Untargeted Metabolomic Profiling of Liver in a Chronic Intermittent Hypoxia Mouse Model.
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ABSTRACT:
SUBMITTER: Chen LD
PROVIDER: S-EPMC8298499 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundChronic hepatopathies present a diagnostic challenge, with different diseases being associated with similar clinical and laboratory findings. Characterization of dogs with chronic hepatopathies can be difficult and require costly diagnostic procedures such as acquisition of a liver biopsy specimen. Noninvasive and inexpensive biomarkers that reliably characterize chronic hepatopathies such as chronic hepatitis or a congenital portosystemic vascular anomaly may decrease the need for costly or invasive diagnostic testing and guide novel therapeutic interventions.ObjectiveTo investigate differences in the serum metabolome among healthy dogs, dogs with congenital portosystemic shunts, and dogs with chronic hepatitis.AnimalsStored serum samples from 12 healthy dogs, 10 dogs with congenital portosystemic shunts, and 6 dogs with chronic hepatitis were analyzed.MethodsThe serum metabolome was analyzed with an untargeted metabolomics approach using gas chromatography-quadrupole time of flight mass spectrometry.ResultsPrincipal component analysis and heat dendrogram plots of the metabolomics data showed clustering among individuals in each group. Random forest analysis showed differences in the abundance of various metabolites including increased aromatic amino acids and xylitol in dogs with congenital portosystemic shunts. Based on the univariate statistics, 50 metabolites were significantly different among groups.Conclusions and clinical importanceThe serum metabolome varies among healthy dogs, dogs with congenital portosystemic shunts, and dogs with chronic hepatitis. Statistical analysis identified several metabolites that differentiated healthy dogs from dogs with vascular or parenchymal liver disease. Further targeted assessment of these metabolites is needed to confirm their diagnostic reliability.
| S-EPMC6524095 | biostudies-literature
Project description:Chagas disease is caused by Trypanosoma cruzi which is endemic in Latin America. T. cruzi infection results in a latent infection with approximately a third of latently infected patients developing chronic Chagas cardiomyopathy (CCM). CCM is a common cause of cardiomyopathy in endemic regions and has a poor prognosis compared to other cardiomyopathies. The factors responsible for the transition from the asymptomatic indeterminate latent stage of infection to CCM are poorly understood. Our previous studies demonstrated that lipid metabolism and diet are important determinants of disease progression. In the present study, we analyzed various serum metabolomic biomarkers such as acylcarnitines, amino acids, biogenic amines, glycerophospholipids, and sphingolipids in murine models of CCM, where the mice specifically develop either left or right ventricular cardiomyopathy based on the diets fed during the indeterminate stage in a murine model of Chagas disease. Our data provide new insights into the metabolic changes that may predispose patients to CCM and biomarkers that may help predict the risk of developing cardiomyopathy from T. cruzi infection. Author Summary. Chronic Chagas cardiomyopathy (CCM) is a parasitic disease prevalent in Latin America. Currently, no effective drugs or vaccines are available to prevent or cure CCM. The factors involved in the disease severity and progression are poorly understood to design new therapeutic interventions. In order to rapidly identify Chagas patients with a higher risk to develop CCM, a new set of biomarkers specific to Chagas disease is needed. We performed serum metabolomic analyses in chronic T. cruzi-infected mice fed on different diets and identified cardiac ventricular-specific metabolite biomarkers that could define CCM severity. In this paper, we present the results of serum metabolomic analyses and discuss its correlations to the diet-induced metabolic regulations in the pathogenesis of CCM in a murine model of Chagas disease.
