PubMed

Toxicon. 2024 Aug 21:108076. doi: 10.1016/j.toxicon.2024.108076. Online ahead of print.ABSTRACTMimosa tenuiflora (Fabaceae) is popularly known in Brazil as "Jurema preta". From the bark of its root, "jurema wine" is obtained, a psychedelic drink used in Indigenous religious rituals in Northeastern Brazil. This work aimed to investigate the chemical composition and acute oral toxicity of the ethanolic extract of the root bark from M. tenuiflora (EEMt). EEMt was analyzed by UPLC-QToF-MS/MS and DI-ESI-IT-MSn. Oral administration of EEMt was performed once at doses of 300 and 2000 mg/kg in female Swiss mice. Signs and symptoms of intoxication, as well as mortality were monitored for 14 days. Thirteen compounds were annotated in EEMt: eight type B proanthocyanidins, three alkaloids, a glycosylated flavonol, and a dihydrochalcone derivative. The acute administration of 300 and 2000 mg/kg of EEMt did not show mortality. It also did not change the food intake or body weight of the animals. However, the relative weights of the kidneys were significantly changed for both doses. Changes in hematological and biochemical parameters were found. In addition, histopathological changes were also observed in the heart, liver, and kidneys. Thus, based on our findings, EEMt presented an LD50 greater than 2000 mg/kg and was therefore classified in category 5 of the Globally Harmonized Classification System (GHS). EEMt showed acute oral toxicity by altering hematological, biochemical and histological parameters.PMID:39179178 | DOI:10.1016/j.toxicon.2024.108076

Neurobiol Dis. 2024 Aug 21:106645. doi: 10.1016/j.nbd.2024.106645. Online ahead of print.ABSTRACTNicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD+), has robust cognitive benefits and alleviates neuroinflammation in AD mouse models without decreasing beta-amyloid plaque pathology. Such effects may be mediated by the reactive species interactome (RSI), at the metabolome level. In this study, we employed in vitro and in vivo models of oxidative stress/aging/AD to profile the effects of NR on neuronal survival, RSI, and the whole proteome characterization of cortex and hippocampus. RSI analysis yielded a complex modulation upon NR treatment. We constructed protein co-expression networks and correlated them to NR treatment and all measured reactive species. We observed brain-area specific effects of NR on co-expressed protein modules of oxidative phosphorylation, fatty acid oxidation, and neurotransmitter regulation pathways, which correlated with RSI components. The current study contributes to the understanding of modulation of the metabolome, specifically after NR, in AD and how it may play disease-modifying roles.PMID:39179121 | DOI:10.1016/j.nbd.2024.106645

J Ethnopharmacol. 2024 Aug 21:118715. doi: 10.1016/j.jep.2024.118715. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Si-Ni-San (SNS), a traditional Chinese medicinal formula derived from Treatise on Febrile Diseases, is considered effective in the treatment of inflammatory bowel diseases based upon thousands of years of clinical practice. However, the bioactive ingredients and underlying mechanisms are still unclear and need further investigation.AIM OF THE STUDY: This study aimed to evaluate the effect, explore the bioactive ingredients and the underlying mechanisms of SNS in ameliorating ulcerative colitis (UC) and associated liver injury in dextran sodium sulphate (DSS)-induced mouse colitis models.MATERIALS AND METHODS: The effect of SNS (1.5, 3, 6g/kg) on 3% DSS-induced acute murine colitis was evaluated by disease activity index (DAI), colon length, inflammatory cytokines, hematoxylin-eosin (H&E) staining, tight junction proteins expression, ALT, AST, and oxidative stress indicators. HPLC-ESI-IT/TOF MS was used to analyze the chemical components of SNS and the main xenobiotics in the colon of UC mice after oral administration of SNS. Network pharmacological study was then conducted based on the main xenobiotics. Flow cytometry and immunohistochemistry techniques were used to demonstrate the inhibitory effect of SNS on Th17 cells differentiation and the amelioration of Th17/Treg cell imbalance. LC-MS/MS, Real-time quantitative polymerase chain reaction (RT-qPCR), and western blotting techniques were performed to investigate the oxysterol-Liver X receptor (LXRs) signaling activity in colon. Targeted bile acids metabolomics was conducted to reveal the change of the two major pathways of bile acid synthesis in the liver, and the expression of key metabolic enzymes of bile acids synthesis was characterized by RT-qPCR and western blotting techniques.RESULTS: SNS (1.5, 3, 6g/kg) decreased the DAI scores, protected intestinal mucosa barrier, suppressed the production of pro-inflammatory cytokines, improved hepatic and splenic enlargement and alleviated liver injury in a dose-dependent manner. A total of 22 components were identified in the colon of SNS (6g/kg) treated colitis mice, and the top 10 components ranked by relative content were regarded as the potential effective chemical components of SNS, and used to conduct network pharmacology research. The efficacy of SNS was mediated by a reduction of Th17 cell differentiation, restoration of Th17/Treg cell homeostasis in the colon and spleen, and the experimental results were consistent with our hypothesis and the biological mechanism predicted by network pharmacology. Mechanistically, SNS regulated the concentration of 25-OHC and 27-OHC by up-regulated CH25H, CYP27A1 protein expression in colon, thus affected the expression and activity of LXR, ultimately impacted Th17 differentiation and Th17/Treg balance. It was also found that SNS repressed the increase of hepatic cholesterol and reversed the shift of BA synthesis to the acidic pathway in UC mice, which decreased the proportion of non-12-OH BAs in total bile acids (TBAs) and further ameliorated colitis and concomitant liver injury.CONCLUSIONS: This study set the stage for considering SNS as a multi-organ benefited anti-colitis prescription based on the significant effect of ameliorating intestinal and liver damage, and revealed that derivatives of cholesterol, namely oxysterols and bile acids, were closely involved in the mechanism of SNS anti-colitis effect.PMID:39179058 | DOI:10.1016/j.jep.2024.118715

