PubMed

Metabolomics. 2024 Jun 16;20(4):65. doi: 10.1007/s11306-024-02134-x.ABSTRACTBACKGROUND: Preeclampsia is a pregnancy-specific clinical syndrome and can be subdivided into early-onset preeclampsia (EOPE) and late-onset preeclampsia (LOPE) according to the gestational age of delivery. Patients with preeclampsia have aberrant lipid metabolism. This study aims to compare serum lipid profiles of normal pregnant women with EOPE or LOPE and screening potential biomarkers to diagnose EOPE or LOPE.METHODS: Twenty normal pregnant controls (NC), 19 EOPE, and 19 LOPE were recruited in this study. Untargeted lipidomics based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to compare their serum lipid profiles.RESULTS: The lipid metabolism profiles significantly differ among the NC, EOPE, and LOPE. Compared to the NC, there were 256 and 275 distinct lipids in the EOPE and LOPE, respectively. Furthermore, there were 42 different lipids between the LOPE and EOPE, of which eight were significantly associated with fetal birth weight and maternal urine protein. The five lipids that both differed in the EOPE and LOPE were DGTS (16:3/16:3), LPC (20:3), LPC (22:6), LPE (22:6), PC (18:5e/4:0), and a combination of them were a potential biomarker for predicting EOPE or LOPE. The receiver operating characteristic analysis revealed that the diagnostic power of the combination for distinguishing the EOPE from the NC and for distinguishing the LOPE from the NC can reach 1.000 and 0.992, respectively. The association between the lipid modules and clinical characteristics of EOPE and LOPE was investigated by the weighted gene co-expression network analysis (WGCNA). The results demonstrated that the main different metabolism pathway between the EOPE and LOPE was enriched in glycerophospholipid metabolism.CONCLUSIONS: Lipid metabolism disorders may be a potential mechanism of the pathogenesis of preeclampsia. Lipid metabolites have the potential to serve as biomarkers in patients with EOPE or LOPE. Furthermore, lipid metabolites correlate with clinical severity indicators for patients with EOPE and LOPE, including fetal birth weight and maternal urine protein levels.PMID:38879866 | DOI:10.1007/s11306-024-02134-x

Sci Rep. 2024 Jun 15;14(1):13862. doi: 10.1038/s41598-024-64586-4.ABSTRACTAcute kidney injury (AKI) is a systemic disease that affects energy metabolism in various remote organs in murine models of ischemic AKI. However, AKI-mediated effects in the liver have not been comprehensively assessed. After inducing ischemic AKI in 8-10-week-old, male C57BL/6 mice, mass spectrometry metabolomics revealed that the liver had the most distinct phenotype 24 h after AKI versus 4 h and 7 days. Follow up studies with in vivo [13C6]-glucose tracing on liver and kidney 24 h after AKI revealed 4 major findings: (1) increased flux through glycolysis and the tricarboxylic (TCA) cycle in both kidney and liver; (2) depleted hepatic glutathione levels and its intermediates despite unchanged level of reactive oxygen species, suggesting glutathione consumption exceeds production due to systemic oxidative stress after AKI; (3) hepatic ATP depletion despite unchanged rate of mitochondrial respiration, suggesting increased ATP consumption relative to production; (4) increased hepatic and renal urea cycle intermediates suggesting hypercatabolism and upregulation of the urea cycle independent of impaired renal clearance of nitrogenous waste. Taken together, this is the first study to describe the hepatic metabolome after ischemic AKI in a murine model and demonstrates that there is significant liver-kidney crosstalk after AKI.PMID:38879688 | DOI:10.1038/s41598-024-64586-4

