Rhizobacterium-derived diacetyl modulates plant immunity in a phosphate-dependent manner.

Plants establish mutualistic associations with beneficial microbes while deploying the immune system to defend against pathogenic ones. Little is known about the interplay between mutualism and immunity and the mediator molecules enabling such crosstalk. Here, we show that plants respond differentially to a volatile bacterial compound through integral modulation of the immune system and the phosphate-starvation response (PSR) system, resulting in either mutualism or immunity. We found that exposure of Arabidopsis thaliana to a known plant growth-promoting rhizobacterium can unexpectedly have either beneficial or deleterious effects to plants. The beneficial-to-deleterious transition is dependent on availability of phosphate to the plants and is mediated by diacetyl, a bacterial volatile compound. Under phosphate-sufficient conditions, diacetyl partially suppresses plant production of reactive oxygen species (ROS) and enhances symbiont colonization without compromising disease resistance. Under phosphate-deficient conditions, diacetyl enhances phytohormone-mediated immunity and consequently causes plant hyper-sensitivity to phosphate deficiency. Therefore, diacetyl affects the type of relation between plant hosts and certain rhizobacteria in a way that depends on the plant's phosphate-starvation response system and phytohormone-mediated immunity.

Pan-cancer analysis revealed H3K4me1 at bivalent promoters premarks DNA hypermethylation during tumor development and identified the regulatory role of DNA methylation in relation to histone modifications.

BACKGROUND: DNA hypermethylation at promoter CpG islands (CGIs) is a hallmark of cancers and could lead to dysregulation of gene expression in the development of cancers, however, its dynamics and regulatory mechanisms remain elusive. Bivalent genes, that direct development and differentiation of stem cells, are found to be frequent targets of hypermethylation in cancers. RESULTS: Here we performed comprehensive analysis across multiple cancer types and identified that the decrease in H3K4me1 levels coincides with DNA hypermethylation at the bivalent promoter CGIs during tumorigenesis. Removal of DNA hypermethylation leads to increment of H3K4me1 at promoter CGIs with preference for bivalent genes. Nevertheless, the alteration of H3K4me1 by overexpressing or knockout LSD1, the demethylase of H3K4, doesn't change the level or pattern of DNA methylation. Moreover, LSD1 was found to regulate the expression of a bivalent gene OVOL2 to promote tumorigenesis. Knockdown of OVOL2 in LSD1 knockout HCT116 cells restored the cancer cell phenotype. CONCLUSION: In summary, our work identified a universal indicator that can pre-mark DNA hypermethylation in cancer cells, and dissected the interplay between H3K4me1 and DNA hypermethylation in detail. Current study also reveals a novel mechanism underlying the oncogenic role of LSD1, providing clues for cancer therapies.

Evolution of the point defects involved under the action of mechanical forces on mechanically machined fused silica surfaces.

Point defects with different species are concentrated on most mechanically machined fused silica optical surfaces with surface defects, which would sharply decrease the laser damage resistance under intense laser irradiation. Various point defects have distinct roles in affecting the laser damage resistance. Especially, the proportions of various point defects have not been identified, posing the challenge in relating the intrinsic quantitative relationship among various point defects. To fully reveal the comprehensive effect of various point defects, it is necessary to systematically explore the origins, evolution laws and especially the quantitative relationship among point defects. Herein, seven types of point defects are determined. The unbonded electrons in point defects are found to tend to be ionized to induce laser damage and there is a definite quantitative relationship between the proportions of oxygen-deficient point defects and that of peroxide point defects. The conclusions are further verified based on the photoluminescence (PL) emission spectra and the properties (e.g., reaction rule and structural feature) of the point defects. On basis of the fitted Gaussian components and electronic-transition theory, the quantitative relationship between PL and the proportions of various point defects is constructed for the first time. E'-Center accounts for the highest proportion among them. This work is beneficial for fully revealing the comprehensive action mechanisms of various point defects and providing new insights in elucidating the defect-induced laser damage mechanisms of optical components under intense laser irradiation from the atomic scale.

