Changes In Metabolomic Profiles Research Articles

Metabolic alterations in human pulmonary artery smooth muscle cells treated with PDGF-BB.

Metabolic abnormalities are considered to play a key regulatory role in vascular remodeling of pulmonary arterial hypertension. However, to date, there is a paucity of research documenting the changes in metabolome profiles within the supernatants of pulmonary artery smooth muscle cells (PASMC) during their transition from a contractile to a synthetic phenotype. CCK-8 and Edu staining assays were used to evaluate the cell viability and proliferation of human PASMCs. IncuCyte ZOOM imaging system was used to continuously and automatically detect the migration of the PASMCs. A targeted metabolomics profiling was performed to quantitatively analyze 121 metabolites in the supernatant. Orthogonal partial least squares discriminant analysis was used to discriminate between PDGF-BB-induced PASMCs and controls. Metabolite set enrichment analysis was adapted to exploit the most disturbed metabolic pathways. Human PASMCs exhibited a transformation from contractile phenotype to synthetic phenotype after PDGF-BB induction, along with a significant increase in cell viability, proliferation, and migration. Metabolites in the supernatants of PASMCs treated with or without PDGF-BB were well profiled. Eleven metabolites were found to be significantly upregulated, whereas seven metabolites were downregulated in the supernatants of PASMCs induced by PDGF-BB compared to the vehicle-treated cells. Fourteen pathways were involved, and pyruvate metabolism pathway was ranked first with the highest enrichment impact followed by glycolysis/gluconeogenesis and pyrimidine metabolism. Significant and extensive metabolic abnormalities occurred during the phenotypic transformation of PASMCs. Disturbance of pyruvate metabolism pathway might contribute to pulmonary vascular remodeling.

Gut microbiota and metabolomic profile changes play critical roles in tacrolimus-induced diabetes in rats.

Hyperglycemia is one of the adverse effects of tacrolimus (TAC), but the underlying mechanism is not fully identified. We used multi-omics analysis to evaluate the changes in the gut microbiota and metabolic profile of rats with TAC-induced diabetes. To establish a diabetic animal model, Sprague Dawley rats were divided randomly into two groups. Those in the TAC group received intraperitoneal injections of TAC (3 mg/kg) for 8 weeks, and those in the CON group served as the control. 16S rRNA sequencing was used to analyze fecal microbiota. The metabolites of the two groups were detected and analyzed by nontargeted and targeted metabolomics, including amino acids (AAs), bile acids (BAs), and short-chain fatty acids (SCFAs). The rats treated with TAC exhibited hyperglycemia as well as changes in the gut microbiota and metabolites. Specifically, their gut microbiota had significantly higher abundances of Escherichia-Shigella, Enterococcus, and Allobaculum, and significantly lower abundances of Ruminococcus, Akkermansia, and Roseburia. In addition, they had significantly reduced serum levels of AAs including asparagine, aspartic acid, glutamic acid, and methionine. With respect to BAs, they had significantly higher serum levels of taurocholic acid (TCA), and glycochenodeoxycholic acid (GCDCA), but significantly lower levels of taurodeoxycholic acid (TDCA) and tauroursodeoxycholic acid (TUDCA). There were no differences in the levels of SCFAs between the two groups. Correlations existed among glucose metabolism indexes (fasting blood glucose and fasting insulin), gut microbiota (Ruminococcus and Akkermansia), and metabolites (glutamic acid, hydroxyproline, GCDCA, TDCA, and TUDCA). Both AAs and BAs may play crucial roles as signaling molecules in the regulation of TAC-induced diabetes.

Multi‐omics analyses reveal the signatures of metabolite transfers across trophic levels in a high‐CO2 ocean

