PubMed

J Biomol Struct Dyn. 2023 Sep 21:1-18. doi: 10.1080/07391102.2023.2257322. Online ahead of print.ABSTRACTHuntington's disease is associated with increased CAG repeat resulting in an expanded polyglutamine tract in the protein Huntingtin (HTT) leading to its aggregation resulting in neurodegeneration. Previous studies have shown that N-terminal HTT with 46Q aggregated in the stationary phase but not the logarithmic phase in the yeast model of HD. We carried out a metabolomic analysis of logarithmic and stationary phase yeast model of HD expressing different polyQ lengths attached to N-terminal HTT tagged with enhanced green fluorescent protein (EGFP). The results show significant changes in the metabolic profile and deregulated pathways in stationary phase cells compared to logarithmic phase cells. Comparison of metabolic pathways obtained from logarithmic phase 46Q versus 25Q with those obtained for presymptomatic HD patients from our previous study and drosophila model of HD showed considerable overlap. The arginine biosynthesis pathway emerged as one of the key pathways that is common in stationary phase yeast compared to logarithmic phase and HD patients. Treatment of yeast with arginine led to a significant decrease, while transfer to arginine drop-out media led to a significant increase in the size of protein aggregates in both logarithmic and stationary phase yeast model of HD. Knockout of arginine transporters in the endoplasmic reticulum and vacuole led to a significant decrease in mutant HTT aggregation. Overall our results highlight arginine as a critical metabolite that modulates the aggregation of mutant HTT and disease progression in HD.Communicated by Ramaswamy H. Sarma.PMID:37732342 | DOI:10.1080/07391102.2023.2257322

Front Vet Sci. 2023 Sep 5;10:1228360. doi: 10.3389/fvets.2023.1228360. eCollection 2023.ABSTRACTINTRODUCTION: Ochratoxin A (OTA) is a widely distributed mycotoxin. Nano-selenium (Nano-Se) is an emerging form of selenium known for its superior bioavailability, remarkable catalytic efficiency, and robust adsorbing capacity. Despite these characteristics, its impact on the microbial community and metabolomics in the cecum of chickens exposed to OTA has been infrequently investigated. This research examined the microbiota and metabolomic alterations linked to OTA in chickens, with or without Nano-Se present.METHODS: A cohort of 80 healthy chickens at the age of 1 day was randomly distributed into four groups of equal numbers, namely the Se cohort (1 mg/kg Nano-Se), the OTA cohort (50 μg/kg OTA), the OTA-Se cohort (50 μg/kg OTA + 1 mg/kg Nano-Se), and the control group. Each chicken group's caecal microbiome and metabolome were characterized using 16S rRNA sequencing and Liquid chromatography coupled with mass spectrometry (LC-MS) analyses.RESULTS AND DISCUSSION: Our results showed that the on day 21, the final body weight was significantly reduced in response to OTA treatments (p < 0.05), the average daily gain in the OTA group was found to be inferior to the other groups (p < 0.01). In addition, Nano-Se supplementation could reduce the jejunum and liver pathological injuries caused by OTA exposure. The 16S rRNA sequencing suggest that Nano-Se supplementation in OTA-exposed chickens mitigated gut microbiota imbalances by promoting beneficial microbiota and suppressing detrimental bacteria. Moreover, untargeted metabolomics revealed a significant difference in caecal metabolites by Nano-Se pretreatment. Collectively, the dataset outcomes highlighted that Nano-Se augmentation regulates intestinal microbiota and associated metabolite profiles, thus influencing critical metabolic pathways, and points to a possible food-additive product.PMID:37732141 | PMC:PMC10507861 | DOI:10.3389/fvets.2023.1228360

Research (Wash D C). 2023 Sep 19;6:0216. doi: 10.34133/research.0216. eCollection 2023.ABSTRACTInsufficient sleep can produce a multitude of deleterious repercussions on various domains of human well-being. Concomitantly, the walnut (Juglans mandshurica) confers numerous salutary biological activities pertaining to sleep. Nevertheless, the sedative and hypnotic capacities of walnut's functional constituents remain obscure. In this investigation, we analyzed the sedative and hypnotic components of the walnut Diaphragma juglandis fructus and innovatively discovered a compound, defined as 3-hydroxy-4-iminobutyric acid (HIBA), which disrupts motor activity and enhances sleep duration by regulating the neurotransmitters (GABA, DA, etc.) within the brain and serum of mice. Subsequently, a metabolomics approach of the serum, basal ganglia, hypothalamus, and hippocampus as well as the gut microbiota was undertaken to unravel the underlying molecular mechanisms of sleep promotion. Our data reveal that HIBA can regulate the metabolism of basal ganglia (sphingolipids, acylcarnitines, etc.), possibly in relation to HIBA's influence on the gut microbiome (Muribaculum, Bacteroides, Lactobacillus, etc.). Therefore, we introduce a novel natural product, HIBA, and explicate the modulation of sleep promotion in mice based on the microbiota-gut-brain axis. This study contributes fresh insights toward natural product-based sleep research.PMID:37732131 | PMC:PMC10508226 | DOI:10.34133/research.0216