Sci Total Environ. 2024 Aug 21:175702. doi: 10.1016/j.scitotenv.2024.175702. Online ahead of print.ABSTRACTCostal eutrophication leads to increased sulfide levels in sediments, which has been identified as a major cause of the global decline in seagrass beds. The seagrass Thalassia hemprichii, a dominant tropical species in the Indo-Pacific, is facing a potential threat from sulfide, which can be easily reduced from sulfate in porewater under the influence of global climate change and eutrophication. However, its metabolic response and tolerance mechanisms to high sulfide remain unclear. Thus, the current study investigated the physiological responses and programmed metabolic networks of T. hemprichii through a three-week mesocosm experiment, integrating physiology, stable isotope, widely targeted metabolomics, transcriptomics, and microbial diversity assessments. High sulfide reduced the sediment microbial diversity, while increased sediment sulfate reduced bacterial abundance and δ34S. The exposure to sulfide enhanced root δ34S while decreased leaf δ34S in T. hemprichii. High sulfide was shown to inhibit photosynthesis via damaging PSII, which further reduced ATP production. In response, abundant up-regulated differentially expressed genes in energy metabolism, especially in oxidative phosphorylation, were activated to compensate high energy requirement. High sulfide also promoted autophagy by overexpressing the genes related to phagocytosis and phagolysosome. Meanwhile, metabolomic profiling revealed that the contents of many primary metabolites, such as carbohydrates and amino acids, were reduced in both leaves and roots, likely to provide more energy and synthesize stress-responsive secondary metabolites. Genes related to nitrate reduction and transportation were up-regulated to promote N uptake for sulfide detoxification. High sulfide levels specifically enhanced thiamine in roots, while increased jasmonic acid and flavonoid levels in leaves. The distinct differences in metabolism between roots and leaves might be related to sulfide levels and the growth-defense trade-off. Collectively, our work highlights the specific mechanisms underlying the response and tolerance of T. hemprichii to high sulfide, providing new insights into seagrass strategies for resisting sulfide.PMID:39179040 | DOI:10.1016/j.scitotenv.2024.175702