AbstractAlthough the diverse impacts of elevated dissolved CO2 and warming on organisms within various trophic levels in marine food webs are well documented, we have yet to explore the biological links across different levels of biological organization from primary producers to secondary producers on an evolutionary time scale in a high‐CO2 ocean. Here, we cultured a model marine diatom Phaeodactylum tricornutum (primary producer) in predicted future high‐CO2 and/or warming conditions for ~ 1250 d with an experimental evolution approach and then fed them to the clam Coelomactra antiquata (secondary producer). We present an in‐depth multi‐omics analysis along the methylome (primary producer)–transcriptome (primary producer)–metabolome (primary producer)–metabolome (secondary producer) continuum. Our results showed that the downregulated terpenoid backbone biosynthesis in the methylome and transcriptome lead to decreased pyruvate levels and upregulation of some pathways (such as phenylalanine metabolism) in the metabolome of the primary producer in the long‐term warming conditions. These changes in metabolomic profile in the primary producer were then transferred to the secondary producer, resulting in changes in abundance of some metabolites, such as decreases in pyruvate, and in pyruvaldhyde (also known as methylglyoxal), and increases in 2‐hydroxylamino‐4,6‐dinitrotoluene. Our study provides a new insight into the molecular mechanisms underlying the trophic transfer from primary to secondary producers in a future high‐CO2 ocean and may provide more accurate projections of marine ecosystem services and functions over the next century.

Gut microbiota and fecal volatilome profile inspection in metabolically healthy and unhealthy obesity phenotypes

BackgroundPeople with metabolically healthy (MHO) and metabolically unhealthy obesity (MUO) differ for the presence or absence of cardio-metabolic complications, respectively.ObjectiveBased on these differences, we are interested in deepening whether these obesity phenotypes could be linked to changes in microbiota and metabolome profiles. In this respect, the overt role of microbiota taxa composition and relative metabolic profiles is not completely understood. At this aim, biochemical and nutritional parameters, fecal microbiota, metabolome and SCFA compositions were inspected in patients with MHO and MUO under a restrictive diet regimen with a daily intake ranging from 800 to 1200 kcal.MethodsBlood, fecal samples and food questionnaires were collected from healthy controls (HC), and an obese cohort composed of both MHO and MUO patients. Most impacting biochemical/anthropometric variables from an a priori sample stratification were detected by applying a robust statistics approach useful in lowering the background noise. Bacterial taxa and volatile metabolites were assessed by qPCR and gas chromatography coupled with mass spectrometry, respectively. A targeted GC–MS analyses on SCFAs was also performed.ResultsInstructed to follow a controlled and restricted daily calorie intake, MHO and MUO patients showed differences in metabolic, gut microbial and volatilome signatures. Our data revealed higher quantities of specific pro-inflammatory taxa (i.e., Desulfovibrio and Prevotella genera) and lower quantities of Clostridium coccoides group in MUO subset. Higher abundances in alkane, ketone, aldehyde, and indole VOC classes together with a lower amount of butanoic acid marked the faecal MUO metabolome.ConclusionsCompared to MHO, MUO subset symptom picture is featured by specific differences in gut pro-inflammatory taxa and metabolites that could have a role in the progression to metabolically unhealthy status and developing of obesity-related cardiometabolic diseases. The approach is suitable to better explain the crosstalk existing among dysmetabolism-related inflammation, nutrient intake, lifestyle, and gut dysbiosis.

Metabolomic Profiling and Characterization of a Novel 3D Culture System for Studying Chondrocyte Mechanotransduction.

Articular chondrocytes synthesize and maintain the avascular and aneural articular cartilage. In vivo these cells are surrounded by a 3D pericellular matrix (PCM) containing predominantly collagen VI. The PCM protects chondrocytes and facilitates mechanotransduction, and PCM stiffness is critical in transmitting biomechanical signals to chondrocytes. Various culture systems with different hydrogels have been used to encapsulate chondrocytes for 3D culture, but many lack either the PCM or the in vivo stiffness of the cartilage matrix. Here, we demonstrate that primary chondrocytes cultured in alginate will form a pericellular matrix and display a phenotype similar to in vivo conditions. We found that primary human and bovine chondrocytes, when cultured in alginate beads with addition of sodium L-ascorbate for 7 days, had a pronounced PCM, retained their phenotype, and synthesized both collagens VI and II. This novel culture system enables alginate-encapsulated chondrocytes to develop a robust PCM thereby creating a model system to study mechanotransduction. We also observed distinct compression-induced changes in metabolomic profiles between the monolayer-agarose and alginate-released agarose-embedded chondrocytes indicating physiological changes in cell metabolism. Our data suggest that 3D preculture of chondrocytes in alginate before encapsulation in physiologically-stiff agarose leads to a pronounced development of pericellular matrix that is sustained in the presence of ascorbate. This novel model can be useful in studying the mechanism by which chondrocytes respond to cyclical compression and other types of loading simulating in vivo physiological conditions.

