PubMed

Arthritis Rheumatol. 2023 Oct 2. doi: 10.1002/art.42722. Online ahead of print.ABSTRACTOBJECTIVES: Patients with juvenile-onset systemic lupus erythematosus (JSLE) have increased atherosclerosis risk. This study investigated novel atherosclerosis progression biomarkers in the APPLE trial, the largest investigator-led randomised control trial of atorvastatin versus placebo for atherosclerosis progression in JSLE, using carotid intima-media thickness (CIMT) as primary outcome.METHODS: Unsupervised clustering of baseline CIMT and CIMT-progression over 36 months was used to stratify JSLE patients. Disease characteristics, cardio-vascular risk scores and baseline serum metabolome were investigated in CIMT-stratified patients. Machine learning techniques were used to identify/validate a serum metabolomic signature of CIMT progression.RESULTS: Baseline CIMT stratified JSLE patients (N=151) into three groups with distinct high, intermediate, and low CIMT trajectories irrespective of treatment allocation, despite most patients having low cardiovascular disease-risk based on recommended assessment criteria. In the placebo group (N=60), patients with high vs, low CIMT-progression had higher total (P=0.001) and low-density lipoprotein (LDL) (P=0.002) cholesterol levels, although within the normal range. Furthermore, a robust baseline metabolomic signature predictive of high CIMT-progression was identified in the placebo arm (area under the curve-AUC 80.7%). Patients treated with atorvastatin (N=61) had reduced LDL cholesterol levels after 36 months as expected, however, despite this, 36% still had high atherosclerosis progression, which was not predicted by metabolomic biomarkers, suggesting non-lipid drivers of atherosclerosis in JSLE with management implications for this subset of patients.CONCLUSION: Significant baseline heterogeneity and distinct subclinical atherosclerosis progression trajectories exist in JSLE. Metabolomic signatures can predict atherosclerosis progression in some JSLE patients with relevance for clinical trial stratification.PMID:37786302 | DOI:10.1002/art.42722

Int J Radiat Oncol Biol Phys. 2023 Oct 1;117(2S):e207. doi: 10.1016/j.ijrobp.2023.06.1091.ABSTRACTPURPOSE/OBJECTIVE(S): Approximately 95% of breast cancer (BC) patients receiving radiotherapy (RT) develop varying degrees of radiation dermatitis (RD), which can greatly affect the patient's quality of life and aesthetics. Severe acute RD can lead to interruption or delay of RT. Currently, there is no consensus on the prevention and management of RD. The skin microbiota (SM), which are mainly composed of bacteria and fungi, are essential for skin homeostasis and microbial dysbiosis is correlated with the onset and progression of many common skin diseases. However, to date, research on the role of the SM in RD remains scarce. This prospective, longitudinal study aims to analyze the association of SM with RD.MATERIALS/METHODS: We collected 200 SM samples both before and after RT from the region in the irradiated chest wall of 100 BC patients receiving RT after reconstructive surgery and samples from the corresponding region in the contralateral breast for bacterial 16S and fungal ITS (internal transcribed spacer) rRNA sequencing. Acute RD was graded according to the Toxicity Criteria of the Radiation Therapy Oncology Group (RTOG). Patients were divided into no or mild dermatitis (N/MD, RTOG grade 0 or 1) and severe dermatitis (SD, RTOG grade 2 and above). The compositional differences across groups were compared using STAMP and high-dimensional class comparisons by linear discriminant analysis of effect size (LEfSe). Differences in metabolic function between groups were predicted by the Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) method.RESULTS: Significant differences were observed in the diversity and composition of the SM between N/MD and SD both before and after RT. Analysis of bacterial 16S sequencing (n = 89, 63 N/MD, 26 SD) showed significantly higher relative abundance of particular taxa such as Ralstonia, Truepera, Methyloversatilis genera and lower abundance of particular taxa including Staphylococcus, Corynebacterium genera in N/MD patients. Besides, analysis of fungal ITS sequencing (n = 71, 53 N/MD, 18 SD) showed significantly higher relative abundance of particular taxa such as Hypocreaceae family and lower abundance of particular taxa such as Sporidiobolus genus in N/MD patients. Pathways including fatty acid synthesis were predicted to be enriched in N/MD patients.CONCLUSION: The SM and pathway markers were identified in this study to be associated with the severity of acute RD in BC patients undergoing RT after reconstructive surgery. More patient data is needed to verify the current findings and the results of metagenomic, metatranscriptomic, and metabolomic analyses will further mine key biomarkers at the compositional and functional level.PMID:37784866 | DOI:10.1016/j.ijrobp.2023.06.1091

