PubMed

Cancer Sci. 2024 Mar 25. doi: 10.1111/cas.16154. Online ahead of print.ABSTRACTOvercoming resistance to immune checkpoint inhibitors is an important issue in patients with non-small-cell lung cancer (NSCLC). Transcriptome analysis shows that adenocarcinoma can be divided into three molecular subtypes: terminal respiratory unit (TRU), proximal proliferative (PP), and proximal inflammatory (PI), and squamous cell carcinoma (LUSQ) into four. However, the immunological characteristics of these subtypes are not fully understood. In this study, we investigated the immune landscape of NSCLC tissues in molecular subtypes using a multi-omics dataset, including tumor-infiltrating leukocytes (TILs) analyzed using flow cytometry, RNA sequences, whole exome sequences, metabolomic analysis, and clinicopathologic findings. In the PI subtype, the number of TILs increased and the immune response in the tumor microenvironment (TME) was activated, as indicated by high levels of tertiary lymphoid structures, and high cytotoxic marker levels. Patient prognosis was worse in the PP subtype than in other adenocarcinoma subtypes. Glucose transporter 1 (GLUT1) expression levels were upregulated and lactate accumulated in the TME of the PP subtype. This could lead to the formation of an immunosuppressive TME, including the inactivation of antigen-presenting cells. The TRU subtype had low biological malignancy and "cold" tumor-immune phenotypes. Squamous cell carcinoma (LUSQ) did not show distinct immunological characteristics in its respective subtypes. Elucidation of the immune characteristics of molecular subtypes could lead to the development of personalized immune therapy for lung cancer. Immune checkpoint inhibitors could be an effective treatment for the PI subtype. Glycolysis is a potential target for converting an immunosuppressive TME into an antitumorigenic TME in the PP subtype.PMID:38527308 | DOI:10.1111/cas.16154

PLoS Comput Biol. 2024 Mar 25;20(3):e1011814. doi: 10.1371/journal.pcbi.1011814. Online ahead of print.ABSTRACTAs terabytes of multi-omics data are being generated, there is an ever-increasing need for methods facilitating the integration and interpretation of such data. Current multi-omics integration methods typically output lists, clusters, or subnetworks of molecules related to an outcome. Even with expert domain knowledge, discerning the biological processes involved is a time-consuming activity. Here we propose PathIntegrate, a method for integrating multi-omics datasets based on pathways, designed to exploit knowledge of biological systems and thus provide interpretable models for such studies. PathIntegrate employs single-sample pathway analysis to transform multi-omics datasets from the molecular to the pathway-level, and applies a predictive single-view or multi-view model to integrate the data. Model outputs include multi-omics pathways ranked by their contribution to the outcome prediction, the contribution of each omics layer, and the importance of each molecule in a pathway. Using semi-synthetic data we demonstrate the benefit of grouping molecules into pathways to detect signals in low signal-to-noise scenarios, as well as the ability of PathIntegrate to precisely identify important pathways at low effect sizes. Finally, using COPD and COVID-19 data we showcase how PathIntegrate enables convenient integration and interpretation of complex high-dimensional multi-omics datasets. PathIntegrate is available as an open-source Python package.PMID:38527092 | DOI:10.1371/journal.pcbi.1011814

Plant Signal Behav. 2024 Dec 31;19(1):2332019. doi: 10.1080/15592324.2024.2332019. Epub 2024 Mar 25.ABSTRACTTobacco black shank (TBS), caused by Phytophthora nicotianae, is a severe disease. Plant root exudates play a crucial role in mediating plant-pathogen interactions in the rhizosphere. However, the specific interaction between key secondary metabolites present in root exudates and the mechanisms of disease resistance remains poorly understood. This study conducted a comprehensive comparison via quasi-targeted metabolomic analysis on the root exudate metabolites from the tobacco cultivar Yunyan87 and K326, both before and after inoculation with P. nicotianae. The results showed that the root exudate metabolites changed after P. nicotianae inoculation, and the root exudate metabolites of different tobacco cultivar was significantly different. Furthermore, homovanillic acid, lauric acid, and isoliquiritigenin were identified as potential key compounds for TBS resistance based on their impact on the mycelium growth of the pathogens. The pot experiment showed that isoliquiritigenin reduced the incidence by 55.2%, while lauric acid reduced it by 45.8%. This suggests that isoliquiritigenin and lauric acid have potential applications in the management of TBS. In summary, this study revealed the possible resistance mechanisms of differential metabolites in resistance of commercial tobacco cultivar, and for the first time discovered the inhibitory effects of isoliquiritigenin and homovanillic acid on P. nictianae, and attempt to use plants secondary metabolites of for plant protection.PMID:38527068 | DOI:10.1080/15592324.2024.2332019

