• bioinformatic
• covid-19
• molecular docking
• network pharmacology
• pulmonary fibrosis
• remdesivir

• Humans
• Adenosine Monophosphate/analogs & derivatives
• Adenosine Monophosphate/therapeutic use
• Adenosine Monophosphate/pharmacology
• Antiviral Agents/therapeutic use
• Antiviral Agents/pharmacology
• Alanine/analogs & derivatives
• Alanine/therapeutic use
• Alanine/pharmacology
• Computational Biology/methods
• COVID-19 Drug Treatment
• Molecular Docking Simulation
• SARS-CoV-2
• Pulmonary Fibrosis/drug therapy
• Network Pharmacology/methods
• COVID-19/complications
• Protein Interaction Maps
• Signal Transduction/drug effects

• Special Project for Research and Development in Key areas of Guangdong Province

• Antifibrotic
• Antioxidant
• Oxidative stress
• Proliferation
• Pulmonary fibrosis
• Scleroderma

• Mice
• Animals
• Pulmonary Fibrosis/chemically induced
• Pulmonary Fibrosis/drug therapy
• Pulmonary Fibrosis/metabolism
• Quercetin/therapeutic use
• Quercetin/pharmacology
• Fibrosis
• Collagen/metabolism
• Bleomycin/adverse effects
• Scleroderma, Systemic/metabolism
• Disease Models, Animal
• Lung/pathology

• bronchopulmonary dysplasia
• hyperoxia
• neonates
• pulmonary
• single-cell RNA sequencing

• Infant, Newborn
• Male
• Female
• Animals
• Mice
• Humans
• Bronchopulmonary Dysplasia/metabolism
• Transcriptome/genetics
• Hyperoxia/metabolism
• Animals, Newborn
• Lung/metabolism
• Disease Models, Animal

• R01 HL130129 NHLBI NIH HHS
• K99 HL155845 NHLBI NIH HHS
• R01 HL128374 NHLBI NIH HHS
• R01 HL153511 NHLBI NIH HHS
• R01 HL162937 NHLBI NIH HHS
• HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)

• AECII
• ATII
• EMT
• TGF-beta
• alveolar epithelial type II cells
• autofluorescence
• flow cytometry
• homeostasis
• miRNAs
• pathway analysis
• type II pneumocytes

• Alveolar Epithelial Cells
• Animals
• Epithelial-Mesenchymal Transition/genetics
• Humans
• Lung/metabolism
• Mice
• MicroRNAs/genetics
• MicroRNAs/metabolism
• RNA, Messenger/genetics

• R01 HL141380 NHLBI NIH HHS
• R01 HL146519 NHLBI NIH HHS

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, irreversible, and highly fatal disease. It is characterized by the increased activation of both fibroblast and myofibroblast that results in excessive extracellular matrix (ECM) deposition. Extracellular vesicles (EVs) have been described as key mediators of intercellular communication in various pathologies. However, the role of EVs in the development of IPF remains poorly understood. This study aimed to characterize the differentially expressed proteins contained within EVs cargo derived from the fibroblast cell lines LL97A (IPF-1) and LL29 (IPF-2) isolated from lungs bearing IPF as compared to those derived from the fibroblast cell lines CCD8Lu (NL-1) and CCD19Lu (NL-2) isolated from healthy donors. Isolated EVs were subjected to label-free quantitative proteomic analysis by LC-MS/MS, and as a result, 331 proteins were identified. Differentially expressed proteins were obtained after the pairwise comparison, including all experimental groups. A total of 86 differentially expressed proteins were identified in either one or more comparison groups. Of note, proteins involved in fibrogenic processes, such as tenascin-c (TNC), insulin-like-growth-factor-binding protein 7 (IGFBP7), fibrillin-1 (FBN1), alpha-2 collagen chain (I) (COL1A2), alpha-1 collagen chain (I) (COL1A1), and lysyl oxidase homolog 1 (LOXL1), were identified in EVs cargo isolated from IPF cell lines. Additionally, KEGG pathway enrichment analysis revealed that differentially expressed proteins participate in focal adhesion, PI3K-Akt, and ECM–receptor interaction signaling pathways. In conclusion, our findings reveal that proteins contained within EVs cargo might play key roles during IPF pathogenesis.

