Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

PubMed

Extraembryonic metabolism of corticosterone protects against effects of exposure

Fri, 29/12/2023 - 12:00
Gen Comp Endocrinol. 2023 Dec 27;347:114439. doi: 10.1016/j.ygcen.2023.114439. Online ahead of print.ABSTRACTWhen females experience stress during reproduction, developing embryos can be exposed to elevated levels of glucocorticoids, which can permanently affect offspring development, physiology, and behavior. However, the embryo can regulate exposure to glucocorticoids. In placental species, the placenta regulates embryonic exposure to maternal steroids via metabolism. In a comparable way, recent evidence has shown the extraembryonic membranes of avian species also regulate embryonic exposure to a number of maternal steroids deposited in the yolk via metabolism early in development. However, despite the known effects of embryonic exposure to glucocorticoids, it is not yet understood how glucocorticoids are metabolized early in development. To address this knowledge gap, we injected corticosterone into freshly laid chicken (Gallus gallus) eggs and identified corticosterone metabolites, located metabolomic enzyme transcript expression, tracked metabolomic enzyme transcript expression during the first six days of development, and determined the effect of corticosterone and metabolites on embryonic survival. We found that yolk corticosterone was metabolized before day four of development into two metabolites: 5β-corticosterone and 20β-corticosterone. The enzymes, AKR1D1 and CBR1 respectively, were expressed in the extraembryonic membranes. Expression was dynamic during early development, peaking on day two of development. Finally, we found that corticosterone exposure is lethal to the embryos, yet exposure to the metabolites is not, suggesting that metabolism protects the embryo. Ultimately, we show that the extraembryonic membranes of avian species actively regulate their endocrine environment very early in development.PMID:38158163 | DOI:10.1016/j.ygcen.2023.114439

Gap-free genome assembly and <em>CYP450</em> gene family analysis reveal the biosynthesis of anthocyanins in <em>Scutellaria baicalensis</em>

Fri, 29/12/2023 - 12:00
Hortic Res. 2023 Nov 17;10(12):uhad235. doi: 10.1093/hr/uhad235. eCollection 2023 Dec.ABSTRACTScutellaria baicalensis Georgi, a member of the Lamiaceae family, is a widely utilized medicinal plant. The flavones extracted from S. baicalensis contribute to numerous health benefits, including anti-inflammatory, antiviral, and anti-tumor activities. However, the incomplete genome assembly hinders biological studies on S. baicalensis. This study presents the first telomere-to-telomere (T2T) gap-free genome assembly of S. baicalensis through the integration of Pacbio HiFi, Nanopore ultra-long and Hi-C technologies. A total of 384.59 Mb of genome size with a contig N50 of 42.44 Mb was obtained, and all sequences were anchored into nine pseudochromosomes without any gap or mismatch. In addition, we analysed the major cyanidin- and delphinidin-based anthocyanins involved in the determination of blue-purple flower using a widely-targeted metabolome approach. Based on the genome-wide identification of Cytochrome P450 (CYP450) gene family, three genes (SbFBH1, 2, and 5) encoding flavonoid 3'-hydroxylases (F3'Hs) and one gene (SbFBH7) encoding flavonoid 3'5'-hydroxylase (F3'5'H) were found to hydroxylate the B-ring of flavonoids. Our studies enrich the genomic information available for the Lamiaceae family and provide a toolkit for discovering CYP450 genes involved in the flavonoid decoration.PMID:38156283 | PMC:PMC10753160 | DOI:10.1093/hr/uhad235

Dual antibacterial mechanism of [K4K15]CZS-1 against <em>Salmonella</em> Typhimurium: a membrane active and intracellular-targeting antimicrobial peptide

Fri, 29/12/2023 - 12:00
Front Microbiol. 2023 Dec 14;14:1320154. doi: 10.3389/fmicb.2023.1320154. eCollection 2023.ABSTRACTSalmonella genus is a leading cause of food-borne infections with strong public health impact and economic ramifications. The development of antimicrobial resistance added complexity to this scenario and turned the antibiotic drug discovery into a highly important challenge. The screening of peptides has served as a successful discovery platform to design new antibiotic candidates. Motivated by this, the antimicrobial and cytotoxic properties of three cruzioseptins against Salmonella Typhimurium and RAW 264.7 murine macrophage cells, respectively, were investigated. [K4K15]CZS-1 was the most potent antimicrobial peptide identified in the screening step with a minimum inhibitory concentration (MIC) of 16 μg/mL (7.26 μM) and moderate cytotoxicity. From a structural point of view, in vitro and in silico techniques evidenced that [K4K15]CZS-1 is a α-helical cationic antimicrobial peptide. In order to capture mechanistic details and fully decipher their antibacterial action, we adopted a multidimensional approach, including spectroscopy, electron microscopy and omics analysis. In general lines, [K4K15]CZS-1 caused membrane damage, intracellular alterations in Salmonella and modulated metabolic pathways, such as the tricarboxylic acid (TCA) cycle, fatty acid biosynthesis, and lipid metabolism. Overall, these findings provide deeper insights into the antibacterial properties and multidimensional mode of action of [K4K15]CZS-1 against Salmonella Typhimurium. In summary, this study represents a first step toward the screening of membrane-acting and intracellular-targeting peptides as potential bio-preservatives to prevent foodborne outbreaks caused by Salmonella.PMID:38156004 | PMC:PMC10752938 | DOI:10.3389/fmicb.2023.1320154