J Nutr Biochem. 2024 Aug 21:109746. doi: 10.1016/j.jnutbio.2024.109746. Online ahead of print.ABSTRACTThere is limited data on the effect of UV light exposure versus orally ingested vitamin D3 on vitamin D metabolism and health. A 4-week study with 16 pigs (as a model for human physiology) was conducted. The pigs were either supplemented with 20 µg/d vitamin D3 or exposed to UV light for 19 min/d to standardise plasma 25-hydroxyvitamin D3 levels. Important differences were higher levels of stored vitamin D3 in skin and subcutaneous fat, higher plasma concentrations of 3-epi-25-hydroxyvitamin D3 and increases of cutaneous lumisterol3 in UV-exposed pigs compared to supplemented pigs. UV light exposure compared to vitamin D3 supplementation resulted in lower hepatic cholesterol, higher circulating plasma nitrite, a marker of the blood pressure-lowering nitric oxide, and a reduction in the release of pro- and anti-inflammatory cytokines from stimulated peripheral blood mononuclear cells. However, plasma metabolome and stool microbiome analyses did not reveal any differences between the two groups. To conclude, the current data show important health relevant differences between oral vitamin D3 supplementation and UV light exposure. The findings may also partly explain the different vitamin D effects on health parameters obtained from association and intervention studies.PMID:39178919 | DOI:10.1016/j.jnutbio.2024.109746

J Pediatr (Rio J). 2024 Aug 20:S0021-7557(24)00102-5. doi: 10.1016/j.jped.2024.07.009. Online ahead of print.ABSTRACTOBJECTIVES: This study aimed to investigate changes in the blood metabolic profiles of newborns with varying intrauterine growth conditions. Specifically, we analyzed the levels of amino acids, carnitine, and succinylacetone among full-term newborns, including small for gestational age (SGA), appropriate for gestational age (AGA), and large for gestational age (LGA). We aim to identify differential metabolites and metabolic pathways that may offer insights into clinical interventions.METHODS: A total of 5106 full-term newborns were included in the study. Blood samples were obtained from all newborns between 3 and 5 days after birth and analyzed using tandem mass spectrometry to detect blood metabolites. Subsequently, we screened for different metabolites and metabolic pathways among the groups using the MetaboAnalystR package (Version 1.0.1) in R software (R-3.6.0).RESULTS: The levels of blood amino acids and carnitine metabolism differed significantly among newborns with varying intrauterine growth conditions. Full-term SGA newborns exhibited a decrease in multiple amino acids and an increase in multiple carnitines, while full-term LGA newborns showed an increase in multiple amino acids and acylcarnitines.CONCLUSION: Continuous monitoring of the short-term and long-term growth and metabolic status of full-term SGA and LGA newborns is warranted with individualized dietary and nutritional adjustments to promote healthy growth in a timely manner. The findings of this research contribute to the broader understanding of SGA/LGA and shall inform future research on metabolomics, interventions, and long-term outcomes.PMID:39178913 | DOI:10.1016/j.jped.2024.07.009

Ecotoxicol Environ Saf. 2024 Aug 22;284:116901. doi: 10.1016/j.ecoenv.2024.116901. Online ahead of print.ABSTRACTGlyphosate is the active ingredient in the herbicide (i.e., Roundup, Touchdown and Erasure), the safety of which has become a social concern. Hawthorn-leaf flavonoid (HF) possesses various biological functions, including antioxidant, regulating lipid metabolism and intestinal microbiota. Whether HF could reduce the health risk of pure glyphosate to birds remain unknown. The experiment aimed to evaluate the effects of pure glyphosate (25 mg/kg added to water) on the intestinal health and microbiota of chicks and the protective roles of HF (60 mg/kg added to the diet). Exposure to glyphosate decreased growth performance, ileal morphology structure, and antioxidant capacity, and increased the serum level of lipid and pro-inflammatory factors. 16S rRNA sequencing indicated that glyphosate decreased bacterial richness and the abundance of Lactobacillus, and increased proportions of pathogens in the ileum. Metabolomic results revealed that glyphosate increased the level of the cholic acid and fatty acids in the ileac digesta. Meanwhile, glyphosate down-regulated the protein expression associated with lipid transport, antioxidant and tight junction in the ileal mucosal tissue, and up-regulated the pro-inflammatory, oxidative stress proteins. However, dietary HF supplementation effectively mitigated the adverse effects of glyphosate and improved intestinal health of chicks. Therefore, dietary HF can ameliorate the harmful effects of glyphosate on birds, which highlights the potential application of HF in reducing the health risks.PMID:39178762 | DOI:10.1016/j.ecoenv.2024.116901