Int J Radiat Oncol Biol Phys. 2023 Oct 1;117(2S):e113-e114. doi: 10.1016/j.ijrobp.2023.06.895.ABSTRACTPURPOSE/OBJECTIVE(S): Enhanced lipid metabolism has emerged as a central metabolic node in glioblastoma, serving as a 'gain of function' that allows these cells to efficiently adapt to their dynamic tumor microenvironment. Seemingly contradictory to this, pre-clinical studies have demonstrated anti-tumor activity in mice fed a high-fat/low-carbohydrate ketogenic diet (KD), both alone and in combination with radiation therapy (RT). In this study, we sought to identify mechanisms underlying the antitumor activity of a KD in glioblastoma from a metabolic perspective to better understand factors contributing to this apparent disconnect.MATERIALS/METHODS: Immunocompromised and immunocompetent mice were injected orthotopically with human and mouse-derived glioblastoma cell lines and randomized to four treatment arms. Mice were fed ad libitum a standard diet (SD), KD (Bio-Serve), or a modified unsaturated fatty acid (uFA) rich diet (MD; 60/30/10: fat/protein/carb) alone or in combination with hypofractionated RT (6 Gy x 3). Global metabolomic profiling of tumors and serum were carried out using LC/GC-MS. Lipid droplets were analyzed by flow cytometer and confocal microscopy using BODIPY staining and free fatty acids were measured using a commercially available kit.RESULTS: A KD demonstrated independent anti-tumor activity and potent synergy with RT in two aggressive glioblastoma models. Metabolomic profiling of tumors revealed significant changes in tumor metabolism in KD-fed mice when compared to SD, with an accumulation of uFAs being a key finding. We therefore sought to determine if this accumulation of fatty acids in KD mice contributed towards the observed anti-tumor activity. Consistent with in vivo results, in vitro studies using the uFA linoleic acid demonstrated anti-proliferative activity, reduced clonogenic capacity, and potent synergy when combined with RT in glioblastoma cells. Through a series of investigations, we went on to determine that this anti-tumor activity was attributed to the ability of uFA to override lipid storage homeostasis in glioblastoma cells, resulting in lipotoxicity. Based on these findings, we hypothesized high fat concentrations, rather than carbohydrate restriction, contributed to the anti-tumor activity of a KD. To test this, we generated a MD rich in uFA that did not require carbohydrate restriction. Similar to a KD, mice fed a MD demonstrated both independent anti-tumor activity and potent synergy when combined with RT.CONCLUSION: High concentrations of uFA represents a key factor underlying the anti-tumor activity of a KD in glioblastoma by targeting lipid homeostasis. A MD consisting of high concentrations of uFA without carbohydrate restriction demonstrates promising anti-tumor activity in glioblastoma models. As a major limitation of a KD is tolerability, particularly in glioblastoma patients, a MD represents a promising form of dietary modification that may be translated clinically.PMID:37784654 | DOI:10.1016/j.ijrobp.2023.06.895

Int J Radiat Oncol Biol Phys. 2023 Oct 1;117(2S):e101. doi: 10.1016/j.ijrobp.2023.06.870.ABSTRACTPURPOSE/OBJECTIVE(S): High grade gliomas (HGGs) are aggressive brain tumors with altered cellular metabolism. HGGs can carry mutations in the tricarboxylic acid (TCA) cycle enzyme isocitrate dehydrogenase 1 (IDH1), conferring distinct biology and improved patient prognosis compared to IDH wildtype (wt) tumors. Using metabolomic analyses of tumor tissue, we previously showed that IDH wt and IDH mutant (IDH mut) tumors have unique metabolomic signatures that correlate with different survival outcomes. Among this cohort of 69 HGG samples, we identified two unique patient tumors that metabolically clustered with IDH mut tumors, but lacked both the IDH mutation and its product 2-hydroxyglutarate. We aimed to discover unique mutations in these two tumors that may impart an IDH mutant-like phenotype in the absence of an IDH1 or IDH2 mutation.MATERIALS/METHODS: Whole exome sequencing (WES) was performed on frozen tumor samples from two patients diagnosed as glioblastoma (GBM), IDH wt via Agilent v5 + IncRNA platform. Alignment to the hg38 genome and variant calling were completed using an accelerated implementation of GATK's BWA and MuTect2 algorithms from Sentieon. Variants were filtered based on supporting reads and variant allele thresholds, with synonymous variants and common SNPs removed. High-confidence variants were further filtered by membership in the four KEGG pathways associated with IDH1 and IDH2. Identified variants were corroborated with metabolomics data from the two unique IDH wt tumors compared with classical GBM IDH wt, oligodendrogliomas IDH mut and astrocytomas IDH mut to identify putative drivers of an IDH mutant-like metabolomic phenotype in these unique IDH wt tumors.RESULTS: Despite the lack of an IDH mutation, one patient survived 45.6 months and the other patient remains alive at last follow up 64 months post diagnosis, much longer than the 16-18-month median survival typical of patients with GBM IDH wt. WES of outlier IDH wt tumor samples revealed 65 unique mutations in the queried KEGG pathways, of which 34 had a variant allele frequency > = 0.15. These variants were processed in Gprofiler, confirming expected enrichment of the carboxylic acid metabolic biologic process, a functional gene set consisting of TCA genes, among these variants (p = 0.002, 3.6-fold enrichment). Accordingly, metabolite levels of intermediates of the TCA cycle, including malate and isocitrate were decreased in the outlier tumor samples compared to classic GBMs IDH wt (p<0.001). Presence of genetic alterations in key variants of the carboxylic acid metabolic biologic process (including ME1, GYP4F3, PTGIS, PFKL, PSPH, AKR1A1, HK2, NOS1) correlated with improved overall survival among GBM patients in the TCGA (p = 0.04). Laboratory validation of these findings in preclinical GBM models is ongoing.CONCLUSION: Disruption of the TCA cycle independent of an IDH mutation is associated with favorable survival in GBM. Pharmacologic inhibition of these pathways may be a promising strategy to improve GBM outcomes.PMID:37784627 | DOI:10.1016/j.ijrobp.2023.06.870