Exploration of the mechanism of Qi-Xian decoction in asthmatic mice using metabolomics combined with network pharmacology

Fri, 29/12/2023 - 12:00
Front Mol Biosci. 2023 Dec 13;10:1263962. doi: 10.3389/fmolb.2023.1263962. eCollection 2023.ABSTRACTIntroduction: Qi-Xian Decoction (QXD), a traditional Chinese medicine (TCM) formula consisting of eight herbs, has been clinically used to treat asthma. However, the underlying mechanisms have not been completely elucidated. This study aimed to combine metabolomics and network pharmacology to reveal the mechanism of action of QXD in asthma treatment. Methods: An ovalbumin (OVA)-induced asthma mouse model was constructed to evaluate the therapeutic effects of QXD. Serum metabolomics and network pharmacology were combined to study the mechanism of anti-asthma action as well as the potential target, and related biological functions were validated. Results: The QXD treatment has demonstrated significant protective effects in OVA-induced asthmatic mice, as evidenced by its ability to inhibit inflammation, IgE, mucus overproduction, and airway hyperreactivity (AHR). Metabolomic analysis has revealed a total of 140 differential metabolites associated with QXD treatment. In addition, network pharmacology has identified 126 genes that are linked to the effects of QXD, including TNF, IL-6, IL1β, STAT3, MMP9, EGFR, JUN, CCL2, TLR4, MAPK3 and MAPK8. Through comprehensive gene-metabolite interaction network analysis, seven key metabolites have been identified and associated with the potential anti-asthmatic effect of QXD, with palmitic acid (PA) being the most notable among them. In vitro validation studies have confirmed the gene-metabolite interaction involving PA, IL-6, and MAPK8. Furthermore, our research has demonstrated that QXD treatment can effectively inhibit PA-promoted IL-6 expression in MH-S cells and reduce PA concentration in OVA-induced asthmatic mice. Conclusion: The regulation of metabolic pathways by QXD was found to be associated with its anti-asthmatic action, which provides insight into the mechanism of QXD in treating asthma.PMID:38155957 | PMC:PMC10753777 | DOI:10.3389/fmolb.2023.1263962

Dose-response technique combined with stable isotope tracing for drug metabolite profiling by using high-resolution mass spectrometry

Fri, 29/12/2023 - 12:00
Front Pharmacol. 2023 Dec 13;14:1293540. doi: 10.3389/fphar.2023.1293540. eCollection 2023.ABSTRACTBackground: Mass spectrometry metabolomics-based data-processing approaches have been developed for drug metabolite profiling. However, existing approaches cannot be used to comprehensively identify drug metabolites with high efficacy. Methods: Herein, we propose a two-stage data-processing approach for effective and comprehensive drug metabolite identification. The approach combines dose-response experiments with stable isotope tracing (SIT). Rosiglitazone (ROS), commonly used to treat type 2 diabetes, was employed as a model drug. Results: In the first stage of data processing, 1,071 features exhibited a dose-response relationship among 22,597 features investigated. In the second stage, these 1,071 features were screened for isotope pairs, and 200 features with isotope pairs were identified. In time-course experiments, a large proportion of the identified features (69.5%: 137 out of 200 features) were confirmed to be possible ROS metabolites. We compared the validated features identified using our approach with those identified using a previously reported approach [the mass defect filter (MDF) combined with SIT] and discovered that most of the validated features (37 out of 42) identified using the MDF-SIT combination were also successfully identified using our approach. Of the 143 validated features identified by both approaches, 74 had a proposed structure of an ROS-structure-related metabolite; the other 34 features that contained a specific fragment of ROS metabolites were considered possible ROS metabolites. Interestingly, numerous ROS-structure-related metabolites were identified in this study, most of which were novel. Conclusion: The results reveal that the proposed approach can effectively and comprehensively identify ROS metabolites.PMID:38155901 | PMC:PMC10753831 | DOI:10.3389/fphar.2023.1293540