PLoS One. 2024 Mar 25;19(3):e0300719. doi: 10.1371/journal.pone.0300719. eCollection 2024.ABSTRACTClimate change increases global temperatures, which is lethal to both livestock and humans. Heat stress is known as one of the various livestock stresses, and dairy cows react sensitively to high-temperature stress. We aimed to better understand the effects of heat stress on the health of dairy cows and observing biological changes. Individual cows were divided into normal (21-22 °C, 50-60% humidity) and high temperature (31-32 °C, 80-95% humidity), respectively, for 7-days. We performed metabolomic and transcriptome analyses of the blood and gut microbiomes of feces. In the high-temperature group, nine metabolites including linoleic acid and fructose were downregulated, and 154 upregulated and 72 downregulated DEGs (Differentially Expressed Genes) were identified, and eighteen microbes including Intestinimonas and Pseudoflavonifractor in genus level were significantly different from normal group. Linoleic acid and fructose have confirmed that associated with various stresses, and functional analysis of DEG and microorganisms showing significant differences confirmed that high-temperature stress is related to the inflammatory response, immune system, cellular energy mechanism, and microbial butyrate production. These biological changes were likely to withstand high-temperature stress. Immune and inflammatory responses are known to be induced by heat stress, which has been identified to maintain homeostasis through modulation at metabolome, transcriptome and microbiome levels. In these findings, heat stress condition can trigger alteration of immune system and cellular energy metabolism, which is shown as reduced metabolites, pathway enrichment and differential microbes. As results of this study did not include direct phenotypic data, we believe that additional validation is required in the future. In conclusion, high-temperature stress contributed to the reduction of metabolites, changes in gene expression patterns and composition of gut microbiota, which are thought to support dairy cows in withstanding high-temperature stress via modulating immune-related genes, and cellular energy metabolism to maintain homeostasis.PMID:38527055 | DOI:10.1371/journal.pone.0300719

Tree Physiol. 2024 Mar 25:tpae036. doi: 10.1093/treephys/tpae036. Online ahead of print.ABSTRACTThe loss of leaves and needles in tree crowns and tree mortality are increasing worldwide, mostly as a result of more frequent and severe drought stress. Scots pine (Pinus sylvestris L.) is a tree species that is strongly affected by these developments in many regions of Europe and Asia. So far, changes in metabolic pathways and metabolite profiles in needles and roots on the trajectory towards mortality are unknown, although they could contribute to a better understanding of the mortality mechanisms. Therefore, we linked long-term observations of canopy defoliation and tree mortality with the characterization of the primary metabolite profile in needles and fine roots of Scots pines from a forest site in the Swiss Rhone valley. Our results show that Scots pines are able to maintain metabolic homeostasis in needles over a wide range of canopy defoliation levels. However, there is a metabolic tipping point at around 80-85% needle loss. Above this threshold, many stress-related metabolites (particularly osmoprotectants, defense compounds and antioxidants) increase in the needles, whereas they decrease in the fine roots. If this defoliation tipping point is exceeded, the trees are very likely to die within a few years. The different patterns between needles and roots indicate that mainly belowground carbon starvation impairs key functions for tree survival and suggests that this is an important factor explaining the increasing mortality of Scots pines.PMID:38526975 | DOI:10.1093/treephys/tpae036