Front Endocrinol (Lausanne). 2023 Sep 5;14:1159707. doi: 10.3389/fendo.2023.1159707. eCollection 2023.ABSTRACTINTRODUCTION: Yu-Ye Tang (YYT) is a classical formula widely used in treatment of type 2 diabetes mellitus (T2DM). However, the specific mechanism of YYT in treating T2DM is not clear.METHODS: The aim of this study was to investigate the therapeutic effect of YYT on T2DM by establishing a rat model of T2DM. The mechanism of action of YYT was also explored through investigating gut microbiota and serum metabolites.RESULTS: The results indicated YYT had significant therapeutic effects on T2DM. Moreover, YYT could increase the abundance of Lactobacillus, Candidatus_Saccharimonas, UCG-005, Bacteroides and Blautia while decrease the abundance of and Allobaculum and Desulfovibrio in gut microbiota of T2DM rats. Nontargeted metabolomics analysis showed YYT treatment could regulate arachidonic acid metabolism, alanine, aspartate and glutamate metabolism, arginine and proline metabolism, glycerophospholipid metabolism, pentose and glucuronate interconversions, phenylalanine metabolism, steroid hormone biosynthesis, terpenoid backbone biosynthesis, tryptophan metabolism, and tyrosine metabolism in T2DM rats.DISCUSSION: In conclusion, our research showed that YYT has a wide range of therapeutic effects on T2DM rats, including antioxidative and anti-inflammatory effects. Furthermore, YYT corrected the altered gut microbiota and serum metabolites in T2DM rats. This study suggests that YYT may have a therapeutic impact on T2DM by regulating gut microbiota and modulating tryptophan and glycerophospholipid metabolism, which are potential key pathways in treating T2DM.PMID:37732114 | PMC:PMC10507721 | DOI:10.3389/fendo.2023.1159707

Front Psychiatry. 2023 Sep 5;14:1182535. doi: 10.3389/fpsyt.2023.1182535. eCollection 2023.ABSTRACTMuch recent attention has been directed toward the spatial organization of the cell nucleus and the manner in which three-dimensional topologically associated domains and transcription factories are epigenetically coordinated to precisely bring enhancers into close proximity with promoters to control gene expression. Twenty lines of evidence robustly implicate cannabinoid exposure with accelerated organismal and cellular aging. Aging has recently been shown to be caused by increased DNA breaks. These breaks rearrange and maldistribute the epigenomic machinery to weaken and reverse cellular differentiation, cause genome-wide DNA demethylation, reduce gene transcription, and lead to the inhibition of developmental pathways, which contribute to the progressive loss of function and chronic immune stimulation that characterize cellular aging. Both cell lineage-defining superenhancers and the superanchors that control them are weakened. Cannabis exposure phenocopies the elements of this process and reproduces DNA and chromatin breakages, reduces the DNA, RNA protein and histone synthesis, interferes with the epigenomic machinery controlling both DNA and histone modifications, induces general DNA hypomethylation, and epigenomically disrupts both the critical boundary elements and the cohesin motors that create chromatin loops. This pattern of widespread interference with developmental programs and relative cellular dedifferentiation (which is pro-oncogenic) is reinforced by cannabinoid impairment of intermediate metabolism (which locks in the stem cell-like hyper-replicative state) and cannabinoid immune stimulation (which perpetuates and increases aging and senescence programs, DNA damage, DNA hypomethylation, genomic instability, and oncogenesis), which together account for the diverse pattern of teratologic and carcinogenic outcomes reported in recent large epidemiologic studies in Europe, the USA, and elsewhere. It also accounts for the prominent aging phenotype observed clinically in long-term cannabis use disorder and the 20 characteristics of aging that it manifests. Increasing daily cannabis use, increasing use in pregnancy, and exponential dose-response effects heighten the epidemiologic and clinical urgency of these findings. Together, these findings indicate that cannabinoid genotoxicity and epigenotoxicity are prominent features of cannabis dependence and strongly indicate coordinated multiomics investigations of cannabinoid genome-epigenome-transcriptome-metabolome, chromatin conformation, and 3D nuclear architecture. Considering the well-established exponential dose-response relationships, the diversity of cannabinoids, and the multigenerational nature of the implications, great caution is warranted in community cannabinoid penetration.PMID:37732074 | PMC:PMC10507876 | DOI:10.3389/fpsyt.2023.1182535

