PubMed

Chem Biodivers. 2024 Dec 16:e202401676. doi: 10.1002/cbdv.202401676. Online ahead of print.ABSTRACTThe few current metabolomic studies on ferns are mostly restricted to a single species or focused on specific compounds. We performed an untargeted metabolomic study on six of the most common fern species from the cloud forest, followed by a targeted analysis of 64 phenolic compounds, many of which have been associated with herbivore defense. The untargeted analysis revealed a total of 232 putatively identified metabolites from 463 to 1427 signals per fern species, each with its proper chemical signature but not necessarily correlated to their phylogenetic relationship. The flavonoid, flavone, and flavonol biosynthesis were the most expressed pathways in all species except for Marattia laxa. Fern species also differed strongly in the concentrations of the 10 detected phenolic compounds. Our results show that ferns, including the most ancestral species, such as M. laxa, display a high metabolomic diversity comparable to seed plants. Each fern species held a different combination of defensive phenolic compounds. Further research is needed to explore the metabolic diversity, to identify the biochemical defenses of ferns, and, in particular, to detect the chemical compounds that act against their specific herbivorous insects in the cloud forest ecosystem.PMID:39680754 | DOI:10.1002/cbdv.202401676

Plant Biol (Stuttg). 2024 Dec 16. doi: 10.1111/plb.13753. Online ahead of print.ABSTRACTInterspecific hybridization plays an important role in plant evolution, contributing to taxonomic uncertainty through intermediate phenotypes or the emergence of novel traits. The characterization of hybridization is important to elucidate systematic relationships and its role in the diversification of lineages. The genus Cenostigma comprises neotropical legume trees with phylogenetic inconsistencies, and individuals showing intermediate morphology between sympatric species, suggesting natural hybridization. We tested this hypothesis by investigating two endemic species from the Caatinga dry forest in northeast Brazil (C. microphyllum and C. pyramidale) using molecular markers (nuclear and plastid SSRs), geometric morphometrics, non-targeted metabolomics, and ecological analyses. We detected a high plastidial genetic structure among populations, not related to species boundaries but to their geographic distribution. The geometric morphometric analysis showed a clustering of pure individuals of both species with hybrids in an intermediate position, demonstrating the hybridization of these species in Caatinga. Nuclear DNA and metabolite diversity supported the separation of the two species into three clusters, with a subdivision of C. pyramidale in populations from the north (Pernambuco) and south (Bahia). Metabolomics revealed a fourth group formed mostly by hybrids. Later generation hybrids were detected as intermediate morphological forms, and gene flow was assumed as asymmetric among species and populations, being higher from C. pyramidale to C. microphyllum in populations from Bahia State. Ecological data indicated niche overlap. Hence, interspecific gene flow occurs among Cenostigma tree species, contributing to the evolution of the dry forest. Given the karyotypic and genomic similarity among species, as well as molecular and ecological evidence, we infer that the hybrids are fertile, allowing introgression and contributing to systematic complexity in Cenostigma. Hybridization did not significantly increase chemodiversity in terms of novel compounds but differentiated hybrids from parental species. In summary, we highlight the importance of multiple evidence, particularly genetic, morphological, and metabolomic traits, in the identification of hybrids and its evolutionary impact in natural environments.PMID:39680475 | DOI:10.1111/plb.13753