Current Challenges and Future Directions in the Assessment of Glucocorticoid Status.

Glucocorticoid hormones (GC) are secreted in a circadian and ultradian rhythm and play a critical role in maintaining physiological homeostasis, with both excess and insufficient GC associated with adverse effects on health. Current assessment of GC status is primarily clinical, often in conjunction with serum cortisol values, which may be stimulated or suppressed depending on the GC disturbance being assessed. In the setting of extreme perturbations in cortisol levels i.e. markedly low or high levels, symptoms and signs of GC dysfunction may be overt. However, when disturbances in cortisol GC status values are less extreme, such as when assessing optimization of a GC replacement regimen, signs and symptoms can be more subtle or non-specific. Current tools for assessing GC status, are best suited to identifying profound disturbances but may lack sensitivity for confirming optimal GC status. Moreover, single cortisol values do not necessarily reflect an individual's GC status, as they are subject to inter- and intra-individual variation, do not take into account the pulsatile nature of cortisol secretion, variation in binding proteins, or local tissue concentrations as dictated by 11βeta-hydroxysteroid dehydrogenase (11β-HSD) activity, as well as GC receptor sensitivity. In the present review, we evaluate possible alternative methods for the assessment of GC status that do not solely rely on measurement of circulating cortisol levels. We discuss the potential of changes in metabolomic profiles, miRNA, gene expression, epigenetic, and other novel biomarkers such as GDF-15 and osteocalcin, that could in future aid in the objective classification of GC status.

Gut microbiota and serum metabolite signatures along the colorectal adenoma-carcinoma sequence: Implications for early detection and intervention

AimOur study focuses on the microbial and metabolomic profile changes during the adenoma stage, as adenomas can be considered potential precursors to colorectal cancer through the adenoma-carcinoma sequence. Identifying possible intervention targets at this stage may aid in preventing the progression of colorectal adenoma (CRA) to malignant lesions. Furthermore, we evaluate the efficacy of combined microbial and metabolite biomarkers in detecting CRA. MethodsFecal metagenomic and serum metabolomic analyses were performed for the discovery of alterations of gut microbiome and metabolites in CRA patients (n = 26), Colorectal cancer (CRC) patients (n = 19), Familial Adenomatous Polyposis (FAP) patients (n = 10), and healthy controls (n = 20). Finally, analyzing the associations between gut microbes and metabolites was performed by a Receiver Operating Characteristic (ROC) curve. ResultsOur analysis present that CRA patients differ significantly in gut microflora and serum metabolites compared with healthy controls, especially for Lachnospiraceae and Parasutterella. Its main metabolite, butyric acid, concentrations were raised in CRA patients compared with the healthy controls, indicating its role as a promoter of colorectal tumorigenesis. α-Linolenic acid and lysophosphatidylcholine represented the other healthy metabolite for CRA. Combining five microbial and five metabolite biomarkers, we differentiated CRA from CRC with an Area Under the Curve (AUC) of 0.85 out of this performance vastly superior to the specificity recorded by traditional markers CEA and CA199 in such differentiation of these conditions. ConclusionsThe study underlines significant microbial and metabolic alterations in CRA with a novel insight into screening and early intervention of its tumorigenesis.

Changes in urinary metabolomic profile show the effectiveness of a nutritional intervention in children 6-12 years old: The ALINFA study.

Diet plays an essential role in health and disease. Therefore, its determination is an important component of many investigations. The aim of the study was to evaluate the effect of a nutritional intervention on the urinary metabolome in children aged 6-12 years. Also, it was intended to identify biomarkers of diet quality and dietary intake. A 2-month, randomized, controlled, parallel trial was conducted in Spanish children. The analyses focused on the ALINFA group, which followed a full-fixed meal plan including healthy products, ready-to-eat meals, and healthy recipes. Diet quality was assessed by the KIDMED index and dietary intake by a food frequency questionnaire. Untargeted metabolomic analysis on urine samples was carried out, and multivariate analyses were performed for pattern recognition and characteristic metabolite identification. PLS-DA and Volcano plot analyses were performed to identify the discriminating metabolites of this group. 12 putative metabolites were found to be the most relevant to this intervention. Most of them were products derived from protein and amino acid metabolism (N-Ribosylhistidine, indolacrylic acid, and peptides) and lipid metabolism (3-oxo-2-pentylcyclopentane-1-hexanoic acid methyl, Suberoyl-L-carnitine, and 7-Dehydrodichapetalin E). All these metabolites decreased after the intervention, which was mainly associated with a decrease in the consumption of fatty meat and total fat, especially saturated fat. In turn, N-Ribosylhistidine and Suberoyl-L-carnitine were negatively associated with diet quality, as well as able to predict the change in KIDMED index. In conclusion, the changes observed in urinary metabolome demonstrate the effectiveness of the ALINFA nutritional intervention.

