PubMed

Biomed Pharmacother. 2024 May 17:116696. doi: 10.1016/j.biopha.2024.116696. Online ahead of print.NO ABSTRACTPMID:38762427 | DOI:10.1016/j.biopha.2024.116696

J Biosci Bioeng. 2024 May 17:S1389-1723(24)00129-4. doi: 10.1016/j.jbiosc.2024.04.006. Online ahead of print.ABSTRACTThe creation of a self-replicating synthetic cell is an essential to understand life self-replication. One method to create self-replicating artificial cells is to reconstitute the self-replication system of living organisms in vitro. In a living cell, self-replication is achieved via a system called the autonomous central dogma, a system in which central dogma-related factors are autonomously synthesized and genome replication, transcription, and translation are driven by nascent factors. Various studies to reconstitute some processes of the autonomous central dogma in vitro have been conducted. However, in vitro reconstitution of the entire autonomous central dogma system is difficult as it requires balanced expression of several related genes. Therefore, we developed a method to simultaneously quantify and optimize the in vitro expression balance of multiple genes. First, we developed a quantitative mass spectrometry method targeting genome replication-related proteins as a model of central dogma-related factors and acquired in vitro expression profiles of these genes. Additionally, we demonstrated that the in vitro expression balance of these genes can be easily optimized by adjusting the input gene ratio based on the data obtained by the developed method. This study facilitated the easy optimization of the in vitro expression balance of multiple genes. Therefore, extending the scope of this method to other central dogma-related factors will accelerate attempts of self-replicating synthetic cells creation.PMID:38762340 | DOI:10.1016/j.jbiosc.2024.04.006

Adv Protein Chem Struct Biol. 2024;140:493-523. doi: 10.1016/bs.apcsb.2023.12.003. Epub 2024 Mar 13.ABSTRACTImmune-metabolic interactions play a pivotal role in both host defense and susceptibility to various diseases. Immunometabolism, an interdisciplinary field, seeks to elucidate how metabolic processes impact the immune system. In the context of viral infections, macrophages are often exploited by viruses for their replication and propagation. These infections trigger significant metabolic reprogramming within macrophages and polarization of distinct M1 and M2 phenotypes. This metabolic reprogramming involves alterations in standard- pathways such as the Krebs cycle, glycolysis, lipid metabolism, the pentose phosphate pathway, and amino acid metabolism. Disruptions in the balance of key intermediates like spermidine, itaconate, and citrate within these pathways contribute to the severity of viral diseases. In this chapter, we describe the manipulation of metabolic pathways by viruses and how they crosstalk between signaling pathways to evade the immune system. This intricate interplay often involves the upregulation or downregulation of specific metabolites, making these molecules potential biomarkers for diseases like HIV, HCV, and SARS-CoV. Techniques such as Nuclear Magnetic Resonance (NMR) and Mass Spectrometry, are the evaluative ways to analyze these metabolites. Considering the importance of macrophages in the inflammatory response, addressing their metabolome holds great promise for the creating future therapeutic targets aimed at combating a wide spectrum of viral infections.PMID:38762278 | DOI:10.1016/bs.apcsb.2023.12.003