Int J Radiat Oncol Biol Phys. 2023 Oct 1;117(2S):S11. doi: 10.1016/j.ijrobp.2023.06.224.ABSTRACTPURPOSE/OBJECTIVE(S): As a rapidly self-renewing tissue, the small intestine is particularly sensitive to ionizing radiation, which limits the outcomes of radiotherapy against abdominal malignancies, resulting in poor prognosis. The polyphenol (-)-epigallocatechin-3-gallate (EGCG), a major bioactive constituent of green tea, is beneficial in radiation-induced intestinal injury (RIII) alleviation. However, the bioavailability of EGCG in vivo is very low, with only 0.1% to 1.6% being absorbed into the intestine of mice. It is unclear whether gut microbial metabolites mediated by EGCG exert an effect to protect against radiation-induced intestinal injury.MATERIALS/METHODS: Male C57BL/6J mice were subjected to 13 Gy abdominal irradiation after EGCG gavage, and the severity of intestinal tissue damage was evaluated by HE staining, immunohistochemistry, and TUNEL assays. Fresh fecal samples were collected after the end of gavage, and then fecal sterile fecal filtrate (SFF) was obtained. Stool samples were collected 3 d after irradiation. The gut microbiome was detected by 16S rRNA sequencing, the metabolites were detected by GC‒MS analysis, and then the metabolites were applied to male C57BL/6J mice, observing and evaluating the severity of RIII.RESULTS: We first explored the effect of oral EGCG delivery on radiation-induced intestinal injury. Our results revealed that EGCG pre-supplementation prolongs survival time, prevents weight loss in mice and mitigates radiation-induced intestinal injury in irradiated mice. Using 16S rRNA gene-based microbiota analysis, we first found that EGCG ameliorated ionizing radiation-induced gut microbiota dysbiosis and enriched short-chain fatty acid (SCFA)-producing bacteria such as Roseburia, Ruminococcus, and Clostridia_UCG-014. In addition, metabolomic profiling analysis showed that the gut microbiota modulated EGCG-induced metabolic reprogramming in colonic tissues, particularly by enhancing galactose metabolism. Notably, EGCG supplementation resulted in the enrichment of the microbiota-derived galactose metabolism metabolite D-tagatose. Furthermore, exogenous treatment with D-tagatose reproduced similar protective effects as EGCG to protect against radiation-induced intestinal injury (RIII). D-tagatose restored the length of villi and improved the number of goblet cells, Ki-67-positive cells and Lgr5+ ISCs, while the number of TUNEL-positive cells in the intestinal tissues decreased significantly. To validate these discoveries, we performed fecal sterile fecal filtrate (SFF) from EGCG-dosed mice to untreated mice before ionizing radiation. SFF from EGCG-dosed mice alleviated the RIII over SFF from control mice superiorly.CONCLUSION: This study provides the first data indicating that oral EGCG ameliorated radiation-induced intestinal injury (RIII) by regulating the gut microbiota and metabolites. Our findings provide novel insights into D-tagatose derived by gut microbiota from EGCG-mediated remission of RIII.PMID:37784289 | DOI:10.1016/j.ijrobp.2023.06.224

