PubMed

Mol Plant. 2022 Dec 31:S1674-2052(22)00476-2. doi: 10.1016/j.molp.2022.12.022. Online ahead of print.ABSTRACTKiwifruit is a recently domesticated horticultural fruit crop with substantial economic and nutritional value, especially for the high content of vitamin C in fruit. Here, we de novo assembled two telomere-to-telomere kiwifruit genomes of A. chinensis var 'Donghong' (DH) and A. latifolia (KY), with total lengths of 608,327,852 bp and 640,561,626 bp for 29 chromosomes respectively. With burst of structural variants involving inversion, translocations and duplications within 8.39 million years, metabolite content of DH and KY exhibited differences including saccharides, lignans and vitamins. A regulatory ERF098 transcription factor family has expanded in KY and Actinidia. eriantha, both with ultra-high vitamin C content. With each assembly been phased into two complete haplotypes, we identified allelic variations between two sets of haplotypes, leading to protein sequence variations of 26,494 and 27,773 gene loci and allele specific expression (ASE) of 4,687 and 12,238 homozygous gene pairs. Synchronized metabolome and transcriptome changes during DH fruit development indicated the same dynamic patterns in expression and metabolite content levels, including free fatty acids and flavonols accumulated in the early stages, while sugar substances and amino acids in the late stages. An allele dominance AcSWEET9b gene was identified to positively correlate with high sucrose content in fruit. Compared to wild varieties and other Actinidia species, AcSWEET9b promoters were selected in red-flesh kiwifruits, facilitating the boost of fruit sucrose content, which probably explained why red-flesh kiwifruits are sweeter. These two gap-free kiwifruit genomes provide a valuable genetic basis for investigating mechanisms of domestication, opening up genome-based breeding era for kiwifruit.PMID:36588343 | DOI:10.1016/j.molp.2022.12.022

RNA Biol. 2023 Jan;20(1):186-197. doi: 10.1080/15476286.2023.2204586.ABSTRACTHere, we provide an in-depth analysis of the usefulness of single-sample metabolite/RNA extraction for multi-'omics readout. Using pulverized frozen livers of mice injected with lymphocytic choriomeningitis virus (LCMV) or vehicle (Veh), we isolated RNA prior (RNA) or following metabolite extraction (MetRNA). RNA sequencing (RNAseq) data were evaluated for differential expression analysis and dispersion, and differential metabolite abundance was determined. Both RNA and MetRNA clustered together by principal component analysis, indicating that inter-individual differences were the largest source of variance. Over 85% of LCMV versus Veh differentially expressed genes were shared between extraction methods, with the remaining 15% evenly and randomly divided between groups. Differentially expressed genes unique to the extraction method were attributed to randomness around the 0.05 FDR cut-off and stochastic changes in variance and mean expression. In addition, analysis using the mean absolute difference showed no difference in the dispersion of transcripts between extraction methods. Altogether, our data show that prior metabolite extraction preserves RNAseq data quality, which enables us to confidently perform integrated pathway enrichment analysis on metabolomics and RNAseq data from a single sample. This analysis revealed pyrimidine metabolism as the most LCMV-impacted pathway. Combined analysis of genes and metabolites in the pathway exposed a pattern in the degradation of pyrimidine nucleotides leading to uracil generation. In support of this, uracil was among the most differentially abundant metabolites in serum upon LCMV infection. Our data suggest that hepatic uracil export is a novel phenotypic feature of acute infection and highlight the usefulness of our integrated single-sample multi-'omics approach.PMID:37095747 | DOI:10.1080/15476286.2023.2204586

Best Pract Res Clin Gastroenterol. 2023 Feb-Mar;62-63:101830. doi: 10.1016/j.bpg.2023.101830. Epub 2023 Mar 16.ABSTRACTLifestyle modification is the primary intervention to control NAFLD progression, but despite evidence-based effectiveness it is difficult to distinguish the benefits of nutrition from physical activity and the optimal diet composition is not established. Macronutrients as saturated fatty acids, sugars and animal proteins are harmful in NAFLD and the Mediterranean Diet reducing sugar, red meat and refined carbohydrates and increasing unsaturated-fatty-acids was reported to be beneficial. However one size cannot fit all since NAFLD is a multifaceted syndrome encompassing many diseases of unknown etiologies, different clinical severity and outcomes. Studies of the intestinal metagenome, provided new insights into the physio-pathological interplay between intestinal microbiota and NAFLD. How much the microbiota heterogeneity can influence response to diet remains unknown. New knowledge indicates that AI guided personalized nutrition based on clinic-pathologic and genetic data combined with pre/post nutritional intervention gut metagenomics/metabolomics will be part of the future management of NAFLD.PMID:37094914 | DOI:10.1016/j.bpg.2023.101830