J Ethnopharmacol. 2024 May 16:118340. doi: 10.1016/j.jep.2024.118340. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Adinandra nitida Merr. ex Li leaves serve as an herbal tea and hold a significant role in traditional Chinese medicine, being applied to assist in tumor treatment. Flavonoids present the primary bioactive constituents in Adinandra nitida Merr. ex Li leaves.AIM OF THE STUDY: To explore the potential of total flavonoids from Adinandra nitida Merr. ex Li Leaves (TFAN) in inhibiting non-small cell lung cancer (NSCLC) and further elucidate the underlying mechanisms.MATERIALS AND METHODS: Human NSCLC cell lines and normal lung cell line were employed to assess TFAN's impact (0-160 μg/mL for 24, 28 and 72 h) on cell proliferation in vitro. Immunofluorescence (IF) staining gauged p53 expression changes in NSCLC cells under TFAN present condition (150 μg/mL for 24 h). In vivo study utilized NSCLC cell derived xenograft tumors in nude mice, administering TFAN orally (200 and 400 mg/kg) for 14 days. Immunohistochemistry assessed Cleaved Caspase 3 expression change in A549 xenograft tumors treated with TFAN (400 mg/kg for 14 days). RNA-seq and KEGG analysis identified gene changes and enriched processes in A549 xenograft tumors treated with TFAN. CM-H2DCFDA and metabolomics assessed ROS level and GSH/GSSG pool changes in A549 cells under TFAN present condition. Cell viability assay and IF staining assessed A549 cell proliferation and p53 expression changes under H2O2-induced oxidative stress (0-40 μM for 24 h) and TFAN present conditions. GSEA and N-Acetyl-L-cysteine (NAC) rescue (0-1 μM for 24 h) analyzed TFAN's impact on GSH de novo synthesis. NADPH/NADP+ pool measurement and NADPH rescue (0-10 μM for 24 h) analyzed TFAN's impact on GSH salvage synthesis. GC-FID and HPLC-MS were utilized to detect ethanol and ethyl acetate residues, and to characterize the chemical constituents in TFAN, respectively. The total flavonoid content of TFAN was determined using a 330 nm wavelength.RESULTS: TFAN significantly inhibited A549 cells (wild-type p53) but not NCI-H1299 cells (p53-deficient), NCI-H596 cells (p53-mutant) or BEAS-2B in vitro. IF staining validated p53 genotype for the cell lines and revealed an increase in p53 expression in A549 cells after TFAN treatment. In vivo, TFAN selectively inhibited A549 xenograft tumor growth without discernible toxicity, inducing apoptosis evidenced by Cleaved Caspase 3 upregulation. RNA-seq and KEGG analysis suggested ROS biosynthesis was involved in TFAN-induced p53 activation in A549 cells. Elevated ROS level in TFAN-treated A549 cells were observed. Moreover, TFAN sensitized A549 cells to H2O2-induced oxidative stress, with higher p53 expression. Additionally, A549 cells compensated with GSH de novo synthesis under TFAN present condition, confirmed by GSEA and NAC rescue experiment. TFAN disrupted NADPH homeostasis to impair GSH salvage biosynthesis, supported by NADPH/NADP+ change and NADPH rescue experiment. The chemical constituents of TFAN, with acceptable limits for ethanol and ethyl acetate residues and a total flavonoid content of 68.87%, included Catechin, Epicatechin, Quercitroside, Camellianin A, and Apigenin.CONCLUSION: The disruption of NADPH homeostasis by TFAN triggers ROS-dependent p53 activation that leads to apoptotic cell death, ultimately suppressing NSCLC growth. These findings offer potential therapeutic implications of Adinandra nitida Merr. ex Li leaves in combating NSCLC.PMID:38762212 | DOI:10.1016/j.jep.2024.118340

Am J Clin Nutr. 2024 May 16:S0002-9165(24)00473-8. doi: 10.1016/j.ajcnut.2024.05.010. Online ahead of print.ABSTRACTBACKGROUND: High sodium and low potassium intakes are associated with a higher risk of hypertension and cardiovascular disease (CVD), but there are limited data on the circulating metabolomics profiles of 24-hour urinary sodium and potassium excretions in free-living individuals.OBJECTIVES: To characterize metabolomics signatures of a high-sodium and low-potassium diet in a cross-sectional study.METHODS: In 1,028 healthy older adults from the Women's and Men's Lifestyle Validation Studies, we investigated the association of habitual sodium and potassium intakes measured by 2-4 24-hour urine samples with plasma metabolites (quantified using liquid chromatography-tandem mass spectrometry) and metabolomic pathways. Our primary exposures were energy-adjusted 24-hour urinary sodium excretion, potassium excretion, and sodium-to-potassium ratio, calculated based on energy expenditure derived from the Doubly Labelled Water method. Then we assessed the partial correlations of their metabolomics scores, derived from elastic net regressions, with cardiometabolic biomarkers.RESULTS: Higher sodium excretion was associated with 38 metabolites including higher piperine, phosphatidylethanolamine, and C5:1 carnitine. In pathway analysis, higher sodium excretion was associated with enhanced biotin and propanoate metabolism, and enhanced degradation of lysine and branched-chain amino acids (BCAAs). Metabolites associated with higher potassium and lower sodium-to-potassium ratio included quinic acid and proline-betaine. After adjusting for confounding factors, the metabolomics score for sodium-to-potassium ratio positively correlated with fasting insulin (Spearman's rank correlation coefficient ρ=0.27), C-peptide (ρ=0.30), and triglyceride (ρ=0.46), and negatively with adiponectin (ρ=-0.40), and high-density lipoprotein (HDL) cholesterol (ρ=-0.42).CONCLUSIONS: We discovered metabolites and metabolomics pathways associated with a high-sodium diet, including metabolites related to biotin, propanoate, lysine, and BCAA pathways. The metabolomics signature for a higher sodium-low potassium diet is associated with multiple components of elevated cardiometabolic risk.PMID:38762185 | DOI:10.1016/j.ajcnut.2024.05.010