Comparative analysis of circulating metabolomic profiles identifies shared metabolic alterations across distinct multistressor military training exercises.

Military training provides insight into metabolic responses under unique physiological demands that can be comprehensively characterized by global metabolomic profiling to identify potential strategies for improving performance. This study identified shared changes in metabolomic profiles across three distinct military training exercises, varying in magnitude and type of stress. Blood samples collected before and after three real or simulated military training exercises were analyzed using the same untargeted metabolomic profiling platform. Exercises included a 2-wk survival training course (ST, n = 36), a 4-day cross-country ski march arctic training (AT, n = 24), and a 28-day controlled diet- and exercise-induced energy deficit (CED, n = 26). Log2-fold changes of greater than ±1 in 191, 121, and 64 metabolites were identified in the ST, AT, and CED datasets, respectively. Most metabolite changes were within the lipid (57-63%) and amino acid metabolism (18-19%) pathways and changes in 87 were shared across studies. The largest and most consistent increases in shared metabolites were found in the acylcarnitine, fatty acid, ketone, and glutathione metabolism pathways, whereas the largest decreases were in the diacylglycerol and urea cycle metabolism pathways. Multiple shared metabolites were consistently correlated with biomarkers of inflammation, tissue damage, and anabolic hormones across studies. These three studies of real and simulated military training revealed overlapping alterations in metabolomic profiles despite differences in environment and the stressors involved. Consistent changes in metabolites related to lipid metabolism, ketogenesis, and oxidative stress suggest a potential common metabolomic signature associated with inflammation, tissue damage, and suppression of anabolic signaling that may characterize the unique physiological demands of military training.NEW & NOTEWORTHY The extent to which metabolomic responses are shared across diverse military training environments is unknown. Global metabolomic profiling across three distinct military training exercises identified shared metabolic responses with the largest changes observed for metabolites related to fatty acids, acylcarnitines, ketone metabolism, and oxidative stress. These changes also correlated with alterations in markers of tissue damage, inflammation, and anabolic signaling and comprise a potential common metabolomic signature underlying the unique physiological demands of military training.

Pharmacokinetic and Metabolomic Studies with a Promising Radiation Countermeasure, BBT-059 (PEGylated interleukin-11), in Rhesus Nonhuman Primates.

BBT-059, a long-acting PEGylated interleukin-11 (IL-11) analog that is believed to have hematopoietic promoting and anti-apoptotic properties, is being developed as a potential radiation medical countermeasure (MCM) for hematopoietic acute radiation syndrome (H-ARS). This agent has been shown to improve survival in lethally irradiated mice. To further evaluate the drug's toxicity and safety profile, 12 naïve nonhuman primates (NHPs, rhesus macaques) were administered one of three doses of BBT-059 subcutaneously and were monitored for the next 21 days. Blood samples were collected throughout the study to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of the drug as well as its effects on complete blood counts, cytokines, vital signs, and to conduct metabolomic studies. No adverse effects were detected in any treatment group during the study. Short-term changes in metabolomic profiles were present in all groups treated with BBT-059 beginning immediately after drug administration and reverting to near normal levels by the end of the study period. Several pathways and metabolites, particularly those related to inflammation and steroid hormone biosynthesis, were activated by BBT-059 administration. Taken together, these observations suggest that BBT-059 has a good safety profile for further development as a radiation MCM for regulatory approval for human use.

Metabolomic Profiles in Tissues of Nonhuman Primates Exposed to Either Total- or Partial-Body Radiation.

