Roles of TGFβ1 in the expression of phosphoinositide 3-kinase isoform genes and sensitivity and response of lung telocytes to PI3K inhibitors Abstract Background The mouse lung telocyte cell line (TCSV40) recently established provides further opportunities to learn TC biology and functions. The present study aims at investigating regulatory roles of phosphoinositide 3-kinase (PI3K) isoforms in TC proliferation and movement and in TGFβ1-induced sensitivity and response of lung TCs to PI3K inhibitors. Materials and methods Network and molecular interactions of genes coding PI3K family or TGFβ family proteins in mouse primary TCs were defined. Mouse lung TCSV40 proliferation, apoptosis, cell cycle, and dynamical bio-behaviors were measured with or without TGFβ1 stimulation or PI3K catalytic isoform protein (PI3K/mTOR, PI3Kα/δ/β, PI3K p110δ, or pan-PI3K) inhibitions. Results The present study showed the difference of network characteristics and interactions of genes coding PI3K isoform proteins or TGFβ family proteins in primary lung telocytes from mouse lungs compared to those of other cells residing in the lung. TGFβ1 had diverse effects on TC proliferation with altered TC number in G2 or S phase, independent upon the administered dose of TGFβ1. PI3Kα/δ/β, PI3K/mTOR, and PI3K p110δ were involved in TC proliferation, of which PI3Kα/δ/β was more sensitive. The effects of pan-PI3K inhibitor indicate that more PI3K isoforms were stimulated by the administering of external TGFβ1 and contributed to TGFβ1-induced TC proliferation. PI3K p110δ upregulated TC proliferation and movement dynamically without TGFβ1, and downregulated TC proliferation with TGFβ1 stimulation, but not TC movement. PI3Kα/δ/β and PI3K/mTOR were more active in TGFβ1-induced S phase accumulation and had similar dynamic effects to PI3K p110δ. Gene expression of PI3K isoforms in TCs was upregulated after TGFβ1 stimulation. The expression of PIK3CA coding p110-α or PIK3CG coding p110-γ were up- or downregulated in TCs without TGFβ1, respectively, when PI3K/mTOR, PI3Kα/δ/β, PI3K p110δ, or pan-PI3K were inhibited. TGFβ1 upregulated the expression of PIK3CA and PIK3CB, while downregulated the expression of PIK3CD and PIK3CG. Conclusion Our data imply that TGFβ1 plays divergent roles in the expression of PI3K isoform genes in lung TCs and can alter the sensitivity and response of lung TCs to PI3K inhibitors.

Current understanding of the therapeutic benefits of mesenchymal stem cells in acute respiratory distress syndrome Abstract The acute respiratory distress syndrome (ARDS) is a multifaceted lung disorder in which no specific therapeutic intervention is able to effectively improve clinical outcomes. Despite an improved understanding of molecular mechanisms and advances in supportive care strategies, ARDS remains associated with high mortality, and survivors usually face long-term morbidity. In recent years, preclinical studies have provided mounting evidence of the potential of mesenchymal stem cell (MSC)-based therapies in lung diseases and critical illnesses. In several models of ARDS, MSCs have been demonstrated to induce anti-inflammatory and anti-apoptotic effects, improve epithelial and endothelial cell recovery, and enhance microbial and alveolar fluid clearance, thus resulting in improved lung and distal organ function and survival. Early-stage clinical trials have also demonstrated the safety of MSC administration in patients with ARDS, but further, large-scale investigations are required to assess the safety and efficacy profile of these therapies. In this review, we summarize the main mechanisms whereby MSCs have been shown to exert therapeutic effects in experimental ARDS. We also highlight questions that need to be further elucidated and barriers that must be overcome in order to efficiently translate MSC research into clinical practice.

Correction to: Is the clinical lipidomics a potential goldmine? The article Is the clinical lipidomics a potential goldmine?, written by Linlin Zhang, Xianlin Han and Xiangdong Wang, was originally published electronically on the publisher’s internet portal (currently SpringerLink) on 21 July 2018 with open access. With the author(s)’ decision to step

CRISPR-Cas12 and Cas13: the lesser known siblings of CRISPR-Cas9

Genome-wide off-targets of drugs: risks and opportunities

Applying switchable Cas9 variants to in vivo gene editing for therapeutic applications Abstract Progress in targeted gene editing by programmable endonucleases has paved the way for their use in gene therapy. Particularly, Cas9 is an endonuclease with high activity and flexibility, rendering it an attractive option for therapeutic applications in clinical settings. Many disease-causing mutations could potentially be corrected by this versatile new technology. In addition, recently developed switchable Cas9 variants, whose activity can be controlled by an external stimulus, provide an extra level of spatiotemporal control on gene editing and are particularly desirable for certain applications. Here, we discuss the considerations and difficulties for implementing Cas9 to in vivo gene therapy. We put particular emphasis on how switchable Cas9 variants may resolve some of these barriers and advance gene therapy in the clinical setting.

Refining CRISPR-based genome and epigenome editing off-targets

Keeping our eyes on CRISPR: the “Atlas” of gene editing

A new light of proteomics in cell biology and toxicology Abstract We expect more studies on proteomics-dominated multi- and trans-omics to paint out a dynamic, multi-level, multi-dimensional picture of molecular mechanisms in the single-cell or targeted cell population to elucidate the regulation of gene-gene, gene-protein, and protein-protein interactions, and define proteome-wide strategy of disease-specific biomarker and therapeutic target discovery and development. We hope that the current issue will be the initiation and stimulation of proteome-based investigations to explore molecular mechanisms in cell functioning and responses to drugs.

Protein carbonylation in human bronchial epithelial cells exposed to cigarette smoke extract Abstract Cigarette smoke is a well-established exogenous risk factor containing toxic reactive molecules able to induce oxidative stress, which in turn contributes to smoking-related diseases, including cardiovascular, pulmonary, and oral cavity diseases. We investigated the effects of cigarette smoke extract on human bronchial epithelial cells. Cells were exposed to various concentrations (2.5–5–10–20%) of cigarette smoke extract for 1, 3, and 24 h. Carbonylation was assessed by 2,4-dinitrophenylhydrazine using both immunocytochemical and Western immunoblotting assays. Cigarette smoke induced increasing protein carbonylation in a concentration-dependent manner. The main carbonylated proteins were identified by means of two-dimensional electrophoresis coupled to MALDI-TOF mass spectrometry analysis and database search (redox proteomics). We demonstrated that exposure of bronchial cells to cigarette smoke extract induces carbonylation of a large number of proteins distributed throughout the cell. Proteins undergoing carbonylation are involved in primary metabolic processes, such as protein and lipid metabolism and metabolite and energy production as well as in fundamental cellular processes, such as cell cycle and chromosome segregation, thus confirming that reactive carbonyl species contained in cigarette smoke markedly alter cell homeostasis and functions.