Food Funct. 2024 Mar 25. doi: 10.1039/d3fo04078j. Online ahead of print.ABSTRACTAsthma is a chronic inflammatory disorder in airways with typical pathologic features of airway inflammation and mucus hypersecretion. α-Terpineol is a monocyclic terpene found in many natural plants and foods. It has been reported to possess a wide range of pharmacological activities including anti-inflammatory and expectorant effects. However, the role of α-terpineol in asthma and its potential protective mechanism have not been well elucidated. This study is designed to investigate the pharmacological effect and mechanism of α-terpineol on asthmatic mice using the metabolomics platform. A murine model of asthma was established using ovalbumin (OVA) sensitization and then challenged for one week. The leukocyte count and inflammatory cytokines in the bronchoalveolar lavage fluid (BALF), lung histopathology, inflammatory infiltrate and mucus secretion were evaluated. An ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS)-based metabolomics study was performed on lung tissues and serum to explore endogenous small molecule metabolites affected by α-terpineol in asthmatic mice. After α-terpineol treatment, leukocyte count, inflammatory cytokines in the BALF, and peribronchial inflammation infiltration were significantly downregulated. Goblet cell hyperplasia and mucus secretion were attenuated, with the level of Muc5ac in BALF decreased. These results proved the protective effect of α-terpineol against airway inflammation, mucus hypersecretion and Th1/Th2 immune imbalance. To further investigate the underlying mechanisms of α-terpineol in asthma treatment, UPLC-MS/MS-based metabolomics analysis was performed. 26 and 15 identified significant differential metabolites were found in the lung tissues and serum of the control, model and α-terpineol groups, respectively. Based on the above differential metabolites, enrichment analysis showed that arachidonic acid (AA) metabolism was reprogrammed in both mouse lung tissues and serum. 5-Lipoxygenase (5-LOX) and cysteinyl leukotrienes (CysLTs) are the key enzyme and the end product of AA metabolism, respectively. In-depth studies have shown that pretreatment with α-terpineol can alleviate asthma by decreasing the AA level, downregulating the expression of 5-LOX and reducing the accumulation of CysLTs in mouse lung tissues. In summary, this study demonstrates that α-terpineol is a potential agent that can prevent asthma via regulating disordered AA metabolism.PMID:38526853 | DOI:10.1039/d3fo04078j

J Agric Food Chem. 2024 Mar 25. doi: 10.1021/acs.jafc.3c09668. Online ahead of print.ABSTRACTThe need to reduce the use of pesticides in viticulture is increasing the interest in wines produced using fungal-resistant grapevine varieties, which are characterized by relevant contents of both monoglucoside and diglucoside anthocyanins. Aging in wooden barrels induces oxygen permeation into wine, but little is known about diglucoside anthocyanin evolution. Cabernet cortis wine was subjected to addition of oxygen and oak chips, and the anthocyanin changes were followed for 1 month. Decreases of 90% total monoglucosides, 80% acylated monoglucosides, 65% diglucosides, and 90% acylated diglucosides were observed. Monoglucosides formed pyranoanthocyanins, and the lower steric hindrance favored their polymerization with flavanols. Instead, the decrease in diglucosides was correlated to the number of hydroxyl groups of ring B, indicating the predominant oxidation of aglycones. However, three flavonol-anthocyanin-diglucoside derivatives named (epi)catechin-ethyl-Mv-dihexoside, (epi)catechin-ethyl-Pn-dihexoside, and (epi)catechin-Mv-dihexoside A-type were identified in wine for the first time. These research findings are useful for tuning suitable oenological practices to stabilize the color of these wines (type of barrel, aging times, oxygenation practices) and lower the malvin content, which currently is recommended by the OIV at a maximum of 15 mg/L and is a critical issue for their commercialization.PMID:38526294 | DOI:10.1021/acs.jafc.3c09668

Shock. 2024 Mar 25. doi: 10.1097/SHK.0000000000002353. Online ahead of print.ABSTRACTCurrently, the coronavirus disease 2019 (COVID-19) is becoming a serious threat to human health worldwide. Therefore, there is a great need to develop effective drugs against viral pneumonia. Diammonium glycyrrhizinate (DG), derived from Glycyrrhiza glabra L., has been demonstrated with significant anti-inflammatory properties. However, the therapeutic effects and mechanisms of DG on pneumonia require further clarification. In this study, mice received intratracheal injection of polyinosinic-polycytidylic acid (poly(I:C)) to induce pneumonia and were treated with DG. First, we evaluated the therapeutic potential of DG on poly(I:C)-induced pneumonia. Second, the anti-inflammatory and anti-oxidative activities and the impact of DG on the Toll-like receptor 3 (TLR3) pathway were investigated. Third, the mechanism of DG was analyzed through untargeted metabolomics techniques. Our results revealed that DG intervention decreased permeability and reduced abnormal lung alterations in poly(I:C)-induced pneumonia model mice. DG intervention also downregulated cytokine levels in bronchoalveolar lavage fluid. Moreover, DG treatment inhibited the activation of TLR3 pathway. Furthermore, untargeted metabolomics analysis revealed that DG intervention could modulate serum metabolites involved in amino and nucleotide sugar metabolism, fructose and mannose metabolism, tyrosine metabolism, and phenylalanine, tyrosine, and tryptophan biosynthesis pathways. In conclusion, our study showed that DG could ameliorate poly(I:C)-induced pneumonia by inactivating the TLR3 pathway and affecting amino and nucleotide sugar, fructose and mannose metabolism, as well as tryptophan, phenylalanine, and tyrosine biosynthesis.PMID:38526139 | DOI:10.1097/SHK.0000000000002353