• extracellular vesicles
• fibroblasts
• idiopathic pulmonary fibrosis
• mass spectrometry
• proteomic analysis

• NF-kappaB
• PI3K-Akt
• RhoA
• gastric cancer
• integrin.
• signaling pathway

• Animals
• Child
• Female
• GTPase-Activating Proteins/genetics
• Homozygote
• Humans
• Hypertension/genetics
• Leukocytosis/genetics
• Leukocytosis/immunology
• Lung Diseases, Interstitial/genetics
• Lung Diseases, Interstitial/pathology
• Lymphocytosis/genetics
• Lymphocytosis/immunology
• Male
• Mice
• Pedigree
• Exome Sequencing
• rhoA GTP-Binding Protein/genetics
• rhoA GTP-Binding Protein/metabolism

• UL1 TR001863 NCATS NIH HHS
• U54 HG006504 NHGRI NIH HHS
• R01 AR068429 NIAMS NIH HHS
• U54 HD090255 NICHD NIH HHS
• U01 HL122642 NHLBI NIH HHS
• R01 HL142879 NHLBI NIH HHS
• National Institute of Arthritis and Musculoskeletal and Skin Diseases of National Institute of Health
• Research of the Cancer Microenvironment Supporting Cancer Growth and Spread
• National Institutes of Health

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with a poor prognosis. The current coronavirus disease 2019 (COVID-19) shares some similarities with IPF. SARS-CoV-2 related genes have been reported to be broadly regulated by N⁶-methyladenosine (m⁶A) RNA modification. Here, we identified the association between m⁶A methylation regulators, COVID-19 infection pathways, and immune responses in IPF. The characteristic gene expression networks and immune infiltration patterns of m⁶A-SARS-CoV-2 related genes in different tissues of IPF were revealed. We subsequently evaluated the influence of these related gene expression patterns and immune infiltration patterns on the prognosis/lung function of IPF patients. The IPF cohort was obtained from the Gene Expression Omnibus dataset. Pearson correlation analysis was performed to identify the correlations among genes or cells. The CIBERSORT algorithm was used to assess the infiltration of 22 types of immune cells. The least absolute shrinkage and selection operator (LASSO) and proportional hazards model (Cox model) were used to develop the prognosis prediction model. Our research is pivotal for further understanding of the cellular and genetic links between IPF and SARS-CoV-2 infection in the context of the COVID-19 pandemic, which may contribute to providing new ideas for prognosis assessment and treatment of both diseases.

• COVID-19
• N6-methyladenosine
• SARS-CoV-2
• idiopathic pulmonary fibrosis
• immune
• prognosis

• Chronic variable stress
• Major depressive disorder
• Prefrontal cortex
• RNA sequencing
• SLIT1

Deposition of mussel-inspired polydopamine (PDA) has rapidly emerged as a simple yet effective strategy to functionalize the surface of biomaterials.

Recent studies implicate cardiolipin oxidation in several age-related diseases. Atp8b1 encoding Type 4 P-type ATPases is a cardiolipin transporter. Mutation in Atp8b1 gene or inflammation of the lungs impairs the capacity of Atp8b1 to clear cardiolipin from lung fluid. However, the link between Atp8b1 mutation and age-related gene alteration is unknown. Therefore, we investigated how Atp8b1 mutation alters age-related genes.

We performed Affymetrix gene profiling of lungs isolated from young (7-9 wks, n=6) and aged (14 months, 14 M, n=6) C57BL/6 and Atp8b1 mutant mice. In addition, Ingenuity Pathway Analysis (IPA) was performed. Differentially expressed genes were validated by quantitative real-time PCR (qRT-PCR).

Global transcriptome analysis revealed 532 differentially expressed genes in Atp8b1 lungs, 157 differentially expressed genes in C57BL/6 lungs, and 37 overlapping genes. IPA of age-related genes in Atp8b1 lungs showed enrichment of Xenobiotic metabolism and Nrf2-mediated signaling pathways. The increase in Adamts2 and Mmp13 transcripts in aged Atp8b1 lungs was validated by qRT-PCR. Similarly, the decrease in Col1a1 and increase in Cxcr6 transcripts was confirmed in both Atp8b1 mutant and C57BL/6 lungs.

Based on transcriptome profiling, our study indicates that Atp8b1 mutant mice may be susceptible to age-related lung diseases.