Methods Enzymol. 2023;683:153-170. doi: 10.1016/bs.mie.2022.08.039. Epub 2022 Nov 11.ABSTRACTMulti-omics has gained momentum over the past few years especially in plant single cell-type analysis as they aim to understand cellular molecular networks across different levels of genetic information flow. For multi-omics sample preparation, molecular extractions performed non-simultaneously create rooms for variation, inaccurate data, waste of limited samples, resources and labor. Here we optimized a protocol for 3-in-1 simultaneous extraction of RNA, metabolites, and proteins from the same single cell-type sample. We adapted a commercially available RNA kit with a few modifications to obtain high quality starting materials for sequencing and LC-MS/MS-based metabolomics and proteomics. RNAs are bound to the column, metabolites were extracted in a polar solvent and proteins are precipitated using acetone. This creates an all-in-one workflow using a standard RNA kit. Little training is required to carry out this protocol as it is simple and easy to use. It may be used with a wide range of plant species and different amounts of starting materials, including single cells.PMID:37087185 | DOI:10.1016/bs.mie.2022.08.039

Clin Transl Med. 2023 Jan;13(1):e1152. doi: 10.1002/ctm2.1152.ABSTRACTBACKGROUND: Gut-brain axis is widely implicated in the pathophysiology of Parkinson's disease (PD). We take an integrated approach to considering the gut as a target for disease-modifying intervention, using continuous measurements of disease facets irrespective of diagnostic divide.METHODS: We characterised 77 participants with diagnosed-PD, 113 without, by dietary/exogenous substance intake, faecal metabolome, intestinal inflammation, serum cytokines/chemokines, clinical phenotype including colonic transit time. Complete-linkage hierarchical cluster analysis of metabolites discriminant for PD-status was performed.RESULTS: Longer colonic transit was linked to deficits in faecal short-chain-fatty acids outside PD, to a 'tryptophan-containing metabolite cluster' overall. Phenotypic cluster analysis aggregated colonic transit with brady/hypokinesia, tremor, sleep disorder and dysosmia, each individually associated with tryptophan-cluster deficit. Overall, a faster pulse was associated with deficits in a metabolite cluster including benzoic acid and an imidazole-ring compound (anti-fungals) and vitamin B3 (anti-inflammatory) and with higher serum CCL20 (chemotactic for lymphocytes/dendritic cells towards mucosal epithelium). The faster pulse in PD was irrespective of postural hypotension. The benzoic acid-cluster deficit was linked to (well-recognised) lower caffeine and alcohol intakes, tryptophan-cluster deficit to higher maltose intake. Free-sugar intake was increased in PD, maltose intake being 63% higher (p = .001). Faecal calprotectin was 44% (95% CI 5%, 98%) greater in PD [p = .001, adjusted for proton-pump inhibitors (p = .001)], with 16% of PD-probands exceeding a cut-point for clinically significant inflammation compatible with inflammatory bowel disease. Higher maltose intake was associated with exceeding this calprotectin cut-point.CONCLUSIONS: Emerging picture is of (i) clinical phenotype being described by deficits in microbial metabolites essential to gut health; (ii) intestinal inflammation; (iii) a systemic inflammatory response syndrome.PMID:36588088 | DOI:10.1002/ctm2.1152