Nurs Rep. 2024 Mar 22;14(2):675-682. doi: 10.3390/nursrep14020051.ABSTRACTSymptom management remains challenging in cancer care. Emerging from nutritional science, nutritional metabolomics has seen exponential growth over recent years, aiming to discern the relationship between dietary habits and health consequences. This protocol aims to present the rationale and methodology for conducting a scoping review to summarize the extent of evidence on synbiotics utilization in cancer symptom management among adults. The scoping review will be undertaken in accordance with the Joanna Briggs Institute (JBI) principles and the research process guided by the PRISMA 2020 scoping reviews extension. The following electronic databases will be searched from the inception: PubMed, Cinahl, Web of Science and Scopus. The authors expect to map the literature regarding the clinical outcomes, including patient-report measures and patient-experience measures, on which the effects of probiotics were tested, and identify potential gaps. This protocol presents a rigorous methodological approach to map the literature on the clinical outcomes that the utilization of synbiotics might improve. This analysis will shape future researchers to examine the efficacy of probiotics on specific clinical outcomes in oncology care. Nurses are uniquely positioned to influence cancer symptom management through the selection and use of appropriate interventions in the field of nutritional supplements, along with nutritional counseling.PMID:38525697 | DOI:10.3390/nursrep14020051

Chem Res Toxicol. 2024 Mar 25. doi: 10.1021/acs.chemrestox.4c00042. Online ahead of print.ABSTRACTExposure to triclocarban (TCC), a commonly used antibacterial agent, has been shown to induce significant intestine injuries and colonic inflammation in mice. However, the detailed mechanisms by which TCC exposure triggered enterotoxicity remain largely unclear. Herein, intestinal toxicity effects of long-term and chronic TCC exposure were investigated using a combination of histopathological assessments, metagenomics, targeted metabolomics, and biological assays. Mechanically, TCC exposure caused induction of intestinal aryl hydrocarbon receptor (AhR) and its transcriptional target cytochrome P4501A1 (Cyp1a1) leading to dysfunction of the gut barrier and disruption of the gut microbial community. A large number of lipopolysaccharides (LPS) are released from the gut lumen into blood circulation owing to the markedly increased permeability and gut leakage. Consequently, toll-like receptor-4 (TLR4) and NF-κB signaling pathways were activated by high levels of LPS. Simultaneously, classic macrophage phenotypes were switched by TCC, shown with marked upregulation of macrophage M1 and downregulation of macrophage M2 that was accompanied by striking upregulation of proinflammatory factors such as Il-1β, Il-6, Il-17, and Tnf-α in the intestinal lamina propria. These findings provide new evidence for the TCC-induced enterotoxicity.PMID:38525689 | DOI:10.1021/acs.chemrestox.4c00042

S Afr Med J. 2023 Dec 4;113(12):9. doi: 10.7196/SAMJ.2023.v113i12.1507.NO ABSTRACTPMID:38525623 | DOI:10.7196/SAMJ.2023.v113i12.1507

