Genome-wide Mendelian randomization identifies putatively causal gut microbiota for multiple peptic ulcer diseases.

Objective: The pathogenesis of peptic ulcer diseases (PUDs) involves multiple factors, and the contribution of gut microbiota to this process remains unclear. While previous studies have associated gut microbiota with peptic ulcers, the precise nature of the relationship, whether causal or influenced by biases, requires further elucidation. Design: The largest meta-analysis of genome-wide association studies was conducted by the MiBioGen consortium, which provided the summary statistics of gut microbiota for implementation in the Mendelian randomization (MR) analysis. Summary statistics for five types of PUDs were compiled using the FinnGen Consortium R8 release data. Various statistical techniques, including inverse variance weighting (IVW), MR-Egger, weighted median (WM), weighted mode, and simple mode, were employed to assess the causal relationships between gut microbiota and these five PUDs. Result: In the intestinal microbiome of 119 known genera, we found a total of 14 causal associations with various locations of PUDs and reported the potential pathogenic bacteria of Bilophila et al. Among them, four had causal relationships with esophageal ulcer, one with gastric ulcer, three with gastroduodenal ulcer, four with duodenal ulcer, and two with gastrojejunal ulcer. Conclusion: In this study, the pathogenic bacterial genera in the gut microbiota that promote the occurrence of PUDs were found to be causally related. There are multiple correlations between intestinal flora and PUDs, overlapping PUDs have overlapping associated genera. The variance in ulcer-related bacterial genera across different locations underscores the potential influence of anatomical locations and physiological functions.

CD36 regulates LPS-induced acute lung injury by promoting macrophages M1 polarization.

M1 polarization of macrophages works as a promoter in pathogenesis of acute lung injury / acute respiratory distress syndrome (ALI/ARDS) by the secretion of pro-inflammatory cytokines and recruiting other inflammatory cells. Lipopolysaccharide (LPS), a critical component of the wall of gram-negative bacteria, can induce M1 polarization and ALI. Recently, cluster of differentiation 36 (CD36) has been reported to be associated with inflammatory responses. However, it has not yet been clarified whether CD36 in macrophages is involved in LPS-induced ALI. Herein, we demonstrated that in macrophages, LPS-induced ALI was regulated by CD36. Loss of CD36 attenuated LPS-induced ALI by reducing M1 polarization. Mechanistically, CD36 promoted macrophage M1 polarization by regulating CD14 associated with TLR4 during LPS stimulation. The findings of this study, clarified the mechanism of LPS-induced ALI through CD36 in macrophages, which provides a potential target for the prevention and treatment of ALI.

PTENε suppresses tumor metastasis through regulation of filopodia formation.

PTEN is one of the most frequently mutated genes in malignancies and acts as a powerful tumor suppressor. Tumorigenesis is involved in multiple and complex processes including initiation, invasion, and metastasis. The complexity of PTEN function is partially attributed to PTEN family members such as PTENα and PTENß. Here, we report the identification of PTENε (also named as PTEN5), a novel N-terminal-extended PTEN isoform that suppresses tumor invasion and metastasis. We show that the translation of PTENε/PTEN5 is initiated from the CUG816 codon within the 5'UTR region of PTEN mRNA. PTENε/PTEN5 mainly localizes in the cell membrane and physically associates with and dephosphorylates VASP and ACTR2, which govern filopodia formation and cell motility. We found that endogenous depletion of PTENε/PTEN5 promotes filopodia formation and enhances the metastasis capacity of tumor cells. Overall, we identify a new isoform of PTEN with distinct subcellular localization and molecular function compared to the known members of the PTEN family. These findings advance our current understanding of the importance and diversity of PTEN functions.

Microarray Analysis of Long Non-Coding RNAs in Lung Tissues of Patients with COPD and HOXA-AS2 Promotes HPMECs Proliferation via Notch1.