Activation of the sigma-1 receptor exerts cardioprotection in a rodent model of chronic heart failure by stimulation of angiogenesis.

BACKGROUND: Angiogenesis plays a critical role on post-infarction heart failure (PIHF), the presence of which facilitates additional blood supply to maintain the survival of residual cardiomyocytes. The sigma-1 receptor (S1R) has been substantiated to stimulate angiogenesis, with the effect on a model of PIHF remaining unknown. AIMS: This study aims to investigate the effects of S1R on PIHF and the underlying mechanisms involved. METHODS: Rats were implemented left anterior descending artery ligation followed by rearing for 6 weeks to induce a phenotype of heart failure. Daily intraperitoneal injection of S1R agonist or antagonist for 5 weeks was applied from 2nd week after surgery. The effects exerted by S1R were detected by echocardiography, hemodynamic testing, western blot, Sirius red dyeing, ELISA, immunohistochemistry and fluorescence. We also cultured HUVECs to verify the mechanisms in vitro. RESULTS: Stimulation of S1R significantly ameliorated the cardiac function resulted from PIHF, in addition to the observation of reduced fibrosis in the peri-infarct region and the apoptosis of residual cardiomyocytes, which were associated with augmentation of microvascular density in peri-infarct region through activation of the JAK2/STAT3 pathway. We also indicated that suppression of JAK2/STAT3 pathway by specific inhibitor in vitro reversed the pro-angiogenic effects of S1R on HUVECs, which further confirmed that angiogenesis, responsible for PIHF amelioration, by S1R stimulation was in a JAK2/STAT3 pathway-dependent manner. CONCLUSION: S1R stimulation improved PIHF-induced cardiac dysfunction and ventricular remodeling through promoting angiogenesis by activating the JAK2/STAT3 pathway.

MicroRNA-small molecule association identification: from experimental results to computational models.

Small molecule is a kind of low molecular weight organic compound with variety of biological functions. Studies have indicated that small molecules can inhibit a specific function of a multifunctional protein or disrupt protein-protein interactions and may have beneficial or detrimental effect against diseases. MicroRNAs (miRNAs) play crucial roles in cellular biology, which makes it possible to develop miRNA as diagnostics and therapeutic targets. Several drug-like compound libraries were screened successfully against different miRNAs in cellular assays further demonstrating the possibility of targeting miRNAs with small molecules. In this review, we summarized the concept and functions of small molecule and miRNAs. Especially, five aspects of miRNA functions were exhibited in detail with individual examples. In addition, four disease states that have been linked to miRNA alterations were summed up. Then, small molecules related to four important miRNAs miR-21, 122, 4644 and 27 were selected for introduction. Some important publicly accessible databases and web servers of the experimentally validated or potential small molecule-miRNA associations were discussed. Identifying small molecule targeting miRNAs has become an important goal of biomedical research. Thus, several experimental and computational models have been developed and implemented to identify novel small molecule-miRNA associations. Here, we reviewed four experimental techniques used in the past few years to search for small-molecule inhibitors of miRNAs, as well as three types of models of predicting small molecule-miRNA associations from different perspectives. Finally, we summarized the limitations of existing methods and discussed the future directions for further development of computational models.

Bacterial diacetyl suppresses abiotic stress-induced senescence in Arabidopsis.

Premature plant senescence induced by abiotic stresses is a major cause of agricultural losses worldwide. Tools for suppressing stress-induced plant senescence are limited. Here, we report that diacetyl, a natural compound emitted by the plant-beneficial bacterium Bacillus amyloliquefaciens, suppresses abscisic acid -mediated foliar senescence in Arabidopsis thaliana under various abiotic stress conditions. Our results establish diacetyl as an effective protector against stress-induced plant senescence and reveal a molecular mechanism for bacteria-enhanced plant stress resistance.