Phytomedicine. 2024 Aug 17;134:155961. doi: 10.1016/j.phymed.2024.155961. Online ahead of print.ABSTRACTBACKGROUND: The rapid acceleration of female reproductive aging has become a major public health concern. He's Yangchao formula (HSYC), a compound comprising eight herbs, has demonstrated efficacy in enhancing ovarian function. Thus, an in-depth study of its anti-ovarian aging mechanism is required.PURPOSE: To evaluate the anti-ovarian aging effect of HSYC in naturally aged mice and investigate the underlying mechanism by analyzing the gut microbiota (GM), metabolome, and transcriptome.METHODS: Young and advanced maternal age (AMA) mice were selected for this study. Hematoxylin and eosin staining, fluorescence staining, western blotting, and qPCR analyses were used to detect the phenotypes associated with ovarian aging. Subsequently, analyses of the GM, transcriptome, and metabolome analyses were performed to explore the potential mechanisms of action of HSYC. Finally, in vivo and in vitro experiments were performed to verify potential therapeutic mechanisms.RESULTS: HSYC promoted follicular development in AMA mice and ameliorated age-related mitochondrial dysfunction, apoptosis, and defects in DNA damage repair. GM analysis revealed that HSYC treatment significantly increased the abundance of Akkermansia and Turicibacter. Transcriptome and metabolome analyses showed that HSYC might mitigate ovarian aging by regulating metabolic pathways, amino acid metabolism, glutathione metabolism, and the synthesis of pantothenic acid and coenzyme A. Combined transcriptomic and metabolomic analyses identified the glutathione metabolic pathway as the key pathway through which HSYC counteracts ovarian aging. Additional experimental verification confirmed that HSYC upregulated the glutathione metabolic genes GPX8, GSTA1, and GSTA4, increased glutathione-related products (GSH), and reduced ROS levels.CONCLUSIONS: HSYC exerts beneficial therapeutic effects on ovarian aging by regulating multiple endogenous metabolites, targets, and metabolic pathways, with an emphasis on its anti-ovarian aging effects through the glutathione metabolic pathway. These findings underscore the innovative potential of HSYC in addressing ovarian aging and offer a novel therapeutic approach that targets multiple biological pathways to improve the reproductive health of women with AMA..PMID:39178679 | DOI:10.1016/j.phymed.2024.155961

Phytomedicine. 2024 Aug 8;133:155947. doi: 10.1016/j.phymed.2024.155947. Online ahead of print.ABSTRACTBACKGROUND: Silymarin is recognized for its excellent hepato-protective properties. Recent clinical studies have examined the effects of silymarin on metabolic dysfunction-associated steatotic liver disease (MASLD), highlighting the necessity of further exploration into optimal dosages, active components, and mechanisms of action.METHODS AND RESULTS: This study assessed the anti-inflammatory activity of the principal constituents of silymarin at the cellular level. The therapeutic effects of varying silymarin doses and components on MASLD in mouse models induced by a high-fat diet (HFD) were also examined. These findings indicate the superior efficacy of 80 mg kg-1 silymarin in mitigating liver steatosis and reducing lipid accumulation compared to 30 mg kg-1 silymarin or a combination of silybin and isosilybin A. The mechanism of silymarin involves regulating gut microbiota homeostasis and influencing the TLR4/NF-κB signalling pathway through LPS. Bile acid-targeted metabolomics analysis revealed that silymarin significantly decreases the HFD-induced increase in 7-keto-deoxycholic acid (7-KDCA). Further investigations suggested that 7-KDCA as an antagonist targeted farnesoid X receptor (FXR) and that both silybin and isosilybin A could directly interact with FXR.CONCLUSION: These findings elucidate that 80 mg kg-1 of silymarin can exert therapeutic effects on MASLD mice and offer novel insights into the mechanism of silymarin in treating MASLD. Especially, it was found that silymarin could regulate bile acid metabolism, reduce the concentration of 7-KDCA, and thus perform negative feedback regulation on FXR.PMID:39178642 | DOI:10.1016/j.phymed.2024.155947