Front Plant Sci. 2024 Feb 26;15:1339424. doi: 10.3389/fpls.2024.1339424. eCollection 2024.ABSTRACTThe population of Caragana tibetica, situated on the edge of the typical grassland-to-desert transition in the Mu Us Sandy Land, plays a vital ecological role in maintaining stability within the regional fragile ecosystem. Despite the consistent growth of C. tibetica following animal grazing, the biological mechanisms underlying its compensatory growth in response to livestock consumption remain unclear. Analyzing 48 metabolomic profiles from C. tibetica, our study reveals that the grazing process induces significant changes in the metabolic pathways of C. tibetica branches. Differential metabolites show correlations with soluble protein content, catalase, peroxidase, superoxide dismutase, malondialdehyde, and proline levels. Moreover, machine learning models built on these differential metabolites accurately predict the intensity of C. tibetica grazing (with an accuracy of 83.3%). The content of various metabolites, indicative of plant stress responses, including Enterolactone, Narceine, and Folcepri, exhibits significant variations in response to varying grazing intensities (P<0.05). Our investigation reveals that elevated grazing intensity intensifies the stress response in C. tibetica, triggering heightened antioxidative defenses and stress-induced biochemical activities. Distinctive metabolites play a pivotal role in responding to stress, facilitating the plant's adaptation to environmental challenges and fostering regeneration.PMID:38525150 | PMC:PMC10959174 | DOI:10.3389/fpls.2024.1339424

Front Microbiol. 2024 Mar 8;15:1301292. doi: 10.3389/fmicb.2024.1301292. eCollection 2024.ABSTRACTRecently, it has been discovered that certain dairy buffaloes can produce higher milk yield and milk fat yield under the same feeding management conditions, which is a potential new trait. It is unknown to what extent, the rumen microbiome and its metabolites, as well as the host metabolism, contribute to milk yield and milk fat yield. Therefore, we will analyze the rumen microbiome and host-level potential regulatory mechanisms on milk yield and milk fat yield through rumen metagenomics, rumen metabolomics, and serum metabolomics experiments. Microbial metagenomics analysis revealed a significantly higher abundance of several species in the rumen of high-yield dairy buffaloes, which mainly belonged to genera, such as Prevotella, Butyrivibrio, Barnesiella, Lachnospiraceae, Ruminococcus, and Bacteroides. These species contribute to the degradation of diets and improve functions related to fatty acid biosynthesis and lipid metabolism. Furthermore, the rumen of high-yield dairy buffaloes exhibited a lower abundance of methanogenic bacteria and functions, which may produce less methane. Rumen metabolome analysis showed that high-yield dairy buffaloes had significantly higher concentrations of metabolites, including lipids, carbohydrates, and organic acids, as well as volatile fatty acids (VFAs), such as acetic acid and butyric acid. Meanwhile, several Prevotella, Butyrivibrio, Barnesiella, and Bacteroides species were significantly positively correlated with these metabolites. Serum metabolome analysis showed that high-yield dairy buffaloes had significantly higher concentrations of metabolites, mainly lipids and organic acids. Meanwhile, several Prevotella, Bacteroides, Barnesiella, Ruminococcus, and Butyrivibrio species were significantly positively correlated with these metabolites. The combined analysis showed that several species were present, including Prevotella.sp.CAG1031, Prevotella.sp.HUN102, Prevotella.sp.KHD1, Prevotella.phocaeensis, Butyrivibrio.sp.AE3009, Barnesiella.sp.An22, Bacteroides.sp.CAG927, and Bacteroidales.bacterium.52-46, which may play a crucial role in rumen and host lipid metabolism, contributing to milk yield and milk fat yield. The "omics-explainability" analysis revealed that the rumen microbial composition, functions, metabolites, and serum metabolites contributed 34.04, 47.13, 39.09, and 50.14%, respectively, to milk yield and milk fat yield. These findings demonstrate how the rumen microbiota and host jointly affect milk production traits in dairy buffaloes. This information is essential for developing targeted feeding management strategies to improve the quality and yield of buffalo milk.PMID:38525073 | PMC:PMC10959287 | DOI:10.3389/fmicb.2024.1301292

J Pancreatol. 2024 Mar;7(1):21-27. doi: 10.1097/JP9.0000000000000173. Epub 2024 Feb 9.ABSTRACTThe "omics" revolution has transformed the biomedical research landscape by equipping scientists with the ability to interrogate complex biological phenomenon and disease processes at an unprecedented level. The volume of "big" data generated by the different omics studies such as genomics, transcriptomics, proteomics, and metabolomics has led to the concurrent development of computational tools to enable in silico analysis and aid data deconvolution. Considering the intensive resources and high costs required to generate and analyze big data, there has been centralized, collaborative efforts to make the data and analysis tools freely available as "Open Source," to benefit the wider research community. Pancreatology research studies have contributed to this "big data rush" and have additionally benefitted from utilizing the open source data as evidenced by the increasing number of new research findings and publications that stem from such data. In this review, we briefly introduce the evolution of open source omics data, data types, the "FAIR" guiding principles for data management and reuse, and centralized platforms that enable free and fair data accessibility, availability, and provide tools for omics data analysis. We illustrate, through the case study of our own experience in mining pancreatitis omics data, the power of repurposing open source data to answer translationally relevant questions in pancreas research.PMID:38524857 | PMC:PMC10959533 | DOI:10.1097/JP9.0000000000000173

