Biology subjects

Tien, N. T. N.

Publications and source records attributed to Tien, N. T. N..

6 recordsLinked to original sources

bioRxiv2025

Harnessing systemic glycolysis-TCA cycle axis to boost the host defense against newborn infection

Energy metabolism and immune response are tightly connected, but it is poorly understood how this interplay is regulated in early life to dictate host defense strategy, infection risks and severity. This interplay is particularly relevant for preterm, low birthweight or otherwise immunocompromised infants, who have poor metabolic control and increased risks of sepsis. Here, we utilized data from the COPSAC2010 cohort with 700 mother-child pairs and showed that plasma levels of TCA cycle metabolites in early life were associated with reduced childhood risk of bacterial infection and an attenuated systemic inflammatory response. Next, we explored how two distinct nutritional strategies, which were aimed at boosting TCA cycle activity instead of glycolysis, impacted neonatal host defense against a serious bloodstream infection in preterm piglets. Substituting galactose for glucose in parenteral nutrition enhanced disease tolerance in early phase of infection and overall glucose homeostasis, improving survival. Further, combining glucose restriction with supplementation of glucogenic amino acids conferred glycemic control and completely prevented sepsis and abnormal changes of organ injury markers. Mechanistically, this intervention enhanced both disease resistance and tolerance, accompanied by metabolic rewiring from glycolysis towards gluconeogenesis, TCA cycle activity and oxidative phosphorylation. Thus, optimized nutritional strategies controlling the interplay of energy metabolism and host defense may be lifesaving for infected infants. In briefNewborns rely on two distinct defense strategies to combat infections in early life. Disease resistance, fueled by aerobic glycolysis, seeks to actively eliminate microorganisms while disease tolerance, fueled by mitochondrial oxidative phosphorylation, seeks to reduce collateral tissue damage during infections. We found that in healthy human newborns, increased plasma levels of metabolites from the tricarboxylic acid (TCA) cycle were associated with lower burden of childhood infections and reduced pro-inflammatory status. In a newborn animal model of bloodstream infection, nutritional strategies boosting systemic TCA cycle activity, while reducing aerobic glycolysis, enhanced both host disease tolerance and resistance, thereby improving survival. These findings could pave a path for improved infection management in human newborns. HighlightsO_LIIn healthy children, higher plasma levels of TCA cycle metabolites are associated with lower infection risks and systemic inflammation. C_LIO_LIIn a neonatal infection model, the supply of galactose, instead of glucose, improves host glucose homeostasis and TCA cycle activity, improving disease tolerance and survival. C_LIO_LIA combination of glucose restriction and glucogenic amino acid supply also improves TCA cycle activity, enhancing both disease resistance and tolerance and completely preventing lethal sepsis. C_LI

immunology↗

bioRxiv2025

The Lipidome Landscape of Amiodarone Toxicity: An in vivo Lipid-centric Multi-Omics Study

Amiodarone is an effective therapy for arrhythmias, its prolonged management may lead to significant adverse drug reactions. Amiodarone-induced hepatoxicity is described by phospholipidosis, hepatic steatosis, cholestatic hepatitis, and cirrhosis. However, the systemic and hepatic lipidome disturbances and underlying toxicological mechanisms remain comprehensively elucidated. Untargeted lipidomics were utilized to analyze serum and liver samples from the rats orally administered a daily dose of amiodarone of either 100 or 300 mg/kg for one week. Changes in the expression of hepatic lipid-related genes were also examined utilizing transcriptomics. We found a higher magnitude of lipidome alterations in the 300 mg/kg than those in the 100 mg/kg groups. Treated animals showed elevated abundances of phosphatidylcholines, ether-linked phosphatidylcholines, sphingomyelins, and ceramides, and decreased levels of triacylglycerols, ether-linked triacylglycerols, and fatty acids. We also found 199 lipid-related differentially expressed hepatic genes between the 300 mg/kg group versus controls, implying lipid metabolism and signaling pathways disturbances. Specifically, elevation of serum phosphatidylcholines and ether-linked phosphatidylcholines, as well as hepatic bismonoacylglycerophosphates were associated with reduced expression of phospholipase genes and elevated expression of glycerophospholipid biosynthesis genes, possibly driving phospholipidosis. Perturbations of sphingolipid metabolism might also be the key events for amiodarone-induced toxicity. Alterations in gene expression levels related to lipid storage and metabolism, mitochondria functions, and energy homeostasis were also found. Collectively, our study characterized the sophisticated perturbations in the lipidome and transcriptome of amiodarone-treated rats and suggested potential mechanisms responsible for amiodarone-induced hepatotoxicity.

pharmacology and toxicology↗

bioRxiv2024

EasyPubPlot: a shiny web application for rapid omics data exploration and visualization

Computational toolkits for data exploration and visualization from widely used omics platforms often lack flexibility and customization. While many tools generate standardized output, advanced programming skills are necessary to create high-quality visualizations. Therefore, user-friendly tools that simplify this crucial yet time-consuming step are essential. We developed EasyPubPlot (Easy Publishable Plotting), a straightforward, easy-to-use, user experience-oriented, open-source, and shiny web application along with its associated R package to streamline data exploration and visualization for functional omics-empowered research. EasyPubPlot generates publishable scores plots, volcano plots, heatmaps, box plots, dot plots, and bubble plots with minimal necessary steps. The tool was designed to guide new users for accurate and efficient navigation. Step-by-step tutorials for each type of plot are also provided. Herein, we demonstrated EasyPubPlots competent functionality and versatility by showcasing metabolomics and transcriptomics data. Collectively, EasyPubPlot reduces the gap between data analysis and stunning visualization, thereby diminishing friction and focusing on science. The app can be downloaded and installed locally (https://github.com/Pharmaco-OmicsLab/EasyPubPlot) or used through a web application (https://pharmaco-omicslab.shinyapps.io/EasyPubPlot).