Background and Objectives: Long non-coding RNAs (lncRNAs) play an important role in the pathogenesis of many diseases, including cancer, pulmonary fibrosis and chronic obstructive pulmonary disease (COPD). In this study, we intended to identify the differentially expressed lncRNAs and the role of HOXA cluster antisense RNA 2 (HOXA-AS2) in patients with COPD. Methods: We analyzed lncRNA profiles of three non-COPD and seven COPD patients' lungs via microarray and then validated the expression of the top differentially expressed lncRNAs by using real-time polymerase chain reaction (PCR). To identify the mechanism of HOXA-AS2 during COPD pathogenesis and endothelial cell proliferation, we knocked down and overexpressed HOXA-AS2 with siRNA and lentivirus transfection approach in human pulmonary microvascular endothelial cells (HPMECs). Results: Among 29,150 distinct lncRNA transcripts, 353 lncRNAs were significantly (≥2-fold change and P<0.05) upregulated and 552 were downregulated in COPD patients. The fold change of HOXA-AS2 is 9.32; real-time PCR confirmed that HOXA-AS2 was downregulated in COPD patients. In in vitro experiments, cigarette smoke extract (CSE) treatment reduced the expression of HOXA-AS2 and cell proliferation of HPMECs. Knocking down HOXA-AS2 inhibited HPMECs proliferation and the expression of Notch1 in HPMECs. Overexpressing Notch1 could partly rescue the inhibition of cell viability induced by the silence of HOXA-AS2. Conclusion: Our results demonstrated that differentially expressed lncRNAs may act as potential molecular biomarkers for the diagnosis of COPD, and HOXA-AS2 was involved in the pathogenesis of COPD by regulating HPMECs proliferation via Notch1, which may provide a new approach for COPD treatment.

Plasma Metabolomic and Lipidomic Profiling of a Genetically Modified Mouse Model of Scavenger Receptor Class B Type I.

Atherosclerosis is a chronic inflammatory disease of the arterial wall and is becoming the principal cause of death globally. The reverse cholesterol transport (RCT) mediated by scavenger receptor class B type I (SR-BI) is a major protection mechanism against atherosclerosis. To investigate the metabolome changes and to find potential biomarkers involved in RCT, nontargeted metabolomics and nontargeted lipidomics are applied to SR-BI knockout mice that are fed a high fat and high cholesterol diet. SR-BI knockout mice and controls are told apart using multidimensional statistical analysis, and potential biomarkers are found and identified. The pathophysiological meaning of the biomarkers and the perturbed metabolic pathways are also addressed, which could provide new evidence for atherosclerosis studies.

Whole transcriptome analyis of human lung tissue to identify COPD-associated genes.

Identification of the dysfunctional genes in human lung from patients with Chronic obstructive pulmonary disease (COPD) will help understand the pathology of this disease. Here, using transcriptomic data of lung tissue for 91 COPD cases and 182 matched healthy controls from the Genotype-Tissue Expression (GTEx) database. we identified 1359 significant differentially expressed genes (DEG) with 707 upregulated and 602 downregulated respectively. We evaluated the identified DEGs in an independent microarray cohort of 219 COPD and 108 controls, demonstrating the robustness of our result. Functional annotation of COPD-associated genes highlighted the activation of complement cascade, dysregulation of inflammatory response and extracellular matrix organization in the COPD patients. In addition, we identified several novel key-hub genes involved in the COPD pathogenesis using a network analysis method. To our knowledge, our analysis is currently the largest RNA-seq based COPD transcriptomic analyses, providing great resource for the molecular research in the COPD community.

Comprehensive transcriptomic analysis indicates brain regional specific alterations in type 2 diabetes.

Type 2 diabetes (T2D) can result in a number of comorbidities involving various organs including heart, eye, kidney and even the brain. However, little is known about the molecular basis of T2D associated brain disorders. In this study, we performed a comprehensive transcriptomic analysis in a total of 304 T2D samples and 608 matched control samples from thirteen distinct brain regions. We observed prominent difference among transcriptomic profiles of diverse brain regions in T2D. The most striking change was found in caudate with thousands of T2D-associated genes identified, followed by hippocampus, while nearly no transcriptomic change was observed in other brain regions. Functional analysis of T2D-associated genes revealed impaired synaptic functions and an association with neurodegenerative diseases. Co-expression analysis of caudate transcriptomic profiles unveiled a core regional specific module that was disorganized in T2D. Sub-modules consisting of regional markers were enriched in T2D risk single nucleotide polymorphisms (SNPs) and implied a causal link with T2D. Hub genes of this module include NSF and ADD2, the former of which has been associated with T2D and neurogenerative diseases. Thus, our work provides useful information for further studies in T2D associated brain disorders.

Fatty acid synthase downregulation contributes to acute lung injury in murine diet-induced obesity.