Mol Biol Rep. 2024 Dec 16;52(1):52. doi: 10.1007/s11033-024-10175-7.ABSTRACTBACKGROUND: Sepsis-associated acute kidney injury (SA-AKI) stands out as a critical health issue due to its high mortality and morbidity rates. This study aimed to comprehensively investigate the biochemical and metabolic alterations induced by lipopolysaccharide (LPS) in human embryonic kidney cells (HEK-293) using an in vitro model.METHODS AND RESULTS: The study investigated the impact of LPS on HEK-293 cells by evaluating cytotoxicity using the MTT assay, analyzing apoptosis, cell cycle progression, and oxidative stress via flow cytometry, measuring TNF-α levels through ELISA, and assessing amino acid metabolism with LC-MS/MS. The findings demonstrated that LPS significantly reduced cell viability in a dose-dependent manner, increased apoptotic cell populations, induced DNA damage by arresting the cell cycle in the Sub-G1 phase, and activated oxidative stress pathways. Notably, elevated reactive oxygen species (ROS) production and increased secretion of the pro-inflammatory cytokine TNF-α highlighted LPS's inflammatory and cytotoxic effects. Furthermore, systematic analysis revealed LPS-induced disruptions in amino acid metabolism, including marked reductions in alanine, arginine, and aspartic acid levels. KEGG pathway analysis identified significant metabolic alterations in pathways such as the urea cycle, TCA cycle, and glutathione metabolism. Interestingly, elevated citrulline levels suggested a potential adaptive mechanism to counteract LPS-induced inflammation and oxidative stress. Additionally, ROC analysis identified cystine as a highly reliable biomarker, with an AUC value of 1.00, emphasizing its critical role in metabolic reprogramming associated with SA-AKI.CONCLUSIONS: This study provides critical insights into the molecular pathophysiology of SA-AKI and emphasizes the promise of metabolomic approaches in the early diagnosis of sepsis-related complications and the development of targeted therapies.PMID:39680269 | DOI:10.1007/s11033-024-10175-7

Environ Sci Technol. 2024 Dec 16. doi: 10.1021/acs.est.4c09592. Online ahead of print.ABSTRACTExisting air pollution metabolomics studies showed inconsistent results, often limited by small sample size and individual air pollutants effects. We conducted a metabolome-wide association study among 1096 women (68.2 ± 5.7 years) who provided blood samples (1998-2001) within the Cancer Prevention Study-II Nutrition Cohort. Annual average individual exposures to particulate matter, nitrogen dioxide, ozone, sulfur dioxide, and carbon monoxide in the year of blood draw were used. Metabolomics profiling was conducted on serum samples by Metabolon. We evaluated the individual air pollutants effects using multiple linear regression and the mixture effect using quantile g-computation, adjusting for confounders and false discovery rate (FDR). Ninety-five metabolites were significantly associated with at least one air pollutant or mixture (FDR < 0.05). These metabolites were enriched in pathways related to oxidative stress, systemic inflammation, energy metabolism, signals transduction, nucleic acid damage and repair, and xenobiotics. Sixty metabolites were confirmed with level 1 or 2 evidence, among which 21 have been previously linked to air pollution exposure, including taurine, creatinine, and sebacate. Overall, our results replicate prior findings in a large sample and provide novel insights into biological responses to long-term air pollution exposure using mixture analysis.PMID:39680091 | DOI:10.1021/acs.est.4c09592

J Exp Bot. 2024 Dec 16:erae481. doi: 10.1093/jxb/erae481. Online ahead of print.ABSTRACTSterols are produced via complex, multistep biosynthetic pathways involving similar enzymatic conversions in plants, animals and fungi, yielding a variety of sterol metabolites with slightly different chemical properties to exert diverse and specific functions. A tremendously diverse landscape of sterols, and sterol-derived compounds, can be found across the plant kingdom, determining a wide spectrum of functions. Resolving the underlying biosynthetic pathways is thus instrumental to understanding the function and use of these molecules. In only a few plants, sterol biosynthesis has been studied using mutants. In non-model species a pharmacological approach is required. However, this relies on only a few inhibitors. Here, we probed a collection of inhibitors of mammalian cholesterol biosynthesis to identify new inhibitors of plant sterol biosynthesis. We show that imidazole-type fungicides, bifonazole, clotrimazole and econazole inhibit the obtusifoliol 14α-demethylase CYP51 in plants. Moreover, we found that the selective estrogen receptor modulator, clomiphene, inhibits sterol biosynthesis in part by inhibiting the plant-specific cyclopropyl-cycloisomerase CPI1. These results demonstrate that rescreening of inhibitors animal sterol biosynthesis is an easy approach for identifying novel inhibitors of plant sterol biosynthesis. These molecules expand the toolkit for studying and manipulating sterol biosynthesis in the plant kingdom.PMID:39680055 | DOI:10.1093/jxb/erae481