Pinocembrin ameliorates post-infarct heart failure through activation of Nrf2/HO-1 signaling pathway.

BACKGROUND: Oxidative stress is an important factor involved in the progress of heart failure. The current study was performed to investigate whether pinocembrin was able to ameliorate post-infarct heart failure (PIHF) and the underlying mechanisms. METHODS: Rats were carried out left anterior descending artery ligation to induce myocardial infarction and subsequently raised for 6 weeks to produce chronic heart failure. Then pinocembrin was administrated every other day for 2 weeks. The effects were evaluated by echocardiography, western blot, Masson's staining, biochemical examinations, immunohistochemistry, and fluorescence. In vitro we also cultured H9c2 cardiomyocytes and cardiac myofibroblasts to further testify the mechanisms. RESULTS: We found that PIHF-induced deteriorations of cardiac functions were significantly ameliorated by administrating pinocembrin. In addition, the pinocembrin treatment also attenuated collagen deposition and augmented vascular endothelial growth factor receptor 2 in infarct border zone along with an attenuated apoptosis, which were related to an amelioration of oxidative stress evidenced by reduction of reactive oxygen species (ROS) in heart tissue and malondialdehyde (MDA) in serum, and increase of superoxide dismutase (SOD). This were accompanied by upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1) pathway. In vitro experiments we found that specific Nrf2 inhibitor significantly reversed the effects resulted from pinocembrin including antioxidant, anti-apoptosis, anti-fibrosis and neovascularization, which further indicated the amelioration of PIHF by pinocembrin was in a Nrf2/HO-1 pathway-dependent manner. CONCLUSION: Pinocembrin ameliorated cardiac functions and remodeling resulted from PIHF by ROS scavenging and Nrf2/HO-1 pathway activation which further attenuated collagen fibers deposition and apoptosis, and facilitated angiogenesis.

RNA methylation and diseases: experimental results, databases, Web servers and computational models.

Ribonucleic acid (RNA) methylation is a type of posttranscriptional modifications occurring in all kingdoms of life. It is strongly related to important biological process, thus making it linked to a number of human diseases. Owing to the development of high-throughput sequencing technology, plenty of achievement had been obtained in RNA methylation research recently. Meanwhile, various computational models have been developed to analyze and mining increasing RNA methylation data. In this review, we first made a brief introduction about eight types of most popular RNA methylation, the biological functions of RNA methylation, the relationship between RNA methylation and disease and five important RNA methylation-related diseases. The research of RNA methylation is based on sequencing data processing, and effective bioinformatics techniques can benefit better understanding of RNA methylation. We further introduced seven publicly available RNA methylation-related databases, and some important publicly available RNA-methylation-related Web servers and software for RNA methylation site identification, differential analysis and so on. Furthermore, we provided detailed analysis of the state-of-the-art computational models used in these Web servers and software. We also analyzed the limitations of these models and discussed the future directions of developing computational models for RNA methylation research.

Stoichiometric Modeling of Aboveground-Belowground Interaction of Herbaceous Plant and Two Herbivores.

In a grassland ecosystem, the dynamics and coexistence mechanisms of two herbivores competing for one herbaceous plant have been widely studied, while the chemical heterogeneity of herbaceous plant's aboveground and belowground parts is usually ignored in dynamic modeling. Based on the traditional two herbivore-one herbaceous plant competition model, a new stoichiometric competition model, which incorporates the chemical heterogeneity of herbaceous plants, is formulated to investigate effects of the aboveground-belowground interactions and the chemical heterogeneity on the dynamics of the two herbivore-one herbaceous plant system. We perform theoretical analysis for the stability of boundary equilibria and show that a stable coexistent equilibrium is possible with two herbivores on one herbaceous plant. Moreover, numerical simulations reveal that various light intensity and nitrogen input can also allow all populations to coexist in periodic oscillations or irregularly cyclic oscillations. Our findings further indicate that when the nitrogen input is fixed, higher light intensity leads to a dominance of the lower N-demand herbivore, while the light intensity is fixed, higher nitrogen input leads to a dominance of the higher N-demand herbivore. Moderate levels of light and nutrient could promote the coexistence of two herbivores and herbaceous plant. This study also explains the functional mechanism for the decline of species diversity in response to nitrogen enrichment.