J Hazard Mater. 2024 May 14;473:134612. doi: 10.1016/j.jhazmat.2024.134612. Online ahead of print.ABSTRACTMetal pollution caused by deep-sea mining activities has potential detrimental effects on deep-sea ecosystems. However, our knowledge of how deep-sea organisms respond to this pollution is limited, given the challenges of remoteness and technology. To address this, we conducted a toxicity experiment by using deep-sea mussel Gigantidas platifrons as model animals and exposing them to different copper (Cu) concentrations (50 and 500 μg/L) for 7 days. Transcriptomics and LC-MS-based metabolomics methods were employed to characterize the profiles of transcription and metabolism in deep-sea mussels exposed to Cu. Transcriptomic results suggested that Cu toxicity significantly affected the immune response, apoptosis, and signaling processes in G. platifrons. Metabolomic results demonstrated that Cu exposure disrupted its carbohydrate metabolism, anaerobic metabolism and amino acid metabolism. By integrating both sets of results, transcriptomic and metabolomic, we find that Cu exposure significantly disrupts the metabolic pathway of protein digestion and absorption in G. platifrons. Furthermore, several key genes (e.g., heat shock protein 70 and baculoviral IAP repeat-containing protein 2/3) and metabolites (e.g., alanine and succinate) were identified as potential molecular biomarkers for deep-sea mussel's responses to Cu toxicity. This study contributes novel insight for assessing the potential effects of deep-sea mining activities on deep-sea organisms.PMID:38761766 | DOI:10.1016/j.jhazmat.2024.134612

Food Chem. 2024 May 11;453:139628. doi: 10.1016/j.foodchem.2024.139628. Online ahead of print.ABSTRACTUmami taste is a key criteria of green tea quality evaluation. The aim of this study was to comprehensively explore the key umami taste contributors in Longjing tea. The taste and molecular profiles of 36 Longjing green tea infusions were characterized by sensory quantitative descriptive analysis and LC-MS based metabolomics, respectively. By uni-/multi-variate statistical analysis, 84 differential compounds were screened among tea infusions with varied umami perceptions. Among them, 17 substances were identified as candidate umami-enhancing compounds, which showed significant positive correlations with umami intensities. Their natural concentrations were accurately quantified, and their umami taste-modifying effects were further investigated by taste addition into glutamic acid solution. Glutamic acid, aspartic acid, glutamine, theanine, phenylalanine, histidine, theogallin, galloylglucose, 1,2,6-trigalloylglucose significantly enhanced the umami taste. This study uncovered for the first time of some bitter amino acids and galloylglucose homologous series as important umami-enhancers, which provided a novel perspective into the tea taste.PMID:38761731 | DOI:10.1016/j.foodchem.2024.139628