Plant Cell Environ. 2024 Dec 16. doi: 10.1111/pce.15333. Online ahead of print.ABSTRACTLunar farming, often regarded as a myth, is regularly practiced in many places around the world (e.g., India) where framers organized their agricultural activities according to moon phases. Early and recent work showed that exposure to moonlight affects the life cycle of plants, from seed germination and vegetative growth to fruit maturation and dispersal. Here we addressed the long-term effect of short exposure to full moonlight (FML) on cellular activities in Brassica juncea by analyzing protein and metabolite profiles immediately after 3-night-exposure (3NE) or 7 and 15 days after exposure (DAE) to FML. This study shows an increase in nuclear size following 3NE to FML, which was accompanied by changes in protein and metabolite profiles. We identified significant alterations in protein and metabolite profiles between FML and dark-treated plants in conjunction with developmental stages, which persisted long after exposure to FML. Most notable are the changes in composition of metabolite interconversion enzymes (MIEs) at various developmental stages which were intensified in FML-treated plants. Changes in MIEs were accompanied by significant alterations in metabolite composition and level, particularly at 15DAE, including branched-chain amino acids (e.g., valine, leucine), multiple sugars (raffinose, glucose, sucrose) as well as the tricarboxylic acid (TCA) cycle intermediates malic acid and citric acid. Thus, our results show that short-term exposure to FML triggers a developmental switch resulting in a long-term impact on plant performance that brings about an increase in cell activities and consequently enhanced growth. Our results call for meticulous research on this lunar phenomenon and its potential to enhance crop plant growth and development.PMID:39679718 | DOI:10.1111/pce.15333

Gut Microbes. 2024 Jan-Dec;16(1):2405547. doi: 10.1080/19490976.2024.2405547. Epub 2024 Oct 7.ABSTRACTThe intestinal microbiota is increasingly recognized as a crucial player in the development and maintenance of various chronic conditions, including obesity and associated metabolic diseases. While most research focuses on the fecal microbiota due to its easier accessibility, the small intestine, as a major site for nutrient sensing and absorption, warrants further investigation to determine its microbiota composition and functions. Here, we conducted a clinical research project in 30 age- and sex-matched participants with (n = 15) and without (n = 15) obesity. Duodenojejunal fluid was obtained by aspiration during endoscopy. Phenotyping included clinical variables related to metabolic status, lifestyle, and psychosocial factors using validated questionnaires. We performed metagenomic analyses of the oral, duodenojejunal, and fecal microbiome, alongside metabolomic data from duodenojejunal fluid and feces, integrating these data with clinical and lifestyle information. Our results highlight significant associations between duodenojejunal microbiota composition and usual dietary intake, as well as clinical phenotypes, with larger effect sizes than the associations between these variables and fecal microbiota. Notably, we found that the duodenojejunal microbiota of patients with obesity exhibited higher diversity and showed distinct differences in the abundance of several duodenojejunal microbiota species compared with individuals without obesity. Our findings support the relevance of studying the role of the small intestinal microbiota in the pathogenesis of nutrition-related diseases.PMID:39679619 | DOI:10.1080/19490976.2024.2405547

Front Pharmacol. 2024 Nov 28;15:1429960. doi: 10.3389/fphar.2024.1429960. eCollection 2024.ABSTRACTIschemic stroke (IS) is a highly lethal type of cardiovascular and cerebrovascular disease. Improving survival rates and promoting recovery in patients with IS pose significant challenges, however, recent research has identified the gut-brain axis as a therapeutic target. In this study, we evaluated the regulatory effect of Periplaneta americana (L.) extract (PAS840), which has established anti-inflammatory, antioxidant, and neuroprotective effects, on the gut microbiota using a rat model of temporary middle cerebral artery occlusion (tMCAO). We evaluated the protective effects of PAS840 on brain damage in IS rats through TTC (triphenyltetrazolium chloride), Nissl staining, and pathological section analysis. Additionally, we investigated the impact of PAS840 on the gut microbiota and metabolites using 16S rRNA sequencing, untargeted metabolomics of gut contents, and transcriptomics analyses of brain tissues to explore its mechanism of action. PAS840 intervention resulted in significant changes in the gut microbiota, including an increase in the abundance of probiotic flora, decrease in the abundance of harmful flora, and significant changes in metabolite profiles. It also attenuated brain damage, decreased platelet activity, inhibited oxidative stress and genes related to inflammation, and improved neurological function in rats. These findings suggest that PAS840 has preventive and therapeutic effects against IS via the gut-brain axis by regulating the gut microbiota and related metabolites. Accordingly, PAS840 is a candidate therapeutic drug for further research.PMID:39679371 | PMC:PMC11638836 | DOI:10.3389/fphar.2024.1429960