Fish Shellfish Immunol. 2022 Dec 29:108512. doi: 10.1016/j.fsi.2022.108512. Online ahead of print.ABSTRACTAs a pathogen of cultured teleosts, Pseudomonas plecoglossicida has caused significant economic losses. flgC plays an important role in encoding flagellar basal-body rod proteins. Our previous studies revealed the high expression of P. plecoglossicida flgC in infected Epinephelus coioides. To explore the role of flgC in the virulence of P. plecoglossicida and the immune response of E. coioides to the infection of P. plecoglossicida, flgC gene of P. plecoglossicida was knocked down by RNA interference (RNAi). The results showed that the flgC gene in all four mutants of P. plecoglossicida was significantly knocked down, and the mutant with the best knockdown efficiency of 94.3% was selected for subsequent studies. Compared with the NZBD9 strain of P. plecoglossicida, the flgC-RNAi strain showed a significantly decrease in chemotaxis, motility, adhesion, and biofilm formation. Furthermore, compared with the E. coioides infected with the NZBD9 strain, the infection of flgC-RNAi strain resulted in the infected E. coioides a 1.5-day delay in the time of first death and an 80% increase in survival rate, far fewer white nodules upon the spleen surfaces, and lower pathogen load in the spleens. RNAi of flgC significantly influenced the metabolome and transcriptome of the spleen in infected E. coioides. KEGG enrichment analysis exhibited that the Toll-like receptor signaling pathway was the most enriched immune pathway; the most significantly enriched metabolic pathways were associated with Linoleic acid metabolism, Choline metabolism in cancer, and Glycerophospholipid metabolism. Further combined analysis of transcriptome and metabolome indicated significant correlations among pantothenate and CoA biosynthesis, beta-alanine metabolism, lysosome metabolites, and related genes. These results suggested that flgC was a pathogenic gene of P. plecoglossicida; flgC was associated with the regulation of chemotaxis, motility, biofilm formation, and adhesion; flgC influenced the immune response of E. coioides to the infection of P. plecoglossicida.PMID:36587883 | DOI:10.1016/j.fsi.2022.108512

J Ethnopharmacol. 2022 Dec 29:116109. doi: 10.1016/j.jep.2022.116109. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Qifu decoction (QFD) is a famous traditional Chinese medicine (TCM) composed of Astragali Radix (HuangQi) and Aconiti Lateralis Radix Praeparaia (Fuzi), which can alleviate doxorubicin (DOX)-induced cardiotoxicity (DIC). However, its protective mechanism remains obscured.AIM OF THE STUDY: The present study aimed to uncover the cardioprotective mechanism and the synergistic effect of QFD against DIC in mice.MATERIALS AND METHODS: The cardioprotective activity of QFD against DIC was assessed by electrocardiogram, serum biochemical assays and histopathology. Mass spectrometry-based metabolomic approach was conducted to elucidate the preventive mechanisms of QFD, HuangQi decoction (HQD), and Fuzi decoction (FZD) against DIC. QFD, HQD, FZD-targeted metabolic pathways were identified and compared to investigate the synergistic mechanism of QFD by computational systems analysis. Quantitative real-time PCR (qRT-PCR) was further employed to validate the key metabolic pathways at the level of the gene.RESULTS: The electrocardiogram combined with the biochemical analysis and histopathology showed that the protection effects were sorted as QFD > HQD ≈ FZD. A total of 41 metabolites contributing to DIC were identified in the mice serum, among which 32, 12 and 10 metabolites were significantly reverted by QFD, HQD and FZD, respectively. Metabolic pathway analysis revealed that DOX perturbed 12 metabolic pathways, and QFD, HQD, and FZD-treated groups could significantly reverse 12, 7 and 6 metabolic pathways of these 12 metabolic pathways. Metabolic pathway and qRT-PCR revealed that QFD could protect DIC mainly by regulating energy metabolism, amino acids metabolism, arachidonic acid metabolism and glycerophospholipid metabolism, and HQD and FZD mutually reinforced each other.CONCLUSION: These evidences revealed that QFD was a promising drug candidate for DIC by maintaining metabolic homeostasis. Meanwhile, this work provided a useful approach for evaluating the efficacy and the synergistic effects of TCMs against cardiomyopathy.PMID:36587877 | DOI:10.1016/j.jep.2022.116109