Hortic Res. 2023 Aug 16;10(9):uhad164. doi: 10.1093/hr/uhad164. eCollection 2023 Sep.ABSTRACTArtemisia annua is the only known plant source of the potent antimalarial artemisinin, which occurs as the low- and high-artemisinin producing (LAP and HAP) chemotypes. Nevertheless, the different mechanisms of artemisinin producing between these two chemotypes were still not fully understood. Here, we performed a comprehensive analysis of genome resequencing, metabolome, and transcriptome data to systematically compare the difference in the LAP chemotype JL and HAP chemotype HAN. Metabolites analysis revealed that 72.18% of sesquiterpenes was highly accumulated in HAN compared to JL. Integrated omics analysis found a DBR2-Like (DBR2L) gene may be involved in artemisinin biosynthesis. DBR2L was highly homologous with DBR2, belonged to ORR3 family, and had the DBR2 activity of catalyzing artemisinic aldehyde to dihydroartemisinic aldehyde. Genome resequencing and promoter cloning revealed that complicated variations existed in DBR2L promoters among different varieties of A. annua and were clustered into three variation types. The promoter activity of diverse variant types showed obvious differences. Furthermore, the core region (-625 to 0) of the DBR2L promoter was identified and candidate transcription factors involved in DBR2L regulation were screened. Thus, the result indicates that DBR2L is another key enzyme involved in artemisinin biosynthesis. The promoter variation in DBR2L affects its expression level, and thereby may result in the different yield of artemisinin in varieties of A. annua. It provides a novel insight into the mechanism of artemisinin-producing difference in LAP and HAP chemotypes of A. annua, and will assist in a high yield of artemisinin in A. annua.PMID:37731862 | PMC:PMC10508037 | DOI:10.1093/hr/uhad164

iScience. 2023 Aug 29;26(10):107754. doi: 10.1016/j.isci.2023.107754. eCollection 2023 Oct 20.ABSTRACTHepatic fibrosis is a classic pathological manifestation of metabolic chronic hepatopathy. The pathological process might either gradually deteriorate into cirrhosis and ultimately liver cancer with inappropriate nutrition supply, or be slowed down by several multifunctional nutrients, alternatively. Herein, we found diet with excessive phenylalanine (Phe) and tyrosine (Tyr) exacerbated hepatic fibrosis symptoms of liver dysfunction and gut microflora dysbiosis in mice. Chitooligosaccharides (COS) could ameliorate hepatic fibrosis with the regulation of amino acid metabolism by downregulating the mTORC1 pathway, especially that of Phe and Tyr, and also with the alleviation of the dysbiosis of gut microbiota, simultaneously. Conclusively, this work presents new insight into the role of Phe and Tyr in the pathologic process of hepatic fibrosis, while revealing the effectiveness and molecular mechanism of COS in improving hepatic fibrosis from the perspective of metabolites.PMID:37731617 | PMC:PMC10507131 | DOI:10.1016/j.isci.2023.107754

iScience. 2023 Sep 1;26(10):107790. doi: 10.1016/j.isci.2023.107790. eCollection 2023 Oct 20.ABSTRACTDoxorubicin is a wildly used effective anticancer agent. However, doxorubicin use is also related to cardiotoxic side effect in some patients. Mitochondrial damage has been shown to be one of the pathogeneses of doxorubicin-induced myocardial injury. In this study, we demonstrated that mitochondrial transplantation could inhibit doxorubicin-induced cardiotoxicity by directly supplying functional mitochondria. Mitochondrial transplantation improved contractile function and respiratory capacity, reduced cellular apoptosis and oxidative stress in cardiomyocytes. Mitochondria isolated from various sources, including mouse hearts, mouse and human arterial blood, and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), all exerted similar cardioprotective effects. Mechanically, mitochondrial transplantation activates glutamine metabolism in doxorubicin-treated mice heart and blocking glutamine metabolism attenuated the cardioprotective effects of mitochondrial transplantation. Overall, our study demonstrates that mitochondria isolated from arterial blood could be used for mitochondrial transplantation, which might serve as a feasible promising therapeutic option for patients with doxorubicin-induced cardiotoxicity.PMID:37731615 | PMC:PMC10507231 | DOI:10.1016/j.isci.2023.107790