Anim Nutr. 2024 Jul 17;19:453-465. doi: 10.1016/j.aninu.2024.04.024. eCollection 2024 Dec.ABSTRACTThis study was to evaluate the effects of different dietary oils in chicken diets on meat quality, lipid metabolites, the composition of volatile compounds, and gut microbiota. Nine hundred female 817 crossbred broilers at one day old with an average body weight of 43.56 ± 0.03 g were randomly divided into five treatments, each consisting of 6 replicates of 30 birds. The control group received soybean oil (SO); other groups received diets supplemented with rice bran oil (RO), lard (LO), poultry fat (PO), and blended oil (BO), respectively. All diets were formulated as isoenergic and isonitrogenous. Compared with SO, RO decreased ADG and 42 d BW (P < 0.05). Compared with the RO, BO increased ADG and 42 d BW and decreased FCR (P < 0.05). Compared with SO, BO increased 24 h redness (a∗) value and reduced the malondialdehyde concentration (P < 0.05), and further improved drip loss of breast muscle (P > 0.05). The proportions of C18:0 and saturated fatty acid were the highest in LO, and the proportions of C16:1, C18:1, and monounsaturated fatty acids were the highest in BO. The content of C18:2, C18:3, and polyunsaturated fatty acids were the highest in SO. The contents of glyceryl triglycerides and total esters in BO were significantly higher than those in the SO and LO group (P < 0.05). There was a substantial increment in the relative abundance of peroxisome proliferator activated receptor alpha (PPARα), acyl-CoA oxidase 1 (ACOX1), and carnitine palmitoyl-transferase 1 (CPT1A) transcripts in breast of chickens fed BO (P < 0.05). Further, dietary BO increased the relative cecal abundance of Firmicutes phylum, Ruminococcus_torques and Christensenellaceae _R-7 genera, and decreased that of Campylobacterota, Proteobacteria, and Phascolarctobacterium (P < 0.05). Genera g_Lactobacillus and Christensenellaceae _R-7 may mainly be involved in the formation of volatile flavor compounds in breast muscle. In conclusion, dietary BO improved the flavor of chickens by increasing the concentration of triglycerides and volatile flavor compounds, improving gut microbiota structure, and suppressing lipid oxidation. The potential positive effects of BO may be associated with the regulation of lipid metabolism.PMID:39679166 | PMC:PMC11638615 | DOI:10.1016/j.aninu.2024.04.024

Indian J Microbiol. 2024 Dec;64(4):1587-1597. doi: 10.1007/s12088-023-01184-4. Epub 2024 Feb 10.ABSTRACTOur previous study explored the bacterial endophytic diversity in a certain quantity of mustard seeds using culture dependent method by development of new isolation strategies. No bacterial colony was initially observed in supernatant obtained after centrifugation of mustard seed suspension. This was later overcome by usage of surfactant whereas pellet part showed presence of bacterial colonies on media. In our present study, presence of bacteria was examined in supernatant and whether the diversity was similar to that of pellet and seeds by culture independent approach. In addition, growth of bacterial colonies on media is explained using GC-MS. In this study, Proteobacteria was the dominant bacterial phyla followed by Firmicutes in pellet, supernatant and seed. This indicated that bacteria were present in supernatant but may not be viable when plated on media. This is either due to antimicrobial compounds or oil-imposed difficulty during their isolation which might have hindered their survival. GC-MS study revealed the presence of compounds with antimicrobial property as suggested by previous literature. Our research conducts fundamental investigations to address the primary objective of understanding the bacterial diversity in mustard seed, pellet, and supernatant. Further research using workflows of metagenomics and metabolomics approaches can enrich our understanding ofthe diversity of microorganisms in seeds.PMID:39678952 | PMC:PMC11645340 | DOI:10.1007/s12088-023-01184-4