• Atp8b1 mutant
• aging
• gene profiling
• lungs
• transcriptome

Determining sensitive biomarkers in the peripheral blood to identify interstitial lung abnormalities (ILAs) is essential for the simple early diagnosis of ILAs. This study aimed to determine serum metabolic biomarkers of ILAs and the corresponding pathogenesis. Three groups of subjects undergoing health screening, including healthy subjects, subjects with ILAs, and subjects who were healthy initially and with ILAs one year later (Healthy→ILAs), were recruited for this study. The metabolic profiles of all of the subjects’ serum were analyzed by liquid chromatography quadruple time-of-flight mass spectrometry. The metabolic characteristics of the ILAs subjects were discovered, and the corresponding biomarkers were predicted. The metabolomic data from the Healthy→ILAs subjects were collected for further verification. The results indicated that five serum metabolite alterations (up-regulated phosphatidylcholine, phosphatidic acid, betaine aldehyde and phosphatidylethanolamine, as well as down-regulated 1-acylglycerophosphocholine) were sensitive and reliable biomarkers for identifying ILAs. Perturbation of the corresponding biological pathways (RhoA signaling, mTOR/P70S6K signaling and phospholipase C signaling) might be at least partially responsible for the pathogenesis of ILAs. This study may provide a good template for determining the early diagnostic markers of subclinical disease status and for obtaining a better understanding of their pathogenesis.

• biomarkers
• interstitial lung abnormalities
• serum metabolic profiles

• Glaucoma
• Human conjunctival fibroblasts
• Macrophage
• Myofibroblasts
• Rho kinase inhibitor
• Ripasudil (K-115)
• TGF-beta
• Wound healing

C3 exoenzyme from C. botulinum is an ADP-ribosyltransferase that inactivates selectively RhoA, B, and C by coupling an ADP-ribose moiety. Rho-GTPases are involved in various cellular processes, such as regulation of actin cytoskeleton, cell proliferation, and apoptosis. Previous studies of our group with the murine hippocampal cell line HT22 revealed a C3-mediated inhibition of cell proliferation after 48 h and a prevention of serum-starved cells from apoptosis. For both effects, alterations of various signaling pathways are already known, including also changes on the transcriptional level. Investigations on the transcriptional activity in HT22 cells treated with C3 for 48 h identified five out of 48 transcription factors namely Sp1, ATF2, E2F-1, CBF, and Stat6 with a significantly regulated activity. For validation of identified transcription factors, studies on the protein level of certain target genes were performed. Western blot analyses exhibited an enhanced abundance of Sp1 target genes p21 and COX-2 as well as an increase in phosphorylation of c-Jun. In contrast, the level of p53 and apoptosis-inducing GADD153, a target gene of ATF2, was decreased. Our results reveal that C3 regulates the transcriptional activity of Sp1 and ATF2 resulting downstream in an altered protein abundance of various target genes. As the affected proteins are involved in the regulation of cell proliferation and apoptosis, thus the C3-mediated anti-proliferative and anti-apoptotic effects are consequences of the Rho-dependent alterations of the activity of certain transcriptional factors.

• Apoptosis
• C3 exoenzyme
• Proliferation
• RhoA
• Transcription factors

• atrium
• heart disease
• remodeling
• statins
• ventricles

We hypothesized that statin use begun before the diagnosis of interstitial lung disease is associated with reduced mortality.

We studied all patients diagnosed with interstitial lung disease in the entire Danish population from 1995 through 2009, comparing statin use versus no statin use in a nested 1:2 matched study.

The cumulative survival as a function of follow-up time from the date of diagnosis of interstitial lung disease (n = 1,786+3,572) and idiopathic lung fibrosis (n = 261+522) was higher for statin users versus never users (log-rank: P = 7·10⁻⁹ and P = 0.05). The median survival time in patients with interstitial lung disease was 3.3 years in statin users and 2.1 years in never users. Corresponding values in patients with idiopathic lung fibrosis were 3.4 versus 2.4 years. After multivariable adjustment, the hazard ratio for all-cause mortality for statin users versus never users was 0.73 (95% confidence interval, 0.68 to 0.79) in patients with interstitial lung disease and 0.76 (0.62 to 0.93) in patients with idiopathic lung fibrosis. Results were robust in all sensitivity analyses.

Among patients with interstitial lung disease statin use was associated with reduced all-cause mortality.

• Aged
• Denmark
• Female
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Idiopathic Pulmonary Fibrosis/drug therapy
• Idiopathic Pulmonary Fibrosis/mortality
• Lung Diseases, Interstitial/drug therapy
• Lung Diseases, Interstitial/mortality
• Male
• Middle Aged
• Survival Analysis
• Treatment Outcome

• Airway
• Asthma
• COPD
• Fibrosis
• IPF
• Parenchyma

• Asthma
• Farnesyl transferase inhibitors
• Fibrosis
• Geranylgeranyl transferase inhibitors
• Rho GTPase
• Statins