Food Chem. 2024 Aug 8;461:140801. doi: 10.1016/j.foodchem.2024.140801. Online ahead of print.ABSTRACTThe sensory quality of a wine is mainly based on its aroma and flavor. Sweetness contributes in the gustatory balance of red wines. The investigation of compounds involved in this flavor was based on empirical observations, such as the increase in wine sweetness during yeast autolysis, concomitant to post-fermentation maceration in red winemaking. An untargeted metabolomics approach using UHPLC-HRMS has been developed to discover a new sweet molecule released during this stage. Among several markers highlighted, one compound was selected to be isolated by various separative techniques. It was unambiguously identified by NMR as N6-succinyladenosine and is reported for the first time in wine at an average concentration of 3.16 mg/L in 85 red wines. Furthermore, sensory analysis has highlighted its sweetness. In addition to discovering a new sweet compound in wine, this study proposes new tools for studying taste-active compounds in natural matrices.PMID:39178544 | DOI:10.1016/j.foodchem.2024.140801

Comp Biochem Physiol Part D Genomics Proteomics. 2024 Aug 14;52:101312. doi: 10.1016/j.cbd.2024.101312. Online ahead of print.ABSTRACTHolometabolous insects undergo a distinct transition in their development, tightly correlated with shifting feeding patterns from larval stages and some adult phases to non-feeding phases as pupae and during other adult phases. Furthermore, the intricate life cycle of mosquitoes involves a sequence of developmental stages influenced by aquatic and terrestrial factors, demanding precise energy resource orchestration. Lipids serve multifaceted roles, encompassing energy storage, membrane structure, and participation in signal transduction and molecular recognition processes. A significant gap in the current research landscape is the need for a comprehensive study exploring the lipid repertoire throughout the developmental stages of Anopheles stephensi mosquitoes. We undertook an analysis of the An. stephensi metabolome across all life stages. We hypothesized that An. stephensi mosquitoes will have unique lipid metabolite markers for each life stage. A specific extraction and LC-MS based lipidomic approach was used to test this hypothesis. Our findings demonstrated that our methods were successful, with lipids comprising 62.15 % of the analyzed metabolome. Additionally, phospholipids (PL), lysophospholipids (LPL), sphingomyelin (SM), and triglycerides (TG) were abundant and dynamic across all life stages. Interestingly, comparison between the L1 and L2 lipidome revealed a dominant pattern of specific TGs in decreased abundance between these two life stages. Lastly, 20-hydroxyecdysone (20E), was found to be present in similar abundance across all 4 larval stages. These data indicate that there may be lipid metabolome pathways serving unique roles during mosquito development that may be used to explore laboratory management of colonies, parasite resistance, and environmental adaptation.PMID:39178499 | DOI:10.1016/j.cbd.2024.101312

J Neuroimmunol. 2024 Aug 2;395:578422. doi: 10.1016/j.jneuroim.2024.578422. Online ahead of print.ABSTRACTIntestinal microbes play a crucial role in gut health and the immune-mediated central nervous system through the "gut-brain" axis. However, probiotic safety and efficacy in Neuromyelitis optica spectrum disorder (NMOSD) are not well-explored. A pilot clinic trial for NMOSD with probiotic intervention revealed alterations in the microbiota (increased Anaerostipes, Bacteroides; decreased Granulicatella, Streptococcus, Rothia). Metabolite analysis showed elevated 2-methylbutyric and isobutyric acids, reduced lithocholic acid (LCA), and glycodeoxycholic acid (GDCA). Immune markers Interleukin (IL-7), vascular endothelial growth factor (VEGF-A), and B lymphocyte chemoattractant (BLC) decreased, while plasma cells and transitional B cells increased post-probiotics, suggesting potential immunomodulatory effects on NMOSD.PMID:39178494 | DOI:10.1016/j.jneuroim.2024.578422

Sci Adv. 2024 Aug 23;10(34):eadp2254. doi: 10.1126/sciadv.adp2254. Epub 2024 Aug 23.ABSTRACTConsumption of a diet rich in saturated fat increases lipid absorption from the intestine, assembly into chylomicrons, and delivery to metabolic tissues via the lymphatic and circulatory systems. Accumulation of ceramide lipids, composed of sphingosine and a fatty acid, in metabolic tissues contributes to the pathogenesis of cardiovascular diseases, type 2 diabetes mellitus and cancer. Using a mesenteric lymph duct cannulated rat model, we showed that ceramides are generated by the intestine and assembled into chylomicrons, which are transported via the mesenteric lymphatic system. A lipidomic screen of intestinal-derived chylomicrons identified a diverse range of fatty acid, sphingolipid, and glycerolipid species that have not been previously detected in chylomicrons, including the metabolically deleterious C16:0 ceramide that increased in response to high-fat feeding in rats and human high-lipid meal replacement enteral feeding. In conclusion, high-fat feeding increases the export of intestinal-derived C16:0 ceramide in chylomicrons, identifying a potentially unknown mechanism through which ceramides are transported systemically to contribute to metabolic dysfunction.PMID:39178255 | DOI:10.1126/sciadv.adp2254