Plant Physiol Biochem. 2024 May 12;212:108715. doi: 10.1016/j.plaphy.2024.108715. Online ahead of print.ABSTRACTLight plays a pivotal role in regulating anthocyanin biosynthesis in plants, and the early light-responsive signals that initiate anthocyanin biosynthesis remain to be elucidated. In this study, we showed that the anthocyanin biosynthesis in Eucalyptus is hypersensitive to increased light intensity. The combined transcriptomic and metabolomic analyses were conducted on Eucalyptus leaves after moderate (ML; 100 μmol m-2 s-1) and high (HL; 300 μmol m-2 s-1) light intensity treatments. The results identified 1940, 1096, 1173, and 2756 differentially expressed genes at 6, 12, 24, and 36 h after HL treatment, respectively. The metabolomic results revealed the primary anthocyanin types, and other differentially accumulated flavonoids and phenylpropane intermediates that were produced in response to HL, which well aligned with the transcriptome results. Moreover, biochemical analysis showed that HL inhibited peroxidase activity and increased the ROS level in Eucalyptus leaves. ROS depletion through co-application of the antioxidants rutin, uric acid, and melatonin significantly reduced, and even abolished, anthocyanin biosynthesis induced by HL treatment. Additionally, exogenous application of hydrogen peroxide efficiently induced anthocyanin biosynthesis within 24 h, even under ML conditions, suggesting that ROS played a major role in activating anthocyanin biosynthesis. A HL-responsive MYB transcription factor EgrMYB113 was identified to play an important role in regulating anthocyanin biosynthesis by targeting multiple anthocyanin biosynthesis genes. Additionally, the results demonstrated that gibberellic acid and sugar signaling contributed to HL-induced anthocyanin biosynthesis. Conclusively, these results suggested that HL triggers multiple signaling pathways to induce anthocyanin biosynthesis, with ROS acting as indispensable mediators in Eucalyptus.PMID:38761541 | DOI:10.1016/j.plaphy.2024.108715

Curr Opin Plant Biol. 2024 May 17;80:102549. doi: 10.1016/j.pbi.2024.102549. Online ahead of print.ABSTRACTFlowers of Cannabis sativa L. are densely covered with glandular trichomes containing cannabis resin that is used for medicinal and recreational purposes. The highly productive glandular trichomes have been described as 'biofactories.' In this review, we use this analogy to highlight recent advances in cannabis cell biology, metabolomics, and transcriptomics. The biofactory is built by epidermal outgrowths that differentiate into peltate-like glandular trichome heads, consisting of a disc of interconnected secretory cells with unique cellular structures. Cannabinoid and terpenoid products are warehoused in the extracellular storage cavity. Finally, multicellular stalks raise the glandular heads above the epidermis, giving cannabis flower their frosty appearance.PMID:38761520 | DOI:10.1016/j.pbi.2024.102549

Comput Biol Med. 2024 May 13;176:108588. doi: 10.1016/j.compbiomed.2024.108588. Online ahead of print.ABSTRACTBACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition for which there is currently no available medication that can stop its progression. Previous studies suggest that mild cognitive impairment (MCI) is a phase that precedes the disease. Therefore, a better understanding of the molecular mechanisms behind MCI conversion to AD is needed.METHOD: Here, we propose a machine learning-based approach to detect the key metabolites and proteins involved in MCI progression to AD using data from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery Study. Proteins and metabolites were evaluated separately in multiclass models (controls, MCI and AD) and together in MCI conversion models (MCI stable vs converter). Only features selected as relevant by 3/4 algorithms proposed were kept for downstream analysis.RESULTS: Multiclass models of metabolites highlighted nine features further validated in an independent cohort (0.726 mean balanced accuracy). Among these features, one metabolite, oleamide, was selected by all the algorithms. Further in-vitro experiments in rodents showed that disease-associated microglia excreted oleamide in vesicles. Multiclass models of proteins stood out with nine features, validated in an independent cohort (0.720 mean balanced accuracy). However, none of the proteins was selected by all the algorithms. Besides, to distinguish between MCI stable and converters, 14 key features were selected (0.872 AUC), including tTau, alpha-synuclein (SNCA), junctophilin-3 (JPH3), properdin (CFP) and peptidase inhibitor 15 (PI15) among others.CONCLUSIONS: This omics integration approach highlighted a set of molecules associated with MCI conversion important in neuronal and glia inflammation pathways.PMID:38761503 | DOI:10.1016/j.compbiomed.2024.108588