J Ethnopharmacol. 2022 Dec 29:116092. doi: 10.1016/j.jep.2022.116092. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Dengzhan Shengmai capsule (DZSM) is a traditional herb medicine used by Dai, an ethnic-minority community living in Xishuang banna tropical rainforest in Southwest of China. It was originally intended to treat disorders caused by insufficient brain function, characterized by gibberish, unresponsiveness, or confusion. Accumulating clinical evidences exhibited that it is effective on treating ischemic stroke (IS). However, the action of DZSM against IS needs to be further elucidated.AIM OF THE STUDY: To investigate the effect of DZSM and its active components against IS and the way of its action by multi-omics and network pharmacology.MATERIALS AND METHODS: A middle cerebral artery occlusion/reperfusion (MCAO/R) rat model was established to investigate the effect of DZSM on the focal cerebral ischemia/reperfusion injury. An integrated strategy combining metabolomics, network pharmacology and transcriptomics was performed to systematically clarify the underlying mechanism of action of DZSM against IS. AutoDock Vina was applied to conduct molecular docking simulation for the binding between the potential active compounds and targets. Arachidonic acid (AA) induced platelet aggregation and lipopolysaccharide (LPS) stimulated microglial cells BV2 inflammation models were applied for the in vitro validation of effects of DZSM and its potential active compounds.RESULTS: In MCAO/R rats, DZSM could significantly reduce the infarct volume. Putative target prediction and functional enrichment analysis based on network pharmacological indicated that the key targets and the potential active compounds played important roles in DZSM's treatment to IS. The targets included four common genes (PTGS1, PTGS2, NFKB1 and NR1I2) and five key TFs (NFKB1, RELA, HIF1A, ESR1 and HDAC1), whilst 22 potential active compounds were identified. Molecular docking indicated that good binding affinity have been seen between those compounds and NR1I2, NFKB1, and RELA. Multi-omics study revealed that DZSM could regulate glutamate by influencing citrate cycle and glutamate involved pathways, and have showed neuroprotection activity and anti-inflammation activity by inhibiting NF-κB pathway. Neuroprotective effects of DZSM was validated by regulating of NF-κB signaling pathway and its downstream NO, TNF-α and IL-6 cytokines contributed to the activity of DZSM and its active compounds of scutellarin, quercetin 3-O-glucuronide, ginsenoside Rb1, schizandrol A and 3, 5-diCQA, whilst the antithrombotic activity of DZSM and its active compounds of schisanhenol, apigenin and schisantherin B were screened out by anti-platelet aggregation experiment.CONCLUSION: DZSM could against IS via regulating its downstream NO, TNF-α and IL-6 cytokines through NF-κB signaling pathway and alleviating thrombosis.PMID:36587875 | DOI:10.1016/j.jep.2022.116092

Sci Total Environ. 2022 Dec 29:161272. doi: 10.1016/j.scitotenv.2022.161272. Online ahead of print.ABSTRACTBlood pressure medications are used to treat hypertension. However, low concentrations of beta-blockers in water systems can negatively impact aquatic wildlife. Here, we conducted a metabolic and behavioral study investigating atenolol, a beta-blocker frequently detected in global wastewater systems. The objectives were to determine the effects of low-level atenolol exposure on early stages of zebrafish. We measured survival, deformities, heartbeat, mitochondrial function, lipid and amino acid profiles, and locomotor activity to discern mechanisms of metabolic disruption. We hypothesized that atenolol disrupts lipid metabolism, which would negatively impact locomotor activity. Atenolol showed no overt toxicity to larval zebrafish up to 10 μg/L and deformities were infrequent (<5 %), and included cardiac edema and larvae with kinked tails. A hatch delay was observed at 2-day post-fertilization (dpf) for fish exposed to >5 μg/L atenolol. Heart rates were reduced in 2 and 3 dpf in fish treated with >500 ng/L atenolol. There was no change in oxygen consumption rates (basal and maximum respiration) of embryos when exposed to a range of atenolol concentrations, suggesting mitochondrial respiration was intact. Oil red staining for lipid content in larvae showed a global reduction in lipids with 10 μg/L exposure, prompting deeper investigation into the lipid profiles. Lipidomics quantified 86 lipids and revealed reduced abundance in Ceramide 18: 1 16:0 (Cer_NS d18:1_16:0), Ether linked Phosphatidylethanolamine 16:0 22:6 (EtherPE 16:0e_22:6), and Ether linked Phosphatidylcholine 16:0 22:6 (EtherPC 16:0e_22:6). We also quantified 12 amino acids and observed a subtle dose-dependent reduction in the levels of L-Histidine. Exposure to atenolol did not impact larval locomotor activity based on a Visual Motor Response test. Taken together, atenolol at environmentally relevant levels decreased heart rate of developing zebrafish and altered lipid content. As such, exposure to beta-blockers like atenolol may have negative consequences for developmental trajectories and growth of aquatic species.PMID:36587689 | DOI:10.1016/j.scitotenv.2022.161272