A complex cascade of systemic and tissue-specific responses induced by exposure to ionizing radiation can lead to functional impairment over time in the surviving population. Current methods for management of survivors of unintentional radiation exposure episodes rely on monitoring individuals over time for the development of adverse clinical symptoms due to the lack of predictive biomarkers for tissue injury. In this study, we report on changes in metabolomic and lipidomic profiles in multiple tissues of nonhuman primates (NHPs) that received either 4.0 Gy or 5.8 Gy total-body irradiation (TBI) of 60Co gamma rays, and 4.0 or 5.8 Gy partial-body irradiation (PBI) from LINAC-derived photons and were treated with a promising radiation countermeasure, gamma-tocotrienol (GT3). These include small molecule alterations that correlate with radiation effects in the jejunum, lung, kidney, and spleen of animals that either survived or succumbed to radiation toxicities over a 30-day period. Radiation-induced metabolic changes in tissues were observed in animals exposed to both doses and types of radiation, but were partially alleviated in GT3-treated and irradiated animals, with lung and spleen being most responsive. The majority of the pathways protected by GT3 treatment in these tissues were related to glucose metabolism, inflammation, and aldarate metabolism, suggesting GT3 may exert radioprotective effects in part by sparing these pathways from radiation-induced dysregulation. Taken together, the results of our study demonstrate that the prophylactic administration of GT3 results in metabolic and lipidomic shifts that likely provide an overall advantage against radiation injury. This investigation is among the first to highlight the use of a molecular phenotyping approach in a highly translatable NHP model of partial- and total-body irradiation to determine the underlying physiological mechanisms involved in the radioprotective efficacy of GT3.

Global omics study of Tetraselmis chuii reveals time-related metabolic adaptations upon oxidative stress

Microalgae species encounter oxidative stress in their natural environments, prompting the development of species-specific adaptation mechanisms. Understanding these mechanisms can offer valuable insights for biotechnological applications in microalgal metabolic manipulation. In this study, we investigated the response of Tetraselmis chuii, an industrially important microalga, to H2O2-induced oxidative stress. Exposure to 0.5-mM H2O2 resulted in reduced cell viability, and higher concentrations led to a drastic decline. After 1 h of exposure to H2O2, photosynthetic capacity (Qy) was negatively impacted, and this reduction intensified after 6 h of continuous stress. Global multi-omics analysis revealed that T. chuii rapidly responded to H2O2-induced oxidative stress within the first hour, causing significant changes in both transcriptomic and metabolomic profiles. Among the cellular functions negatively affected were carbon and energy flow, with photosynthesis-related PSBQ having a 2.4-fold downregulation, pyruvate kinase decreased by 1.5-fold, and urea content reduced by threefold. Prolonged exposure to H2O2 incurred a high energy cost, leading to unsuccessful attempts to enhance carbon metabolism, as depicted, for example, by the upregulation of photosystems-related PETC and PETJ by more than twofold. These findings indicate that T. chuii quickly responds to oxidative stress, but extended exposure can have detrimental effects on its cellular functions.Key points• 0.5-mM H2O2–induced oxidative stress strongly affects T. chuii• Distinct short- and long-term adaptation mechanisms are induced• Major metabolic adaptations occur within the first hour of exposure

Transcriptomic and metabolomic profile changes in the liver of Sprague Dawley rat offspring after maternal PFOS exposure during gestation and lactation

Epidemiological and experimental research has indicated an association between perfluorooctane sulfonate (PFOS) exposure and liver disease. However, the potential hepatotoxic effects and mechanisms of low-level prenatal PFOS exposure in offspring remain ambiguous. The objective of this research was to examine the alterations in liver transcriptomic and metabolomic profiles in offspring rats at postnatal day (PND) 30 following gestational and lactational exposure to PFOS (from gestational day 1 to 20 and PND 1 to 21). Pregnant Sprague-Dawley rats were separated into a control group (3% starch gel solution, oral gavage) and a PFOS exposure group (0.03 mg/kg body weight per day, oral gavage). Histopathological changes in liver sections were observed by hematoxylin and eosin staining. Biochemical analysis was conducted to evaluate changes in glucose and lipid metabolism. Transcriptomic and metabolomic analyses were utilized to identify significant genes and metabolites associated with alterations of liver glucose and lipid metabolism through an integrated multi-omics analysis. No significant differences were found in the measured biochemical parameters. In total, 167 significant differentially expressed genes (DEGs) related to processes such as steroid biosynthesis, PPAR signaling pathway, and fat digestion and absorption were identified in offspring rats in the PFOS exposure group. Ninety-five altered metabolites were exhibited in the PFOS exposure group, such as heptaethylene glycol, lysoPE (0:0/18:0), lucidenic acid K, and p-Cresol sulfate. DEGs associated with steroid biosynthesis, PPAR signaling pathway, fat digestion and absorption were significantly upregulated in the PFOS exposure group (P < 0.05). The analysis of correlations indicated that there was a significant inverse correlation between all identified differential metabolites and the levels of fasting blood glucose, high-density lipoprotein, and triglycerides in the PFOS exposure group (P < 0.05). Our findings demystify that early-life PFOS exposure can lead to alterations in transcriptomic and metabolomic profiles in the offspring’s liver, which provided mechanistic insights into the potential hepatotoxicity and developmental toxicity associated with environmentally relevant levels of PFOS exposure.