Sci Adv. 2024 Aug 23;10(34):eado6566. doi: 10.1126/sciadv.ado6566. Epub 2024 Aug 23.ABSTRACTXPO1 (Exportin-1/CRM1) is a nuclear export protein that is frequently overexpressed in cancer and functions as a driver of oncogenesis. Currently small molecules that target XPO1 are being used in the clinic as anticancer agents. We identify XPO1 as a target for natural killer (NK) cells. Using immunopeptidomics, we have identified a peptide derived from XPO1 that can be recognized by the activating NK cell receptor KIR2DS2 in the context of human leukocyte antigen-C. The peptide can be endogenously processed and presented to activate NK cells specifically through this receptor. Although high XPO1 expression in cancer is commonly associated with a poor prognosis, we show that the outcome of specific cancers, such as hepatocellular carcinoma, can be substantially improved if there is concomitant evidence of NK cell infiltration. We thus identify XPO1 as a bona fide tumor antigen recognized by NK cells that offers an opportunity for a personalized approach to NK cell therapy for solid tumors.PMID:39178254 | DOI:10.1126/sciadv.ado6566

Shock. 2024 Aug 12. doi: 10.1097/SHK.0000000000002446. Online ahead of print.ABSTRACTCardiopulmonary bypass (CPB), an extracorporeal method necessary for the surgical correction of complex congenital heart defects, incites significant inflammation that affects vascular function. These changes are associated with alterations in cellular metabolism that promote energy production to deal with this stress. Utilizing laser-doppler perfusion monitoring coupled with iontophoresis (LDPMI) in patients undergoing corrective heart surgery, we hypothesized that temporal, untargeted metabolomics could be performed to assess the link between metabolism and vascular function. Globally, we found 2404 unique features in the plasma of patients undergoing CPB. Metabolites related to arginine biosynthesis were the most altered by CPB. Correlation of metabolic profiles with endothelial-dependent (acetylcholine, ACh) or endothelial-independent (sodium nitroprusside, SNP) vascular reactivity identified purine metabolism being most consistently associated with either vascular response. Concerning ACh-mediated responses, acetylcarnitine levels were most strongly associated, while glutamine levels were associated with both ACh and SNP responsiveness. These data provide insight into the metabolic landscape of children undergoing CPB for corrective heart surgery and provide detail into how these metabolites relate to physiological aberrations in vascular function.PMID:39178242 | DOI:10.1097/SHK.0000000000002446

PLoS One. 2024 Aug 23;19(8):e0305185. doi: 10.1371/journal.pone.0305185. eCollection 2024.ABSTRACTA comprehensively analysis of the transcriptomics and metabolomics was conducted to investigate the mechanism of plant growth regulators on the quality of jujube fruit. After the application of plant growth regulators, a total of 3097 differentially expressed genes (DEGs) were identified, which were mainly annotated in 123 pathways such as flavonoid biosynthesis, metabolism of alanine, aspartate, and glutamate. In addition, 1091 differential expressed metabolites (DEMs), including 519 up-regulated and 572 down-regulated metabolites, were significantly altered after application of plant growth regulators. DEGs and DEMs simultaneously annotated 69 metabolic pathways, including biosynthesis of phenylpropane, flavonoid, starch and sucrose. The key genes in flavonoid biosynthesis pathway were revealed, which may play an important role in plant growth regulator regulation quality of jujube fruit. Besides, the application of plant growth regulator during the jujube flowering period increased the contents of gibberellin and indole-3-acetic acid in leaves, and decreased the contents of abscisic acid. The results may help to reveal the metabolic network and molecular mechanism of plant growth regulators in jujube fruit.PMID:39178226 | DOI:10.1371/journal.pone.0305185