Cardiovasc Diabetol. 2024 Jun 15;23(1):205. doi: 10.1186/s12933-024-02296-x.ABSTRACTBACKGROUND: There has been a substantial increase in the use of laparoscopic sleeve gastrectomy (SG) to treat morbid obesity despite observational evidence demonstrating the superiority of Roux-en-Y gastric bypass (RYGB) for reducing low-density lipoprotein (LDL) cholesterol. The main aim was to ascertain whether high LDL cholesterol levels should be considered when selecting the most appropriate surgical procedure for each patient (RYGB or SG).METHODS: In this single-center, randomized clinical trial using intention-to-treat analysis, 38 patients with severe obesity and elevated levels of LDL cholesterol were randomly assigned to undergo RYGB or SG. The primary outcome was LDL cholesterol remission at 12 months, defined as LDL cholesterol < 3.36 nmol/l without lipid-lowering medications. Secondary outcomes included changes in weight, other comorbidities, qualitative lipoprotein traits, cholesterol esters, glycoproteins, cholesterol absorption and synthesis metabolites and complications.RESULTS: Intention-to-treat analysis revealed that LDL cholesterol remission occurred in 66.6% of RYGB patients compared to 27.8% of SG patients (p = 0.019). Among patients completing follow-up, RYGB demonstrated superior remission (80.0% vs. 29.4%, p = 0.005). Exclusive benefits of RYGB included a reduction in large, medium, and small LDL particles. Cholesterol absorption markers showed differential behavior after both techniques: campesterol (Δ -15.2 µg/mg, 95% CI -30.2 to -0.1) decreased after RYGB, and sitosterol (Δ 21.1 µg/mg, 95% CI 0.9 to 41.2), cholestanol (Δ 30.6 µg/mg, 95% CI 14.8 to 57.9) and campesterol (Δ 18.4 µg/mg, 95% CI 4.4 to 32.3) increased after SG. No differences in weight loss, cholesterol esters, glycoproteins, cholesterol synthesis metabolites or postoperative complications were observed between techniques.CONCLUSION: In conclusion, RYGB is superior to SG in terms of short-term of high LDL cholesterol remission. Furthermore, RYGB also led to a greater improvement in lipoprotein parameters that confer an atherogenic profile. Therefore, the presence of elevated levels of LDL cholesterol should be considered when determining the optimal bariatric surgery procedure for each patient.TRIAL REGISTRATION: Clinicaltrials.gov number, NCT03975478).PMID:38879559 | DOI:10.1186/s12933-024-02296-x

Cell Biosci. 2024 Jun 15;14(1):80. doi: 10.1186/s13578-024-01253-1.ABSTRACTBACKGROUND: About 1/3 of primary biliary cholangitis (PBC) patients suffered from poor response worldwide. And these patients present intestinal disturbances. We aimed to identify signatures of microbiota and metabolites in PBC patients with poor response, comparing to patients with response.METHODS: This study enrolled 25 subjects (14 PBC patients with response and 11 PBC patients with poor response). Metatranscriptomics and metabolomics analysis were carried out on their fecal.RESULTS: PBC patients with poor response had significant differences in the composition of bacteria, characterized by decreased Gemmiger etc. and increased Ruminococcus etc. The differential microbiota functions characterized by decreased abundance of elongation factor Tu and elongation factor G base on the KO database, as well as decreased abundance of Replicase large subunit etc. based on the SWISS-PROT database. PBC with poor response also had significant differences in 17 kinds of bacterial metabolites, characterized by decreased level of metabolites vital in bile acids metabolism pathway (L-Cysteine etc.) and the all-trans-Retinoic acid, a kind of immune related metabolite. The altered microbiota was associated with the differential expressed metabolites and clinical liver function indicators. 1 bacterial genera, 2 bacterial species and 9 metabolites simultaneously discriminated PBC with poor response from PBC with response with high accuracy.CONCLUSION: PBC patients with poor response exhibit unique changes in microbiota and metabolite. Gut microbiota and metabolite-based algorithms could be used as additional tools for differential prediction of PBC with poor prognosis.PMID:38879547 | DOI:10.1186/s13578-024-01253-1