The prevalence of obesity is rising worldwide and obese patients comprise a specific population in the intensive care unit. Acute respiratory distress syndrome (ARDS) incidence is increased in obese patients. Exposure of rodents to hyperoxia mimics many of the features of ARDS. In this report, we demonstrate that high fat diet induced obesity increases the severity of hyperoxic acute lung injury in mice in part by altering fatty acid synthase (FASN) levels in the lung. Obese mice exposed to hyperoxia had significantly reduced survival and increased lung damage. Transcriptomic analysis of lung homogenates identified Fasn as one of the most significantly altered mitochondrial associated genes in mice receiving 60% compared to 10% fat diet. FASN protein levels in the lung of high fat diet mice were lower by immunoblotting and immunohistochemistry. Depletion of FASN in type II alveolar epithelial cells resulted in altered mitochondrial bioenergetics and more severe lung injury with hyperoxic exposure, even upon the administration of a 60% fat diet. This is the first study to show that a high fat diet leads to altered FASN expression in the lung and that both a high fat diet and reduced FASN expression in alveolar epithelial cells promote lung injury.

LC-MS-Based Metabolomics and Lipidomics Study of High-Density-Lipoprotein-Modulated Glucose Metabolism with an apoA-I Knockout Mouse Model.

Type 2 diabetes mellitus (T2DM) has become a tremendous problem in public health nowadays. High-density lipoprotein (HDL) refers to a group of heterogeneous particles that circulate in blood, and a recent research finds that HDL acts a pivotal part of glucose metabolism. To understand systemic metabolic changes correlated with HDL in glucose metabolism, we applied LC-MS-based metabolomics and lipidomics to detect metabolomic and lipidomic profiles of plasma from apoA-I knockout mice fed a high-fat diet. Multivariate analysis was applied to differentiate apoA-I knockout mice and controls, and potential biomarkers were found. Pathway analysis demonstrated that several metabolic pathways such as aminoacyl-tRNA biosynthesis, arginine and proline metabolism, and phenylalanine, tyrosine, and tryptophan biosynthesis were dysregulated in apoA-I knockout mice. This study may provide a new insight into the underlying pathogenesis in T2DM and prove that LC-MS-based metabolomics and lipidomics are powerful approaches in finding potential biomarkers and disturbed pathways.

Lipidomic profiling of plasma samples from patients with mitochondrial disease.

Mitochondrial disease (MD) is a rare mitochondrial respiratory chain disorder with a high mortality and extremely challenging to treat. Although genomic, transcriptomic, and proteomic analyses have been performed to investigate the pathogenesis of MD, the role of metabolomics in MD, particularly of lipidomics remains unclear. This study was undertaken to identify potential lipid biomarkers of MD. An untargeted lipidomic approach was used to compare the plasma lipid metabolites in 20 MD patients and 20 controls through Liquid Chromatography coupled to Mass Spectrometry. Volcano plot analysis was performed to identify the different metabolites. Receiver operating characteristic (ROC) curves were constructed and the area under the ROC curves (AUC) was calculated to determine the potentially sensitive and specific biomarkers. A total of 41 lipids were significantly different in MD patients and controls. ROC curve analysis showed the top 5 AUC values of lipids (phosphatidylinositols 38:6, lysoPC 20:0, 19:0, 18:0, 17:0) are more than 0.99. Multivariate ROC curve based exploratory analysis showed the AUC of combination of top 5 lipids is 1, indicating they may be potentially sensitive and specific biomarkers for MD. We propose combination of these lipid species may be more valuable in predicting the development and progression of MD, and this will have important implications for the diagnosis and treatment of MD.

Systematic analysis of gene expression patterns associated with postmortem interval in human tissues.

Postmortem mRNA degradation is considered to be the major concern in gene expression research utilizing human postmortem tissues. A key factor in this process is the postmortem interval (PMI), which is defined as the interval between death and sample collection. However, global patterns of postmortem mRNA degradation at individual gene levels across diverse human tissues remain largely unknown. In this study, we performed a systematic analysis of alteration of gene expression associated with PMI in human tissues. From the Genotype-Tissue Expression (GTEx) database, we evaluated gene expression levels of 2,016 high-quality postmortem samples from 316 donors of European descent, with PMI ranging from 1 to 27 hours. We found that PMI-related mRNA degradation is tissue-specific, gene-specific, and even genotype-dependent, thus drawing a more comprehensive picture of PMI-associated gene expression across diverse human tissues. Additionally, we also identified 266 differentially variable (DV) genes, such as DEFB4B and IFNG, whose expression is significantly dispersed between short PMI (S-PMI) and long PMI (L-PMI) groups. In summary, our analyses provide a comprehensive profile of PMI-associated gene expression, which will help interpret gene expression patterns in the evaluation of postmortem tissues.