Sci Total Environ. 2022 Dec 29:161261. doi: 10.1016/j.scitotenv.2022.161261. Online ahead of print.ABSTRACTPerfluorobutanesulfonate (PFBS), an alternative to perfluorooctanesulfonate (PFOS), has raised many health concerns. However, PFBS toxicity in the mammalian gut remains unclear. C57BL/6 mice were exposed to 10 μg/L and 500 μg/L PFBS or 500 μg/L PFOS in their water supply for 28 days. PFBS toxicity in the ileum and colon was explored and compared to that of PFOS. Biochemical analysis showed that and tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels increased in the ileum exposed to 10 μg/L PFBS, whereas no significant changes were observed in those levels in the colon. Catalase (CAT) activity, malondialdehyde (MDA), TNF-α, and IL-1β levels increased and glutathione (GSH) levels decreased in the ileum of the 500 μg/L-PFBS group, whereas only MDA levels increased in the colon of the 500 μg/L-PFBS group. The results showed that more severe damage occurred in the ileum than in the colon after PFBS exposure, and these align with the 500 μg/L-PFOS group exposure as well. Furthermore, metabolomic analysis revealed glutathione metabolism as a vital factor in inducing PFBS and PFOS toxicities in the ileum. Steroid hormone and amino acid metabolisms were other important factors involved in PFBS and PFOS toxicities, respectively. In the colon, GSH, pyrimidine, and glucose (especially galactose) metabolism was the main contributor to PFBS toxicity, and sulfur amino acid metabolism was the main pathway for PFOS toxicity. This study provides more evidence of the health hazards due to low-dose PFBS exposure in the mammalian gut.PMID:36587682 | DOI:10.1016/j.scitotenv.2022.161261

J Hazard Mater. 2022 Dec 23;446:130659. doi: 10.1016/j.jhazmat.2022.130659. Online ahead of print.ABSTRACTThis study aimed to investigate the relationship among chronic exposure to a low concentration of organochlorine pesticides (OCPs), high-fat diet (HFD)-induced obesity, and caloric restriction in type 2 diabetes (T2D). Thus, female zebrafish were divided into four groups and treated for 12 weeks as follows: (i) negative control, (ii) HFD (obesity) control, (iii) obesity + a mixture of OCPs (OP), and (iv) obesity + a mixture of OCPs + caloric restriction (OPR). We then assessed T2D-related effects via hematological analysis, histopathology, mitochondrial evaluation, and multiomics analyses. The OP group showed a significant increase in glucose levels, whereas the OPR group maintained glucose at nonsignificant levels. Multiomics analyses revealed that the exacerbated metabolic effects in the OP group were associated with molecular alterations in oxidative stress, inflammation, nucleotide metabolism, and glucose/lipid homeostasis. These alterations were histologically verified by the increased numbers of hypertrophic adipocytes and inflammatory cells observed. Caloric restriction activated pathways related to antioxidant response, mitochondrial fatty acid oxidation, and energy metabolism in zebrafish, leading to preserved glucose homeostasis. In conclusion, this study identified molecular mechanisms underlying the synergistic effect of concurrent exposure to a mixture of OCPs and HFD as well as shed light on the beneficial effect of regular caloric restriction in T2D development.PMID:36587596 | DOI:10.1016/j.jhazmat.2022.130659

Nutr Res. 2022 Dec 8;109:58-70. doi: 10.1016/j.nutres.2022.12.002. Online ahead of print.ABSTRACTIntake biomarkers of cranberry juice in women can assess consumption in clinical trials. Discriminant biomarkers in urine may explain urinary tract infection (UTI) preventive activities. We hypothesized that validated and annotated discriminant metabolites in human urine could be used as intake biomarkers in building predictive multivariate models to classify cranberry consumers. Urine samples were collected from 16 healthy women aged 18 to 29 years at baseline and after 3- and 21-day consumption of cranberry or placebo juice in a double-blind, crossover study. Urine metabolomes were analyzed using ultra high-performance liquid chromatography coupled with Orbitrap mass spectrometry. Paired and unpaired multivariate analyses were used to annotate or identify discriminant metabolic features after cranberry consumption. Twenty-six discriminant metabolic features (paired analysis) and 27 (unpaired analysis) after cranberry consumption in an open-label intervention were rediscovered in the blinded study. These metabolites included exogenous (quinic acid) and endogenous ones (hippuric acid). The paired analysis showed better model fitting with partial least-square discriminant analysis models built on all metabolites than the unpaired analysis. Predictive models built on shared metabolites by the unpaired analysis were able to classify cranberry juice consumers with 84.4% to 100% correction rates, overall better than the paired analysis (50%-100%). The double-blind study validated discriminant metabolites from a previous open-label study. These urinary metabolites may be associated with the ability of cranberries to prevent UTIs and serve as potential cranberry intake biomarkers. It reveals the importance of selecting the right predictive models to classify cranberry consumers with higher than 95% correction rates.PMID:36587538 | DOI:10.1016/j.nutres.2022.12.002