Chin Med. 2024 Jun 15;19(1):87. doi: 10.1186/s13020-024-00958-2.ABSTRACTBACKGROUND: Shaoyao Decoction (SYD) is a widely recognized herbal formula utilized in traditional Chinese medicine for the treatment of diarrhea. Although it has demonstrated significant effectiveness in clinical practice for treating ulcerative colitis, the precise mechanisms by which it operates remain largely elusive.METHODS: The active ingredients of SYD were obtained by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), which were used to explore the potential pharmacological mechanism based on TCMSP (Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform) and PANTHER (Protein Analysis Through Evolutionary Relationships) classification system. In a mouse model of dextran sulfate sodium (DSS)-induced colitis, mRNA sequencing, 16S rDNA sequencing and targeted metabolomics techniques were used to elucidate the mechanisms of SYD, and immunohistochemistry, immunofluorescence, enzyme linked immunosorbent assay, real time quantitative polymerase chain reaction and western blot were used to test the key targets. In addition, QGP-1 and H9 cells were performed to validate the discoveries from the animal experiments.RESULTS: In the mouse model of DSS-induced colitis, SYD effectively alleviated symptoms such as bloody stool, tissue damage, inflammation, intestinal flora dysbiosis and abnormal gene expression. Analyses of both differential expressed genes in colonic tissue and predicted 16S rDNA genes, as well as the analyses of targeted genes from TCMSP based on the active ingredients in UPLC-MS/MS of SYD, uncovered the enrichment of pathways involved in the biosynthesis and degredation of 5-hydroxytryptamine (5-HT). Interestingly, SYD suppressed the relative abundance of key genes in 5-HT synthesis, Tph1(Tryptophan hydroxylase 1) and Ddc (Dopa decarboxylase), in faeces from DSS-induced mice, leading to a reduction in the concentration of fecal 5-HT. Moreover, SYD augmented the production of butyric acid. Subsequently, increasing butyric acid influenced the metabolism of 5-HT in the organism through G protein-coupled receptor 43 by impeding its synthesis, facilitating its transport and degredation. These findings were additionally corroborated in a model utilizing enterochromaffin cell (QGP-1 cells). Furthermore, reduced levels of 5-HT hindered the activation of T lymphocytes (H9 cells) via the PKC (Protein kinase C) and NF-κB (Nuclear factor kappa-B) signaling pathways, by means of HTR1A (5-HT receptor 1A) and HTR3 (5-HT receptor 3). Additionally, diminished secretion of 5-HT resulted in reduced secretion of associated cytokines, thereby alleviating inflammation in the colon.CONCLUSION: Through modulation of T lymphocyte activation mediated by 5-HT metabolism in the local colon via the intestinal flora and its metabolite, SYD effectively mitigated colonic inflammation in DSS-induced mice.PMID:38879471 | DOI:10.1186/s13020-024-00958-2

BMC Plant Biol. 2024 Jun 15;24(1):563. doi: 10.1186/s12870-024-05286-z.ABSTRACTBACKGROUND: Drought is a leading environmental factor affecting plant growth. To explore the drought tolerance mechanism of asparagus, this study analyzed the responses of two asparagus varieties, namely, 'Jilv3' (drought tolerant) and 'Pacific Early' (drought sensitive), to drought stress using metabolomics and transcriptomics.RESULTS: In total, 2,567 and 7,187 differentially expressed genes (DEGs) were identified in 'Pacific Early' and 'Jilv3', respectively, by comparing the transcriptome expression patterns between the normal watering treatment and the drought stress treatment. These DEGs were significantly enriched in the amino acid biosynthesis, carbon metabolism, phenylpropanoid biosynthesis, and plant hormone signal transduction pathways. In 'Jilv3', DEGs were also enriched in the following energy metabolism-related pathways: citrate cycle (TCA cycle), glycolysis/gluconeogenesis, and pyruvate metabolism. This study also identified 112 and 254 differentially accumulated metabolites (DAMs) in 'Pacific Early' and 'Jilv3' under drought stress compared with normal watering, respectively. The amino acid, flavonoid, organic acid, and soluble sugar contents were more significantly enhanced in 'Jilv3' than in 'Pacific Early'. According to the metabolome and transcriptome analysis, in 'Jilv3', the energy supply of the TCA cycle was improved, and flavonoid biosynthesis increased. As a result, its adaptability to drought stress improved.CONCLUSIONS: These findings help to better reveal the molecular mechanism underlying how asparagus responds to drought stress and improve researchers' ability to screen drought-tolerant asparagus varieties as well as breed new varieties.PMID:38879466 | DOI:10.1186/s12870-024-05286-z

Trends Immunol. 2024 Jun 14:S1471-4906(24)00122-4. doi: 10.1016/j.it.2024.05.008. Online ahead of print.ABSTRACTMammalian innate-like T cells (ILTCs), including mucosal-associated invariant T (MAIT), natural killer T (NKT), and γδ T cells, are abundant tissue-resident lymphocytes that have recently emerged as orchestrators of hepatic inflammation, tissue repair, and immune homeostasis. This review explores the involvement of different ILTC subsets in liver diseases. We explore the mechanisms underlying the pro- and anti-inflammatory effector functions of ILTCs in a context-dependent manner. We highlight latest findings regarding the dynamic interplay between ILTC functional subsets and other immune and parenchymal cells which may inform candidate immunomodulatory strategies to achieve improved clinical outcomes in liver diseases. We present new insights into how distinct gene expression programs in hepatic ILTCs are induced, maintained, and reprogrammed in a context- and disease stage-dependent manner.PMID:38879436 | DOI:10.1016/j.it.2024.05.008