Metabolomics. 2023 Sep 20;19(10):84. doi: 10.1007/s11306-023-02049-z.ABSTRACTINTRODUCTION: Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. Alteration in lipid metabolism and chemokine expression are considered hallmark characteristics of malignant progression and metastasis of CRC. Validated diagnostic and prognostic biomarkers are urgently needed to define molecular heterogeneous CRC clinical stages and subtypes, as liver dominant metastasis has poor survival outcomes.OBJECTIVES: The aim of this study was to integrate lipid changes, concentrations of chemokines, such as platelet factor 4 and interleukin 8, and gene marker status measured in plasma samples, with clinical features from patients at different CRC stages or who had progressed to stage-IV colorectal liver metastasis (CLM).METHODS: High-resolution liquid chromatography-mass spectrometry (HR-LC-MS) was used to determine the levels of candidate lipid biomarkers in each CRC patient's preoperative plasma samples and combined with chemokine, gene and clinical data. Machine learning models were then trained using known clinical outcomes to select biomarker combinations that best classify CRC stage and group.RESULTS: Bayesian neural net and multilinear regression-machine learning identified candidate biomarkers that classify CRC (stages I-III), CLM patients and control subjects (cancer-free or patients with polyps/diverticulitis), showing that integrating specific lipid signatures and chemokines (platelet factor-4 and interluken-8; IL-8) can improve prognostic accuracy. Gene marker status could contribute to disease prediction, but requires ubiquitous testing in clinical cohorts.CONCLUSION: Our findings demonstrate that correlating multiple disease related features with lipid changes could improve CRC prognosis. The identified signatures could be used as reference biomarkers to predict CRC prognosis and classify stages, and monitor therapeutic intervention.PMID:37731020 | DOI:10.1007/s11306-023-02049-z

Nature. 2023 Sep 20. doi: 10.1038/s41586-023-06546-y. Online ahead of print.ABSTRACTProtective immunity against pathogens or cancer is mediated by the activation and clonal expansion of antigen-specific naive T cells into effector T cells. To sustain their rapid proliferation and effector functions, naive T cells switch their quiescent metabolism to an anabolic metabolism through increased levels of aerobic glycolysis, but also through mitochondrial metabolism and oxidative phosphorylation, generating energy and signalling molecules1-3. However, how that metabolic rewiring drives and defines the differentiation of T cells remains unclear. Here we show that proliferating effector CD8+ T cells reductively carboxylate glutamine through the mitochondrial enzyme isocitrate dehydrogenase 2 (IDH2). Notably, deletion of the gene encoding IDH2 does not impair the proliferation of T cells nor their effector function, but promotes the differentiation of memory CD8+ T cells. Accordingly, inhibiting IDH2 during ex vivo manufacturing of chimeric antigen receptor (CAR) T cells induces features of memory T cells and enhances antitumour activity in melanoma, leukaemia and multiple myeloma. Mechanistically, inhibition of IDH2 activates compensating metabolic pathways that cause a disequilibrium in metabolites regulating histone-modifying enzymes, and this maintains chromatin accessibility at genes that are required for the differentiation of memory T cells. These findings show that reductive carboxylation in CD8+ T cells is dispensable for their effector response and proliferation, but that it mainly produces a pattern of metabolites that epigenetically locks CD8+ T cells into a terminal effector differentiation program. Blocking this metabolic route allows the increased formation of memory T cells, which could be exploited to optimize the therapeutic efficacy of CAR T cells.PMID:37730993 | DOI:10.1038/s41586-023-06546-y