J Proteome Res. 2024 Aug 23. doi: 10.1021/acs.jproteome.4c00142. Online ahead of print.ABSTRACTCardiac hypertrophy is a classical forerunner of heart failure and myocardial structural and metabolic remodeling are closely associated with cardiac hypertrophy. We aim to investigate the characteristics of myocardial structure and central carbon metabolism of cardiac hypertrophy at different stages. Using echocardiography and pathological staining, early and compensatory cardiac hypertrophy were respectively defined as within 7 days and from 7 to 14 days after transverse aortic constriction (TAC) in mice. Among mass-spectrometry-based metabolomics, we identified 45 central carbon metabolites. Differential metabolite analysis showed that six metabolites, including citrate, cis-aconitate and so on, decreased significantly on day 1 after TAC. Ten metabolites, including l-lactate, (S)-2-hydroxyglutarate and so on, were obviously changed on days 10 and 14. Pathway analysis showed that these metabolites were involved in seven metabolic pathways, including carbohydrates, amino acids and so on. Western blot showed the expression of ATP-citrate lyase, malate dehydrogenase 1 and lactate dehydrogenase A in myocardium changed markedly on day 3, while the phosphorylation level of AMP-activated protein kinase did not show significantly difference. We hope our research will promote deeper understanding and early diagnosis of cardiac hypertrophy in clinical practice. All raw data were deposited in MetaboLights (MTBLS10555).PMID:39178178 | DOI:10.1021/acs.jproteome.4c00142

Crit Care Med. 2024 Aug 23. doi: 10.1097/CCM.0000000000006391. Online ahead of print.ABSTRACTOBJECTIVE: To investigate the metabolomic profiles associated with different immune activation states in sepsis patients.DESIGN: Subgroup analysis of the PROVIDE (a Personalized Randomized trial of Validation and restoration of Immune Dysfunction in severe infections and Sepsis) prospective clinical study.SETTING: Results of the PROVIDE study showed that patients with sepsis may be classified into three states of immune activation: 1) macrophage-activation-like syndrome (MALS) characterized by hyperinflammation, sepsis-induced immunoparalysis, and 3) unclassified or intermediate patients without severe immune dysregulation.PATIENTS OR SUBJECTS: Two hundred ten patients from 14 clinical sites in Greece meeting the Sepsis-3 definitions with lung infection, acute cholangitis, or primary bacteremia.INTERVENTIONS: During our comparison, we did not perform any intervention.MEASUREMENTS AND MAIN RESULTS: Untargeted metabolomics analysis was performed on plasma samples from 210 patients (a total of 1394 products). Differential abundance analysis identified 221 significantly different metabolites across the immune states. Metabolites were enriched in pathways related to ubiquinone biosynthesis, tyrosine metabolism, and tryptophan metabolism when comparing MALS to immunoparalysis and unclassified patients. When comparing MALS to unclassified, 312 significantly different metabolites were found, and pathway analysis indicated enrichment in multiple pathways. Comparing immunoparalysis to unclassified patients revealed only two differentially regulated metabolites.CONCLUSIONS: Findings suggest distinct metabolic dysregulation patterns associated with different immune dysfunctions in sepsis: the strongest metabolic dysregulation is associated with MALS.PMID:39178163 | DOI:10.1097/CCM.0000000000006391