My Diet Study: protocol for a two-part observational, longitudinal, psycho-biological study of dieting in Australian youth

Fri, 29/12/2023 - 12:00
Front Public Health. 2023 Dec 14;11:1281855. doi: 10.3389/fpubh.2023.1281855. eCollection 2023.ABSTRACTINTRODUCTION: Self-directed dieting (i.e., unsupervised) is very common among adolescents and young adults but has had almost no direct research. This paper describes the protocol for the My Diet Study, a two-arm observational investigation of the natural progression of dieting among young people over a period of 6-months. The study aims to examine the links between self-directed dieting, general physiological and psychological metrics of wellbeing (e.g., depressive symptoms) and biomarkers of gut-brain axis functions (e.g., microbiome and hormones) that are predicted to influence diet adherence through appetite, mood and metabolism regulation.METHODS: Young people aged 16-25, intending to start a diet will be invited to participate in this observational study. For Part 1 (psychological arm), participants will be asked to complete a set of questionnaires and diaries at the beginning of every month for 6 months, to assess overall mental (e.g., psychological distress, disordered eating) and physical (e.g., weight) health, perceived diet success, food intake and gastrointestinal movements. For Part 2 (biological arm), a subsample of 50 participants will be asked to provide feces, blood and saliva for bio-sampling each month for the first 3-months of their participation in Part 1.DISCUSSION: The My Diet Study will be the first longitudinal, observational study of dieting in young people combining in-depth psychological and biological data. It is anticipated that the findings will yield psychological & biological information about the impacts and effectiveness of self-directed dieting in young people, inform a framework for advice on safety in dieting among young people and help to establish the potential for biomarkers for risk management and improvement of diet-based lifestyle interventions.PMID:38155880 | PMC:PMC10752999 | DOI:10.3389/fpubh.2023.1281855

Effect of continuous planting on <em>Casuarina equisetifolia</em> rhizosphere soil physicochemical indexes, microbial functional diversity and metabolites

Fri, 29/12/2023 - 12:00
Front Plant Sci. 2023 Dec 14;14:1288444. doi: 10.3389/fpls.2023.1288444. eCollection 2023.ABSTRACTContinuous planting has a severe impact on the growth of Casuarina equisetifolia. In this study, the effects of three different long-term monocultures (one, two and three replanting) on the physicochemical indexes, microbial functional diversity, and soil metabolomics were analyzed in C. equisetifolia rhizosphere soil. The results showed that rhizosphere soil organic matter content, cation exchange capacity, total and available nitrogen, total and available phosphorus, and total and available potassium contents significantly decreased with the increasing number of continuous plantings. The evaluation of microbial functional diversity revealed a reduction in the number of soil microorganisms that rely on carbohydrates for carbon sources and an increase in soil microorganisms that used phenolic acid, carboxylic acid, fatty acid, and amines as carbon sources. Soil metabolomics analysis showed a significant decrease in soil carbohydrate content and a significant accumulation of autotoxic acid, amine, and lipid in the C. equisetifolia rhizosphere soil. Consequently, the growth of C. equisetifolia could hinder total nutrient content and their availability. Thus, valuable insights for managing the cultivation of C. equisetifolia and soil remediation were provided.PMID:38155858 | PMC:PMC10752937 | DOI:10.3389/fpls.2023.1288444

Petunia as a model for MYB transcription factor action under salt stress

Fri, 29/12/2023 - 12:00
Front Plant Sci. 2023 Dec 8;14:1286547. doi: 10.3389/fpls.2023.1286547. eCollection 2023.ABSTRACTSalinity is a current and growing problem, affecting crops worldwide by reducing yields and product quality. Plants have different mechanisms to adapt to salinity; some crops are highly studied, and their salinity tolerance mechanisms are widely known. However, there are other crops with commercial importance that still need characterization of their molecular mechanisms. Usually, transcription factors are in charge of the regulation of complex processes such as the response to salinity. MYB-TFs are a family of transcription factors that regulate various processes in plant development, and both central and specialized metabolism. MYB-TFs have been studied extensively as mediators of specialized metabolism, and some are master regulators. The influence of MYB-TFs on highly orchestrated mechanisms, such as salinity tolerance, is an attractive research target. The versatility of petunia as a model species has allowed for advances to be made in multiple fields: metabolomic pathways, quality traits, stress resistance, and signal transduction. It has the potential to be the link between horticultural crops and lab models, making it useful in translating discoveries related to the MYB-TF pathways into other crops. We present a phylogenetic tree made with Petunia axillaris and Petunia inflata R2R3-MYB subfamily sequences, which could be used to find functional conservation between different species. This work could set the foundations to improve salinity resistance in other commercial crops in later studies.PMID:38155855 | PMC:PMC10753185 | DOI:10.3389/fpls.2023.1286547

