Project description:The paper "Metabolomic Machine Learning Predictor for Diagnosis and Prognosis of Gastric Cancer" addresses the need for non-invasive diagnostic tools for gastric cancer (GC). Traditional methods like endoscopy are invasive and expensive. The authors conducted a targeted metabolomics analysis of 702 plasma samples to develop machine learning models for GC diagnosis and prognosis. The diagnostic model, using 10 metabolites, achieved a sensitivity of 0.905, outperforming conventional protein marker-based methods. The prognostic model effectively stratified patients into risk groups, surpassing traditional clinical models.
I have successfully reproduced the diagnosis model from the paper. This machine learning-based system differentiates GC patients from non-GC controls using metabolomics data from plasma samples analyzed by liquid chromatography-mass spectrometry (LC-MS). The model focuses on 10 metabolites, including succinate, uridine, lactate, and serotonin. Employing LASSO regression and a random forest classifier, the model achieved an AUROC of 0.967, with a sensitivity of 0.854 and specificity of 0.926. This model significantly outperforms traditional diagnostic methods and underscores the potential of integrating machine learning with metabolomics for early GC detection and treatment.
Project description:Background: Transient ischemic attack (TIA) induces ischemic tolerance that can reduce the subsequent ischemic damage and improve prognosis of stroke patients. However, the underlying mechanisms remain elusive. Recent advances in plasma metabolomics analysis have made it a powerful tool to investigate human pathophysiological phenotypes and mechanisms of diseases. In this study, we aimed to identify the bioactive metabolites from the plasma of TIA patients for determination of their prophylactic and therapeutic effects on protection against cerebral ischemic stroke, and the mechanism of TIA-induced ischemic tolerance against subsequent stroke. Methods: Metabolomic profiling using liquid chromatography-mass spectrometry was performed to identify the TIA-induced differential bioactive metabolites in the plasma samples of 20 patients at day 1 (time for basal metabolites) and day 7 (time for established chronic ischemic tolerance-associated metabolites) after onset of TIA. Mouse MCAO-induced stroke model was used to verify their prophylactic and therapeutic potentials. Transcriptomics changes in circulating neutrophils of TIA patients were determined by RNA-sequencing. Multivariate statistics and integrative analysis of metabolomics and transcriptomics were performed to elucidate the potential mechanism of TIA-induced ischemic tolerance. Findings: Plasma metabolomics analysis identified five differentially upregulated metabolites associated with TIA-induced ischemic tolerance, namely all-trans 13,14 dihydroretinol (atDR), 20-carboxyleukotriene B4, prostaglandin B2, cortisol and 9-KODE. They were associated with the metabolic pathways of retinol, arachidonic acid, and neuroactive ligand-receptor interaction. Prophylactic treatment of MCAO mice with these five metabolites significantly improved neurological functions. Additionally, post-stroke treatment with atDR or 9-KODE significantly reduced the cerebral infarct size and enhanced sensorimotor functions, demonstrating the therapeutic potential of these bioactive metabolites. Mechanistically, we found in TIA patients that these metabolites were positively correlated with circulating neutrophil counts. Integrative analysis of plasma metabolomics and neutrophil transcriptomics further revealed that TIA-induced metabolites are significantly correlated with specific gene expression in circulating neutrophils which showed prominent enrichment in FoxO signaling pathway and upregulation of the anti-inflammatory cytokine IL-10. Finally, we demonstrated that the protective effect of atDR-pretreatment on MCAO mice was abolished when circulating neutrophils were depleted. Interpretation: TIA-induced ischemic tolerance is associated with upregulation of plasma bioactive metabolites which can protect against cerebral ischemic damage and improve neurological functions through a positive role of circulating neutrophils.
Project description:Comparative gene expression profiling analysis of RNA-seq data from six venom-gland samples belonging to the Ag and Ng groups. The transcriptome data of the venom gland of P. lewisi obtained in this study provide a theoretical foundation for identifying the components and studying the biological functions of P. lewisi venom.