Front Nutr. 2024 Mar 8;11:1388485. doi: 10.3389/fnut.2024.1388485. eCollection 2024.ABSTRACT[This corrects the article DOI: 10.3389/fnut.2024.1327863.].PMID:38524851 | PMC:PMC10959019 | DOI:10.3389/fnut.2024.1388485

Front Nutr. 2024 Mar 8;11:1354486. doi: 10.3389/fnut.2024.1354486. eCollection 2024.ABSTRACTINTRODUCTION: With the increasing demand for protein utilization, exploring new protein resources has become a research hotspot. Sacha Inchi Protein (SIP) is a high-quality plant protein extracted from Sacha Inchi meal. This study aimed to investigate the impact of SIP on mouse metabolomics and gut microbiota diversity and explore the underlying pathways responsible for its health benefits.METHODS: In this study, the structural composition of SIP was investigated, and the effects of SIP on fecal metabolomics and intestinal microorganisms in mice were explored by LC-MS metabolomics technology analysis and 16S rRNA gene sequencing.RESULTS: The results showed that SIP was rich in amino acids, with the highest Manuscript Click here to view linked References content of arginine, which accounted for 22.98% of the total amino acid content; the potential fecal metabolites of mice in the SIP group involved lipid metabolism, sphingolipid metabolism, arginine biosynthesis, and amino acid metabolism; SIP altered the microbial composition of the cecum in mice, decreased the Firmicutes/Bacteroidetes value, and It decreased the abundance of the harmful intestinal bacteria Actinobacteriota and Desulfobacterota, and increased the abundance of the beneficial intestinal bacteria Faecalibaculum, Dubosiella.DISCUSSION: In conclusion, SIP is a high-quality plant protein with great potential for development in lipid-lowering, intestinal health, and mental illness, providing valuable clues for further research on its health-promoting mechanisms.PMID:38524850 | PMC:PMC10959099 | DOI:10.3389/fnut.2024.1354486

Biophys Rep. 2023 Dec 31;9(6):299-308. doi: 10.52601/bpr.2023.230042.ABSTRACTEfficient quantification of fatty-acid (FA) composition (fatty-acidome) in biological samples is crucial for understanding physiology and pathophysiology in large population cohorts. Here, we report a rapid GC-FID/MS method for simultaneous quantification of all FAs in numerous biological matrices. Within eight minutes, this method enabled simultaneous quantification of 50 FAs as fatty-acid methyl esters (FAMEs) in femtomole levels following the efficient transformation of FAs in all lipids including FFAs, cholesterol-esters, glycerides, phospholipids and sphingolipids. The method showed satisfactory inter-day and intra-day precision, stability and linearity (R2 > 0.994) within a concentration range of 2-3 orders of magnitude. FAs were then quantified in typical multiple biological matrices including human biofluids (urine, plasma) and cells, animal intestinal content and tissue samples. We also established a quantitative structure-retention relationship (QSRR) for analytes to accurately predict their retention time and aid their reliable identification. We further developed a novel no-additive retention index (NARI) with endogenous FAMEs reducing inter-batch variations to 15 seconds; such NARI performed better than the alkanes-based classical RI, making meta-analysis possible for data obtained from different batches and platforms. Collectively, this provides an inexpensive high-throughput analytical system for quantitative phenotyping of all FAs in 8-minutes multiple biological matrices in large cohort studies of pathophysiological effects.PMID:38524698 | PMC:PMC10960574 | DOI:10.52601/bpr.2023.230042