Biomed Pharmacother. 2024 May 17;175:116731. doi: 10.1016/j.biopha.2024.116731. Online ahead of print.ABSTRACTNutraceuticals have gained increasing interest, prompting the need to investigate plant extracts for their beneficial properties and potential side effects. This study aimed to assess the nutraceutical effects of environmentally clean extracts from Rosmarinus officinalis and Gongolaria abies-marina (formerly Cystoseira abies-marina (Phaeophyceae)) on the metabolic profile of streptozotocin-induced diabetic rats. We conducted untargeted LC-QTOF-MS metabolic profiling on six groups of rats: three diabetic groups receiving either a placebo, R. officinalis, or G. abies-marina extracts, and three corresponding control groups. The metabolic analysis revealed significant alterations in the levels of various glycerophospholipids, sterol lipids, and fatty acyls. Both extracts influenced the metabolic profile, partially mitigating diabetes-induced changes. Notably, G. abies-marina extract had a more pronounced impact on the animals' metabolic profiles compared to R. officinalis. In conclusion, our findings suggest that environmentally clean extracts from R. officinalis and G. abies-marina possess nutraceutical potential, as they were able to modulate the metabolic profile in streptozotocin-induced diabetic rats. G. abies-marina extract exhibited a more substantial effect on metabolic alterations induced by diabetes compared to R. officinalis. These results warrant further exploration of these plant extracts for their potential in managing diabetes-related metabolic disturbances.PMID:38761421 | DOI:10.1016/j.biopha.2024.116731

Hepatology. 2024 May 16. doi: 10.1097/HEP.0000000000000907. Online ahead of print.ABSTRACTBACKGROUND AIMS: Acute-on-chronic liver failure (ACLF) is a complication of cirrhosis characterized by multiple organ failure and high short-term mortality. The pathophysiology of ACLF involves elevated systemic inflammation leading to organ failure, along with immune dysfunction that heightens susceptibility to bacterial infections. However, it is unclear how these aspects are associated with recovery and non-recovery in ACLF.APPROACH RESULTS: Here we mapped the single-cell transcriptome of circulating immune cells from ACLF-, acute decompensated (AD) cirrhosis patients and healthy individuals. We further interrogate how these findings as well as immunometabolic- and functional profiles associate with ACLF recovery (ACLF-R) or non-recovery (ACLF-NR). Our analysis unveiled two distinct states of classical monocytes (cMon). Hereto, ACLF-R cMons were characterized by transcripts associated with immune- and stress tolerance, including anti-inflammatory genes such as RETN and LGALS1. Additional metabolomic- and functional validation experiments implicated an elevated oxidative phosphorylation metabolic program as well as an impaired ACLF-R cMon functionality. Interestingly, we observed a common stress-induced tolerant state, oxidative phosphorylation program and blunted activation among lymphoid populations in ACLF-R patients. Conversely, ACLF-NR cMon featured elevated expression of inflammatory- and stress response genes such as VIM, LGALS2, and TREM1 along with blunted metabolic activity and increased functionality.CONCLUSIONS: This study identifies distinct immuno-metabolic cellular states that contribute to disease outcome in ACLF patients. Our findings provide valuable insights into the pathogenesis of ACLF, shedding light on factors driving either recovery or non-recovery phenotypes which may be harnessed as potential therapeutic targets in the future.PMID:38761406 | DOI:10.1097/HEP.0000000000000907

Sci China Life Sci. 2024 May 16. doi: 10.1007/s11427-023-2539-1. Online ahead of print.ABSTRACTThe complexities of energy transfer mechanisms in the flagella of mammalian sperm flagella have been intensively investigated and demonstrate significant diversity across species. Enzymatic shuttles, particularly adenylate kinase (AK) and creatine kinase (CK), are pivotal in the efficient transfer of intracellular ATP, showing distinct tissue- and species-specificity. Here, the expression profiles of AK and CK were investigated in mice and found to fall into four subgroups, of which Subgroup III AKs were observed to be unique to the male reproductive system and conserved across chordates. Both AK8 and AK9 were found to be indispensable to male reproduction after analysis of an infertile male cohort. Knockout mouse models showed that AK8 and AK9 were central to promoting sperm motility. Immunoprecipitation combined with mass spectrometry revealed that AK8 and AK9 interact with the radial spoke (RS) of the axoneme. Examination of various human and mouse sperm samples with substructural damage, including the presence of multiple RS subunits, showed that the head of radial spoke 3 acts as an adapter for AK9 in the flagellar axoneme. Using an ATP probe together with metabolomic analysis, it was found that AK8 and AK9 cooperatively regulated ATP transfer in the axoneme, and were concentrated at sites associated with energy consumption in the flagellum. These findings indicate a novel function for RS beyond its structural role, namely, the regulation of ATP transfer. In conclusion, the results expand the functional spectrum of AK proteins and suggest a fresh model regarding ATP transfer within mammalian flagella.PMID:38761355 | DOI:10.1007/s11427-023-2539-1