| S-EPMC6948343 | biostudies-literature
Project description:Chronic hepatic disease can present a diagnostic challenge with different etiologies being associated with similar clinical and laboratory findings. The histopathological assessment of a liver biopsy specimen is usually required in order to make a definitive diagnosis and the availability of non-invasive prognostic biomarkers is limited. The emerging science of metabolomics is used to detect changes in endogenous low molecular weight metabolites in biological samples and offers the possibility of identifying noninvasive markers of disease. The objective of this study was to investigate differences in the urine metabolome between healthy dogs, dogs with chronic hepatitis, dogs with hepatocellular carcinoma, and dogs with a congenital portosystemic shunt. Stored urine samples from 10 healthy dogs, 10 dogs with chronic hepatitis, 6 dogs with hepatocellular carcinoma, and 5 dogs with a congenital portosystemic shunt were analyzed. The urine metabolome was analyzed by gas chromatography-quadrupole time of flight mass spectrometry and 220 known metabolites were identified. Principal component analysis and heat dendrogram plots of the metabolomics data showed clustering between groups. Random forest analysis showed differences in the abundance of various metabolites including putrescine, gluconic acid, sorbitol, and valine. Based on univariate statistics, 37 metabolites were significantly different between groups. In, conclusion, the urine metabolome varies between healthy dogs, dogs with chronic hepatitis, dogs with hepatocellular carcinoma, and dogs with a congenital portosystemic shunt. Further targeted assessment of these metabolites is needed to assess their diagnostic utility.
| S-EPMC6544284 | biostudies-literature
Project description:Obstructive sleep apnea, a condition leading to chronic intermittent hypoxia (CIH), is associated with hyperlipidemia, atherosclerosis, and a high cardiovascular risk. A causal link between obstructive sleep apnea and atherosclerosis has not been established.The objective of the present study was to examine whether CIH may induce atherosclerosis in C57BL/6J mice.Forty male C57BL/6J mice, 8 weeks of age, were fed either a high-cholesterol diet or a regular chow diet and subjected either to CIH or intermittent air (control conditions) for 12 weeks.Nine of 10 mice simultaneously exposed to CIH and high-cholesterol diet developed atherosclerotic lesions in the aortic origin and descending aorta. In contrast, atherosclerosis was not observed in mice exposed to intermittent air and a high-cholesterol diet or in mice exposed to CIH and a regular diet. A high-cholesterol diet resulted in significant increases in serum total and low-density lipoprotein cholesterol levels and a decrease in high-density lipoprotein cholesterol. Compared with mice exposed to intermittent air and a high-cholesterol diet, combined exposure to CIH and a high-cholesterol diet resulted in marked progression of dyslipidemia with further increases in serum total cholesterol and low-density lipoprotein cholesterol (124 +/- 4 vs. 106 +/- 6 mg/dl; p < 0.05), a twofold increase in serum lipid peroxidation, and up-regulation of an important hepatic enzyme of lipoprotein secretion, stearoyl-coenzyme A desaturase-1.CIH causes atherosclerosis in the presence of diet-induced dyslipidemia.
| S-EPMC2176090 | biostudies-other
Project description:ObjectiveSepsis is a life-threatening condition secondary to infection that evolves into a dysregulated host response and is associated with acute organ dysfunction. Sepsis-induced cardiac dysfunction is one of the most complex organ failures to characterize. This study performed comprehensive metabolomic profiling that distinguished between septic patients with and without cardiac dysfunction.MethodPlasma samples collected from 80 septic patients were analysed by untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics. Principal component analysis (PCA), partial least squares discrimination analysis (PLS-DA), and orthogonal partial least square discriminant analysis (OPLS-DA) were applied to analyse the metabolic model between septic patients with and without cardiac dysfunction. The screening criteria for potential candidate metabolites were as follows: variable importance in the projection (VIP) >1, P < 0.05, and fold change (FC) > 1.5 or < 0.7. Pathway enrichment analysis further revealed associated metabolic pathways. In addition, we constructed a subgroup metabolic analysis between the survivors and non-survivors according to 28-day mortality in the cardiac dysfunction group.ResultsTwo metabolite markers, kynurenic acid and gluconolactone, could distinguish the cardiac dysfunction group from the normal cardiac function group. Two metabolites, kynurenic acid and galactitol, could distinguish survivors and non-survivors in the subgroup analysis. Kynurenic acid is a common differential metabolite that could be used as a candidate for both diagnosis and prognosis for septic patients with cardiac dysfunction. The main associated pathways were amino acid metabolism, glucose metabolism and bile acid metabolism.ConclusionMetabolomic technology could be a promising approach for identifying diagnostic and prognostic biomarkers of sepsis-induced cardiac dysfunction.