Pestic Biochem Physiol. 2024 Jun;202:105969. doi: 10.1016/j.pestbp.2024.105969. Epub 2024 May 26.ABSTRACTPopulus pseudo-cathayana × Populus deltoides is a crucial artificial forest tree species in Northeast China. The presence of the fall webworm (Hyphantria cunea) poses a significant threat to these poplar trees, causing substantial economic and ecological damage. This study conducted an insect-feeding experiment with fall webworm on P. pseudo-cathayana × P. deltoides, examining poplar's physiological indicators, transcriptome, and metabolome under different lengths of feeding times. Results revealed significant differences in phenylalanine ammonia-lyase activity, total phenolic content, and flavonoids at different feeding durations. Transcriptomic analysis identified numerous differentially expressed genes, including AP2/ERF, MYB, and WRKY transcription factor families exhibiting the highest expression variations. Differential metabolite analysis highlighted flavonoids and phenolic acid compounds of poplar's leaves as the most abundant in our insect-feeding experiment. Enrichment analysis revealed significant enrichment in the plant hormone signal transduction and flavonoid biosynthetic pathways. The contents of jasmonic acid and jasmonoyl-L-isoleucine increased with prolonged fall webworm feeding. Furthermore, the accumulation of dihydrokaempferol, catechin, kaempferol, and naringenin in the flavonoid biosynthesis pathway varied significantly among different samples, suggesting their crucial role in response to pest infestation. These findings provide novel insights into how poplar responds to fall webworm infestation.PMID:38879313 | DOI:10.1016/j.pestbp.2024.105969

Pestic Biochem Physiol. 2024 Jun;202:105950. doi: 10.1016/j.pestbp.2024.105950. Epub 2024 May 7.ABSTRACTHypoaconitine (HA), a major secondary metabolite of aconite (a plant-derived rodenticide), is a highly toxic di-ester alkaloidal constituent. The toxicity of HA is intense with a low LD50. However, studies on its toxicity mechanism have mainly focused on cardiotoxicity, with few reports on the mechanism of hepatotoxicity. In this study, we combined metabolomics and network toxicology to investigate the effects of HA on the liver and analyzed the mechanisms by which it causes hepatotoxicity. The results of metabolomics studies indicated diethylphosphate, sphingosine-1-phosphate, glycerophosphorylcholine, 2,8-quinolinediol, guanidinosuccinic acid, and D-proline as differential metabolites after HA exposure. These metabolites are involved in eight metabolic pathways including arginine and proline metabolism, ether lipid metabolism, β-alanine metabolism, sphingolipid metabolism, glutathione metabolism, and glycerophospholipid metabolism. Network toxicology analysis of HA may affect the HIF-1 signaling pathway, IL-17 signaling pathway, PI3K-Akt signaling pathway, MAPK signaling pathway, and so on by regulating the targets of ALB, HSP90AA1, MMP9, CASP3, and so on. Integrating the results of metabolomics and network toxicology, it was concluded that HA may induce hepatotoxicity by triggering physiological processes such as oxidative stress, inflammatory response, and inducing apoptosis in hepatocytes.PMID:38879305 | DOI:10.1016/j.pestbp.2024.105950

Anal Chim Acta. 2024 Aug 1;1315:342793. doi: 10.1016/j.aca.2024.342793. Epub 2024 Jun 8.NO ABSTRACTPMID:38879208 | DOI:10.1016/j.aca.2024.342793