Acta Neuropathol. 2024 May 18;147(1):88. doi: 10.1007/s00401-024-02739-5.NO ABSTRACTPMID:38761253 | DOI:10.1007/s00401-024-02739-5

J Physiol. 2024 May 18. doi: 10.1113/JP285339. Online ahead of print.ABSTRACTHypoxia-inducible factor (HIF)-1α is continuously synthesized and degraded in normoxia. During hypoxia, HIF1α stabilization restricts cellular/mitochondrial oxygen utilization. Cellular stressors can stabilize HIF1α even during normoxia. However, less is known about HIF1α function(s) and sex-specific effects during normoxia in the basal state. Since skeletal muscle is the largest protein store in mammals and protein homeostasis has high energy demands, we determined HIF1α function at baseline during normoxia in skeletal muscle. Untargeted multiomics data analyses were followed by experimental validation in differentiated murine myotubes with loss/gain of function and skeletal muscle from mice without/with post-natal muscle-specific Hif1a deletion (Hif1amsd). Mitochondrial oxygen consumption studies using substrate, uncoupler, inhibitor, titration protocols; targeted metabolite quantification by gas chromatography-mass spectrometry; and post-mitotic senescence markers using biochemical assays were performed. Multiomics analyses showed enrichment in mitochondrial and cell cycle regulatory pathways in Hif1a deleted cells/tissue. Experimentally, mitochondrial oxidative functions and ATP content were higher with less mitochondrial free radical generation with Hif1a deletion. Deletion of Hif1a also resulted in higher concentrations of TCA cycle intermediates and HIF2α proteins in myotubes. Overall responses to Hif1amsd were similar in male and female mice, but changes in complex II function, maximum respiration, Sirt3 and HIF1β protein expression and muscle fibre diameter were sex-dependent. Adaptive responses to hypoxia are mediated by stabilization of constantly synthesized HIF1α. Despite rapid degradation, the presence of HIF1α during normoxia contributes to lower mitochondrial oxidative efficiency and greater post-mitotic senescence in skeletal muscle. In vivo responses to HIF1α in skeletal muscle were differentially impacted by sex. KEY POINTS: Hypoxia-inducible factor -1α (HIF1α), a critical transcription factor, undergoes continuous synthesis and proteolysis, enabling rapid adaptive responses to hypoxia by reducing mitochondrial oxygen consumption. In mammals, skeletal muscle is the largest protein store which is determined by a balance between protein synthesis and breakdown and is sensitive to mitochondrial oxidative function. To investigate the functional consequences of transient HIF1α expression during normoxia in the basal state, myotubes and skeletal muscle from male and female mice with HIF1α knockout were studied using complementary multiomics, biochemical and metabolite assays. HIF1α knockout altered the electron transport chain, mitochondrial oxidative function, signalling molecules for protein homeostasis, and post-mitotic senescence markers, some of which were differentially impacted by sex. The cost of rapid adaptive responses mediated by HIF1α is lower mitochondrial oxidative efficiency and post-mitotic senescence during normoxia.PMID:38761133 | DOI:10.1113/JP285339

Oncologist. 2024 May 18:oyae075. doi: 10.1093/oncolo/oyae075. Online ahead of print.ABSTRACTOBJECTIVE: Patients with radioiodine-refractory (RAIR) differentiated thyroid carcinoma (DTC; RAIR-DTC) have a poor prognosis. The aim of this study was to provide new insights and possibilities for the diagnosis and treatment of RAIR-DTC.METHODS: The metabolomics of 24 RAIR-DTC and 18 non-radioiodine-refractory (NonRAIR) DTC patients samples were analyzed by liquid chromatograph-mass spectrometry. Cellular radioiodine uptake was detected with γ counter. Sodium iodide symporter (NIS) expression and thyroid stimulating hormone receptor (TSHR) were measured by Western blot analysis. CCK8 and colony formation assays were used to measure cellular proliferation. Scratch and transwell assays were performed to assess cell migration and invasion. Annexin V/PI staining was used to detect cell apoptosis. Cell growth in vivo was evaluated by a tumor xenograft model. The acetoacetate (AcAc) level was measured by ELISA. Pathological changes, Ki67, NIS, and TSHR expression were investigated by immunohistochemistry.RESULTS: The metabolite profiles of RAIR could be distinguished from those of NonRAIR, with AcAc significantly lower in RAIR. The significantly different metabolic pathway was ketone body metabolism. AcAc increased NIS and TSHR expression and improved radioiodine uptake. AcAc inhibited cell proliferation, migration, and invasion, and as well promoted cell apoptosis. Ketogenic diet (KD) elevated AcAc levels and significantly suppressed tumor growth, as well as improved NIS and TSHR expression.CONCLUSION: Significant metabolic differences were observed between RAIR and NonRAIR, and ketone body metabolism might play an important role in RAIR-DTC. AcAc improved cellular iodine uptake and had antitumor effects for thyroid carcinoma. KD might be a new therapeutic strategy for RAIR-DTC.PMID:38760956 | DOI:10.1093/oncolo/oyae075