JAMA Netw Open. 2024 Aug 1;7(8):e2429702. doi: 10.1001/jamanetworkopen.2024.29702.ABSTRACTIMPORTANCE: Prophylactic administration of antibiotics before skin incision is an important component in the prevention of periprosthetic joint infection in arthroplasty surgery. For antibiotics to be effective, the local tissue concentration (LTC) must exceed the minimum inhibitory concentration of typical infecting organisms; however, the LTC of cefazolin during arthroplasty is poorly understood.OBJECTIVE: To compare the systemic concentration of cefazolin in serum with the LTC in fat, synovium, and bone during primary total knee arthroplasty (TKA) while assessing the effect of tourniquet inflation.DESIGN, SETTING, AND PARTICIPANTS: This prospective randomized clinical trial was conducted from March 1, 2022, to June 30, 2023, in patients undergoing TKA at a single academic center.INTERVENTION: Total knee arthroplasty with or without a limb tourniquet.MAIN OUTCOMES AND MEASURES: Systemic blood and local tissues from the surgical site (fat, synovium, and bone) were harvested at regular intervals during the surgery. The primary outcome was the LTC of cefazolin, quantified using the liquid chromatography-tandem mass spectrometry technique.RESULTS: A total of 59 patients were included in the study, with 29 in the tourniquet group (mean [SD] age, 69.3 [9.6] years; 23 [79.3%] female) and 30 in the no tourniquet group (mean [SD] age, 69.9 [9.7] years; 21 [70.0%] female). In patients undergoing TKA without a tourniquet, the mean concentration of cefazolin in serum was 71.9 μg/mL (95% CI, 66.4-77.5 μg/mL), whereas the mean LTCs were 13.9 μg/g (95% CI, 12.1-15.7 μg/g) in fat, 27.7 μg/g (95% CI, 24.3-31.0 μg/g) in synovium, and 17.7 μg/g (95% CI, 14.8-20.5 μg/g) in bone. For patients undergoing TKA with a tourniquet, the mean concentration of cefazolin in serum was 72.0 μg/mL (95% CI, 66.3-77.7 μg/mL), and the mean LTCs were 9.9 μg/g (95% CI, 8.7-11.1 μg/g) in fat, 21.8 μg/g (95% CI, 18.7-25.0 μg/g) in synovium, and 13.0 μg/g (95% CI, 10.8-15.2 μg/g) in bone. The use of a tourniquet resulted in significantly lower mean LTCs by 60 minutes after cefazolin infusion (10.8 μg/g [95% CI, 9.1-12.4 μg/g] vs 16.9 μg/g [95% CI, 14.1-19.6 μg/g], P = .001 in fat; 18.9 μg/g [95% CI, 14.1-23.6 μg/g] vs 25.8 μg/g [95% CI, 21.4-30.3 μg/g], P = .03 in synovium; and 11.8 μg/g [95% CI, 9.3-14.2 μg/g] vs 19.4 μg/g [95% CI, 14.5-24.4 μg/g], P = .007 in bone).CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the concentration of cefazolin was lower in local tissues (fat, synovium, and bone) than in systemic blood, and the use of a limb tourniquet further significantly reduced these concentrations. Although the current prophylactic dosing regimen for cefazolin provides sufficient serum concentrations, the levels in the periarticular tissue during TKA may be insufficient to prevent periprosthetic joint infection.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05604157.PMID:39178000 | DOI:10.1001/jamanetworkopen.2024.29702

Arch Dermatol Res. 2024 Aug 23;316(8):565. doi: 10.1007/s00403-024-03294-5.ABSTRACTOBJECTIVE: Two-sample Mendelian randomization (TSMR) was employed to examine the association between lipidome and five inflammatory skin diseases.METHOD: To evaluate the association between various molecular subtypes of lipidome and the risk of five inflammatory skin diseases, we analyzed a comprehensive GWAS dataset comprising 179 lipidome. The Two-Sample Mendelian Randomization (TSMR) method was employed to investigate causal relationships. Heterogeneity and pleiotropy were assessed using Cochran's Q test, MR-Egger intercept test, and MR-PRESSO global test. Additionally, a sensitivity analysis was conducted to evaluate the influence of individual single nucleotide polymorphisms on Mendelian Randomization study.RESULTS: Using 179 serum lipidome as exposures and five common inflammatory skin diseases as outcomes, we investigated their associations in this large-scale study. Our findings reveal significant impacts of glycerophospholipids, glycerolipids, and sphingomyelins on inflammatory skin diseases. Glycerophospholipids were protective against pemphigus but predominantly posed risks for other inflammatory skin diseases. Specifically, phosphatidylcholine (16:0_0:0) exhibited the most significant risk association with lichen planus (OR = 1.25, 95% CI 1.11-1.40, P < 0.001). Conversely, glycerolipids showed no effect on lichen planus but were protective against pemphigus while potentially posing risks for other conditions. Triacylglycerol (46:2) showed the most substantial risk association with vitiligo (OR = 1.99, 95% CI 1.35-2.93, P < 0.001). Furthermore, sphingomyelins had no effect on atopic dermatitis but posed potential risks for other inflammatory skin diseases. Sphingomyelin (d40:1) notably emerged as a significant risk factor for pemphigus (OR = 1.91, 95% CI 1.37-2.66, P < 0.001).CONCLUSIONS: This study has elucidated the potential harmful effects of glycerophospholipids, glycerolipids, and sphingomyelins on inflammatory skin diseases, while also providing valuable insights for future research into the pathophysiology, prevention and treatment of these conditions.PMID:39177801 | DOI:10.1007/s00403-024-03294-5