Am J Transl Res. 2024 Nov 15;16(11):6423-6434. doi: 10.62347/IDUA6983. eCollection 2024.ABSTRACTOBJECTIVES: Early-onset schizophrenia (EOS) is a severe and chronic mental disease that manifests during childhood and adolescence. There are currently no objective biomarkers to diagnose this psychosis. Recent research has shown that metabolic disorders are closely associated with the onset of schizophrenia, but there is a lack of evidence among children and adolescent populations. This study will analyze the metabolic characteristics of patients with early-onset schizophrenia through plasma metabolomics.METHODS: We analyzed plasma from 13 EOS patients and 15 healthy controls using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS) technology to identify potential biomarkers for EOS. The discriminative potential biomarkers in delineating EOS patients from controls.RESULTS: A total of 22 different metabolites were found to be effective in differentiating EOS patients from healthy controls. EOS patients demonstrated statistically significant differences compared to the healthy control group, with 6 metabolites registering lower levels and 16 metabolites showing higher levels (P < 0.05). The main metabolic pathways involved include arachidonic acid metabolism, histidine metabolism, non-natural amino acid metabolism, tryptophan metabolism, and metabolism of exogenous substances mediated by cytochrome P450.CONCLUSIONS: These metabolites suggest that disturbances in amino acid and energy metabolism may be involved in the pathogenesis of EOS. The findings provide important clues for further understanding the pathogenesis of EOS and offer potential biomarkers for the diagnosis and treatment of the disease.PMID:39678582 | PMC:PMC11645623 | DOI:10.62347/IDUA6983

Am J Transl Res. 2024 Nov 15;16(11):7036-7053. doi: 10.62347/RQBJ2018. eCollection 2024.ABSTRACTConstipation is a clinical condition characterized by reduced intestinal motility, dry and hardened stool, and prolonged retention. Common constipation medicines are less stable, and prolonged use can lead to dependency and side effects. Cistanche deserticola Ma, a well-known Traditional Chinese Medicine, is frequently used to alleviate constipation. In this study, we established a loperamide-induced constipation model in mice to investigate the effects of Cistanche polysaccharides (CDPS) and to explore its underlying pharmacological mechanism. The serum levels of inflammatory factors, gastrointestinal hormones and neurotransmitters of mice were measured by enzyme-linked immunosorbent assay (ELISA). Intestinal tight junction integrity was evaluated using immunohistochemistry, and Western blot was used to detect tight junction protein levels. Gut microbial community structure and metabolite content were determined using 16S rRNA sequencing and metabolomics analysis. Oral CDPS enhanced the intestinal tight junction integrity, improved barrier function of intestinal mucosa, reduced inflammation, restored intestinal microbiota balance, and regulated metabolite levels. Notably, CDPS increased the abundance of beneficial bacteria, including Prevotellaceae UCG-001, Odoribacter, Clostridiales vadin BB60 group, Alistipes, Lactobacillaceae, and Rikenellaceae, while decreasing the abundance of harmful bacteria such as Parabacteroides and Proteobacteria. In summary, CDPS may prevent and treat constipation by modulating intestinal flora composition, influencing metabolite profiles, and reinforcing mucosal barrier function.PMID:39678557 | PMC:PMC11645619 | DOI:10.62347/RQBJ2018

Front Mol Biosci. 2024 Nov 29;11:1503412. doi: 10.3389/fmolb.2024.1503412. eCollection 2024.NO ABSTRACTPMID:39678199 | PMC:PMC11638043 | DOI:10.3389/fmolb.2024.1503412