Int J Radiat Oncol Biol Phys. 2023 Oct 1;117(2S):S103. doi: 10.1016/j.ijrobp.2023.06.059.ABSTRACTPURPOSE/OBJECTIVE(S): The tumor microenvironment (TME) in HPV-unrelated head and neck cancer (HNC) is considered to be immunologically "cold," and immunometabolic adaptations to radiotherapy (RT) can exacerbate these conditions and lead to radioresistance. Peroxisome proliferator-activated receptor-α (PPARα) agonism may improve the immune response to RT by reducing glucose scarcity through upregulation of fatty acid utilization in cancer cells. Our clinical trial data shows that high serum oleic acid (OA), a PPAR ligand, correlates with response to radioimmunotherapy.MATERIALS/METHODS: Orthotopic buccal tumor implantations of MOC2 and LY2 HNC cell lines were performed in C57BL/6 and BALB/c mice, respectively. Mice were placed on a high OA diet (38% kcal from OA) 3 weeks prior to tumor implantation. Control diet consisted of 1% kcal from OA. In vitro RT was performed to characterize the metabolic effects on the cancer cell lines. For in vivo studies, tumors were irradiated upon reaching 100 mm^3 with three 8 Gy fractions, given every 4-5 days. The PPARα agonist fenofibrate (FF, 100mg/kg/day) was given via oral gavage or intraperitoneal injection starting 5 days after RT. Tumor volume and overall survival were measured as objective outcomes, and flow cytometry was used to characterize the immune landscape of the tumor, blood, and lymph nodes. Mass spectrometry was employed for bulk proteomics and metabolomics on serum samples, and stable isotope labeling was performed on CD8 T cells from treated mice ex vivo. Extracellular flux analyses were performed on tumor cells and CD8 T cells to determine metabolic phenotypic changes.RESULTS: In vitro cytotoxicity was met for MOC2 and LY2 cancer cells in 100 uM FF and OA in comparison to solvent (p<0.01). Extracellular flux analyses show that RT upregulates the glycolytic phenotype of MOC2 and LY2 cancer cells; and that FF and/or OA decrease the glycolytic capacity of the cancer cells. Ex vivo extracellular flux analyses showed increased glycolytic capacity of CD8 T cells in mice treated with FF in comparison to RT alone. RT in combination with FF significantly improved tumor volume response in comparison to RT alone (mean 99.4 vs 182.7 mm^3, p = 0.001) and was comparable to combination radioimmunotherapy (with anti-PDL1 therapy; mean 99.4 vs. 132.3 mm^3). Unexpectedly, OA negated this improvement in efficacy in both MOC2 and LY2 tumor models; mice on the high OA diet had significantly higher average body weight (p<0.01). Significant changes in adaptive immune response were observed within the TME with the addition of FF. This was mirrored by changes in serum metabolomics.CONCLUSION: PPARα agonism improved the efficacy of RT in murine HNC models and could be considered in future translational clinical trial design.PMID:37784273 | DOI:10.1016/j.ijrobp.2023.06.059

J Immunol Res. 2023 Sep 21;2023:5577850. doi: 10.1155/2023/5577850. eCollection 2023.ABSTRACTThere remains a lack of standard models that have all the characteristics of human diseases. Especially in immunological hepatic fibrosis, the bovine serum albumin (BSA)-induced liver fibrosis models have the same developmental mechanisms as human liver fibrosis models, but have received little attention. We standardized a BSA-induced liver fibrosis model in rats and thoroughly assessed its pathological characteristics. We also used 16S sequencing to assess homeostasis of the intestinal microflora of rats with BSA-induced liver fibrosis and detected various differential metabolites in the serum of these rats using ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). We observed stable and unambiguous histological changes in liver tissue morphology and remarkably high concentrations of inflammatory markers in the serum of BSA-induced liver fibrosis rats. In keeping with the fact that BSA induction can cause gut microbiota disorders in rats. UHPLC-MS/MS analysis of rat serum samples in positive-ion mode and negative-ion mode revealed 17 and 25 differential metabolites, respectively. Network analysis revealed that phenylalanine or tyrosine metabolites (e.g., PAGln) were the predominant metabolites in the sera of BSA-induced liver fibrosis rats. Taken together, our results suggest that disorders of amino acid metabolism caused by the gut microbiota may play an important role in the progression of immunological hepatic fibrosis.PMID:37781475 | PMC:PMC10539088 | DOI:10.1155/2023/5577850

Sci Total Environ. 2023 Sep 30:167513. doi: 10.1016/j.scitotenv.2023.167513. Online ahead of print.ABSTRACTHeavy metal pollution is a significant threat to both the environment and living organisms. This is especially vital considering the persistent and cumulative nature of heavy metal exposure, which can lead to severe and chronic health consequences for individuals. Therefore, implementing effective treatments is critical to addressing the serious public health issues posed by heavy metal pollution. In this study, nontargeted metabolomics was carried out to investigate the metabolic changes associated with long-term low-dose intake of mixed heavy metal pollutants (MHMPs) in liver, kidney, and plasma samples of Sprague-Dawley (SD) rats with and without treatment to reveal the underlying toxic effects of MHMPs and the effects of chemoprevention agents, including epigallocatechin-3-gallate (EGCG), trisodium citrate dihydrate (TCD), and glutathione (GSH). In the liver, kidney, and plasma, we observed a total of 21, 69, and 16 metabolites, respectively, exhibiting significant differences (P < 0.05, fold change >1.2 or <0.83, and VIP ≥ 1) between the control group and the mixture group. The findings demonstrated that exposure to MHMPs leads to the dysregulation of numerous metabolic pathways, with a particular emphasis on purine metabolism and aminoacyl-tRNA biosynthesis with upregulated renal purine metabolites and downregulated hepatic purine metabolites as well as renal aminoacyl-tRNA biosynthesis-related metabolites. However, the application of chemical protectants was shown to partially restore the metabolic alterations induced by MHMPs, particularly purine metabolism-related metabolites, including hepatic adenine and renal adenine, guanine, guanosine, adenosine monophosphate (AMP), and hypoxanthine. In addition, liver adenosine, kidney inosine and L-phenylalanine were considered the main regulated sites based on their significant correlations with multiple heavy metals. Our study provides crucial insights into the toxicological mechanisms of heavy metal pollution and has the potential to guide the development of effective preventive strategies.PMID:37783434 | DOI:10.1016/j.scitotenv.2023.167513