Sci Rep. 2023 Sep 20;13(1):15559. doi: 10.1038/s41598-023-42497-0.ABSTRACTSeaweeds of the intertidal zone are subjected to diverse stresses due to environmental changes in radiation, salinity, water quality, herbivore communities, etc. Thus, marine seaweeds developed various unique compounds to deal with environmental fluctuations. Therefore, they are a good source of unique novel compounds. Here, we explored the seasonal metabolomic changes in Jania rubens and found notable changes between extracts of different seasons in the metabolomic profile and in their anticancer activity. The most bioactive extract was from samples collected during the Fall season, which demonstrated an LC50 of 178.39 (± 10.02 SD) µg/ml toward Non Small Cell Lung Cancer (NSCLC) followed by the Winter season extract. The Fall and Winter extracts also displayed more resemblance in their metabolic profile relative to Spring and Summer extracts. The Fall extract was fractionated and tested for cytotoxic activity toward an array of cancer cell lines. Eventually, using a bio-guided assay and multiple fractionation steps, we isolated and identified the essential fatty acid, eicosapentaenoic acid, as the active anticancer agent, showing an LC50 of 5.23 (± 0.07 SD) µg/ml toward NSCLC. Our results emphasize the potential use of J. rubens as a source of beneficial fatty acids and stress the importance of environmental effects on metabolic constitutes.PMID:37730882 | DOI:10.1038/s41598-023-42497-0

Sci Rep. 2023 Sep 20;13(1):15633. doi: 10.1038/s41598-023-42167-1.ABSTRACTThe release of neutrophil extracellular traps (NETs) can be either beneficial or detrimental for the host, thus it is necessary to maintain a balance between formation and clearance of NETs. Multiple physiological factors eliciting NET release have been identified, yet the studies on natural signals limiting NET formation have been scarce. Accordingly, our aim was to analyze whether cytokines or immune cells can inhibit NET formation. To that end, human granulocytes were incubated with interleukin (IL)-4, IL-10, transforming growth factor beta-2 or adenosine and then stimulated to release NETs. Additionally, neutrophils were cultured in the presence of natural killer (NK) cells, regulatory T cells (Tregs), pro-inflammatory or anti-inflammatory macrophages (M1 or M2 macrophages), or in the presence of NK/Tregs/M1 macrophages or M2 macrophages-conditioned medium and subsequently stimulated to release NETs. Our studies showed that secretome of M1 and M2 macrophages, but not of NK cells and Tregs, diminishes NET formation. Co-culture experiments did not reveal any effect of immune cells on NET release. No effect of cytokines or adenosine on NET release was found. This study highlights the importance of paracrine signaling at the site of infection and is the first to show that macrophage secretome can regulate NET formation.PMID:37730741 | PMC:PMC10511515 | DOI:10.1038/s41598-023-42167-1

Arthritis Res Ther. 2023 Sep 20;25(1):176. doi: 10.1186/s13075-023-03161-0.ABSTRACTBACKGROUND: Synovial fibroblasts in rheumatoid arthritis (RAFLS) exhibit a pathological aberration of glycolysis and glutaminolysis. Henceforth, we aimed to investigate if dual inhibition of these pathways by phytobiological compound c28MS has the potential of synergistic therapy for arthritis by targeting both glucose and glutamine metabolism.METHODS: The presence of HK2 and GLS across various cell types and associated gene expression in human synovial cells and a murine model of arthritis was evaluated by scRNA-seq. The metabolic profiling of RAFLS cells was done using H1-nuclear magnetic resonance spectroscopy under glycolytic and glutaminolytic inhibitory conditions by incubating with 3-bromopyruvate, CB839, or dual inhibitor c28MS. FLS functional analysis was conducted under similar conditions. ELISA was employed for the quantification of IL-6, CCL2, and MMP3. K/BxN sera was administered to mice to induce arthritis for in vivo arthritis experiments.RESULTS: scRNA-seq analysis revealed that many fibroblasts expressed Hk2 along with Gls with several genes including Ptgs2, Hif1a, Timp1, Cxcl5, and Plod2 only associated with double-positive fibroblasts, suggesting that dual inhibition can be an attractive target for fibroblasts. Metabolomic and functional analysis revealed that c28MS decreased the aggressive behavior of RAFLS by targeting both upregulated glycolysis and glutaminolysis. c28MS administered in vivo significantly decreased the severity of arthritis in the K/BxN model.CONCLUSION: Our findings imply that dual inhibition of glycolysis and glutaminolysis could be an effective approach for the treatment of RA. It also suggests that targeting more than one metabolic pathway can be a novel treatment approach in non-cancer diseases.PMID:37730663 | DOI:10.1186/s13075-023-03161-0