RNA-splicing factor SART3 regulates translesion DNA synthesis.

Translesion DNA synthesis (TLS) is one mode of DNA damage tolerance that uses specialized DNA polymerases to replicate damaged DNA. DNA polymerase η (Polη) is well known to facilitate TLS across ultraviolet (UV) irradiation and mutations in POLH are implicated in skin carcinogenesis. However, the basis for recruitment of Polη to stalled replication forks is not completely understood. In this study, we used an affinity purification approach to isolate a Polη-containing complex and have identified SART3, a pre-mRNA splicing factor, as a critical regulator to modulate the recruitment of Polη and its partner RAD18 after UV exposure. We show that SART3 interacts with Polη and RAD18 via its C-terminus. Moreover, SART3 can form homodimers to promote the Polη/RAD18 interaction and PCNA monoubiquitination, a key event in TLS. Depletion of SART3 also impairs UV-induced single-stranded DNA (ssDNA) generation and RPA focus formation, resulting in an impaired Polη recruitment and a higher mutation frequency and hypersensitivity after UV treatment. Notably, we found that several SART3 missense mutations in cancer samples lessen its stimulatory effect on PCNA monoubiquitination. Collectively, our findings establish SART3 as a novel Polη/RAD18 association regulator that protects cells from UV-induced DNA damage, which functions in a RNA binding-independent fashion.

PipelineDog: a simple and flexible graphic pipeline construction and maintenance tool.

Summary: Analysis pipelines are an essential part of bioinformatics research, and ad hoc pipelines are frequently created by researchers for prototyping and proof-of-concept purposes. However, most existing pipeline management system or workflow engines are too complex for rapid prototyping or learning the pipeline concept. A lightweight, user-friendly and flexible solution is thus desirable. In this study, we developed a new pipeline construction and maintenance tool, PipelineDog. This is a web-based integrated development environment with a modern web graphical user interface. It offers cross-platform compatibility, project management capabilities, code formatting and error checking functions and an online repository. It uses an easy-to-read/write script system that encourages code reuse. With the online repository, it also encourages sharing of pipelines, which enhances analysis reproducibility and accountability. For most users, PipelineDog requires no software installation. Overall, this web application provides a way to rapidly create and easily manage pipelines. Availability and implementation: PipelineDog web app is freely available at http://web.pipeline.dog. The command line version is available at http://www.npmjs.com/package/pipelinedog and online repository at http://repo.pipeline.dog. Contact: ysun@kean.edu or xing@biology.rutgers.edu or ysun@diagnoa.com. Supplementary information: Supplementary data are available at Bioinformatics online.

Prediction of Small Molecule-MicroRNA Associations by Sparse Learning and Heterogeneous Graph Inference.

As microRNAs (miRNAs) have been reported to be a type of novel high-value small molecule (SM) drug targets for disease treatments, many researchers are engaged in the field of exploring new SM-miRNA associations. Nevertheless, because of the high cost, adopting traditional biological experiments constrains the efficiency of discovering new associations between SMs and miRNAs. Therefore, as an important auxiliary tool, reliable computational models will be of great help to reveal SM-miRNA associations. In this article, we developed a computational model of sparse learning and heterogeneous graph inference for small molecule-miRNA association prediction (SLHGISMMA). Initially, the sparse learning method (SLM) was implemented to decompose the SM-miRNA adjacency matrix. Then, we integrated the reacquired association information together with the similarity information of SMs and miRNAs into a heterogeneous graph to infer potential SM-miRNA associations. Here, the main innovation of SLHGISMMA lies in the introduction of SLM to eliminate noises of the original adjacency matrix to some extent, which plays an important role in performance improvement. In addition, to assess SLHGISMMA' performance, four different kinds of cross-validations were performed based on two datasets. As a result, based on dataset 1 (dataset 2), SLHGISMMA achieved area under the curves of 0.9273 (0.7774), 0.9365 (0.7973), 0.7703 (0.6556), and 0.9241 ± 0.0052 (0.7724 ± 0.0032) in global leave-one-out cross-validation (LOOCV), miRNA-fixed local LOOCV, SM-fixed local LOOCV, and 5-fold cross-validation, respectively. Moreover, in the case study on three important SMs via removing their known associations, the results showed that most of the top 50 predicted miRNAs were confirmed by the database SM2miR v1.0 or the experimental literature.