Gastroenterol Rep (Oxf). 2024 Dec 13;12:goae106. doi: 10.1093/gastro/goae106. eCollection 2024.ABSTRACTBACKGROUND: Early detection of colorectal cancer (CRC) is crucial to enhance the disease treatment and prognosis of patients. Colonoscopy remains the gold standard for CRC detection; however, it requires trained personnel with expensive tools. Currently, serum metabolites have been discovered to be used to discriminate patients with polyps and CRC. This study aimed to identify the most commonly detected predictive serum metabolites for polyps and CRC.METHODS: A systematic search of the Web of Science, PubMed, and Cochrane Library databases was conducted using PRISMA guidelines. Ten studies investigating serum metabolite biomarkers of CRC and polyps using different analytical platforms and study populations were included. QUADOMICS tool was used to analyse the quality of the included studies. All reported metabolites were then enriched into the pathways using MetaboAnalyst 5.0.RESULTS: We found that several potential signature metabolites overlapped between studies, including tyrosine, lysine, cystine, arabinose, and lactate for CRC and lactate and glutamate for polyps. The most affected pathways related to CRC were the urea cycle, glutathione metabolism, purine metabolism, glutamate metabolism, and ammonia recycling. In contrast, those affected in the polyps were the urea cycle, glutamate metabolism, glutathione metabolism, arginine and proline metabolism, and carnitine synthesis.CONCLUSIONS: This review has found commonly detected serum metabolites for polyps and CRC with huge potential to be used in clinical settings. However, the differences between altered pathways in polyps and CRC, other external factors, and their effects on the regulation level, sensitivity, and specificity of each identified metabolite remained unclear, which could benefit from a further extensive cohort study and well-defined analysis equipment.PMID:39678161 | PMC:PMC11646065 | DOI:10.1093/gastro/goae106

bioRxiv [Preprint]. 2024 Dec 2:2024.11.26.625478. doi: 10.1101/2024.11.26.625478.ABSTRACTNon-steroidal anti-inflammatory drugs (NSAIDs) are popular choices for the mitigation of pain and inflammation; however, they are accompanied by side effects in the gastrointestinal and cardiovascular systems. We compared the effects of naproxen, a traditional NSAID, and celecoxib, a cyclooxygenase -2 (Cox-2) inhibitor, in humans. Our findings showed a decrease in tryptophan and kynurenine levels in plasma of volunteers treated with naproxen. We further validated this result in mice. Additionally, we find that the depression of tryptophan was independent of both Cox-1 and Cox-2 inhibition, but rather was due to the displacement of bound tryptophan by naproxen. Supplementation of tryptophan in naproxen-treated mice rescued fecal blood loss and inflammatory gene expression driven by IL-1β in the heart.PMID:39677795 | PMC:PMC11642787 | DOI:10.1101/2024.11.26.625478

bioRxiv [Preprint]. 2024 Dec 3:2024.11.27.625762. doi: 10.1101/2024.11.27.625762.ABSTRACTPancreatic ductal adenocarcinoma has a unique tumor microbiome and the systemic depletion of bacteria or fungi using antibiotic/antifungal cocktails leads to a decrease in pancreatic tumor burden in mice. However, functional studies remain rare due to the limited availability of clinically relevant microbiota. Here, we describe in detail the isolation of bacteria and fungi from the small intestine and tumor of pancreatic cancer patients at the Rogel Cancer Center. We then further characterized the impact of a newly isolated Klebsiella oxytoca strain ( UMKO1 ) on the pancreatic tumor microenvironment using bacterial genome sequencing, untargeted and targeted metabolomics, as well as an ex vivo tumor transplant system. We found that UMKO1 possesses a gene for the long form of cytidine deaminase, which can inactivate the standard PDAC chemotherapeutic agent gemcitabine. In addition, we found that UMKO1 can produce several indoles when grown in tumor-like conditions, metabolites that can lead to an immune suppressive environment and interfere with therapy outcome. To test this in detail, we assessed changes in immune populations in pancreatic tumor explants upon exposure to the supernatant of UMKO1 and other isolated bacteria grown in tumor Interstitial fluid media (TIFM). We found that while none of the bacterial supernatants changed the abundance of CD8 T cells, granzyme B positive CD8 T cells were the lowest in tumor explants exposed to UMKO1 , and not other isolated Klebsiella species or the non-pathogenic laboratory strain E. coli K12 . In summary, the isolated collection of bacteria and fungi from this study are a valuable toolbox to study the impact of microbiota on pancreatic cancer.PMID:39677718 | PMC:PMC11642792 | DOI:10.1101/2024.11.27.625762