Cell Commun Signal. 2023 Sep 20;21(1):245. doi: 10.1186/s12964-023-01271-5.ABSTRACTBACKGROUND: Several studies show that natural foods are a source of compounds with anticancer properties that affect the gut microbiota and its metabolites. In the present study, we investigate the effect of a delactosed buffalo milk whey by-product (DMW) on colorectal carcinogenesis.METHODS: The effect of DMW on colorectal carcinoma (CRC) was investigated in the established mouse model of azoxymethane (AOM)-induced colon carcinoma, which closely resembles the human clinical condition of CRC. The effect of DMW on CRC immortalized cell lines was also evaluated to further identify the antineoplastic mechanism of action.RESULTS: Pretreatment of AOM-treated mice with DMW significantly (P < 0.05) reduced the percentage of mice bearing both aberrant crypt foci with more than four crypts (which are early precancerous lesions that progress to CRC) and tumors. In addition, DMW completely counteracted the effect of AOM on protein expression of caspase-9, cleaved caspase-3 and poly ADP-ribose polymerase in colonic tissue. Administration of DMW alone (i.e. without AOM) resulted in changes in the composition of the gut microbiota, leading to enrichment or depletion of genera associated with health and disease, respectively. DMW was also able to restore AOM-induced changes in specific genera of the gut microbiota. Specifically, DMW reduced the genera Atopobiaceae, Ruminococcus 1 and Lachnospiraceae XPB1014 and increased the genera Parabacteroides and Candidatus Saccharimonas, which were increased and reduced, respectively, by AOM. Blood levels of butyric acid and cancer diagnostic markers (5-methylcytidine and glycerophosphocholine), which were increased by AOM treatment, were reduced by DMW. Furthermore, DMW exerted cytotoxic effects on two human CRC cell lines (HCT116 and HT29) and these effects were associated with the induction of apoptotic signaling.CONCLUSIONS: Our results suggest that DMW exerts chemopreventive effects and restores the gut microbiota in AOM-induced CRC, and induces cytotoxic effect on CRC cells. DMW could be an important dietary supplement to support a healthy gut microbiota and reduce the prevalence of CRC in humans. Video Abstract.PMID:37730576 | DOI:10.1186/s12964-023-01271-5

J Dairy Sci. 2023 Sep 18:S0022-0302(23)00681-1. doi: 10.3168/jds.2023-23752. Online ahead of print.ABSTRACTThe objective of this experiment was to examine the effects of supplementation and dose of rumen-protected choline (RPC) on markers of inflammation and metabolism in liver and mammary tissue during an intramammary lipopolysaccharide (LPS) challenge. Parous Holstein cows were blocked by calving month and randomly assigned within block to receive 45 g/d of RPC (20.4 g/d of choline ions; CHOL45), 30 g/d of RPC (13.6 g/d of choline ions; CHOL30), or no RPC (CON) as a top-dress starting 24 d before expected calving until 21 d postpartum. Cows were alternately assigned within treatment group to either receive an intramammary LPS challenge (200 μg in each rear quarter; Escherichia coli O111:B4) or not at 17 DIM (CHOL45, n = 9; CHOL45-LPS, n = 9; CHOL30, n = 11; CHOL30-LPS, n = 10; CON, n = 10; CON-LPS, n = 9). Hepatic and mammary tissue were collected from all cows on d 17 postpartum. Hepatic and mammary tissue were collected at ∼7.5 and 8 h, respectively, after the LPS challenge. An additional mammary biopsy was conducted on LPS-challenged cows (CHOL45-LPS, CHOL30-LPS, and CON-LPS) at 48 h post-challenge. Hepatic and mammary RNA copy numbers were quantified for genes involved in apoptosis, methylation, inflammation, oxidative stress, and mitochondrial function using NanoString technology. Targeted metabolomics was conducted only on mammary tissue samples (both 8 and 48 h biopsies) to quantify 143 metabolites including choline metabolites, amino acids, biogenic amines and derivatives, organic acids, carnitines, and glucose. Hepatic IFNG was greater in CHOL45 as compared with CON in unchallenged cows, suggesting an improvement in type 1 immune responses. Hepatic CASP3 was greater in CHOL45-LPS as compared with CON-LPS, suggesting greater apoptosis. Mammary IL6 was reduced in CHOL30-LPS cows as compared with CHOL45-LPS and CON-LPS (8 and 48 h). Mammary GPX4 and COX5A were reduced in CHOL30-LPS as compared with CON-LPS (8 h), and SDHA was reduced in CHOL30-LPS as compared with CON-LPS (8 and 48h). Both CHOL30-LPS and CHOL45-LPS cows had lesser mammary ATP5J than CON-LPS, suggesting that dietary RPC supplementation altered mitochondrial function following LPS challenge. Treatment did not impact mammary concentrations of any metabolite in unchallenged cows, and only 4 metabolites were impacted by CHOL treatment in LPS-challenged cows. Mammary concentrations of isobutyric acid and 2 acyl-carnitines (C4:1 and C10:2) were reduced in CHOL45-LPS as compared with CHOL30-LPS and CON-LPS. Concentrations of C18:1 were greater in both CHOL45-LPS and CHOL30-LPS as compared with CON-LPS, suggesting reduced fatty acid oxidation. Although the intramammary LPS challenge profoundly impacted markers for inflammation and metabolism in liver and mammary tissue, dietary RPC supplementation had minimal impact on inflammatory markers and the mammary metabolome.PMID:37730173 | DOI:10.3168/jds.2023-23752