Advancing understanding of <em>Ficus carica</em>: a comprehensive genomic analysis reveals evolutionary patterns and metabolic pathway insights

Fri, 29/12/2023 - 12:00
Front Plant Sci. 2023 Dec 7;14:1298417. doi: 10.3389/fpls.2023.1298417. eCollection 2023.ABSTRACTFicus carica L. (dioecious), the most significant commercial species in the genus Ficus, which has been cultivated for more than 11,000 years and was one of the first species to be domesticated. Herein, we reported the most comprehensive F. carica genome currently. The contig N50 of the Orphan fig was 9.78 Mb, and genome size was 366.34 Mb with 13 chromosomes. Based on the high-quality genome, we discovered that F. carica diverged from Ficus microcarpa ~34 MYA, and a WGD event took place about 2─3 MYA. Throughout the evolutionary history of F. carica, chromosomes 2, 8, and 10 had experienced chromosome recombination, while chromosome 3 saw a fusion and fission. It is worth proposing that the chromosome 9 experienced both inversion and translocation, which facilitated the emergence of the F. carica as a new species. And the selections of F. carica for the genes of recombination chromosomal fragment are compatible with their goal of domestication. In addition, we found that the F. carica has the FhAG2 gene, but there are structural deletions and positional jumps. This gene is thought to replace the one needed for female common type F. carica to be pollinated. Subsequently, we conducted genomic, transcriptomic, and metabolomic analysis to demonstrate significant differences in the expression of CHS among different varieties of F. carica. The CHS playing an important role in the anthocyanin metabolism pathway of F. carica. Moreover, the CHS gene of F. carica has a different evolutionary trend compared to other Ficus species. These high-quality genome assembly, transcriptomic, and metabolomic resources further enrich F. carica genomics and provide insights for studying the chromosomes evolution, sexual system, and color characteristics of Ficus.PMID:38155853 | PMC:PMC10754049 | DOI:10.3389/fpls.2023.1298417

NSC48160 targets AMPKα to ameliorate nonalcoholic steatohepatitis by inhibiting lipogenesis and mitochondrial oxidative stress

Fri, 29/12/2023 - 12:00
iScience. 2023 Dec 2;27(1):108614. doi: 10.1016/j.isci.2023.108614. eCollection 2024 Jan 19.ABSTRACTHepatic steatosis, which is triggered by dysregulation of lipid metabolism and redox equilibrium in the liver, is regarded as a risk factor in the non-alcoholic fatty liver disease (NAFLD). However, pharmacologic engagement of this process is difficult. We identified the small molecule NSC48160 as an effective agent against nonalcoholic steatohepatitis (NASH). We found that NSC48160 significantly lowered hepatic lipid levels in vitro and in vivo by activating the AMPKα-dependent pathway. AMPKα regulated its downstream pathway involved in lipogenesis (SREBP-1c/FASN pathway) and fatty acid oxidation (PPARα pathway). Metabonomics analysis combined with RNA-sequencing profiling revealed that NSC48160-induced lipogenesis is modulated by lipid metabolism. Moreover, NSC48160 dramatically reduces reactive oxygen species (ROS) production, restores the levels of the membrane potential and NAD+/NADH ratio, and improves mitochondrial respiration. These findings suggest that NSC48160 is a promising hit compound in the pursuit of a pharmacological approach in the treatment of NASH.PMID:38155777 | PMC:PMC10753068 | DOI:10.1016/j.isci.2023.108614

Diverse Metabolic Effects of Cooking Oil Fume from Four Edible Oils on Human BEAS-2B Cells: Implications for Health Guidelines

Fri, 29/12/2023 - 12:00
Environ Sci Technol. 2023 Dec 29. doi: 10.1021/acs.est.3c05984. Online ahead of print.ABSTRACTThe 2021 WHO guidelines stress the importance of measuring ultrafine particles using particle number concentration (PNC) for health assessments. However, commonly used particle metrics such as aerodynamic diameter and number concentrations do not fully capture the diverse chemical makeup of complex particles. To address this issue, our study used high-throughput mass spectrometry to analyze the properties of cooking oil fumes (COFs) in real time and evaluate their impact on BEAS-2B cell metabolism. Results showed insignificant differences in COF number size distributions between soybean oil and olive oil (peak concentrations of 5.20 × 105/cm3), as well as between corn oil and peanut oil (peak concentrations of 4.35 × 105/cm3). Despite the similar major chemical components among the four COFs, variations in metabolic damage were observed, indicating that the relatively small amount of chemical components of COFs can also influence particle behavior within the respiratory system, thereby impacting biological responses. Additionally, interactions between accompanying gaseous COFs and particles may alter their chemical composition through various mechanisms, introducing additional chemicals and modifying existing proportions. Hence, the chemical composition and gaseous components of COFs hold equal importance to the particle number concentration (PNC) when assessing their impact on human health. The absence of these considerations in the current guidelines underscores a research gap. It is imperative to acknowledge that for a more comprehensive approach to safeguarding public health, guidelines must be regularly updated to reflect new scientific findings and robust epidemiological evidence.PMID:38155590 | DOI:10.1021/acs.est.3c05984