| S-EPMC9978788 | biostudies-literature
Project description:Intermittent hypoxia (IH) is a prominent feature of obstructive sleep apnea (OSA) which is increasingly recognized as a key risk factor for liver injury. Circular RNAs (circRNAs) has been suggested to act as a regulator of multiple biological processes. However, there is no study evaluating circRNAs alterations and potential role of circRNAs in OSA-related liver injury. The present study aimed to investigate circRNA expression profiles in vitro model of IH-induced liver injury, as well as potential functional characterization of the differentially expressed circRNAs (DE circRNAs). BRL-3A cells were exposed to IH or normoxia. Cell apoptosis and cell viability were evaluated using flow cytometry and cell counting kit-8, respectively. The expression profile of circRNAs was depicted by circRNA sequencing. The selected circRNAs were verified by quantitative real-time PCR (qRT-PCR). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) analyses were employed to predict DE circRNAs functions. The circRNA-miRNA-mRNA regulatory network was constructed. IH treatment caused cell injury in BRL-3A cells. 98 circRNAs were identified as being dysregulated in IH-treated BRL-3A cells. Among them, 58 were up-regulated and 40 were down-regulated. Go and KEGG analyses suggested that the DE circRNAs were predominantly enriched in the biological process such as positive regulation of NF-kappaB transcription factor activity and pathways such as circadian entrainment, Wnt signaling pathway, MAPK signaling pathway, and protein export. 3 up-regulated circRNAs and 3 down-regulated circRNAs with high number of back-splicing sites were chosen for qRT-PCR validation and were consistent with the sequencing data. CircRNA1056 and circRNA805 were predicted to interact with microRNAs that might thereby regulate downstream genes. The study characterized a profile of dysregulated circRNAs in IH-induced BRL-3A cell injury. DE circRNAs may play vital roles in the pathophysiology of IH-induced liver injury. Our findings provide preliminary support for further research in mechanisms and a new theory for the pathogenesis of OSA-related liver injury.
| S-EPMC9515621 | biostudies-literature
Project description:Selected Australian native fruits such as Davidson's plum, finger lime and native pepperberry have been reported to demonstrate potent antioxidant activity. However, comprehensive metabolite profiling of these fruits is limited, therefore the compounds responsible are unknown, and further, the compounds of nutritional value in these native fruits are yet to be described. In this study, untargeted and targeted metabolomics were conducted using the three fruits, together with assays to determine their antioxidant activities. The results demonstrate that targeted free and hydrolysed protein amino acids exhibited high amounts of essential amino acids. Similarly, important minerals like potassium were detected in the fruit samples. In antioxidant activity, Davidson's plum reported the highest activity in ferric reducing power (FRAP), finger lime in antioxidant capacity (ABTS), and native pepperberry in free radical scavenging (DPPH) and phosphomolybdenum assay. The compounds responsible for the antioxidant activity were tentatively identified using untargeted GC×GC-TOFMS and UHPLC-QqQ-TOF-MS/MS metabolomics. A clear discrimination into three clusters of fruits was observed using principal component analysis (PCA) and partial least squares (PLS) analysis. The correlation study identified a number of compounds that provide the antioxidant activities. GC×GC-TOFMS detected potent aroma compounds of limonene, furfural, and 1-R-α-pinene. Based on the untargeted and targeted metabolomics, and antioxidant assays, the nutritional potential of these Australian bush fruits is considerable and supports these indigenous fruits in the nutraceutical industry as well as functional ingredients for the food industry, with such outcomes benefiting Indigenous Australian communities.