RFSMMA: A New Computational Model to Identify and Prioritize Potential Small Molecule-MiRNA Associations.

More and more studies found that many complex human diseases occur accompanied by aberrant expression of microRNAs (miRNAs). Small molecule (SM) drugs have been utilized to treat complex human diseases by affecting the expression of miRNAs. Several computational methods were proposed to infer underlying associations between SMs and miRNAs. In our study, we proposed a new calculation model of random forest based small molecule-miRNA association prediction (RFSMMA) which was based on the known SM-miRNA associations in the SM2miR database. RFSMMA utilized the similarity of SMs and miRNAs as features to represent SM-miRNA pairs and further implemented the machine learning algorithm of random forest to train training samples and obtain a prediction model. In RFSMMA, integrating multiple kinds of similarity can avoid the bias of single similarity and choosing more reliable features from original features can represent SM-miRNA pairs more accurately. We carried out cross validations to assess predictive accuracy of RFSMMA. As a result, RFSMMA acquired AUCs of 0.9854, 0.9839, 0.7052, and 0.9917 ± 0.0008 under global leave-one-out cross validation (LOOCV), miRNA-fixed local LOOCV, SM-fixed local LOOCV, and 5-fold cross validation, respectively, under data set 1. Based on data set 2, RFSMMA obtained AUCs of 0.8456, 0.8463, 0.6653, and 0.8389 ± 0.0033 under four cross validations according to the order mentioned above. In addition, we implemented a case study on three common SMs, namely, 5-fluorouracil, 17ß-estradiol, and 5-aza-2'-deoxycytidine. Among the top 50 associated miRNAs of these three SMs predicted by RFSMMA, 31, 32, and 28 miRNAs were verified, respectively. Therefore, RFSMMA is shown to be an effective and reliable tool for identifying underlying SM-miRNA associations.

GM13133 is a negative regulator in mouse white adipocytes differentiation and drives the characteristics of brown adipocytes.

Obesity is tightly associated with the disturbance of white adipose tissue storing excess energy. Thermogenic adipocytes (brown and beige) exert a critical role of oxidizing nutrients at the high rates through non-shivering thermogenesis. The recruitment of brown characteristics in white adipocytes, termed browning, has been considered as a promising strategy for treating obesity and associated metabolic complications. Recently, long noncoding RNAs play a crucial role in regulating tissue development and participating in disease pathogenesis, yet their effects on the conversion of white into brown-like adipocytes and thermogenic function were not totally understood. Here, we identified a mouse brown adipose specific expressed lncRNA, termed GM13133. Moreover, a considerable amount of GM13133 is expressed in adipocytes and actively modulated by cold, ß3 -adrenergic agonist and cAMP stimuli, implying a potential role in the conversion from white to brown adipocytes. Overexpression of GM13133 did not affect the proliferation of mouse white pre-adipocytes, but inhibited white adipocyte differentiation by decreasing lipid accumulation. The forced expression of GM13133 also significantly drove the conversion of white into brown-like adipocytes with the enhanced mitochondrial biogenesis and the induced expression of brown adipocytes specific markers. A global mRNA analysis further indicated the possible regulatory role of cAMP signaling pathway in GM13133 mediated white-to-brown adipocytes conversion. Our results identified a lncRNA-mediated modulation in primary mouse white adipocyte differentiation and indicate the functional significance of GM13133 in promoting browning of white adipocytes and maintenance of thermogenesis, further providing a potential strategy to treating obesity.