Chemosphere. 2023 Sep 30:140329. doi: 10.1016/j.chemosphere.2023.140329. Online ahead of print.ABSTRACTNext-generation risk assessment (NGRA) for environmental chemicals involves a weight of evidence (WoE) framework integrating a suite of new approach methodologies (NAMs) based on points of departure (PoD) obtained from in vitro assays. Among existing NAMs, the omic-based technologies are of particular importance based on the premise that any apical endpoint change indicative of impaired health must be underpinned by some alterations at the omics level, such as transcriptome, proteome, metabolome, epigenome and genome. Transcriptomic assay plays a leading role in providing relatively conservative PoDs compared with apical endpoints. However, it is unclear whether and how parameters measured with other omics techniques predict the cellular response to chemical perturbations, especially at exposure levels below the transcriptomically defined PoD. Multi-omics coverage may provide additional sensitive or confirmative biomarkers to complement and reduce the uncertainty in safety decisions made using targeted and transcriptomics assays. In the present study, we conducted multi-omics studies of transcriptomics, proteomics and phosphoproteomics on two prototype compounds, coumarin and 2,4-dichlorophenoxyacetic acid (2,4-D), with multiple chemical concentrations and time points, to understand the sensitivity of the three omics techniques in response to chemically-induced changes in HepG2. We demonstrated that, phosphoproteomics alterations occur not only earlier in time, but also more sensitive to lower concentrations than proteomics and transcriptomics when the HepG2 cells were exposed to various chemical treatments. The phosphoproteomics changes appear to approach maximum when the transcriptomics alterations begin to initiate. Therefore, it is proximal to the very early effects induced by chemical exposure. We concluded that phosphoproteomics can be utilized to provide a more complete coverage of chemical-induced cellular alteration and supplement transcriptomics-based health safety decision making.PMID:37783352 | DOI:10.1016/j.chemosphere.2023.140329

Semin Cancer Biol. 2023 Sep 30:S1044-579X(23)00127-X. doi: 10.1016/j.semcancer.2023.09.005. Online ahead of print.ABSTRACTAs data-driven science, artificial intelligence (AI) has paved a promising path toward an evolving health system teeming with thrilling opportunities for precision oncology. Notwithstanding the tremendous success of oncological AI in such fields as lung carcinoma, breast tumor and brain malignancy, less attention has been devoted to investigating the influence of AI on gynecologic oncology. Hereby, this review sheds light on the ever-increasing contribution of state-of-the-art AI techniques to the refined risk stratification and whole-course management of patients with gynecologic tumors, in particular, cervical, ovarian and endometrial cancer, centering on information and features extracted from clinical data (electronic health records), cancer imaging including radiological imaging, colposcopic images, cytological and histopathological digital images, and molecular profiling (genomics, transcriptomics, metabolomics and so forth). However, there are still noteworthy challenges beyond performance validation. Thus, this work further describes the limitations and challenges faced in the real-word implementation of AI models, as well as potential solutions to address these issues.PMID:37783319 | DOI:10.1016/j.semcancer.2023.09.005

Eur J Pharmacol. 2023 Sep 30:176082. doi: 10.1016/j.ejphar.2023.176082. Online ahead of print.ABSTRACTAndrographolide (AGP) exerts pharmacological effects when used for the treatment of cardiovascular disease, but the molecular mechanisms underlying its inhibitory effects on the proliferation and migration of vascular smooth muscle cells (VSMCs) and intimal hyperplasia (IH) are unknown. The proliferation and migration of cultured VSMCs were examined using the CCK-8, flow cytometry, and wound healing assays. Expression levels of proteins related to cell proliferation and apoptosis were quantified. A multi-omics analysis with RNA-seq and metabolome was used to explore the potential molecular mechanism of AGP treatment. Additionally, an in vivo model was established through ligation of the left common carotid artery to identify the therapeutic potential of AGP in IH. Molecular docking and western blotting were performed to verify the mechanism discovered with multi-omics analysis. The results showed that AGP inhibited the proliferation and migration of cultured VSMCs in a dose-dependent manner and alleviated IH-related vascular stenosis. AGP significantly downregulated the protein levels of CDK1, CCND1, and BCL2 and upregulated the protein level of BAX. Gene expression profiles showed a total of 3,298 differentially expressed genes (DEGs) after AGP treatment, of which 1,709 DEGs had upregulated expression and 1,589 DEGs had downregulated expression. KEGG enrichment analysis highlighted the PI3K/AKT signaling pathway, verified with the detection of the activation of PI3K and AKT phosphorylation. Further GO enrichment combined with metabolomics analysis showed that AGP inhibition in cultured VSMCs involved the amino acid metabolic process, and the expression levels of the two key factors PRDM16 and EZH2, identified with PPI and docking analysis, were significantly inhibited by AGP treatment. In conclusion, our study showed that AGP inhibited VSMCs proliferation and migration by suppressing the PI3K/AKT signaling pathway and amino acid metabolism, which, in turn, improved IH.PMID:37783303 | DOI:10.1016/j.ejphar.2023.176082