J Affect Disord. 2023 Sep 18:S0165-0327(23)01153-9. doi: 10.1016/j.jad.2023.09.021. Online ahead of print.ABSTRACTBACKGROUND: Postpartum depression (PPD), the depressive episodes following delivery, is a serious and frequent psychiatric disorder. While numerous screening tools existed for depressive episodes, e.g., the Edinburgh Postnatal Depression Scale (EPDS), there are no objective biological measures for predicting PPD. Despite several studies done to identify biomarkers in PPD, there has been limited exploration into cerebrospinal fluid (CSF) which directly interfaces with the brain. Consequently, novel potential biomarkers of CSF are required to predict PPD, so as to target specific preventive interventions.METHODS: Seventy-five parturients undergoing caesarean delivery were enrolled for CSF collection at delivery. Of the twenty-eight subjects who didn't meet any exclusion criteria, the number of the healthy parturients whose score of EPDS 6-weeks postpartum (6-wpp) < 5 and PPD patients whose EPDS 6-wpp ≥ 13 was ten respectively. Gas chromatography-mass spectrometry (GC-MS) analysis of CSF was used for metabolomic assessments.RESULTS: We found that capric acid, dodecanoic acid, arachidic acid and behenic acid in CSF were significantly negatively correlated with PPD symptoms, meanwhile L-tryptophan had an obvious positive correlation. Moreover, these five biomarkers can be used as effective predictive biomarkers for PPD.LIMITATIONS: The main limitations are the inclusion of only parturients who underwent caesarean sections and a small sample size.CONCLUSIONS: This study innovatively investigated potential predictive biomarkers of PPD before the onset through intrapartum maternal CSF metabolomics, which offered a more objective approach to predict and diagnose PPD, leading to help identify high-risk parturients for early initiation of secondary prevention to reduce global PPD burden.PMID:37730149 | DOI:10.1016/j.jad.2023.09.021

Sci Total Environ. 2023 Sep 18:167129. doi: 10.1016/j.scitotenv.2023.167129. Online ahead of print.ABSTRACTAs pollution has attracted attention due to its wide distribution. An environmental concern that may be overlooked is that NPs additives are easily released into the environment due to their physical combination with NPs. However, the knowledge gaps still exist about the interfacial reactions of NPs and the additives (e.g. flame retardants) and the joint ecological effect. In the present study, fourier transform infrared (FTIR) spectrometer coupled with 2D correlation spectroscopy (2D-COS) analysis revealed the interfacial reactions between polystyrene nanoplastics (PSNPs) and Dechlorane Plus (DP). Results showed that carbon‑oxygen bonds and carbon‑chlorine bonds were the important binding sites during adhesion and DP could reduce the colloidal stability. Single and joint ecological effects of PSNPs and DP on the microalgae Chlorella vulgaris were further deliberated. Reduced photosynthetic efficiency (reduced Fv/Fm by 0.03 %), higher growth inhibition (16.15 %) and oxidative damage (increased ROS by 152 %) were observed in algae under co-exposure. Notably, DP could significantly increase the attachment of PSNPs to the surface of the algae. Metabolomics further revealed that co-exposure significantly down-regulated amino acid metabolism and tricarboxylic acid cycle (TCA) cycle, and up-regulated fatty acid metabolism. The present study provides new insights into the risk assessment of NPs in aquatic environment by investigating the interfacial reaction mechanism and combined ecotoxicity of NPs and additives.PMID:37730039 | DOI:10.1016/j.scitotenv.2023.167129