Project description:Background The generalist dipteran pupal parasitoid Nasonia vitripennis injects 79 venom peptides into the host before egg laying. This venom induces several important changes in the host, including developmental arrest, immunosuppression, and alterations to normal metabolism. It is hoped that diverse and potent bioactivities of N. vitripennis venom provide an opportunity for the design of novel acting drugs. However, currently very little is known about the individual functions of N. vitripennis venom peptides and less than half can be bioinformatically annotated. The paucity of annotation information complicates the design of studies that seek to better understand the potential mechanisms underlying the envenomation response. Although the RNA interference system of N. vitripennis provides an opportunity to functionally characterise venom encoding genes, with 79 candidates this represents a daunting task. For this reason we were interested in determining the expression levels of venom encoding genes in the venom gland, such that this information could be used to rank candidate venoms. To do this we carried out deep sequencing of the transcriptome of the venom gland and neighbouring ovary tissue and used RNA-seq to measure expression from the 79 venom encoding genes. The generation of a specific venom gland transcriptome dataset also provides further opportunities to investigate novel features of this highly specialised organ. Results High throughput sequencing and RNA-seq revealed that the highest expressed venom encoding gene in the venom gland was a serine protease called Nasvi2EG007167, which has previously been implicated in the apoptotic activity of N. vitripennis venom. As expected the RNA-seq confirmed that the N. vitripennis venom encoding genes are almost exclusively expressed in the venom gland relative to the neighbouring ovary tissue. Novel peptides appear to perform key roles in N. vitripennis venom function as only four of the highest 15 expressed venom encoding genes are bioinformatically annotationed. The high throughput sequencing data also provided evidence for the existence of an additional 471 novel genes in the Nasonia genome that are expressed in the venom gland and ovary. Finally, metagenomic analysis of venom gland transcripts identified viral transcripts that may play an important part in the N. vitripennis venom function. Conclusions The expression level information provided here for the 79 venom encoding genes provides an unbiased dataset that can be used by the N. vitripennis community to identify high value candidates for further functional characterisation. These candidates represent bioactive peptides that have value in drug development pipelines.
Project description:Sea nettle jellyfish cause millions of painful stings annually with little known about how their venom works and no rational treatments available. Here we perform a systematic analysis of sea nettle venom / host interactions. The venom shows dose-dependent cytotoxic activity in human cells and this can be blocked by dual inhibition of apoptosis and necroptosis. Using whole-genome CRISPR screening we identified human genes and pathways that modify venom action. The top gene cluster identified regulates proteoglycan biosynthesis. We show exogenous heparin, a drug used clinically as an anticoagulant, blocks venom cytotoxicity at a physiologically relevant dose. This effect was therapeutic, inhibiting venom even one hour after exposure. Importantly, in vivo, heparin protected against acute spontaneous pain, thermal hyperalgesia, and mechanical allodynia induced by venom. This provides the exciting possibility of repurposing heparin, a safe, commercially available drug as a prophylactic or therapeutic to reduce the impact of sea nettle stings.
Project description:Mucuna pruriens extract MPE pretreatment may have a direct protective effect on heart (other than immunological neutralization of the venom neurotoxin and phospholipase A2 by the anti-MPE antibodies) that renders the heart more resistant to the toxic action of the venom The direct protective effect probably involves functional changes to the cardiac tissue that enable the heart to resist the reduction of contractility and rate induced by the cobra venom.To explore the possibility of the direct action of MPE pretreatment on heart and to understand the molecular events involved in the protection of MPE pretreatment against the lethal action of Naja sputatrix venom, gene expression studies were carried out using microarray analysis. Rats were divided into four groups (n=6): negative control (abbreviated as ‘negative’ group), MPE pretreated group (abbreviated as ‘MPE’ group), N. sputatrix venom-challenge group (abbreviated as ‘NS’ group) and N. sputatrix venom-challenge to MPE pretreated animals group (abbreviated as ‘MPE-NS’ group). In the ‘MPE’ group, rats were injected with MPE at a dose of 21 mg/kg (i.p.), on day 0, 7 and 14, and sacrificed on day 21. In the ‘negative’ group (the untreated, control group), rats were injected with saline of the same volume and sacrificed also on day 21. Hearts were then harvested immediately. In the N. sputatrix venom-challenge group (‘NS’ group), untreated rats were challenged with 1.5 LD50 (1.25 ?g/g) of N. sputatrix venom whereas in the venom challenge to MPE pretreated animals group (the ‘MPE-NS’ group), MPE pretreated rats were challenged with 1.5 LD50 (1.25 ?g/g) of N. sputatrix venom, both on day 21. For the ‘NS’ and ‘MPE-NS’ group, the rats were observed for 24 h after venom challenged and hearts were harvested as soon as death occurred or 24 h after the venom injection, whichever occurred first.
Project description:Diabetic cardiomyopathy (DbCM) is an important clinical syndrome of diabetes and cause great burden to the people's life and health. Understanding its intrinsic epigenetic and metabolic alterations is critical to develop drugs for the treatment of DbCM. Multiple omics technology provides a feasible way for parsing the epigenetic characteristics and metabolic signatures associated with DbCM. The heart isolated from Male db/db mice and db/m mice were used for the analysis of high-throughput sequencing. Non-targeted metabolomics and amino acid-targeted metabolomics analyses were performed to detect the metabolites in plasma and heart tissues. Additionally, RNA-seq, proteomics, and ATAC-seq were employed to elucidate the underlying transcriptional-metabolic regulatory network mechanism in DbCM.