| S-EPMC7143387 | biostudies-literature
Project description:At least one-third of adults in the United States experience intermittent hypoxia (IH) due to health or living conditions. The majority of these adults suffer with sleep breathing conditions and associated circadian rhythm disorders. The impact of IH on the circadian clock is not well characterized. In the current study, we used an IH mouse model to understand the impact of IH on the circadian gene expression of the canonical clock genes in the central (the brain) and peripheral (the liver) tissues. Gene expression was measured using a Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR). CircaCompare was used to evaluate the differential rhythmicity between normoxia and IH. Our observations suggested that the circadian clock in the liver was less sensitive to IH compared to the circadian clock in the brain.
| S-EPMC8535273 | biostudies-literature
Project description:Sphagnum mosses dominate peatlands by employing harsh ecosystem tactics to prevent vascular plant growth and microbial degradation of these large carbon stores. Knowledge about Sphagnum-produced metabolites, their structure and their function, is important to better understand the mechanisms, underlying this carbon sequestration phenomenon in the face of climate variability. It is currently unclear which compounds are responsible for inhibition of organic matter decomposition and the mechanisms by which this inhibition occurs. Metabolite profiling of Sphagnum fallax was performed using two types of mass spectrometry (MS) systems and 1H nuclear magnetic resonance spectroscopy (1H NMR). Lipidome profiling was performed using LC-MS/MS. A total of 655 metabolites, including one hundred fifty-two lipids, were detected by NMR and LC-MS/MS-329 of which were novel metabolites (31 unknown lipids). Sphagum fallax metabolite profile was composed mainly of acid-like and flavonoid glycoside compounds, that could be acting as potent antimicrobial compounds, allowing Sphagnum to control its environment. Sphagnum fallax metabolite composition comparison against previously known antimicrobial plant metabolites confirmed this trend, with seventeen antimicrobial compounds discovered to be present in Sphagnum fallax, the majority of which were acids and glycosides. Biological activity of these compounds needs to be further tested to confirm antimicrobial qualities. Three fungal metabolites were identified providing insights into fungal colonization that may benefit Sphagnum. Characterizing the metabolite profile of Sphagnum fallax provided a baseline to understand the mechanisms in which Sphagnum fallax acts on its environment, its relation to carbon sequestration in peatlands, and provide key biomarkers to predict peatland C store changes (sequestration, emissions) as climate shifts.
| S-EPMC6848953 | biostudies-literature
Project description:Chronic constant hypoxia (CCH), such as in pulmonary diseases or high altitude, and chronic intermittent hypoxia (CIH), such as in sleep apnea, can lead to major changes in the heart. Molecular mechanisms underlying these cardiac alterations are not well understood. We hypothesized that changes in gene expression could help to delineate such mechanisms. The current study used a neonatal mouse model in CCH or CIH combined with cDNA microarrays to determine changes in gene expression in the CCH or CIH mouse heart. Both CCH and CIH induced substantial alterations in gene expression. In addition, a robust right ventricular hypertrophy and cardiac enlargement was found in CCH- but not in CIH-treated mouse heart. On one hand, upregulation in RNA and protein levels of eukaryotic translation initiation factor-2alpha and -4E (eIF-2alpha and eIF-4E) was found in CCH, whereas eIF-4E was downregulated in 1- and 2-wk CIH, suggesting that eIF-4E is likely to play an important role in the cardiac hypertrophy observed in CCH-treated mice. On the other hand, the specific downregulation of heart development-related genes (e.g., notch gene homolog-1, MAD homolog-4) and the upregulation of proteolysis genes (e.g., calpain-5) in the CIH heart can explain the lack of hypertrophy in CIH. Interestingly, apoptosis was enhanced in CCH but not CIH, and this was correlated with an upregulation of proapoptotic genes and downregulation of anti-apoptotic genes in CCH. In summary, our results indicate that 1) the pattern of gene response to CCH is different from that of CIH in mouse heart, and 2) the identified expression differences in certain gene groups are helpful in dissecting mechanisms responsible for phenotypes observed.
| S-EPMC2856928 | biostudies-literature