BMC Microbiol. 2023 Oct 3;23(1):282. doi: 10.1186/s12866-023-02983-x.ABSTRACTBACKGROUND: The pathogenesis of intrahepatic cholestasis of pregnancy (ICP) remains unknown. The gut microbiome and its metabolites play important roles in bile acid metabolism, and previous studies have indicated the association of the gut microbiome with ICP.METHODS: We recruited a cohort of 5100 participants, and 20 participants were enrolled in the severe ICP group, matched with 20 participants in the mild ICP group and 20 controls. 16S rRNA sequencing and nontargeting metabolomics were adapted to explore the gut microbiome and fecal metabolites.RESULTS: An increase in richness and a dramatic deviation in composition were found in the gut microbiome in ICP. Decreased Firmicutes and Bacteroidetes abundances and increased Proteobacteria abundances were found in women with severe but not mild ICP compared to healthy pregnant women. Escherichia-Shigella and Lachnoclostridium abundances increased, whereas Ruminococcaceae abundance decreased in ICP group, especially in severe ICP group. The fecal metabolite composition and diversity presented typical variation in severe ICP. A significant increase in bile acid, formate and succinate levels and a decrease in butyrate and hypoxanthine levels were found in women with severe ICP. The MIMOSA model indicated that genera Ruminococcus gnavus group, Lachnospiraceae FCS020 group, and Lachnospiraceae NK4A136 group contributed significantly to the metabolism of hypoxanthine, which was significantly depleted in subjects with severe ICP. Genus Acinetobacter contributed significantly to formate metabolism, which was significantly enriched in subjects with severe ICP.CONCLUSIONS: Women with severe but not mild ICP harbored a unique gut microbiome and fecal metabolites compared to healthy controls. Based on these profiles, we hypothesized that the gut microbiome was involved in bile acid metabolism through metabolites, affecting ICP pathogenesis and development, especially severe ICP.PMID:37784030 | DOI:10.1186/s12866-023-02983-x

BMC Microbiol. 2023 Oct 3;23(1):281. doi: 10.1186/s12866-023-03029-y.ABSTRACTBACKGROUND: Angelica polysaccharides (AP) have numerous benefits in relieving type 2 diabetes (T2D). However, the underlying mechanisms have yet to be fully understood. Recent many reports have suggested that altering gut microbiota can have adverse effects on the host metabolism and contribute to the development of T2D. Here, we successfully established the T2D model using the male KKAy mice with high-fat and high-sugar feed. Meanwhile, the male C57BL/6 mice were fed with a normal feed. T2D KKAy mice were fed either with or without AP supplementation. In each group, we measured the mice's fasting blood glucose, weight, and fasting serum insulin levels. We collected the cecum content of mice, the gut microbiota was analyzed by targeted full-length 16S rRNA metagenomic sequencing and metabolites were analyzed by untargeted-metabolomics.RESULTS: We found AP effectively alleviated glycemic disorders of T2D KKAy mice, with the changes in gut microbiota composition and function. Many bacteria species and metabolites were markedly changed in T2D KKAy mice and reversed by AP. Additionally, 16 altered metabolic pathways affected by AP were figured out by combining metagenomic pathway enrichment analysis and metabolic pathway enrichment analysis. The key metabolites in 16 metabolic pathways were significantly associated with the gut microbial alteration. Together, our findings showed that AP supplementation could attenuate the diabetic phenotype. Significant gut microbiota and gut metabolite changes were observed in the T2D KKAy mice and AP intervention.CONCLUSIONS: Administration of AP has been shown to improve the composition of intestinal microbiota in T2D KKAy mice, thus providing further evidence for the potential therapeutic application of AP in the treatment of T2D.PMID:37784018 | DOI:10.1186/s12866-023-03029-y

Nat Metab. 2023 Oct 2. doi: 10.1038/s42255-023-00893-w. Online ahead of print.ABSTRACTSustained responses to transient environmental stimuli are important for survival. The mechanisms underlying long-term adaptations to temporary shifts in abiotic factors remain incompletely understood. Here, we find that transient cold exposure leads to sustained transcriptional and metabolic adaptations in brown adipose tissue, which improve thermogenic responses to secondary cold encounter. Primary thermogenic challenge triggers the delayed induction of a lipid biosynthesis programme even after cessation of the original stimulus, which protects from subsequent exposures. Single-nucleus RNA sequencing and spatial transcriptomics reveal that this response is driven by a lipogenic subpopulation of brown adipocytes localized along the perimeter of Ucp1hi adipocytes. This lipogenic programme is associated with the production of acylcarnitines, and supplementation of acylcarnitines is sufficient to recapitulate improved secondary cold responses. Overall, our data highlight the importance of heterogenous brown adipocyte populations for 'thermogenic memory', which may have therapeutic implications for leveraging short-term thermogenesis to counteract obesity.PMID:37783943 | DOI:10.1038/s42255-023-00893-w