Peripheral Inflammatory and Immune Landscape in Multiple System Atrophy: A Cross-Sectional Study

Fri, 29/12/2023 - 12:00
Mov Disord. 2023 Dec 28. doi: 10.1002/mds.29674. Online ahead of print.ABSTRACTBACKGROUND: Neuroinflammation might contribute to the pathogenesis of multiple systemic atrophy (MSA). However, specific alterations in the peripheral inflammatory and immune profiles of patients with MSA remain unclear.OBJECTIVES: To determine the peripheral inflammatory and immune profiles of patients with MSA and their potential value as biomarkers for facilitating clinical diagnosis and monitoring disease severity.METHODS: This cross-sectional study included 235, 240, and 235 patients with MSA, patients with Parkinson's disease (PD), and healthy controls (HCs), respectively. Inflammatory and immune parameters were measured in peripheral blood, differences between groups were assessed, and clusters were analyzed. Associations between the parameters and clinical characteristics of MSA were assessed using Spearman and partial correlation analyses.RESULTS: Significant differences were observed especially in monocytes, neutrophils-to-lymphocyte ratio (NLR) and neutrophils-to-lymphocyte ratio (MPV) between MSA patients and HCs (P < 0.01). Monocytes and uric acid (UA) levels were also significantly different between the MSA and PD patients (P < 0.05). The combination of NLR and MPV distinguished MSA-P patients from HCs (areas under the curve = 0.824). In addition, complement components C4 and C3 were significantly correlated with the Scale Outcomes in PD for Autonomic Symptoms and Wexner scale, whereas immunoglobulin G (IgG) was significantly correlated with scores of Unified Multiple System Atrophy Rating Scale (P < 0.05).CONCLUSIONS: In MSA patients, monocytes, NLR and MPV might serve as potential diagnostic biomarkers, whereas MLR, C3, C4, and IgG significantly correlate with disease severity. © 2023 International Parkinson and Movement Disorder Society.PMID:38155513 | DOI:10.1002/mds.29674

A comprehensive metabolite fingerprint of fibrostenosis in patients with Crohn's disease

Thu, 28/12/2023 - 12:00
Sci Rep. 2023 Dec 27;13(1):23036. doi: 10.1038/s41598-023-50461-1.ABSTRACTIntestinal fibrostenosis in patients with Crohn's disease (CD) is a common and untreatable comorbidity that is notoriously difficult to monitor. We aimed to find metabolites associated with the presence of fibrostenosis in patients with CD using targeted and untargeted metabolomics analyses of serum and primary cell cultures using hyphenated ultra-high performance liquid chromatography high-resolution mass spectrometry. Targeted metabolomics revealed 11 discriminating metabolites in serum, which were enriched within the arginine and proline metabolism pathway. Based on untargeted metabolomics and discriminant analysis, 166 components showed a high predictive value. In addition, human intestinal fibroblasts isolated from stenotic tissue were characterized by differential levels of medium-chain dicarboxylic acids, which are proposed as an energy source through beta-oxidation, when oxidative phosphorylation is insufficient. Another energy providing pathway in such situations is anaerobic glycolysis, a theory supported by increased expression of hexokinase 2 and solute carrier family 16 member 1 in stenotic fibroblasts. Of interest, four (unannotated) metabolic components showed a negative correlation with hexokinase 2 gene expression. Together, this study provides a discriminative metabolic fingerprint in the serum and in intestinal fibroblasts of stenotic and non-stenotic patients with CD suggestive for increased production of building blocks for collagen synthesis and increased glycolysis.PMID:38155265 | DOI:10.1038/s41598-023-50461-1

Hippocampal metabolic profile during epileptogenesis in the pilocarpine model of epilepsy