Mar Pollut Bull. 2022 Dec 30;187:114534. doi: 10.1016/j.marpolbul.2022.114534. Online ahead of print.ABSTRACTAnalyses of the transcriptome and metabolome were conducted to clarify alterations of key genes and metabolites in pearl oysters following exposure to short-term hypoxic treatment. We totally detected 209 DEGs between the control and hypoxia groups. Enrichment analysis indicated the enrichment of GO terms including "oxidation-reduction process", "ECM organization", "chaperone cofactor-dependent protein refolding", and "ECM-receptor interaction" KEGG pathway by the DEGs. In addition, between the two groups, a total of 28 SDMs were identified, which were implicated in 13 metabolic pathways, such as "phenylalanine metabolism", "D-amino acid metabolism", and "aminoacyl-tRNA biosynthesis". Results suggest that pearl oysters are exposed to oxidative stress and apoptosis under short-term hypoxia. Also, pearl oysters might adapt to short-term hypoxic treatment by increasing antioxidant activity, modulating immune and biomineralization activities, maintaining protein homeostasis, and reorganizing the cytoskeleton. The results of our study help unveil the mechanisms by which pearl oysters respond adaptively to short-term hypoxia.PMID:36587532 | DOI:10.1016/j.marpolbul.2022.114534

Mol Oncol. 2023 Jan 1. doi: 10.1002/1878-0261.13372. Online ahead of print.ABSTRACTPreclinical studies have proven that nanosecond pulsed electric field (nsPEF) ablation can be a safe and effective treatment for humans with unresectable liver cancer that are ineligible for thermal ablation. The concomitant activation of anti-tumor immunity by nsPEF can also potentially prevent tumor recurrence. However, whether nsPEF exhibits similar efficacy in a clinical setting remains to be investigated. A prospective clinical trial (clinicaltrials.gov identifier: NCT04039747) was conducted to evaluate the safety and efficacy of ultrasound (US)-guided nsPEF ablation in 15 patients with unresectable liver cancer that were ineligible for thermal ablation. We found that nsPEF ablation was safe and produced a 12-month recurrence-free survival (RFS) and local RFS of 60% (9/15) and 86.7% (13/15), respectively, in the enrolled patients. Integrative proteomic and metabolomic analysis showed that sphingolipid metabolism was the most significantly enriched pathway in patient sera after nsPEF without recurrence within 8 months. A similar upregulation of sphingolipid metabolism was observed in the intratumoral mononuclear phagocytes (MNPs), rather than other immune and nonimmune cells, of an nsPEF-treated mouse model. We then demonstrated that lymphocyte antigen 6 complex, locus C2-positive (Ly6c2+ ) monocytes first differentiated into Ly6c2+ monocyte-derived macrophages (MDMs) with an increase in sphingolipid metabolic activity, and subsequently into Ly6c2+ dendritic cells (DCs). Ly6c2+ DCs communicated with CD8+ T cells and increased the proportions of IFN-γ+ CD8+ memory T cells after nsPEF, and this finding was subsequently confirmed by depletion of liver Ly6c2+ MNPs. In conclusion, nsPEF was a safe and effective treatment for liver cancer. The alteration of sphingolipid metabolism induced by nsPEF was associated with the differentiation of Ly6c2+ MNPs, and subsequently induced the formation of memory CD8+ T cells with potent anti-tumor effect.PMID:36587393 | DOI:10.1002/1878-0261.13372