J Cancer Res Clin Oncol. 2023 Oct 2. doi: 10.1007/s00432-023-05376-9. Online ahead of print.ABSTRACTPURPOSE: The incidence and mortality of lung cancer are continuously rising in recent years. Mitochondrial energy metabolism malfunction is found to be crucial in cancer proliferation and bioenergetic reprogramming, especially for lung cancer. In this study, we attempted to use mitochondrial-targeted drug therapy to change the energy metabolism pattern of cancer cells to inhibit the development of lung cancer, and investigated its mechanism of action and key targets through multi-omics studies.METHODS: In this study, we established the in vivo tumor mouse mode, treated mice with multiple mitochondrial-targeted drug combinations and DDP, severally. Then, we investigated the differences between the 7-drug group with the control group and the DDP treatment group by transcriptomics, proteomics and metabolomics to find the therapeutic targets.RESULTS: We found that mitochondria-targeting drug cocktail therapy, especially the 7-drug regimen, effectively improved mitochondrial metabolism, changed energy supply patterns in lung cancer cells, significantly increased NK cells in tumor tissues, and decreased tumor markers in plasma. Multi-omics analysis informed that the combination of 7-drug could up-regulate mitochondrial oxidative phosphorylation, ATP synthesis and autophagy related genes, and down-regulate proliferation and immune-related genes compared with the control group. By further mapping the protein interaction network, we identified a key target for 7-drug therapy to reverse tumor metabolic reprogramming and validated it in metabolomics.CONCLUSIONS: Mitochondrial-targeted drug cocktail therapy can effectively inhibit the occurrence and development of tumors, through the reprogramming of energy metabolism and the increase in immune cells in tumor tissues. Thus, we provide a novel approach for the treatment of lung cancer and present evidence-based clues for the combined use of targeted mitochondrial drugs.PMID:37783930 | DOI:10.1007/s00432-023-05376-9

Commun Biol. 2023 Oct 2;6(1):1000. doi: 10.1038/s42003-023-05379-9.ABSTRACTEnhancing the dietary properties of rice is crucial to contribute to alleviating hidden hunger and non-communicable diseases in rice-consuming countries. Germination is a bioprocessing approach to increase the bioavailability of nutrients in rice. However, there is a scarce information on how germination impacts the overall nutritional profile of pigmented rice sprouts (PRS). Herein, we demonstrated that germination resulted to increase levels of certain dietary compounds, such as free phenolics and micronutrients (Ca, Na, Fe, Zn, riboflavin, and biotin). Metabolomic analysis revealed the preferential accumulation of dipeptides, GABA, and flavonoids in the germination process. Genome-wide association studies of the PRS suggested the activation of specific genes such as CHS1 and UGT genes responsible for increasing certain flavonoid compounds. Haplotype analyses showed a significant difference (P < 0.05) between alleles associated with these genes. Genetic markers associated with these flavonoids were incorporated into the random forest model, improving the accuracy of prediction of multi-nutritional properties from 89.7% to 97.7%. Deploying this knowledge to breed rice with multi-nutritional properties will be timely to address double burden nutritional challenges.PMID:37783812 | DOI:10.1038/s42003-023-05379-9

Sci Rep. 2023 Oct 2;13(1):16522. doi: 10.1038/s41598-023-43490-3.ABSTRACTGlobally, coral reefs face increasing disease prevalence and large-scale outbreak events. These outbreaks offer insights into microbial and functional patterns of coral disease, including early indicators of disease that may be present in visually-healthy tissues. Outbreak events also allow investigation of how reef-building corals, typically colonial organisms, respond to disease. We studied Pocillopora damicornis during an acute tissue loss disease outbreak on Guam to determine whether dysbiosis was present in visually-healthy tissues ahead of advancing disease lesions. These data reveal that coral fragments with visual evidence of disease are expectedly dysbiotic with high microbial and metabolomic variability. However, visually-healthy tissues from the same colonies lacked dysbiosis, suggesting disease containment near the affected area. These results challenge the idea of using broad dysbiosis as a pre-visual disease indicator and prompt reevaluation of disease assessment in colonial organisms such as reef-building corals.PMID:37783737 | DOI:10.1038/s41598-023-43490-3

Nat Commun. 2023 Oct 2;14(1):5818. doi: 10.1038/s41467-023-41372-w.ABSTRACTLower respiratory tract infections caused by Streptococcus pneumoniae (Spn) are a leading cause of death globally. Here we investigate the bronchial epithelial cellular response to Spn infection on a transcriptomic, proteomic and metabolic level. We found the NAD+ salvage pathway to be dysregulated upon infection in a cell line model, primary human lung tissue and in vivo in rodents, leading to a reduced production of NAD+. Knockdown of NAD+ salvage enzymes (NAMPT, NMNAT1) increased bacterial replication. NAD+ treatment of Spn inhibited its growth while growth of other respiratory pathogens improved. Boosting NAD+ production increased NAD+ levels in immortalized and primary cells and decreased bacterial replication upon infection. NAD+ treatment of Spn dysregulated the bacterial metabolism and reduced intrabacterial ATP. Enhancing the bacterial ATP metabolism abolished the antibacterial effect of NAD+. Thus, we identified the NAD+ salvage pathway as an antibacterial pathway in Spn infections, predicting an antibacterial mechanism of NAD+.PMID:37783679 | DOI:10.1038/s41467-023-41372-w