Thu, 28/12/2023 - 12:00
Biomed Chromatogr. 2023 Dec 28:e5820. doi: 10.1002/bmc.5820. Online ahead of print.ABSTRACTTemporal lobe epilepsy (TLE) is a common form of refractory epilepsy in adulthood. The metabolic profile of epileptogenesis is still poorly investigated. Elucidation of such a metabolic profile using animal models of epilepsy could help identify new metabolites and pathways involved in the mechanisms of epileptogenesis process. In this study, we evaluated the metabolic profile during the epileptogenesis periods. Using a pilocarpine model of epilepsy, we analyzed the global metabolic profile of hippocampal extracts by untargeted metabolomics based on ultra-performance liquid chromatography-high-resolution mass spectrometry, at three time points (3 h, 1 week, and 2 weeks) after status epilepticus (SE) induction. We demonstrated that epileptogenesis periods presented different hippocampal metabolic profiles, including alterations of metabolic pathways of amino acids and lipid metabolism. Six putative metabolites (tryptophan, N-acetylornithine, N-acetyl-L-aspartate, glutamine, adenosine, and cholesterol) showed significant different levels during epileptogenesis compared to their respective controls. These putative metabolites could be associated with the imbalance of neurotransmitters, mitochondrial dysfunction, and cell loss observed during both epileptogenesis and epilepsy. With these findings, we provided an overview of hippocampal metabolic profiles during different stages of epileptogenesis that could help investigate pathways and respective metabolites as predictive tools in epilepsy.PMID:38154955 | DOI:10.1002/bmc.5820

Interactome analysis identifies the role of BZW2 in promoting endoplasmic reticulum-mitochondrial contact and mitochondrial metabolism

Thu, 28/12/2023 - 12:00
Mol Cell Proteomics. 2023 Dec 26:100709. doi: 10.1016/j.mcpro.2023.100709. Online ahead of print.ABSTRACTUnderstanding the molecular functions of less-studied proteins is an important task of life science research. Despite reports of BZW2 (Basic leucine zipper and W2 domain-containing protein 2) promoting cancer progression first emerging in 2017, little is known about its molecular function. Using a quantitative proteomic approach to identify its interacting proteins, we found that BZW2 interacts with both endoplasmic reticulum (ER) and mitochondrial proteins. We thus hypothesized that BZW2 localizes to and promotes the formation of ER-mitochondrial contact sites, and that such localization would promote calcium transport from ER to the mitochondria and promote ATP production. Indeed, we found that BZW2 localized to ER-mitochondria contact sites and that BZW2 knockdown decreased ER-mitochondrial contact, mitochondrial calcium levels, and ATP production. These findings provide key insights into molecular functions of BZW2, the potential role of BZW2 in cancer progression, and highlight the utility of interactome data in understanding the function of less-studied proteins.PMID:38154691 | DOI:10.1016/j.mcpro.2023.100709

New insight into PAH4 induced hepatotoxicity and the dose-response assessment in rats model

Thu, 28/12/2023 - 12:00
Chemosphere. 2023 Dec 26:141042. doi: 10.1016/j.chemosphere.2023.141042. Online ahead of print.ABSTRACTPAH4 (sum of benzo[a]pyrene, chrysene, benz[a]anthracene and benzo[b]fluoranthene) has been proposed as better marker than benzo[a]pyrene to assess total PAHs exposure in foodstuffs. However, the toxicological behaviors of PAH4 combined exposure remain unclear. This study aimed to investigate PAH4 toxicity effects with non-targeted metabolomics approach and evaluate the external and internal dose-response relationships based on benchmark dose (BMD) analysis. Male Sprague-Dawley rats were treated by gavage with vehicle (corn oil) or four doses of PAH4 (10, 50, 250, 1000 μg/kg·bw) for consecutive 30 days. After the final dose, the liver, blood and urine samples of rats were subsequently collected for testing. The concentrations of urinary mono-hydroxylated PAHs metabolites (OH-PAHs) including 3-hydroxybenzo[a]pyrene (3-OHB[a]P), 3-hydroxychrysene (3-OHCHR) and 3-hydroxybenz[a]anthracene (3-OHB[a]A) were determined to reflect internal PAH4 exposure. Our results showed PAH4 exposure increased relative liver weight and serum aspartate aminotransferase (AST) activity and caused hepatocyte swelling and degeneration, implying hepatotoxicity induced by PAH4. Serum metabolomics suggested PAH4 exposure perturbed lipid metabolism through upregulating the expression of glycerolipids metabolites, which was evidenced by markedly increased serum triglyceride (TG) level and hepatic TG content. Additionally, urinary OH-PAHs concentrations presented strong positive correlations with the external dose, indicating they were able to reflect PAH4 exposure. Furthermore, PAH4 exposure led to a dose-response increase of hepatic TG content, based on which the 95% lower confidence of BMDs (BMDLs) for external and internal doses were estimated as 5.45 μg/kg·bw and 0.11 μmol/mol·Cr, respectively. In conclusion, this study suggested PAH4 exposure could induce hepatotoxicity and lipid metabolism disorder, evaluating the involved dose-response relationships and providing a basis for the risk assessment of PAHs.PMID:38154670 | DOI:10.1016/j.chemosphere.2023.141042