bioRxiv [Preprint]. 2024 Dec 5:2024.12.01.626207. doi: 10.1101/2024.12.01.626207.ABSTRACTIn previous work, we found that short sleep caused sensitivity to oxidative stress; here we set out to characterize the physiological state of a diverse group of chronically short-sleeping mutants during hyperoxia as an acute oxidative stress. Using RNA-sequencing analysis, we found that short-sleeping mutants had a normal transcriptional oxidative stress response relative to controls. In both short-sleeping mutants and controls, hyperoxia led to downregulation of glycolytic genes and upregulation of genes involved in fatty acid metabolism, reminiscent of metabolic shifts during sleep. We hypothesized that short-sleeping mutants may be sensitive to hyperoxia because of defects in metabolism. Consistent with this, short-sleeping mutants were sensitive to starvation. Using metabolomics, we identified a pattern of low levels of long chain fatty acids and lysophospholipids in short-sleeping mutants relative to controls during hyperoxia, suggesting a defect in lipid metabolism. Though short-sleeping mutants did not have common defects in many aspects of lipid metabolism (basal fat stores, usage kinetics during hyperoxia, respiration rates, and cuticular hydrocarbon profiles), they were all sensitive to dehydration, suggesting a general defect in cuticular hydrocarbons, which protect against dehydration. To test the bi-directionality of sleep and lipid metabolism, we tested flies with both diet-induced obesity and genetic obesity. Flies with diet-induced obesity had no sleep or oxidative stress phenotype; in contrast, the lipid metabolic mutant, brummer , slept significantly more than controls but was sensitive to oxidative stress. Previously, all short sleepers tested were sensitive and all long sleepers resistant to oxidative stress. brummer mutants, the first exceptions to this rule, lack a key enzyme required to mobilize fat stores, suggesting that a defect in accessing lipid stores can cause sensitivity to oxidative stress. Taken together, we found that short-sleeping mutants have many phenotypes in common: sensitivity to oxidative stress, starvation, dehydration, and defects in lipid metabolites. These results argue against a specific role for sleep as an antioxidant and suggest the possibility that lipid metabolic defects underlie the sensitivity to oxidative stress of short-sleeping mutants.PMID:39677628 | PMC:PMC11642809 | DOI:10.1101/2024.12.01.626207

medRxiv [Preprint]. 2024 Dec 8:2024.12.06.24318612. doi: 10.1101/2024.12.06.24318612.ABSTRACTThe lack of accurate, cost-effective, and clinically relevant biomarkers remains a major barrier to incorporating omic data into clinical practice. Previous studies have shown that DNA methylation algorithms have utility as surrogate measures for selected proteins and metabolites. We expand upon this work by creating DNAm surrogates, termed epigenetic biomarker proxies (EBPs), across clinical laboratories, the metabolome, and the proteome. After screening >2,500 biomarkers, we trained and tested 1,694 EBP models and assessed their incident relationship with 12 chronic diseases and mortality, followed up to 15 years. We observe broad clinical relevance: 1) there are 1,292 and 4,863 FDR significant incident and prevalent associations, respectively; 2) most of these associations are replicated when looking at the lab-based counterpart, and > 62% of the shared associations have higher odds and hazard ratios to disease outcomes than their respective observed measurements; 3) EBPs of current clinical biochemistries detect deviations from normal with high sensitivity and specificity. Longitudinal EBPs also demonstrate significant changes corresponding to the changes observed in lab-based counterparts. Using two cohorts and > 30,000 individuals, we found that EBPs validate across healthy and sick populations. While further study is needed, these findings highlight the potential of implementing EBPs in a simple, low-cost, high-yield framework that benefits clinical medicine.PMID:39677461 | PMC:PMC11643242 | DOI:10.1101/2024.12.06.24318612

