotic rate of lung adenocarcinoma cells were also increased following gemcitabine treatment and the combined application of gemcitabine and ERp29 siRNA synergistically increased apoptotic rates further. It was also revealed that gemcitabine and ERp29 siRNA synergistically increased the ratio of phosphorylated to total HSP27 protein. In addition, downregulation of HSP27 significantly reduced lung adenocarcinoma chemosensitivity to gemcitabine. These data indicate that ERp29 affects lung adenocarcinoma cell chemosensitivity to gemcitabine by regulating phosphorylated HSP27. ERp29 is a novel target, which may be used to enhance the therapeutic effect of lung adenocarcinoma treatment with gemcitabine.

Oxidative stress does not contribute to the release of proinflammatory cytokines through activating the Nod-like receptor protein 3 inflammasome in patients with obstructive sleep apnoea.

PURPOSE: The study was conducted to test the hypothesis that oxidative stress leads to the release of proinflammatory cytokines by activating the Nod-like receptor protein (NLRP)3 inflammasome in patients with obstructive sleep apnoea (OSA). METHODS: The study recruited 247 participants who were divided into cases and healthy control groups. OSA patients were subdivided into four subgroups according to sex, blood pressure, body mass index (BMI), and severity of disease. No significant differences were found between cases and controls with respect to age or sex. Peripheral blood samples were collected for analysis after examination, and the serum concentrations of oxidative stress (8-isoprostane), inflammation (interleukin (IL)-18, IL-1ß, IL-6, tumour necrosis factor (TNF)-α), and NLRP3 inflammasome components (NLRP3, caspase-1, and ASC) were detected by enzyme-linked immunosorbent assay. RESULTS: The serum concentrations of both oxidative stress and proinflammatory factors were higher in OSA patients than healthy controls. Subgroup analysis also revealed significant differences according to the apnoea-hypopnea index and BMI. Additionally, correlations were identified between 8-isoprostane and proinflammatory factors (IL-1ß, IL-18, and TNF-α). Multiple regression analysis suggested that sleep parameters and BMI affected inflammation. However, no differences were observed in the serum level of NLRP3 inflammasome components between patients and controls. Furthermore, stratified analysis revealed no additional differences. CONCLUSIONS: The current study suggests that oxidative stress leads to inflammation by mechanisms other than activation of the NLRP3 inflammasome in OSA patients. Furthermore, both sleep apnoea and BMI influenced the serum concentration of inflammatory mediators.

The level of lipopolysaccharide-binding protein is elevated in adult patients with obstructive sleep apnea.

BACKGROUND: lipopolysaccharide-binding protein (LBP) has been to be a surrogate marker of inflammation in OSA. This study aimed to test the hypothesis that the concentration of LBP is elevated in adult patients with obstructive sleep apnea (OSA). METHODS: A total of 90 patients were enrolled into the study, 50 subjects were divided into OSA groups and 40 in healthy control according to PSG examination. Subsequently, patients with apnea-hypopnea index (AHI) ≧ 5, were divided into different subgroups according to blood pressure, gender, body mass index (BMI) and AHI. Venous blood samples were collected for detection after polysomnography. The serum levels of LBP and proinflammatory cytokines (interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α) were tested by ELISA. RESULTS: The present study demonstrated that the serum levels of both LBP and proinflammatory cytokines were elevated in OSA patients. A stratified analysis conducted to analyze differences among subgroups indicated that OSA patients with a higher AHI or BMI had an increased level of LBP and proinflammatory cytokines (all p < 0.05). Furthermore, a significant correlations were observed between LBP and inflammation and AHI. Multivariate regression analysis also demonstrated that AHI, LSaO2 and BMI had impact on the concentration of LBP. CONCLUSION: The research showed that the serum level of LBP and proinflammatory cytokines were elevated in adult patients with OSA, and an association with severity of disease and BMI were established. Furthermore, sleep apnea and BMI had effect on the concentration of LBP.

Clinical significance of calcium-binding protein S100A8 and S100A9 expression in non-small cell lung cancer.

BACKGROUND: The purpose of this study was to evaluate the correlation between calcium-binding protein S100A8 and S100A9 expression in non-small cell lung cancer (NSCLC) and patients' clinical features. METHODS: Fifty-two NSCLC patients who underwent surgery at Zhejiang Hospital from February 2014 to January 2016 were included in this study. Calcium-binding protein S100A8 and S100A9 expression patterns in cancer and para-cancer tissues were examined by immunohistochemistry assay. The correlation between calcium-binding protein S100A8 and S100A9 expression patterns and NSCLC patients' clinical characteristics, including age, gender, tumor node metastasis stage, and pathology type, were evaluated. RESULTS: S100A8 and S100A9 were generally expressed on the cytoplasm and nucleus of NSCLC cells, mainly located in the cytoplasm, stained with brown particles, and distributed evenly. The positive expression rates of S100A8 and S100A9 in cancer tissues were 71.2% and 76.9%, respectively, which were significantly higher than in para-cancer tissues at 11.5% and 19.2%, respectively, with statistical significance (P < 0.05). S100A8 and S100A9 positive expression was associated with tumor differentiation degree (P < 0.05) but were not correlated with age, gender, smoking history, tumor diameter, pathology type, tumor node metastasis stage, or pleural effusion (Pall > 0.05). CONCLUSION: S100A8 and S100A9 positive expression in cancer tissues was significantly higher than in para-cancer tissues and was correlated with tumor differentiation, which may be a potential marker for poor prognosis.