iScience. 2024 Feb 26;27(3):109121. doi: 10.1016/j.isci.2024.109121. eCollection 2024 Mar 15.ABSTRACTDysregulation of liver metabolism associated with obesity during feeding and fasting leads to the breakdown of metabolic homeostasis. However, the underlying mechanism remains unknown. Here, we measured multi-omics data in the liver of wild-type and leptin-deficient obese (ob/ob) mice at ad libitum feeding and constructed a differential regulatory trans-omic network of metabolic reactions. We compared the trans-omic network at feeding with that at 16 h fasting constructed in our previous study. Intermediate metabolites in glycolytic and nucleotide metabolism decreased in ob/ob mice at feeding but increased at fasting. Allosteric regulation reversely shifted between feeding and fasting, generally showing activation at feeding while inhibition at fasting in ob/ob mice. Transcriptional regulation was similar between feeding and fasting, generally showing inhibiting transcription factor regulations and activating enzyme protein regulations in ob/ob mice. The opposite metabolic dysregulation between feeding and fasting characterizes breakdown of metabolic homeostasis associated with obesity.PMID:38524370 | PMC:PMC10960062 | DOI:10.1016/j.isci.2024.109121

Open Forum Infect Dis. 2024 Feb 27;11(3):ofae111. doi: 10.1093/ofid/ofae111. eCollection 2024 Mar.ABSTRACTBACKGROUND: Subtype-specific amino acid variations in viral proteins of human immunodeficiency virus type 1 (HIV-1) influence disease progression. Furthermore, Vpr sequence variation correlates with chronic inflammation, a central mechanism in HIV-1 (neuro)pathogenesis. Nevertheless, no clinical study has investigated the link between Vpr sequence variation and peripheral inflammation in people with HIV (PWH). The aim of this pilot study was to ascertain whether specific Vpr amino acid variants were associated with immune markers in PWH.METHODS: We included a unique cohort of 48 treatment-naive South African PWH to determine the association between blood-derived Vpr sequence variation and peripheral immune marker levels using Sanger sequencing and enzyme-linked immunosorbent assay analysis, respectively.RESULTS: Our findings indicate that among the many neuropathogenic Vpr amino acid variants and immune markers examined, after applying Bonferroni corrections (P = .05/3) and adjusting for sex and locality, soluble urokinase plasminogen activator receptor (suPAR) was nearing significance for higher levels in participants with the G41 amino acid variant compared to those with the S41 variant (P = .035). Furthermore, amino acid variations at position 41 (between G41 and S41) exhibited a significant association with suPAR (adjusted R2 = 0.089, β = .386 [95% confidence interval, .125-3.251]; P = .035).CONCLUSIONS: These findings suggest that Vpr amino acid sequence variations might contribute to dysregulated inflammation, which could explain the observed association between specific Vpr variants and HIV-1 (neuro)pathogenesis found in prior research. These Vpr variants merit further investigation to fully understand their roles in HIV-1 pathogenesis and neuropathogenesis.PMID:38524224 | PMC:PMC10960601 | DOI:10.1093/ofid/ofae111

Front Aging Neurosci. 2024 Mar 8;16:1356086. doi: 10.3389/fnagi.2024.1356086. eCollection 2024.ABSTRACTINTRODUCTION: The differential expression of emotional reactivity from early to late adulthood may involve maturation of prefrontal cortical responses to negative valence stimuli. In mice, age-related changes in affective behaviors have been reported, but the functional neural circuitry warrants further investigation.METHODS: We assessed age variations in affective behaviors and functional connectivity in male and female C57BL6/J mice. Mice aged 10, 30 and 60 weeks (wo) were tested over 8 weeks for open field activity, sucrose preference, social interactions, fear conditioning, and functional neuroimaging. Prefrontal cortical and hippocampal tissues were excised for metabolomics.RESULTS: Our results indicate that young and old mice differ significantly in affective behavioral, functional connectome and prefrontal cortical-hippocampal metabolome. Young mice show a greater responsivity to novel environmental and social stimuli compared to older mice. Conversely, late middle-aged mice (60wo group) display variable patterns of fear conditioning and during re-testing in a modified context. Functional connectivity between a temporal cortical/auditory cortex network and subregions of the anterior cingulate cortex and ventral hippocampus, and a greater network modularity and assortative mixing of nodes was stronger in young versus older adult mice. Metabolome analyses identified differences in several essential amino acids between 10wo mice and the other age groups.DISCUSSION: The results support differential expression of 'emotionality' across distinct stages of the mouse lifespan involving greater prefrontal-hippocampal connectivity and neurochemistry.PMID:38524115 | PMC:PMC10957556 | DOI:10.3389/fnagi.2024.1356086