bioinformatics↗

bioRxiv2024

Endoplasmic reticulum stress inhibition preserves mitochondrial function and cell survival during early onset of isoniazid-induced oxidative stress

A comprehensive understanding of isoniazid (INH)-mediated hepatotoxic effects is essential for developing strategies to predict and prevent severe liver toxicity in tuberculosis treatment. Our study utilized multi-omics profiling to investigate the toxic effects of INH, revealing significant involvement of endoplasmic reticulum (ER) stress, mitochondrial impairment, redox imbalance, and altered metabolism. Followed-up mechanistic studies revealed that INH triggered the generation of cytosolic reactive oxygen species (ROS) and the activation of the Nrf2 signaling pathway prior to mitochondrial ROS accumulation. Subsequently, INH disrupted mitochondrial function by impairing respiratory complexes I-IV and caused mitochondrial membrane proton leaks without affecting ATP synthase activity, together leading to mitochondrial depolarization and reduced ATP production. These disturbances enhanced mitochondrial fission and mitophagy. While much attention has been given to mitochondrial dysfunction and oxidative stress in INH-induced hepatotoxicity, our findings highlight the potential of inhibiting ER stress during early INH exposure to mitigate cytosolic and mitochondrial oxidative stress. We further revealed the critical role of Nrf2 signaling in protecting liver cells under INH-induced oxidative stress by maintaining redox homeostasis and enabling metabolic reprogramming via regulating the expression of antioxidant genes and cellular lipid abundance. We also identified other antioxidant pathways (e.g., selenocompound metabolism, HIF-1 signaling pathway, and pentose phosphate pathway) as potential alternative mechanisms besides Nrf2 signaling in response to INH-induced oxidative stress. In conclusion, our research emphasizes the importance of ER stress, redox imbalance, metabolic changes, and mitochondrial dysfunction underlying INH-induced hepatotoxicity.

pharmacology and toxicology↗

bioRxiv2024

Multi-omics phenotyping characterizes molecular divergence underlying different clinical scenarios of inflammatory bowel disease

Clinically heterogeneous spectrum and molecular phenotypes of inflammatory bowel disease (IBD) remain to be comprehensively elucidated. This study set out to explore the serum molecular profiles (I) of IBD subtypes; in association with (II) elevated fecal calprotectin and (III) disease activity states; (IV) upon treatment escalation; and (V) in patients who needed treatment escalation. The serum proteome, metabolome, and lipidome of 75 treated IBD patients were profiled. Single- and multi-omic data analysis was performed to determine differential analytes and integrative biosignatures. (I) Chronic inflammation, and phosphatidylcholine and bile acid homeostasis disturbances underlined the differences between Crohns disease (CD) and ulcerative colitis. (II) Elevated calprotectin was associated with higher levels of inflammatory proteins and sphingomyelins (SM) and lower levels of bile acids, amino acids, and triacylglycerols (TG). Relative to patient remission, active disease state (III) was characterized by decreased SMs and increased inflammatory proteins and TGs. (IV) Treatment escalation was associated with augmented levels of inflammatory response-related proteins and reduced levels of amino acids. Most TG species increased in the post-treatment escalation. Moreover, needed-treatment-escalation patients had significantly lower levels of TGs (V). They also showed increased SMs and decreased signaling receptor binding proteins. Multi-omics analysis revealed biosignatures that captured the differences between groups of each scenario. Eight analytes, including NFASC, ANGPTL4, and chenodeoxycholate, were found in at least three biosignatures. Collectively, disturbances in immune response, bile acid homeostasis, amino acids, and lipids alteration potentially underlie the clinically heterogeneous spectrum of IBD.

systems biology↗

bioRxiv2024

Regulation of defense strategies and host metabolism to survive neonatal infection

Two distinct defense strategies, resistance and tolerance, enable a host to survive infectious diseases. Newborns, constrained by limited energy reserves, predominantly rely on tolerance to cope with infection. However, this approach may fail as pathogen levels surpass a critical threshold, prompting a shift to resistance that can lead to dysregulated immune responses and sepsis. The mechanisms governing the interplay between tolerance and resistance in newborns remain poorly understood. Here, we compare metabolic traits and defense strategies between survivors and non- survivors in Staphylococcus epidermidis (S. epidermidis)-infected preterm piglets, mimicking infection in preterm infants. Relative to non-survivors, survivors displayed elevated resistance during the early phase of infection, followed by stronger tolerance in later stages. Conversely, animals succumbing to sepsis showed clear signs of respiratory and metabolic acidosis, together with exaggerated inflammation and organ dysfunctions. Hepatic transcriptomics revealed a strong association between the tolerance phenotype and heightened oxidative phosphorylation in survivors, coupled with suppressed glycolysis and immune signaling. Plasma metabolomics supported the finding of enhanced mitochondrial metabolism in survivors. Our findings suggest a link between mitochondrial metabolism, disease tolerance, and ultimately improved survival during infections in newborns. Metabolic regulations related to tolerance may be exploited to discover novel therapeutics for neonatal infection. Conflict-of-interest statementThe authors have declared that no conflict of interest exists.

immunology↗