Antimicrobial activity and mechanism of the human milk-sourced peptide Casein201.

INTRODUCTION: Casein201 is one of the human milk sourced peptides that differed significantly in preterm and full-term mothers. This study is designed to demonstrate the biological characteristics, antibacterial activity and mechanisms of Casein201 against common pathogens in neonatal infection. METHODOLOGY: The analysis of biological characteristics was done by bioinformatics. Disk diffusion method and flow cytometry were used to detect the antimicrobial activity of Casein201. Killing kinetics of Casein201 was measured using microplate reader. The antimicrobial mechanism of Casein201 was studied by electron microscopy and electrophoresis. RESULTS: Bioinformatics analysis indicates that Casein201 derived from ß-casein and showed significant sequence overlap. Antibacterial assays showed Casein201 inhibited the growth of S taphylococcus aureus and Y ersinia enterocolitica. Ultrastructural analyses revealed that the antibacterial activity of Casein201 is through cytoplasmic structures disintegration and bacterial cell envelope alterations but not combination with DNA. CONCLUSION: We conclude the antimicrobial activity and mechanism of Casein201. Our data demonstrate that Casein201 has potential therapeutic value for the prevention and treatment of pathogens in neonatal infection.

Antimicrobial activity and mechanism of PDC213, an endogenous peptide from human milk.

Human milk has always been considered an ideal source of elemental nutrients to both preterm and full term infants in order to optimally develop the infant's tissues and organs. Recently, hundreds of endogenous milk peptides were identified in human milk. These peptides exhibited angiotensin-converting enzyme inhibition, immunomodulation, or antimicrobial activity. Here, we report the antimicrobial activity and mechanism of a novel type of human antimicrobial peptide (AMP), termed PDC213 (peptide derived from ß-Casein 213-226 aa). PDC213 is an endogenous peptide and is present at higher levels in preterm milk than in full term milk. The inhibitory concentration curve and disk diffusion tests showed that PDC213 had obvious antimicrobial against S. aureus and Y. enterocolitica, the common nosocomial pathogens in neonatal intensive care units (NICUs). Fluorescent dye methods, electron microscopy experiments and DNA-binding activity assays further indicated that PDC213 can permeabilize bacterial membranes and cell walls rather than bind intracellular DNA to kill bacteria. Together, our results suggest that PDC213 is a novel type of AMP that warrants further investigation.

iTRAQ-based chromatin proteomic screen reveals CHD4-dependent recruitment of MBD2 to sites of DNA damage.

Many DNA repair proteins can be recruited to DNA damage sites upon genotoxic stress. In order to search potential DNA repair proteins involved in cellular response to mitomycin C treatment, we utilized a quantitative proteome to uncover proteins that manifest differentially enrichment in the chromatin fraction after DNA damage. 397 proteins were identified, among which many factors were shown to be involved in chromatin modification and DNA repair by GO analysis. Specifically, methyl-CpG-binding domain protein 2 (MBD2) is revealed to be recruited to DNA damage sites after laser microirradiation, which was mediated through MBD domain and MBD2 C-terminus. Additionally, the recruitment of MBD2 is dependent on poly (ADP-ribose) and chromodomain helicase DNA-binding protein 4 (CHD4). Moreover, knockdown of MBD2 by CRISPR-Cas9 technique results in MMC sensitivity in mammalian cells.

Complete Khoisan and Bantu genomes from southern Africa.