Exp Hematol. 2024 Jun 13:104253. doi: 10.1016/j.exphem.2024.104253. Online ahead of print.ABSTRACTAcute myeloid leukemias are a group of hematological malignancies characterized by a poor prognosis for survival. The discovery of oncogenic mutations in the FLT3 gene has led to the development of tyrosine kinase inhibitors such as Quizartinib. However, achieving complete remission in patients remains challenging because these new TKIs are unable to completely eradicate all leukemic cells. Residual leukemic cells persist during Quizartinib treatment, leading to the rapid emergence of drug-resistant leukemia. Given that mitochondrial oxidative metabolism promotes the survival of leukemic cells after exposure to multiple anticancer drugs, we characterized the metabolism of leukemic cells that persisted during Quizartinib treatment and developed metabolic strategies to eradicate them. In our study, employing biochemical and metabolomics approaches, we confirmed that the survival of leukemic cells treated with FLT3 inhibitors critically depends on maintaining mitochondrial metabolism, specifically through glutamine oxidation. We uncovered a synergistic interaction between the FLT3 inhibitor Quizartinib and L-Asparaginase, operating through anti-metabolic mechanisms. Utilizing various models of persistent leukemia, we demonstrated that leukemic cells resistant to Quizartinib are susceptible to L-Asparaginase. This combined therapeutic strategy shows promise in reducing the development of resistance to FLT3 inhibitors, offering a potential strategy to enhance treatment outcomes.PMID:38879112 | DOI:10.1016/j.exphem.2024.104253

Clin Chim Acta. 2024 Jun 13:119814. doi: 10.1016/j.cca.2024.119814. Online ahead of print.ABSTRACTBACKGROUND: Hepatocellular cancer (HCC) is one of the most harmful tumors to human health. Currently, there is still a lack of highly sensitive and specific HCC biomarkers in clinical practice. In this study, we aimed to explore the diagnostic performance of prostaglandin A2 (PGA2) for the early detection of HCC.METHODS: Untargeted metabolomic analyses on normal control (NC) and HCC participants in the discovery cohort were performed, and PGA2 was identified to be dysregulated in HCC. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for detecting serum PGA2 was established and applied to validate the dysregulation of PGA2 in another independent validation cohort. Receiver operating characteristic (ROC), decision curve analysis (DCA) and some other statistical analyses were performed to evaluate the diagnostic performance of PGA2 for HCC.RESULTS: At first, PGA2 was found to be dysregulated in HCC in untargeted metabolomic analyses. Then a precise quantitative LC-MS/MS method for PGA2 has been established and has passed rigorous method validation. Targeted PGA2 analyses confirmed that serum PGA2 was decreased in HCC compared to normal-risk NC and high-risk cirrhosis group. Subsequently, PGA2 was identified as a novel biomarker for the diagnosis of HCC, with an area under the ROC curve (AUC) of 0.911 for differentiating HCC from the combined NC + cirrhosis groups. In addition, PGA2 exhibited high performance for differentiating small-size (AUC = 0.924), early-stage (AUC = 0.917) and AFP (-) HCC (AUC = 0.909) from the control groups. The combination of PGA2 and AFP might be useful in the surveillance of risk population for HCC and early diagnosis of HCC.CONCLUSION: This study establishes that PGA2 might be a novel diagnostic biomarker for HCC.PMID:38879063 | DOI:10.1016/j.cca.2024.119814

Sci Total Environ. 2024 Jun 13:174001. doi: 10.1016/j.scitotenv.2024.174001. Online ahead of print.ABSTRACTMicro- and nano-plastics (MNPs) in the soil can impact the microbial diversity within rhizospheres and induce modifications in plants' morphological, physiological, and biochemical parameters. However, a significant knowledge gap still needs to be addressed regarding the specific effects of varying particle sizes and concentrations on the comprehensive interplay among soil dynamics, root exudation, and the overall plant system. In this sense, different omics techniques were employed to clarify the mechanisms of the action exerted by four different particle sizes of polyethylene plastics considering four different concentrations on the soil-roots exudates-plant system was studied using lettuce (Lactuca sativa L. var. capitata) as a model plant. The impact of MNPs was investigated using a multi-omics integrated approach, focusing on the tripartite interaction between the root metabolic process, exudation pattern, and rhizosphere microbial modulation. Our results showed that particle size and their concentrations significantly modulated the soil-roots exudates-plant system. Untargeted metabolomics highlighted that fatty acids, amino acids, and hormone biosynthesis pathways were significantly affected by MNPs. Additionally, they were associated with the reduction of rhizosphere bacterial α-diversity, following a size-dependent trend for specific taxa. The omics data integration highlighted a correlation between Pseudomonadata and Actinomycetota phyla and Bacillaceae family (Peribacillus simplex) and the exudation of flavonoids, phenolic acids, and lignans in lettuce exposed to increasing sizes of MNPs. This study provides a novel insight into the potential effects of different particle sizes and concentrations of MNPs on the soil-plant continuum, providing evidence about size- and concentration-dependent effects, suggesting the need for further investigation focused on medium- to long-term exposure.PMID:38879040 | DOI:10.1016/j.scitotenv.2024.174001