Poult Sci. 2023 Sep 11;102(12):103102. doi: 10.1016/j.psj.2023.103102. Online ahead of print.ABSTRACTHydrogen sulfide (H2S) is one of the most irritant gases present in rearing stalls that suppress broilers' healthy growth, which is seriously required an effective alleviation method. In this study, Lactobacillus was supplemented to investigate the alleviative effects on broilers reared under consecutive H2S exposure. A total of 180 healthy 1-day-old male AA broilers with similar body weight (40.8 ± 1.0 g) were randomly allotted into the control treatment (CON), the hydrogen sulfide treatment (H2S), and the Lactobacillus supplement under H2S exposure treatment (LAC) for a 42-d-long feeding process. Growth and carcass performances, immunity-related parameters, intestinal development and cecal microbial communities, and blood metabolites were measured. Results showed that Lactobacillus supplement significantly increased the body weight gain (BWG) while reduced the mortality rate, abdominal fat and bursa of fabricius weight during the whole rearing time compared with H2S treatment (P < 0.05). Serum LPS, IL-1β, IL-2, and IL-6 contents were observed significantly increased after H2S treatment while remarkably decreased after Lactobacillus supplementation(P < 0.05). Intestinal morphology results showed a significant higher in the development of ileum villus height (P < 0.05). Cecal microbiota results showed the bacterial composition was significantly altered after Lactobacillus supplement (P < 0.05). Specifically, Lactobacillus supplement significantly decreased the relative abundance of Faecalibacterium, while significantly proliferated the relative abundance of Lactobacillus, Bifidobacterium, Clostridium, and Campylobacter (P<0.05). Metabolic results indicated that Lactobacillus supplement may alleviate the harmful effects caused by H2S through regulating the pyrimidine metabolism, starch and sucrose metabolism, fructose and mannose degradation, and beta-alanine metabolism. In summary, Lactobacillus supplement effectively increased BWG and decreased mortality rate of broilers under H2S exposure by enhancing the body's immune capacity, proliferating beneficial microbes (e.g., Lactobacillus and Bifidobacterium), and regulating the physiological pyrimidine metabolism, starch and sucrose metabolism, and beta-alanine metabolism.PMID:37783191 | DOI:10.1016/j.psj.2023.103102

Phytomedicine. 2023 Sep 21;121:155086. doi: 10.1016/j.phymed.2023.155086. Online ahead of print.ABSTRACTBACKGROUND: Astragaloside IV (AS-IV) is the main active component of "Astragalus membranaceus (Fisch.) Bunge, a synonym of Astragalus propinquus Schischkin (Fabaceae)", which demonstrated to be useful for the treatment of intracerebral hemorrhage (ICH). However, due to the low bioavailability and barrier permeability of AS-IV, the gut microbiota may be an important key regulator for AS-IV to work.OBJECTIVE: To explore the influences of gut microbiota on the effects of AS-IV on ICH.METHODS: Mice were randomly divided into five groups: sham, ICH, and AS-IV-treated groups (25 mg/kg, 50 mg/kg, and 100 mg/kg). Behavioral tests, brain histopathology, and immunohistochemistry analysis were used to evaluate the degree of brain injury. Western blot was employed to verify peri‑hematoma inflammation. The plasma lipopolysaccharide (LPS) leakage, the fluorescein isothiocyanate-dextran permeability, the colonic histopathology, and immunohistochemistry were detected to evaluate the barrier function of intestinal mucosal. Moreover, 16S rDNA sequencing and metabolomic analysis was applied to screen differential bacteria and metabolites, respectively. The correlation analysis was adopted to determine the potential relationship between differential bacteria and critical metabolites or neurological deficits.RESULTS: AS-IV alleviated neurological deficits, neuronal injury and apoptosis, and blood-brain barrier disruption. This compound reduced tumor necrosis factor (TNF)-α expression, increased arginase (Arg)-1 and interleukin (IL)-33 levels around the hematoma. Next, 16S rRNA sequencing indicated that AS-IV altered the gut microbiota, and inhibited the production of conditional pathogenic bacteria. Metabolomic analysis demonstrated that AS-IV regulated the serum metabolic profiles, especially the aminoacid metabolism and peroxisome proliferator-activated receptor (PPAR) signaling pathway. Additionally, AS-IV mitigated intestinal barrier damage and LPS leakage.CONCLUSION: This study provides a new perspective on the use of AS-IV for the treatment of ICH. Among them, gut microbiota and its metabolites may be the key regulator of AS-IV in treating ICH.PMID:37783132 | DOI:10.1016/j.phymed.2023.155086