The genetic structure of the indigenous hunter-gatherer peoples of southern Africa, the oldest known lineage of modern human, is important for understanding human diversity. Studies based on mitochondrial and small sets of nuclear markers have shown that these hunter-gatherers, known as Khoisan, San, or Bushmen, are genetically divergent from other humans. However, until now, fully sequenced human genomes have been limited to recently diverged populations. Here we present the complete genome sequences of an indigenous hunter-gatherer from the Kalahari Desert and a Bantu from southern Africa, as well as protein-coding regions from an additional three hunter-gatherers from disparate regions of the Kalahari. We characterize the extent of whole-genome and exome diversity among the five men, reporting 1.3 million novel DNA differences genome-wide, including 13,146 novel amino acid variants. In terms of nucleotide substitutions, the Bushmen seem to be, on average, more different from each other than, for example, a European and an Asian. Observed genomic differences between the hunter-gatherers and others may help to pinpoint genetic adaptations to an agricultural lifestyle. Adding the described variants to current databases will facilitate inclusion of southern Africans in medical research efforts, particularly when family and medical histories can be correlated with genome-wide data.

A method for de novo nucleic acid diagnostic target discovery.

MOTIVATION: A proper target or marker is essential in any diagnosis (e.g. an infection or cancer). An ideal diagnostic target should be both conserved in and unique to the pathogen. Currently, these targets can only be identified manually, which is time-consuming and usually error-prone. Because of the increasingly frequent occurrences of emerging epidemics and multidrug-resistant 'superbugs', a rapid diagnostic target identification process is needed. RESULTS: A new method that can identify uniquely conserved regions (UCRs) as candidate diagnostic targets for a selected group of organisms solely from their genomic sequences has been developed and successfully tested. Using a sequence-indexing algorithm to identify UCRs and a k-mer integer-mapping model for computational efficiency, this method has successfully identified UCRs within the bacteria domain for 15 test groups, including pathogenic, probiotic, commensal and extremophilic bacterial species or strains. Based on the identified UCRs, new diagnostic primer sets were designed, and their specificity and efficiency were tested by polymerase chain reaction amplifications from both pure isolates and samples containing mixed cultures. AVAILABILITY AND IMPLEMENTATION: The UCRs identified for the 15 bacterial species are now freely available at http://ucr.synblex.com. The source code of the programs used in this study is accessible at http://ucr.synblex.com/bacterialIdSourceCode.d.zip CONTACT: yazhousun@synblex.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Itaconic acid regulation of TFEB-mediated autophagy flux alleviates hyperoxia-induced bronchopulmonary dysplasia.

BACKGROUND: Premature infants often require oxygen supplementation, which can elicit bronchopulmonary dysplasia (BPD) and lead to mitochondrial dysfunction. Mitochondria play important roles in lung development, in both normal metabolism and apoptosis. Enhancing our comprehension of the underlying mechanisms in BPD development can facilitate the effective treatments. METHODS: Plasma samples from BPD and non-BPD infants were collected at 36 weeks post-menstrual age and used for metabolomic analysis. Based on hyperoxia-induced animal and cell models, changes in mitophagy and apoptosis were evaluated following treatment with itaconic acid (ITA). Finally, the mechanism of action of ITA in lung development was comprehensively demonstrated through rescue strategies and administration of corresponding inhibitors. RESULTS: An imbalance in the tricarboxylic acid (TCA) cycle significantly affected lung development, with ITA serving as a significant metabolic marker for the outcomes of lung development. ITA improved the morphological changes in BPD rats, promoted SP-C expression, and inhibited the degree of alveolar type II epithelial cells (AEC II) apoptosis. Mechanistically, ITA mainly promotes the nuclear translocation of transcription factor EB (TFEB) to facilitate dysfunctional mitochondrial clearance and reduces apoptosis in AEC II cells by regulating autophagic flux. CONCLUSION: The metabolic imbalance in the TCA cycle is closely related to lung development. ITA can improve lung development by regulating autophagic flux and promote the nuclear translocation of TFEB, implying its potential therapeutic utility in the treatment of BPD.