Systemic lupus erythematosus patients have unique changes in serum metabolic profiles across age associated with cardiometabolic risk.

Cardiovascular disease through accelerated atherosclerosis is a leading cause of mortality for patients with systemic lupus erythematosus (SLE), likely due to increased chronic inflammation and cardiometabolic defects over age. We investigated age-associated changes in metabolomic profiles of SLE patients and healthy controls (HCs). Serum NMR metabolomic profiles from female SLE patients (n = 164, age = 14-76) and HCs (n = 123, age = 13-72) were assessed across age by linear regression and by age group between patients/HCs (Group 1, age ≤ 25, n = 62/46; Group 2, age = 26-49, n = 50/46; Group 3, age ≥ 50, n = 52/31) using multiple t tests. The impact of inflammation, disease activity and treatments were assessed, and UK Biobank disease-wide association analysis of metabolites was performed. Age-specific metabolomic profiles were identified in SLE patients vs HCs, including reduced amino acids (Group 1), increased very-low-density lipoproteins (Group 2), and increased low-density lipoproteins (Group 3). Twenty-five metabolites were significantly altered in all SLE age groups, dominated by decreased atheroprotective high-density lipoprotein (HDL) subsets, HDL-bound apolipoprotein (Apo)A1 and increased glycoprotein acetyls (GlycA). Furthermore, ApoA1 and GlycA were differentially associated with disease activity and serological measures, as well as atherosclerosis incidence and myocardial infarction mortality risk through disease-wide association. Separately, glycolysis pathway metabolites (acetone/citrate/creatinine/glycerol/lactate/pyruvate) uniquely increased with age in SLE, significantly influenced by prednisolone (increased pyruvate/lactate) and hydroxychloroquine (decreased citrate/creatinine) treatment and associated with type 1 and type 2 diabetes by disease-wide association. Increasing HDL (ApoA1) levels through therapeutic/nutritional intervention, whilst maintaining low disease activity, in SLE patients from a young age could improve cardiometabolic disease outcomes. Biomarkers from the glycolytic pathway could indicate adverse metabolic effects of current therapies.

Metabolome and Transcriptome Association Analysis Reveals the Link Between Pigmentation and Nutrition Utilization in the Juveniles of Sea Cucumber Holothuria leucospilota.

The sea cucumber Holothuria leucospilota is an economically and ecologically important tropical species. Following development into juveniles, H. leucospilota undergoes a color change from white to black, involving a pigmentation process for over a period of several months. In this study, a combination of liquid chromatography-tandem mass spectrometry (LC-MS/MS) and Next-Generation sequencing (NGS) were employed to investigate the changes in metabolomic and transcriptomic profiles during pigmentation in H. leucospilota juveniles. The metabolomic analysis identified a total of 341 metabolites, of which 52 were found to be differentially regulated (P < 0.05 and VIP > 1), with 27 being upregulated in white individuals and 25 in black individuals. Additionally, 632 differentially expressed genes (DEGs) were identified, with 380 genes upregulated in white samples and 252 genes upregulated in black samples. Interestingly, the melanin content and tyrosinase transcript levels did not display significant differences between the two groups. Metabolomic data suggested the involvement of the linoleic acid metabolic pathway in pigmentation. Transcriptomic analysis, coupled with realtime PCR validation, revealed a decrease in the transcript levels of digestive enzymes like α-amylase, maltase-glucoamylase, and trehalase after the juveniles changed to black. Furthermore, the mRNA expressions of major yolk proteins showed a decline, indicating a shift in the accumulation of protein nutrient sources. Overall, our findings suggest that during the pigmentation process in H. leucospilota, no significant changes were observed in the classical melanin pathway, while notable alterations were observed in their nutritional status. This study provides valuable insights into the regulatory mechanisms of pigmentation in marine organisms.