J Dairy Sci. 2022 Dec 29:S0022-0302(22)00761-5. doi: 10.3168/jds.2022-22654. Online ahead of print.ABSTRACTBrown goat milk products have gained popularity for their unique taste and flavor. The emergence of chain-reversal phenomenon makes the design and development of goat milk products gradually tend to a consumer-oriented model. However, the precise mechanism of how browning and fermentation process causes characteristics is not clear. In an effort to understand how the treatments potentially lead to certain metabolite profile changes in goat milk, comprehensive, quantitative metabolomics and peptidomics analysis of goat milk samples after browning and fermentation were undertaken. An intelligent hybrid z-score standardization-principal components algorithm-multimodal denoizing autoencoder was used for feature fusion and hidden layer fusion in high-dimensional variable space. The fermentation process significantly improved the flavor of brown goat yogurt through the tricarboxylic acid-urea-glycolysis composite pathway. Bitter peptides HPFLEWAR, PPGLPDKY, and PPPPPKK have strong interactions with both putative dipeptidyl peptidase IV and angiotensin-converting enzyme, proving that brown goat yogurt can be considered as effective provider of potential putative dipeptidyl peptidase IV and angiotensin-converting enzyme inhibitors. The level of health-promoting bioactive components and sensory contributed to consumer selection. The proposed multimodal data integrative analysis platform was applicable to explain the effect of the dynamic changes of metabolites and peptides on consumer preferences.PMID:36586795 | DOI:10.3168/jds.2022-22654

Neuroimage. 2022 Dec 28:119843. doi: 10.1016/j.neuroimage.2022.119843. Online ahead of print.ABSTRACTMediation analysis is used to investigate the role of intermediate variables (mediators) that lie in the path between an exposure and outcome variable. While significant research has focused on developing methods for assessing the influence of mediators on the exposure-outcome relationship, current approaches do not easily extend to settings where the mediator is high-dimensional (e.g., neuroimaging, genomics, and metabolomics). Here we introduce a novel machine learning based method for identifying high-dimensional mediators. The proposed algorithm is agnostic to the machine learning model used, providing significant flexibility in the types of situations it can be applied. We illustrate the proposed methodology using data from two functional Magnetic Resonance Imaging studies. In both, our multivariate mediation model links exposure variables, high dimensional brain measures and behavioral outcomes into a single unified model. Using the proposed approach, we identify brain-based measures that simultaneously encode the exposure variable and correlate with the behavioral outcome.PMID:36586543 | DOI:10.1016/j.neuroimage.2022.119843

J Ethnopharmacol. 2022 Dec 28:116013. doi: 10.1016/j.jep.2022.116013. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Cough variant asthma (CVA) is a chronic inflammatory disease characterized by cough as the main symptom. Suhuang antitussive capsule (Suhuang), one of traditional Chinese patent medicines, mainly treats CVA clinically. Previous studies have shown that Suhuang significantly improved CVA, post-infectious cough (PIC), sputum obstruction and airway remodeling. However, the effect of Suhuang on ovalbumin-induced (OVA-induced) metabolic abnormalities in CVA is unknown.AIM OF THE STUDY: This study aimed to identify potential metabolites associated with efficacy of Suhuang in the treatment of CVA, and determined how Suhuang regulates metabolites, and differential metabolites reduce inflammation and oxidative stress.MATERIALS AND METHODS: Rats were given 1 mg OVA/100 mg aluminum hydroxide in the 1st and 7th days by intraperitoneal injection and challenged by atomizing inhalation of 1% OVA saline solution after two weeks to establish the CVA model. Rats were intragastrically (i.g.) administrated with Suhuang at 1.4 g/kg and β-hydroxybutyric acid (β-HB) were given with different concentrations (87.5 and 175 mg/kg/day) by intraperitoneal injection for 2 weeks. After 26 days, GC-MS-based metabolomic approach was applied to observe metabolic changes and search differential metabolites. The number of coughs, coughs latencies, enzyme-linked immunosorbent assay (ELISA), histological analysis and quantitative-polymerase chain reaction (Q-PCR) were used to investigate the effects of Suhuang. Then β-HB on CVA rats, NLRP3 inflammasome and GSK3β/AMPK/Nrf2 signalling pathway were detected by western blotting.RESULTS: The results showed that Suhuang treatment significantly enhanced the serum level of β-HB. Interestingly, exposure to exogenous β-HB was also protective against OVA-induced CVA. β-HB significantly reduced the number of coughs and lengthened coughs latencies, improved lung injury, reduced the secretion of various cytokines, and directly inhibited the NLRP3 inflammasome. In addition, β-HB increased the nuclear accumulation of Nrf2 by activating the GSK3β/AMPK signaling axis, and then inactivating the NF-κB signaling pathway, effectively protecting OVA-induced CVA from oxidative stress and inflammation.CONCLUSIONS: The results of this study shows that β-HB can reduce inflammation and oxidative stress, the increased production of β-HB in serum might be the crucial factor for Suhuang to exert its effect in the treatment of CVA.PMID:36586526 | DOI:10.1016/j.jep.2022.116013