Exploring the hidden chemical landscape: Non-target and suspect screening analysis for investigating solid waste-associated environments

Thu, 28/12/2023 - 12:00
Environ Res. 2023 Dec 26:118006. doi: 10.1016/j.envres.2023.118006. Online ahead of print.ABSTRACTSolid waste is an inevitable consequence of urbanization. It can be safely managed in municipal landfills and processing plants for volume reduction or material reuse, including organic solid waste. However, solid waste can also be discarded in (un-)authorized dumping sites or inadvertently released into the environment. Legacy and emerging contaminants have the potential to leach from solid waste, making it a significant pathway to the environment. Non-target screening (NTS) and suspect screening analysis (SSA) have become helpful tools in environmental science for the simultaneous analysis of a wide range of chemical compounds. However, the application of these analytical approaches to environmental samples related to Raw or Processed Solid Waste (RPSW) has been largely neglected so far. This perspective review examines the potential and policy relevance of NTS and SSA applied to waste-related samples (liquid, gaseous and solid). It addresses the hurdles associated with the chemical safety of solid waste accumulation, processing, and reuse, and the need for landfill traceability, as well as effectiveness of leachate treatments. We reviewed the current applications of NTS and SSA to environmental samples of RPSW, as well as the potential adaptation of NTS and SSA techniques from related fields, such as oilfield and metabolomics, to the solid waste domain. Despite the ongoing technical challenges, this review highlights the significant potential for the implementation of NTS and SSA approaches in solid waste management and related scientific fields and provides support and guidance to the regulatory authorities.PMID:38154568 | DOI:10.1016/j.envres.2023.118006

A comparative urinary proteomic and metabolomic analysis between renal aa amyloidosis and membranous nephropathy with clinicopathologic correlations

Thu, 28/12/2023 - 12:00
J Proteomics. 2023 Dec 26:105064. doi: 10.1016/j.jprot.2023.105064. Online ahead of print.ABSTRACTUrinary omics has become a powerful tool for elucidating pathophysiology of glomerular diseases. However, no urinary omics analysis has been performed yet on renal AA amyloidosis. Here, we performed a comparative urine proteomic and metabolomic analysis between recently diagnosed renal AA amyloidosis (AA) and membranous nephropathy (MN) patients. Urine samples of 22 (8 AA, 8 MN and 6 healthy control) patients were analyzed with nLC-MS/MS and GC/MS for proteomic and metabolomic studies, respectively. Pathological specimens were scored for glomerulosclerosis and tubulointerstitial fibrosis grades. Functional enrichment analysis between AA and control groups showed enrichment in cell adhesion related sub-domains. Uromodulin (UMOD) was lower, whereas ribonuclease 1 (RNase1) and α-1-microglobulin/bikunin precursor (AMBP) were higher in AA compared to MN group. Correlations were demonstrated between UMOD-proteinuria (r = -0.48, p = 0.03) and AMBP-eGFR (r = -0.69, p = 0.003) variables. Metabolomic analysis showed myo-inositol and urate were higher in AA compared to MN group. A positive correlation was detected between RNase1 and urate independent of eGFR values (r = 0.63, p = 0.01). Enrichment in cell adhesion related domains suggested a possible increased urinary shear stress due to amyloid fibrils. UMOD, AMBP and myo-inositol were related with tubulointerstitial damage, whereas RNase1 and urate were believed to be related with systemic inflammation in AA amyloidosis. SIGNIFICANCE: Urinary omics studies have become a standard tool for biomarker studies. However, no urinary omics analysis has been performed yet on renal AA amyloidosis. Here, we performed a comparative urinary omics analysis between recently diagnosed renal AA amyloidosis (AA), membranous nephropathy (MN) patients and healthy controls. Pathological specimens were scored with glomerulosclerosis (G) and tubulointerstitial fibrosis (IF) grades to consolidate the results of the omics studies and correlation analyzes. Functional enrichment analysis showed enrichment in cell adhesion related sub-domains due to downregulation of cadherins; which could be related with increased urinary shear stress due to amyloid deposition and disruption of tissue micro-architecture. In comparative proteomic analyzes UMOD was lower, whereas RNase1 and AMBP were higher in AA compared to MN group. Whereas in metabolomic analyzes; myo-inositol, urate and maltose were higher in AA compared to MN group. Correlations were demonstrated between UMOD-proteinuria (r = -0.48, p = 0.03), AMBP-eGFR (r = -0.69, p = 0.003) and between RNase1-Urate independent of eGFR values (r = 0.63, p = 0.01). This study is the first comprehensive urinary omics analysis focusing on renal AA Amyloidosis to the best of our knowledge. Based on physiologic roles and clinicopathologic correlations of the molecules; UMOD, AMBP and myo-inositol were related with tubulointerstitial damage, whereas RNase1 and urate were believed to be increased with systemic inflammation and endothelial damage in AA amyloidosis.PMID:38154551 | DOI:10.1016/j.jprot.2023.105064