Early-life noise exposure causes cognitive impairment in a sex-dependent manner by disrupting homeostasis of the microbiota–gut–brain axis

Epidemiological investigations show that noise exposure in early life is associated with health and cognitive impairment. The gut microbiome established in early life plays a crucial role in modulating developmental processes that subsequently affect brain function and behavior. Here, we examined the impact of early-life exposure to noise on cognitive function in adolescent rats by analyzing the gut microbiome and metabolome to elucidate the underlying mechanisms. Chronic noise exposure during early life led to cognitive deficits, hippocampal injury, and neuroinflammation. Early-life noise exposure showed significant difference on the composition and function of the gut microbiome throughout adolescence, subsequently causing axis-series changes in fecal short-chain fatty acid (SCFA) metabolism and serum metabolome profiles, as well as dysregulation of endothelial tight junction proteins, in both intestine and brain. We also observed sex-dependent effects of microbiota depletion on SCFA-related beneficial bacteria in adolescence. Experiments on microbiota transplantation and SCFA supplementation further confirmed the role of intestinal bacteria and related SCFAs in early-life noise-exposure-induced impairments in cognition, epithelial integrity, and neuroinflammation. Overall, these results highlight the homeostatic imbalance of microbiota–gut–brain axis as an important physiological response toward environmental noise during early life and reveals subtle differences in molecular signaling processes between male and female rats.

Changes in Metabolomic Profiles Induced by Switching from an Erythropoiesis-Stimulating Agent to a Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor in Hemodialysis Patients: A Pilot Study.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of medications for managing renal anemia in patients with chronic kidney disease (CKD). In addition to their erythropoietic activity, HIF-PHIs exhibit multifaceted effects on iron and glucose metabolism, mitochondrial metabolism, and angiogenesis through the regulation of a wide range of HIF-responsive gene expressions. However, the systemic biological effects of HIF-PHIs in CKD patients have not been fully explored. In this prospective, single-center study, we comprehensively investigated changes in plasma metabolomic profiles following the switch from an erythropoiesis-stimulating agent (ESA) to an HIF-PHI, daprodustat, in 10 maintenance hemodialysis patients. Plasma metabolites were measured before and three months after the switch from an ESA to an HIF-PHI. Among 106 individual markers detected in plasma, significant changes were found in four compounds (erythrulose, n-butyrylglycine, threonine, and leucine), and notable but non-significant changes were found in another five compounds (inositol, phosphoric acid, lyxose, arabinose, and hydroxylamine). Pathway analysis indicated decreased levels of plasma metabolites, particularly those involved in phosphatidylinositol signaling, ascorbate and aldarate metabolism, and inositol phosphate metabolism. Our results provide detailed insights into the systemic biological effects of HIF-PHIs in hemodialysis patients and are expected to contribute to an evaluation of the potential side effects that may result from long-term use of this class of drugs.

Toxicity comparison of perfluorooctanoic acid (PFOA), hexafluoropropylene oxide dimer acid (HFPO-DA), and hexafluoropropylene oxide trimer acid (HFPO-TA) in zebrafish gut

Hexafluoropropylene oxide dimer acid (HFPO-DA) and hexafluoropropylene oxide trimer acid (HFPO-TA) are considered as alternatives to perfluorooctanoic acid (PFOA). In this study, zebrafish were exposed to different concentrations of PFOA, HFPO-DA, and HFPO-TA (5 μg/L and 500 μg/L), and the toxic effects on oxidative damage, inflammation, and cell apoptosis in the gut were compared. Additionally, changes in gut metabolome profiles and microbial community structure were analyzed. The results revealed that exposures to HFPO-DA and HFPO-TA led to lower levels of oxidative damage compared to PFOA exposure. However, all three treatments had comparable effects on inflammation and apoptosis. The main biological pathways affected by all three exposures were lipid metabolism, nucleotide metabolism, amino acid metabolism, and environmental information processing. The effects on metabolome profiles were much higher for HFPO-DA and HFPO-TA compared to PFOA at a concentration of 5 μg/L. At a concentration of 500 μg/L, HFPO-DA and HFPO-TA showed similar effects to PFOA. This study also examined the Pearson correlations between gut microbiota and the toxic effects mentioned above. The abundance of specific apoptosis-related genera differed among the three target chemicals, suggesting they may act differently in inducing apoptosis. The correlations between HFPO-DA and HFPO-TA were mostly similar, which helps explain the similar effects observed in their respective treatment groups on metabolic profiles. Overall, this study indicates that HFPO-DA and HFPO-TA may not be safe alternatives to PFOA and provides valuable insights into their toxic effects and risk assessment in water environments.