Food Chem. 2022 Dec 28;409:135342. doi: 10.1016/j.foodchem.2022.135342. Online ahead of print.ABSTRACTAs a common food processing technology, microbial fermentation is becoming increasingly popular to promote the bioactivity of materials. This study aims to enhance rape bee pollen bioactivity through fermentation and trace the potential components associated with its bioactivity. The antioxidant and anti-inflammatory activities of unfermented bee pollen and fermented bee pollen were evaluated, and their correlation with differential metabolites was analyzed. The results indicated that fermentation significantly (p < 0.05) improved the antioxidant (>2.3-fold) and anti-inflammatory (>1.36-fold) activities of bee pollen, and increased the contents of total phenolics and flavonoids by 1.99 and 1.53 folds. Moreover, the correlation analysis results indicated that 15 components, including three phenolamides, one flavonoid aglycone, seven fatty acids, three amino acids and one ketone compound, were positively correlated with bee pollen antioxidant and anti-inflammatory activities. These results suggest that fermentation is a promising approach to increase the bioactivity of bee pollen.PMID:36586262 | DOI:10.1016/j.foodchem.2022.135342

Curr Opin Chem Biol. 2022 Dec 29;72:102256. doi: 10.1016/j.cbpa.2022.102256. Online ahead of print.ABSTRACTDespite being a relatively new addition to the Omics' landscape, lipidomics is increasingly being recognized as an important tool for the identification of druggable targets and biochemical markers. In this review we present recent advances of lipid analysis in drug discovery and development. We cover current state of the art technologies which are constantly evolving to meet demands in terms of sensitivity and selectivity. A careful selection of important examples is then provided, illustrating the versatility of lipidomics analysis in the drug discovery and development process. Integration of lipidomics with other omics', stem-cell technologies, and metabolic flux analysis will open new avenues for deciphering pathophysiological mechanisms and the discovery of novel targets and biomarkers.PMID:36586190 | DOI:10.1016/j.cbpa.2022.102256

BMC Cancer. 2022 Dec 30;22(1):1366. doi: 10.1186/s12885-022-10457-y.ABSTRACTBACKGROUND: The gut microbiome plays an important role in immune modulation. Specifically, presence or absence of certain gut bacterial taxa has been associated with better antitumor immune responses. Furthermore, in trials using fecal microbiota transplantation (FMT) to treat melanoma patients unresponsive to immune checkpoint inhibitors (ICI), complete responses (CR), partial responses (PR), and durable stable disease (SD) have been observed. However, the underlying mechanism determining which patients will or will not respond and what the optimal FMT composition is, has not been fully elucidated, and a discrepancy in microbial taxa associated with clinical response has been observed between studies. Furthermore, it is unknown whether a change in the microbiome itself, irrespective of its origin, or FMT from ICI responding donors, is required for reversion of ICI-unresponsiveness. To address this, we will transfer microbiota of either ICI responder or nonresponder metastatic melanoma patients via FMT.METHODS: In this randomized, double-blinded phase Ib/IIa trial, 24 anti-PD1-refractory patients with advanced stage cutaneous melanoma will receive an FMT from either an ICI responding or nonresponding donor, while continuing anti-PD-1 treatment. Donors will be selected from patients with metastatic melanoma treated with anti-PD-1 therapy. Two patients with a good response (≥ 30% decrease according to RECIST 1.1 within the past 24 months) and two patients with progression (≥ 20% increase according to RECIST 1.1 within the past 3 months) will be selected as ICI responding or nonresponding donors, respectively. The primary endpoint is clinical benefit (SD, PR or CR) at 12 weeks, confirmed on a CT scan at 16 weeks. The secondary endpoint is safety, defined as the occurrence of grade ≥ 3 toxicity. Exploratory endpoints are progression-free survival and changes in the gut microbiome, metabolome, and immune cells.DISCUSSION: Transplanting fecal microbiota to restore the patients' perturbed microbiome has proven successful in several indications. However, less is known about the potential role of FMT to improve antitumor immune response. In this trial, we aim to investigate whether administration of FMT can reverse resistance to anti-PD-1 treatment in patients with advanced stage melanoma, and whether the ICI-responsiveness of the feces donor is associated with its effectiveness.TRIAL REGISTRATION: ClinicalTrials.gov: NCT05251389 (registered 22-Feb-2022). Protocol V4.0 (08-02-2022).PMID:36585700 | DOI:10.1186/s12885-022-10457-y