Chemosphere. 2024 Jun 13:142611. doi: 10.1016/j.chemosphere.2024.142611. Online ahead of print.ABSTRACTBromophenols has been proven to synthesize hydroxylated polybrominated diphenyl ethers (OH-PBDEs), which may pose additional environmental and health risks in the process of bioremediation. In this study, the removal of 2,4-dibromophenol (2,4-DBP) and 2,4,6-tribromophenol (2,4,6-TBP) and the biosynthetic of OH-PBDEs by Prorocentrum donghaiense were explored. The removal efficiencies of 2,4-DBP and 2,4,6-TBP ranged from 32.71% to 76.89% and 31.15% to 78.12%, respectively. Low concentrations of 2,4-DBP stimulated algal growth, while high concentrations were inhibitory. Furthermore, exposure to 10.00 mg L-1 2,4-DBP resulted in the detection of 2'-hydroxy-2,3',4,5'-tetrabromodiphenyl ether (2'-OH-BDE-68) within P. donghaiense. In contrast, increasing concentrations of 2,4,6-TBP considerably inhibited P. donghaiense growth, with 4'-hydroxy-2,3',4,5',6-pentabromodiphenyl ether (4'-OH-BDE-121) detected within P. donghaiense under 5.00 mg L-1 2,4,6-TBP. Metabolomic analysis further revealed that the synthesized OH-PBDEs exhibited higher toxicity than their precursors and identified the oxidative coupling as a key biosynthetic mechanism. These findings confirm the capacity of P. donghaiense to remove bromophenols and biosynthesize OH-PBDEs from bromophenols, offering valuable insights into formulating algal bioremediation to mitigate bromophenol contamination.PMID:38878983 | DOI:10.1016/j.chemosphere.2024.142611

J Proteomics. 2024 Jun 13:105227. doi: 10.1016/j.jprot.2024.105227. Online ahead of print.ABSTRACTPolygoni Orientalis Fructus (POF), a dried ripe fruit of Polygonum orientale L., is commonly used in China for liver disease treatment. However, its therapeutic mechanism remains unclear. The aim of this study was to elucidate the effects of POF on the regulation of endogenous metabolites and identify its key therapeutic targets in HF rats by integrating network pharmacology and metabolomics approaches. First, serum liver indices and histopathological analyses were used to evaluate the therapeutic effects of POF on carbon tetrachloride (CCl4)-induced hepatic fibrosis (HF). Subsequently, differential metabolites and potential therapeutic targets of POF were identified using plasma metabolites and network pharmacology, respectively. The key targets of POF were identified by overlapping differential metabolite-associated targets with the potential targets and validated by molecular docking and ELISA. The results showed that POF effectively alleviated HF in rats. A total of 51 metabolites related to HF were screened, and 24 were associated with POF. 232 potential therapeutic targets were identified by network pharmacology analysis. Finally, six key targets were identified through a combined analysis. Furthermore, molecular docking and ELISA validation revealed that AGXT, PAH, and NOS3 are targets of POF action, while CBS, ALDH2, and ARG1 were identified as potential targets. SIGNIFICANCE: POF is now commonly used in the treatment of liver disease, but its mechanism of action remains unclear. Current studies on metabolomics of liver disease primarily focuse on the interpretation of differential metabolites and related metabolic pathways. This research delves into the intricate details of metabolomics findings via network pharmacology to uncover the targets and pathways of drug action.PMID:38878880 | DOI:10.1016/j.jprot.2024.105227