J Ethnopharmacol. 2023 Sep 18:117156. doi: 10.1016/j.jep.2023.117156. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Fungal pathogens can cause deadly invasive infections and have become a major global public health challenge. There is an urgent need to find new treatment options beyond established antifungal agents, as well as new drug targets that can be used to develop novel antifungal agents. Cinnamomum cassia is a tropical aromatic plant that has a wide range of applications in traditional Chinese medicine, especially in the treatment of bacterial and fungal infections.AIM OF THE STUDY: The present study aimed to explore the mechanism of action and functional components of Cinnamomum cassia essential oil (CEO) against Candida albicans using an integrated strategy combining network-based metabolomics and pharmacology, the greedy algorithm and molecular docking.MATERIALS AND METHODS: CEO was extracted using hydrodistillation and its chemical composition was identified by GC-MS. Cluster analysis was performed on the compositions of 19 other CEOs from the published literature, as well as the sample obtained in this study. The damages of C. albicans cells upon treatment with CEO was observed using a scanning electron microscope. The mechanisms of its antifungal effect at a subinhibitory concentration of 0.1 × MIC were determined using microbial metabolomics and network analysis. The functional components were studied using the greedy algorithm and molecular docking.RESULTS: A total of 69 compounds were identified in the chemical analysis of CEO, which accounted for 90% of the sample. The major compounds were terpenoids (34.04%), aromatic compounds (4.52%), aliphatic compounds (0.9%), and others. Hierarchical cluster analysis of the compositions of 20 essential oils extracted from Cinnamomum cassia grown in different geographical locations showed a wide diversity of chemical composition with four major chemotypes. CEO showed strong antifungal activity and caused destruction of cell membranes in a concentration-dependent way. Metabolic fingerprint analysis identified 29 metabolites associated with lipid metabolism, which were mapped to 23 core targets mainly involved in fatty acid biosynthesis and metabolism. Six antifungal functional components of CEO were identified through network construction, greedy algorithm and molecular docking, including trans-cinnamaldehyde, δ-cadinol, ethylcinnamate, safrole, trans-anethole, and trans-cinnamyl acetate, which showed excellent binding with specific targets of AKR1B1, PPARG, BCHE, CYP19A1, CYP2C19, QPCT, and CYP51A1.CONCLUSION: s: This study provides a systematic understanding of the antifungal activity of CEO and offers an integrated strategy for deciphering the potential metabolism and material foundation of complex component drugs.PMID:37729978 | DOI:10.1016/j.jep.2023.117156

Pharmacol Res. 2023 Sep 18:106933. doi: 10.1016/j.phrs.2023.106933. Online ahead of print.ABSTRACTBoth environmental and genetic factors contribute to the etiology of autoimmune thyroid disease (AITD) including Graves' disease (GD) and Hashimoto's thyroiditis (HT). However, the exact pathogenesis and interactions that occur between environmental factors and genes remain unclear, and therapeutic targets require further investigation due to limited therapeutic options. To solve such problems, this study utilized single-cell transcriptome, whole transcriptome, full-length transcriptome (Oxford nanopore technology), and metabolome sequencing to examine thyroid lesion tissues from 2 HT patients and 2 GD patients as well as healthy thyroid tissue from 1 control subject. HT patients had increased ATF4-positive thyroid follicular epithelial (ThyFoEp) cells, which significantly increased endoplasmic reticulum stress. The enhanced sustained stress resulted in cell death mainly including apoptosis and necroptosis. The ATF4-based global gene regulatory network and experimental validation revealed that N6-methyladenosine (m6A) reader hnRNPC promoted the transcriptional activity, synthesis, and translation of ATF4 through mediating m6A modification of ATF4. Increased ATF4 expression initiated endoplasmic reticulum stress signaling, which when sustained, caused apoptosis and necroptosis in ThyFoEp cells, and mediated HT development. Targeting hnRNPC and ATF4 notably decreased ThyFoEp cell death, thus ameliorating disease progression. Collectively, this study reveals the mechanisms by which microenvironmental cells in HT and GD patients trigger and amplify the thyroid autoimmune cascade response. Furthermore, we identify new therapeutic targets for the treatment of autoimmune thyroid disease, hoping to provide a potential way for targeted therapy.PMID:37729957 | DOI:10.1016/j.phrs.2023.106933

Cell Rep Med. 2023 Sep 19;4(9):101011. doi: 10.1016/j.xcrm.2023.101011.ABSTRACTRisk prediction tools for pancreatic cancer are urgently sought to facilitate screening. Irajizad et al.1 describe the performance of a risk predication model based on circulating microbial- and non-microbial metabolites for assessment of 5-year pancreatic cancer risk.PMID:37729875 | DOI:10.1016/j.xcrm.2023.101011