Microb Cell Fact. 2024 May 17;23(1):141. doi: 10.1186/s12934-024-02414-0.ABSTRACTBACKGROUND: The oleaginous yeast Rhodotorula toruloides is a promising chassis organism for the biomanufacturing of value-added bioproducts. It can accumulate lipids at a high fraction of biomass. However, metabolic engineering efforts in this organism have progressed at a slower pace than those in more extensively studied yeasts. Few studies have investigated the lipid accumulation phenotype exhibited by R. toruloides under nitrogen limitation conditions. Consequently, there have been only a few studies exploiting the lipid metabolism for higher product titers.RESULTS: We performed a multi-omic investigation of the lipid accumulation phenotype under nitrogen limitation. Specifically, we performed comparative transcriptomic and lipidomic analysis of the oleaginous yeast under nitrogen-sufficient and nitrogen deficient conditions. Clustering analysis of transcriptomic data was used to identify the growth phase where nitrogen-deficient cultures diverged from the baseline conditions. Independently, lipidomic data was used to identify that lipid fractions shifted from mostly phospholipids to mostly storage lipids under the nitrogen-deficient phenotype. Through an integrative lens of transcriptomic and lipidomic analysis, we discovered that R. toruloides undergoes lipid remodeling during nitrogen limitation, wherein the pool of phospholipids gets remodeled to mostly storage lipids. We identify specific mRNAs and pathways that are strongly correlated with an increase in lipid levels, thus identifying putative targets for engineering greater lipid accumulation in R. toruloides. One surprising pathway identified was related to inositol phosphate metabolism, suggesting further inquiry into its role in lipid accumulation.CONCLUSIONS: Integrative analysis identified the specific biosynthetic pathways that are differentially regulated during lipid remodeling. This insight into the mechanisms of lipid accumulation can lead to the success of future metabolic engineering strategies for overproduction of oleochemicals.PMID:38760782 | DOI:10.1186/s12934-024-02414-0

BMC Vet Res. 2024 May 17;20(1):206. doi: 10.1186/s12917-024-04018-7.ABSTRACTBACKGROUND: In livestock, identifying the physiological and reproductive stages is valuable in guiding management decisions related to nutrition, veterinary procedures, and breeding programs. To achieve this goal, a cohort of Barki ewes in this research underwent observation across three pivotal physiological conditions: pre-pregnancy, late pregnancy, and early lactation. Blood samples were collected to investigate the changes in serum metabolic profile as well as gene expression pattern of cytokines and antioxidants markers during these stages.RESULTS: Our results showed that during late pregnancy, there was a significant (P < 0.05) increase in red blood cells (11.9 ± 0.5 1012/L), hemoglobin (10.8 ± 0.4 g/dl) and neutrophils count (7 ± 0.1 109/L) with significant decrease (P < 0.05) of total white blood cell count (9.1 ± 0.05 109/L). The packed cell volume (%) and monocyte count showed a significant (P < 0.05) decrease during both late pregnancy and early lactation stages. The serum concentrations of glucose, cholesterol, GSH, GPx, SOD and catalase displayed significant (P < 0.05) decrease during late pregnancy and early-lactation. Notably, during late pregnancy, there was a significant (P < 0.05) increase in the serum concentrations of albumin, globulin, urea, IGF-1, and malondialdehyde with significant decrease (P < 0.05) of total protein (4.9 ± 0.08 g/dl). Additionally, during early lactation, there was a significant (P < 0.05) increase in the serum levels of non-esterified fatty acids, triiodothyronine (T3), and thyroxin (T4). The gene expression profiles of cytokines (IL-4, IL-6, IL-8, and NFKB) were decreased in the ewes during late pregnancy compared to pre-pregnant and early lactation stages. In addition, the expression profile of antioxidant genes (SOD, CAT, GPX, and Nrf2) was significantly upsurged in the non-pregnant ewes compared to late pregnancy and early lactation ones.CONCLUSIONS: The results concluded that different physiological status significantly affects the blood metabolic profile and gene expression pattern in Barki sheep. Our findings can be helpful in monitoring animal health and applying in breeding programs of Barki sheep under harsh environmental conditions.PMID:38760770 | DOI:10.1186/s12917-024-04018-7