Am J Transplant. 2024 Jun 13:S1600-6135(24)00346-0. doi: 10.1016/j.ajt.2024.05.018. Online ahead of print.ABSTRACTCold and ischemia/reperfusion (IR)-associated injuries are seemingly inevitable during liver transplantation and hepatectomy. As Syrian hamsters demonstrate intrinsic tolerance to transplantation-like stimuli, cross-species comparative metabolomic analyses were conducted with hamster, rat and donor liver samples to seek hepatic cold and IR-adaptive mechanisms. Lower hepatic phosphocholine contents were found in early graft-dysfunctioned recipients with virus-caused cirrhosis or high MELD scores (≥30). Choline/phosphocholine deficiency in cultured human THLE-2 hepatocytes and animal models weakened hepatocellular cold tolerance and recovery of glutathione and ATP production, which was rescued by phosphocholine supplements. Among the biological processes impacted by choline/phosphocholine deficiency, three lipid-related metabolic processes were downregulated, whilst phosphocholine elevated the expression of genes in methylation processes. Consistently, in THLE-2, phosphocholine enhanced the overall RNA m6A methylation, among which the transcript stability of Fatty acid desaturase 6 (FADS6) was improved. FADS6 functioned as a key phosphocholine effector in the production of polyunsaturated fatty acids, which may facilitate the hepatocellular recovery of energy and redox homeostasis. Thus, our study reveals the choline-phosphocholine metabolism and its downstream FADS6 functions in hepatic adaptation to cold and IR, which may inspire new strategies to monitor donor liver quality and improve recipient recovery from the LT process.PMID:38878865 | DOI:10.1016/j.ajt.2024.05.018

J Ethnopharmacol. 2024 Jun 13:118456. doi: 10.1016/j.jep.2024.118456. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Liver fibrosis is a generic fibrous scarring event resulting from accumulation of extracellular matrix (ECM) proteins, easily progressing to end-stage liver diseases. Tao-Hong-Si-Wu-Tang (THSWT) is a traditional Chinese medicine formula applied in clinics to treat gynecological and chronic liver diseases. However, the role of THSWT on thioacetamide (TAA)-induced hepatic fibrosis and the specific mechanisms remains unclear.AIM OF THE STUDY: To investigate the improving effects of THSWT on TAA-insulted hepatic fibrosis and the underlying mechanisms.MATERIALS AND METHODS: UHPLC-MS/MS was performed to explore the chemical characterization of THSWT. Mice were orally administered with THSWT once daily for 6 weeks along with TAA challenge. Liver function was reflected through serum biomarkers and histopathological staining. RNA sequencing, non-targeted metabolomics and molecular biology experiments were applied to investigate the underlying mechanisms.RESULTS: THSWT profoundly repaired lipid metabolism dysfunction and blocked collagen accumulation both in TAA-stimulated mice and in hepatocytes. Results of RNA sequencing and non-targeted metabolomics revealed that the anti-fibrotic effects of THSWT mostly relied on lipid metabolism repairment by increasing levels of acetyl-CoA, phosphatidylcholine, phosphatidylethanolamine, lysophosphatidylcholine and lysophosphatidylethanolamine, and decreasing relative abundances of acyl-CoA, total cholesterol, diacylglycerol, triacylglycerol and phosphatidylinositol. Mechanically, long-chain acyl-CoA synthetases 4 (ACSL4) was a key profibrotic target both in human and mice by disrupting lipid oxidation and metabolism in hepatic mitochondria. THSWT effectively blocked ACSL4 and promoted mitophagy to reverse above outcomes, which was verified by mitophagy depletion.CONCLUSION: THSWT may be a promising therapeutic option for treating hepatic fibrosis and its complications by modulating lipid metabolism and promoting mitophagy in livers.PMID:38878839 | DOI:10.1016/j.jep.2024.118456