The simultaneous rise in the prevalence of asthma and obesity has prompted epidemiologic studies that establish obesity as a risk factor for asthma. The alterations in cell signaling that explain this link are not well understood and warrant investigation so that therapies that target this asthma phenotype can be developed. We identified a significant increase in expression of the small GTPase RhoA in nasal epithelial cells and tracheal smooth muscle cells from leptin-deficient (ob/ob) mice compared to their wild-type counterparts. Since RhoA function is dependent on isoprenoid modification, we sought to determine the role of isoprenoid-mediated signaling in regulating the viability and proliferation of human airway smooth muscle cells (ASM) and normal human lung fibroblasts (NHLF). Inhibiting isoprenoid signaling with mevastatin significantly decreased the viability of ASM and NHLF. This inhibition was reversed by geranylgeranyl pyrophosphate (GGPP), but not farnesyl pyrophosphate (FPP), suggesting specificity to the Rho GTPases. Conversely, increasing isoprenoid synthesis significantly increased ASM proliferation and RhoA protein expression. RhoA expression is inherently increased in airway tissue from ob/ob mice, and obesity-entrained alterations in this pathway may make it a novel therapeutic target for treating airway disease in the obese population.

Lung cancer is the leading cause of cancer-related mortality. Therapies against non-small cell lung cancer (NSCLC) are particularly needed, as this type of cancer is relatively insensitive to chemotherapy and radiation therapy. We recently identified GGTI compounds that are designed to block geranylgeranylation and membrane association of signaling proteins including the Rho family G-proteins. One of the GGTIs is P61A6 which inhibits proliferation of human cancer cells, causes cell cycle effects with G1 accumulation and exhibits tumor-suppressing effects with human pancreatic cancer xenografts. In this paper, we investigated effects of P61A6 on non-small cell lung cancer (NSCLC) cells in vitro and in vivo.

Three non-small cell lung cancer cell lines were used to test the ability of P61A6 to inhibit cell proliferation. Further characterization involved analyses of geranylgeranylation, membrane association and activation of RhoA, and anchorage-dependent and –independent growth, as well as cell cycle effects and examination of cell cycle regulators. We also generated stable cells expressing RhoA-F, which bypasses the geranylgeranylation requirement of wild type RhoA, and examined whether the proliferation inhibition by P61A6 is suppressed in these cells. Tumor xenografts of NSCLC cells growing in nude mice were also used to test P61A6’s tumor-suppressing ability.

P61A6 was shown to inhibit proliferation of NSCLC lines H358, H23 and H1507. Detailed analysis of P61A6 effects on H358 cells showed that P61A6 inhibited geranylgeranylation, membrane association of RhoA and caused G1 accumulation associated with decreased cyclin D1/2. The effects of P61A6 to inhibit proliferation could mainly be ascribed to RhoA, as expression of the RhoA-F geranylgeranylation bypass mutant rendered the cells resistant to inhibition by P61A6. We also found that P61A6 treatment of H358 tumor xenografts growing in nude mice reduced their growth as well as the membrane association of RhoA in the tumors.

Thus, P61A6 inhibits proliferation of NSCLC cells and causes G1 accumulation associated with decreased cyclin D1/2. The result with the RhoA-F mutant suggests that the effect of P61A6 to inhibit proliferation is mainly through the inhibition of RhoA. P61A6 also shows efficacy to inhibit growth of xenograft tumor.

• connective tissue diseases
• pleiotropic effect
• rheumatology
• statins

• connective tissue growth factor
• fasudil
• plasminogen activator inhibitor-1
• pulmonary fibrosis
• transforming growth factor-β1

• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives
• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology
• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/therapeutic use
• Animals
• Bleomycin
• Cytokines/metabolism
• Drug Evaluation, Preclinical
• Lung/drug effects
• Lung/immunology
• Lung/pathology
• Lymphocytes/immunology
• Macrophages/immunology
• Male
• Mice, Inbred C57BL
• Myosin-Light-Chain Kinase/metabolism
• Myosin-Light-Chain Phosphatase
• Neutrophil Infiltration
• Pulmonary Fibrosis/chemically induced
• Pulmonary Fibrosis/drug therapy
• Pulmonary Fibrosis/immunology
• Pulmonary Fibrosis/metabolism
• rho-Associated Kinases/antagonists & inhibitors

Multigenes and multigene interaction are involved in the development, recurrence and metastasis of hepatocellular carcinoma, while aberrant gene expression is the significant cause of recurrence and metastasis. Researches on gene changes and gene interaction in hepatitis, liver cirrhosis and hepatocellular carcinoma are important for identifying the development, elucidating the pathogenesis, and guiding the prognosis and therapy of hepatocellular carcinoma.

• Hepatocellular carcinoma
• Gene expression
• Interaction