The changes in metabolomics profile induced by intermittent theta burst stimulation in major depressive disorder: an exploratory study

BackgroundRecently, there has been an ongoing interest in the mechanism of intermittent theta burst stimulation (iTBS) in major depressive disorder. Studying the metabolite changes induced by iTBS may help to understand the mechanism.MethodsEleven participants with major depressive disorder received 10 days iTBS treatment. Magnetic resonance imaging (MRI) was used to target the region of the left dorsolateral prefrontal cortex (DLPFC) in each participant. We analyzed the effects of iTBS on metabolites using high-throughput profiling and assessed its impact on depressive symptoms. These analyses were considered exploratory, and no correction for multiple comparisons was applied.ResultsAmong the 318 measured metabolites, a significant increase in cystine, asymmetric dimethylarginine (ADMA), 1-methylhistidine, indoleacetic acid (IAA), diethanolamine (DEA), dopa, riboflavin-5′-monophosphate (FMN), and a significant decrease in alphalinolenic acid (ALA), gamma-linolenic acid (GLA), serotonin, linoleic acid (LA) (p < 0.05) were detected in the patients after iTBS treatment. In Pearson correlation analysis, the plasma levels of LA, FMN and ADMA at baseline were significantly related to the reduction rate of the 17‐item Hamilton Depression Rating Scale and the Patient Health Questionnaire-9 scores (p < 0.05).ConclusionsOur study highlights that LA, FMN, ADMA and their relationship with oxidative stress, may be key factors in the antidepressant efficacy of iTBS.

Dietary sulfur amino acid restriction to prevent Alzheimer’s Disease

AbstractBackgroundHigh serum homocysteine is a risk factor for Alzheimer’s Disease (AD). It has been reported to influence the accumulation of its characteristic lesions ‐ senile plaques (SP) and neurofibrillary tangles (NFT) ‐ containing amyloid β protein (Abeta) and microtubule‐associated protein Tau (MAPT), respectively. Reduced food or calorie intake or branched‐chain amino acids are reported to benefit AD model mice. Restriction of Methionine (Met), an essential amino acid, contributes to increased longevity without calorie restriction.MethodWe treated APP/PS1 transgenic mice with a 75% Met restricted (MR) diet and compared it to an isocaloric isonitrogenous complete diet (CD) for up to 12 months. We subsequently evaluated amyloid loads by ELISA and other APP metabolites by western blotting as described previously (Barnwell et al., 2014, Teich et al., 2018). We collected fecal matter from the colon, extracted DNA, and evaluated the gut microbiome.ResultOur data show that MR treatment substantially lowered brain soluble Abeta at 3 and 6 months. Abeta levels are excessively and presumably saturated in older mice, accounting for the lack of statistically significant differences between the different diets evaluated after twelve months. Nevertheless, older mice showed substantial improvement in behavior in a novel object recognition task after MR treatment. MR treatment is known to be senolytic, and therefore, we are currently examining related processes, such as preservation of lysosomal capacity changes in metabolome, mRNA, and miRNA profiles. Future work involves evaluating methionine and branch‐chain amino acid restriction in AD animal models, such as in human tau‐overexpressing Tg mice, and evaluating miRNAs.MR diets significantly alter gut microbiota. As expected, the bacteria that metabolize Met and Cys were decreased. Specifically, several major species of bacteria were reduced, and the overall diversity of microbiota was increased. Senolysis and improvements in AD pathology may also be mediated by reduced inflammation due to the increased diversification of the microbiome. Thus, such diets may play an important role in strategies to prevent AD, retinal degeneration, and other age‐associated disorders.ConclusionSulfur amino acid restriction reduces amyloid production and preserves cognitive function in mice. Reduced protein diets may be useful in preventing proteinopathies that lead to neurodegeneration.