Genomics. 2024 Jun 13:110884. doi: 10.1016/j.ygeno.2024.110884. Online ahead of print.ABSTRACTCynanchum thesioides, a xerophytic species utilized both as a medicinal herb and a food source, plays a significant role in arid and desert ecosystem management. Its inflorescence is an umbellate cyme, each carrying nearly a thousand flowers; however, its fruiting rate remains remarkably low. The normal development of the anther is a necessary prerequisite for plants to produce seeds. However, our understanding of the anther development process in Cynanchum thesioides remains limited. To better understand the pollen development process in Cynanchum thesioides, the stages of pollen development were determined through paraffin sectioning, and observations were made on the distribution characteristics of polysaccharides and lipid droplets in the pollen development of Cynanchum thesioides using Periodic Acid-Schiff stain (PAS) and 0.5% Sudan Black B tissue staining. Concurrently, the gene expression patterns and metabolite profiles were delineated across various developmental stages of Cynanchum thesioides anthers (T1: microspore stage, T2: tetrad stage, T3: mononuclear stage, and T4: maturation stage). The findings revealed that Cynanchum thesioides pollen is in an aggregate form. Polysaccharides gradually accumulate during maturation and lipid droplets form a surrounding membrane, thereby preventing pollen dispersion. Furthermore, transcriptomic and metabolomic analyses across distinct developmental phases uncovered a plethora of differentially expressed genes and metabolites associated with the flavonoid biosynthesis pathway. Flavonoid levels exhibited dynamic changes concurrent with anther development, aligning with the gene regulatory patterns of the corresponding biosynthetic pathways. The study identified 63 differentially accumulated flavonoid compounds and 21 differentially expressed genes associated with flavonoid biosynthesis. Weighted gene co-expression network analysis revealed six MYB and ten bHLH transcription factors as key candidates involved in flavonoid biosynthesis, with CtbHLH (Cluster-6587.1050) and CtMYB (Cluster-6587.31743) specifically regulating structural genes within the pathway. These findings underscore the pivotal role of flavonoid biosynthesis in anther development of Cynanchum thesioides. In conclusion, this research offers a comprehensive insight into the anther development process in Cynanchum thesioides.PMID:38878835 | DOI:10.1016/j.ygeno.2024.110884

Biochim Biophys Acta Mol Basis Dis. 2024 Jun 13:167299. doi: 10.1016/j.bbadis.2024.167299. Online ahead of print.ABSTRACTSTING (stimulator of interferon genes) is a critical immunoregulatory protein in sepsis and is regulated by various mechanisms, especially palmitoylation. FASN (fatty acid synthase) is the rate-limiting enzyme to generate cellular palmitic acid (PA) via acetyl-CoA and malonyl-CoA and participates in protein palmitoylation. However, the mechanisms underlying the interaction between STING and FASN have not been completely understood. In this study, STING-knockout mice were used to confirm the pivotal role of STING in sepsis-induced liver injury. Metabolomics confirmed the dyslipidemia in septic mice and patients. The compounds library was screened, revealing that FASN inhibitors exerted a significant inhibitory effect on the STING pathway. Mechanically, the regulatory effect of FASN on the STING pathway was dependent on palmitoylation. Further experiments indicated that the upstream of FASN, malonyl-CoA inhibited STING pathway possibly due to C91 (palmitoylated residue) of STING. Overall, this study reveals a novel paradigm of STING regulation and provides a new perspective on immunity and metabolism.PMID:38878833 | DOI:10.1016/j.bbadis.2024.167299

Biomed Pharmacother. 2024 Jun 14;177:116894. doi: 10.1016/j.biopha.2024.116894. Online ahead of print.ABSTRACTBACKGROUND: To explore the neuroprotective mechanism of artemisinin against ischemic stroke from the perspective of NLRP3-mediated pyroptosis.METHODS: Serum metabolomics technology was used to analyze the serum samples of mice, and KEGG metabolic pathway was analyzed for the different metabolites in the samples. PIT model and OGD/R model were used to simulate ischemic stroke damage in vivo and in vitro. Hoechst 33342 staining, Annexin V-FITC/PI staining and TUNEL staining were used to detect the pyroptosis rate of cells. The contents of IL-1β and IL-18 in PC12 cells and serum of mice were detected by ELISA. The expressions of NLRP3, ASC-1, Caspase-1 and TXNIP in PC12 cells and mouse brain tissue were detected by Western Blot.RESULTS: Serum metabolic profiles of animal models identified 234 different metabolites and 91 metabolic pathways. Compared with the Sham group and the Stroke+ART group, the KEGG pathway in the Stroke group was concentrated in the Necroptosis pathway associated with cell growth and death, and the NLRP3 inflammasome-mediated pyroptosis pathway was activated in the Necroptosis pathway after ischemic stroke. The results of in vivo and in vitro experiments showed that pretreatment with 10 μM artemisinin reduced ROS production, decreased Δψm, reduced pyroptosis, maintained neuronal cell morphology, and down-regulated the contents of IL-1β and IL-18 as well as the expression of key proteins of NLRP3, ASC-1, Caspase-1 and TXNIP(p<0.01).CONCLUSION: Artemisinin can reduce neuronal pyroptosis induced by ischemic stroke by inhibiting ROS/TXNIP/NLRP3/Caspase-1 signaling pathway.PMID:38878634 | DOI:10.1016/j.biopha.2024.116894