Ganoderma lucidum ethanol extracts ameliorate hepatic fibrosis and promote the communication between metabolites and gut microbiota g_Ruminococcus through the NF-κB and TGF-β1/Smads pathways

Thu, 28/12/2023 - 12:00
J Ethnopharmacol. 2023 Dec 26:117656. doi: 10.1016/j.jep.2023.117656. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Ganoderma lucidum, a traditional edible medicinal mushroom, has been widely reported to improve liver diseases as a dietary intervention for people. Ganoderma lucidum extracts, primarily total triterpenoids (GLTTs), are one of the bioactive ingredients that have excellent beneficial effects on hepatic fibrosis. Therefore, its prevention and reversal are particularly critical due to the increasing number of patients with chronic liver diseases worldwide.AIM OF THE STUDY: The study aimed to evaluate whether GLTTs had a hepatoprotective effect against hepatic fibrosis through metabolic perturbations and gut microbiota changes and its underlying mechanisms.MATERIALS AND METHODS: The compound compositions of GLTTs were quantified, and carbon tetrachloride (CCl4)-induced hepatic fibrosis rats were used to investigate the cause of the improvement in various physiological states with GLTTs treatment, and to determine whether its consequent effect was associated with endogenous metabolites and gut microbiota using UPLC-Q-TOF-MSE metabolomics and 16S rRNA gene sequencing technology.RESULTS: GLTTs alleviated physical status, reduced liver pathological indicators, proinflammatory cytokines, and deposition of hepatic collagen fibers via regulating the NF-κB and TGF-β1/Smads pathways. The untargeted metabolomics analysis identified 16 potential metabolites that may be the most relevant metabolites for gut microbiota dysbiosis and the therapeutic effects of GLTTs in hepatic fibrosis. Besides, although GLTTs did not significantly affect the α-diversity indexes, significant changes were observed in the composition of microflora structure. In addition, Spearman analysis revealed strong correlations between endogenous metabolites and gut microbiota g_Ruminococcus with hepatic fibrosis.CONCLUSION: GLTTs could provide a potential target for the practical design and application of novel functional food ingredients or drugs in the therapy of hepatic fibrosis.PMID:38154526 | DOI:10.1016/j.jep.2023.117656

Exploring the metabolomic landscape: Perilla frutescens as a promising enhancer of production, flavor, and nutrition in Tan lamb meat

Thu, 28/12/2023 - 12:00
Meat Sci. 2023 Dec 24;209:109419. doi: 10.1016/j.meatsci.2023.109419. Online ahead of print.ABSTRACTAddressing health-related concerns linked to the metabolite profile of lamb meat has become paramount, in line with the growing demand for enhanced flavor and taste. We examined the impact of Perilla frutescens seeds on Tan lamb growth, carcass traits, and metabolite profiles. Three diets were employed: a low-concentrate group (LC), a high-concentrate group (HC), and a PFS group (the LC diet supplemented with 3% Perilla frutescens seeds) on a dry matter basis. Forty-five male Tan-lambs (approximately six months) with similar body weights (25.1 kg ± 1.12 SD) were randomly assigned to one of these three groups for 84-day feeding, including an initial 14-day adjustment phase. The supplementation of PFS resulted in increased average daily gain (P < 0.01) and improved carcass quality and meat color (P < 0.05). Additionally, it led to an enhancement in omega-3 polyunsaturated fatty acids (P < 0.05) and a reduction in the omega-6/omega-3 ratio (P < 0.05). Using gas chromatography-mass spectrometry, 369 volatile compounds were identified with enhanced levels of acetaldehyde and 1,2,4-trimethyl-benzene associated with PFS (P < 0.05). Among the 807 compounds identified by ultra-high performance liquid chromatography-mass spectrometry, there were 66 significantly differential compounds (P < 0.05), including 43 hydrophilic metabolites and 23 lipids. PFS supplementation led to significant alterations in 66 metabolites, with three metabolites including 2,5-diisopropyl-3-methylphenol, 3-hydroxydecanoic acid, and lysophosphatidylcholine (15:0) emerging as potential PFS-related biomarkers. The study indicates that PFS supplementation can enhance Tan-lamb growth, feed efficiency, and meat quality, potentially providing lamb meat with improved flavor and nutritional characteristics.PMID:38154372 | DOI:10.1016/j.meatsci.2023.109419

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