Biofactors. 2024 May 17. doi: 10.1002/biof.2076. Online ahead of print.ABSTRACTAngiopoietin-like protein 4 (ANGPTL4) is a secretory glycoprotein involved in regulating glucose homeostasis in non-pregnant subjects. However, its role in glucose metabolism during pregnancy and the pathophysiology of gestational diabetes mellitus (GDM) remains elusive. Thus, this study aimed to clarify the relationship between ANGPTL4 and GDM and investigate the pathophysiology of placental ANGPTL4 in glucose metabolism. We investigated this issue using blood and placenta samples in 957 pregnant women, the human 3A-sub-E trophoblast cell line, and the L6 skeletal muscle cell line. We found that ANGPTL4 expression in the placenta was higher in obese pregnant women than in lean controls. Palmitic acid significantly induced ANGPTL4 expression in trophoblast cells in a dose-response manner. ANGPTL4 overexpression in trophoblast cells resulted in endoplasmic reticulum (ER) stress, which stimulated the expression and secretion of growth hormone-variant (GH2) but not human placental lactogen. In L6 skeletal muscle cells, soluble ANGPTL4 suppressed insulin-mediated glucose uptake through the epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinases 1/2 (ERK 1/2) pathways. In pregnant women, plasma ANGPTL4 concentrations in the first trimester predicted the incidence of GDM and were positively associated with BMI, plasma triglyceride, and plasma GH2 in the first trimester. However, they were negatively associated with insulin sensitivity index ISI0,120 in the second trimester. Overall, placental ANGPTL4 is induced by obesity and is involved in the pathophysiology of GDM via the induction of ER stress and GH2 secretion. Soluble ANGPTL4 can lead to insulin resistance in skeletal muscle cells and is an early biomarker for predicting GDM.PMID:38760159 | DOI:10.1002/biof.2076

Food Res Int. 2024 May;183:114234. doi: 10.1016/j.foodres.2024.114234. Epub 2024 Mar 13.ABSTRACTBitterness is one of the five basic tastes generally considered undesirable. The widespread presence of bitter compounds can negatively affect the palatability of foods. The classification and sensory evaluation of bitter compounds have been the focus in recent research. However, the rigorous identification of bitter tastes and further studies to effectively mask or remove them have not been thoroughly evaluated. The present paper focuses on identification of bitter compounds in foods, structural-based activation of bitter receptors, and strategies to reduce bitter compounds in foods. It also discusses the roles of metabolomics and virtual screening analysis in bitter taste. The identification of bitter compounds has seen greater success through metabolomics with multivariate statistical analysis compared to conventional chromatography, HPLC, LC-MS, and NMR techniques. However, to avoid false positives, sensory recognition should be combined. Bitter perception involves the structural activation of bitter taste receptors (TAS2Rs). Only 25 human TAS2Rs have been identified as responsible for recognizing numerous bitter compounds, showcasing their high structural diversity to bitter agonists. Thus, reducing bitterness can be achieved through several methods. Traditionally, the removal or degradation of bitter substances has been used for debittering, while the masking of bitterness presents a new effective approach to improving food flavor. Future research in food bitterness should focus on identifying unknown bitter compounds in food, elucidating the mechanisms of activation of different receptors, and developing debittering techniques based on the entire food matrix.PMID:38760147 | DOI:10.1016/j.foodres.2024.114234