World J Nucl Med. 2024 Jul 11;23(4):270-274. doi: 10.1055/s-0044-1788334. eCollection 2024 Dec.ABSTRACTIntroduction Equilibrium radionuclide angiography (ERNA) has long been assumed as the preferred method to assess cardiac volumes as well as left ventricular systolic and diastolic indices. ERNA was used to diagnose subtle changes in cardiac function during chemotherapy or early stages of heart failure. Gated myocardial perfusion SPECT (GMPS) was introduced as a more feasible and versatile alternative to ERNA, but the precision of GMPS to assess systolic and diastolic indices has not yet been fully reviewed. Method We studied the left ventricular systolic and diastolic functional indices measured by a 16-frame GMPS and compared the results with those of ERNA in 25 patients. All the images were analyzed visually, semi-quantitatively, and quantitatively using quantitative gated SPECT (QGS), quantitative blood pool SPECT (QBS), and planar gated blood pool (PGBP) software. The left ventricular functional indices calculated using QGS compared with those obtained using QBS and PGBP Result Our study found a significant correlation between the left ventricular ejection fraction (LVEF) calculated using the PGBP, QGS, and QBS methods. There was a significant correlation between the LV peak ejection rate (LVPER) calculated by the PGBP and QGS analyses, and there was no significant difference in the LVPER calculated with the QGS and QBS methods. This study also revealed a significant correlation between the LV peak filling rate (LVPFR) calculated by QBS and QGS, with no significant difference between them. We also found a significant correlation between LV end systolic volume (LVESV) calculated using QGS and QBS and between LV end diastolic volume (LVEDV) calculated using QGS and QBS software. This study also revealed a significant correlation between the LV mean filling rate over the first third of diastole (LVMFR/3) calculated using the QGS and QBS software. Conclusion Considering the significant correlation between LVEF, LVPER, LVPFR, LVESV, LVMFR/3, and LVEDV calculated using the QGS and QBS methods in our study, the 16-frame GMPS could be regarded as an acceptable substitute for ERNA in the investigation of systolic and diastolic indices.PMID:39677339 | PMC:PMC11637634 | DOI:10.1055/s-0044-1788334

J Inflamm Res. 2024 Dec 10;17:10849-10869. doi: 10.2147/JIR.S493892. eCollection 2024.ABSTRACTPURPOSE: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease influenced by environmental triggers, including the commensal microbiota. Recent research has highlighted distinctive features of the gut microbiota in RA patients. This study investigates the therapeutic potential of berberine (BBR), a gut microbiota modulator known for its significant anti-RA effects, and elucidates the underlying mechanisms.METHODS: Utilizing the collagen-induced arthritis (CIA) rat model, we comprehensively evaluated the anti-rheumatoid arthritis effects of BBR in vivo through various indices, such as paw edema, arthritis index, ankle diameter, inflammatory cytokine levels, pathological conditions, and micro-CT analysis. Employing network pharmacology, we identified potential targets involved in RA alleviation by BBR. To analyze comprehensive metabolic profiles and identify underlying metabolic pathways, we conducted a serum-based widely targeted metabolomics analysis utilizing LC-MS technology. An integrated network encompassing metabolomics and network pharmacology data was constructed using Cytoscape. The potential therapeutic targets and signaling pathways of BBR in the management of RA were predicted using network pharmacology. Key targets and pathways were further validated by molecular docking and immunofluorescent staining, which integrated findings from serum metabolomics and network pharmacology analysis. Additionally, we analyzed the gut microbiota composition in rats employing 16S rDNA sequencing and investigated the effects of BBR on the microbiota of CIA rats through bioinformatics and statistical methods.RESULTS: Our results showed that BBR demonstrated significant efficacy in alleviating RA symptoms in CIA rats, as evidenced by improvements in paw redness and swelling, attenuation of bone and cartilage damage, reduction in synovial hyperplasia, inflammatory cell infiltration, and suppression of proinflammatory cytokines IL-1β, IL-6, IL-17A, and TNF-α. KEGG analysis highlighted the PI3K/AKT signaling pathway as a key mediator of BBR's anti-RA effects. Metabolomics profiling via LC-MS revealed 22 potential biomarkers. Arginine and proline metabolism, cutin, suberine and wax biosynthesis, glycine, serine and threonine metabolism and taurine and hypotaurine metabolism are the most related pathways of BBR anti-RA. Molecular docking studies corroborated high affinities between BBR and key targets. Furthermore, 16S analysis demonstrated BBR's capacity to modulate gut bacteria composition, including an increase in the abundance of Lachnoclostridium, Akkermansia, Blautia, Romboutsia, and Faecalibacterium genera, alongside a decrease in Prevotella_9 abundance in genus level. Integrated analysis underscored a strong correlation between serum microbiota and fecal metabolites.CONCLUSION: Our findings elucidate the multifaceted mechanisms underlying BBR's therapeutic efficacy in RA, involving inhibition of the PI3K/AKT pathway, modulation of intestinal flora, and regulation of host metabolites. These insights provide novel perspectives on BBR's role in RA management.PMID:39677295 | PMC:PMC11645930 | DOI:10.2147/JIR.S493892