PubMed

Front Vet Sci. 2023 Jul 4;10:1231996. doi: 10.3389/fvets.2023.1231996. eCollection 2023.ABSTRACTThis research aimed to assess the impact of fermented Citri Sarcodactylis Fructus by-products (FCSF) on the growth performance, gut digestive enzyme activity, nutrient utilization efficiency, gut microbiota, and their metabolites in broiler chickens. A total of 1,080 male broiler chickens were allocated into four groups (T1-T4) consisting of 6 replicates per group, each containing 45 chickens. The basal diet was provided to group T1, while groups T2, T3, and T4 were supplemented with 1%, 3%, and 5% FCSF in the basal diet, respectively. The experimental period was 42 days. The findings revealed that supplementing FCSF improved the FW and ADG of broiler chickens, and led to a reduction in the F/G, ADFI, and mortality rate of broiler chickens (p < 0.05). Furthermore, supplementation with 3% and 5% FCSF improved the thigh yield, semi-eviscerated carcass yield, slaughter yield, and lipase activity in the duodenum and ileum of birds (p < 0.05). Additionally, supplementing 3% FCSF enhanced the activity of protease in the duodenum of broilers (p < 0.05). Moreover, supplementing 3% FCSF enhanced the utilization of total phosphorus, dry matter, crude protein, and crude ash in the feed by broilers (p < 0.05). Compared with the control group, supplementation of 3% and 5% FCSF reduced the serine content in broiler chicken breast meat (p < 0.05). Supplementing 1% FCSF significantly increased the C14:0, C14:1, and C20:1 content in the breast meat compared to the other experimental groups (p < 0.05). The levels of C20:4n6 and C23:0 in the breast meat of birds of FCSF supplemented groups were lower than in T1 (p < 0.05). Furthermore, the content of ∑ω-3PUFA decreased after supplementing with 3% and 5% FCSF (p < 0.05). 16SrDNA showed that supplementing 3% FCSF reduced the ACE, Chao1, and Shannon indices in the cecum of birds (p < 0.05). Supplementing 3% FCSF also decreased the abundance of the phylum Desulfobacterota and improved genera Coprobacter and Prevotella in the cecum of broiler chickens (p < 0.05). Metabolomic analysis of the gut microbiota revealed that supplementing 3% FCSF upregulated 6 metabolites and downregulated 16 metabolites (p < 0.05). Moreover, supplementing 3% FCSF downregulated 12 metabolic pathways and upregulated 3 metabolic pathways (p < 0.05). In summary our findings indicate that supplementing FCSF can improve the growth performance of broiler chickens by enhancing intestinal digestive enzyme activity, nutrient utilization, improving gut microbial diversity, and influencing the metabolism of gut microbiota.PMID:37470069 | PMC:PMC10352846 | DOI:10.3389/fvets.2023.1231996

PNAS Nexus. 2023 Jul 18;2(7):pgad216. doi: 10.1093/pnasnexus/pgad216. eCollection 2023 Jul.ABSTRACTEnhancing crop yields is a major challenge because of an increasing human population, climate change, and reduction in arable land. Here, we demonstrate that long-lasting growth enhancement and increased stress tolerance occur by pretreatment of dark grown Arabidopsis seedlings with ethylene before transitioning into light. Plants treated this way had longer primary roots, more and longer lateral roots, and larger aerial tissue and were more tolerant to high temperature, salt, and recovery from hypoxia stress. We attributed the increase in plant growth and stress tolerance to ethylene-induced photosynthetic-derived sugars because ethylene pretreatment caused a 23% increase in carbon assimilation and increased the levels of glucose (266%), sucrose/trehalose (446%), and starch (87%). Metabolomic and transcriptomic analyses several days posttreatment showed a significant increase in metabolic processes and gene transcripts implicated in cell division, photosynthesis, and carbohydrate metabolism. Because of this large effect on metabolism, we term this "ethylene-mediated metabolic priming." Reducing photosynthesis with inhibitors or mutants prevented the growth enhancement, but this was partially rescued by exogenous sucrose, implicating sugars in this growth phenomenon. Additionally, ethylene pretreatment increased the levels of CINV1 and CINV2 encoding invertases that hydrolyze sucrose, and cinv1;cinv2 mutants did not respond to ethylene pretreatment with increased growth indicating increased sucrose breakdown is critical for this trait. A model is proposed where ethylene-mediated metabolic priming causes long-term increases in photosynthesis and carbohydrate utilization to increase growth. These responses may be part of the natural development of seedlings as they navigate through the soil to emerge into light.PMID:37469928 | PMC:PMC10353721 | DOI:10.1093/pnasnexus/pgad216

Front Pharmacol. 2023 Jul 4;14:1164425. doi: 10.3389/fphar.2023.1164425. eCollection 2023.ABSTRACTObjective: Traditional Chinese medicine (TCM) has been used as a complementary treatment for cancer patients, but there has been no quantitative comprehensive analysis of TCM's efficacy. The purpose of this paper is to explore the current status and hotspots of TCM in cancer research from 2002 to 2022 and to provide a reference for future research. Methods: We retrieved articles published between 2002 and 2022 from the Web of Science database and analyzed them using R software, VOSviewer, and CiteSpace software. Results: A total of 7,129 articles were included in this study. The publication rate of TCM cancer research increased steadily from 2002 to 2022, with a rapid increase from 2010 to 2021. China was the country with the most published articles, followed by the United States, Republic of Korea, Germany, and Japan. China was also the country with the most international collaborations, and China Medical University and Shanghai University of Traditional Chinese Medicine were the most representative cooperation centers. The Journal of Ethnopharmacology was the most published and cited journal. Apoptosis, expression, in vitro, activation, and other related keywords were commonly used in these articles. Breast cancer, colorectal cancer, gastric cancer, liver cancer, and lung cancer were the most studied cancer types in TCM research. Pathway-related apoptosis, anti-inflammation, and oxidative stress were the hotspots and trends of TCM's anti-cancer mechanism. Metabolomics combined with network pharmacology was the main research method. Conclusion: Traditional Chinese medicine as an anti-cancer drug has received increasing attention from researchers worldwide, and it is expected to be a hotspot for developing new anti-cancer drugs in the future. Our study provides a comprehensive analysis of the current status and hotspots of TCM cancer research, which could serve as a valuable reference for future studies.PMID:37469862 | PMC:PMC10352617 | DOI:10.3389/fphar.2023.1164425

Front Mol Biosci. 2023 Jul 4;10:1218518. doi: 10.3389/fmolb.2023.1218518. eCollection 2023.ABSTRACTThe tRNA adaptation index (tAI) is a translation efficiency metric that considers weighted values (S ij values) for codon-tRNA wobble interaction efficiencies. The initial implementation of the tAI had significant flaws. For instance, generated S ij weights were optimized based on gene expression in Saccharomyces cerevisiae, which is expected to vary among different species. Consequently, a species-specific approach (stAI) was developed to overcome those limitations. However, the stAI method employed a hill climbing algorithm to optimize the S ij weights, which is not ideal for obtaining the best set of S ij weights because it could struggle to find the global maximum given a complex search space, even after using different starting positions. In addition, it did not perform well in computing the tAI of fungal genomes in comparison with the original implementation. We developed a novel approach named genetic tAI (gtAI) implemented as a Python package (https://github.com/AliYoussef96/gtAI), which employs a genetic algorithm to obtain the best set of S ij weights and follows a new codon usage-based workflow that better computes the tAI of genomes from the three domains of life. The gtAI has significantly improved the correlation with the codon adaptation index (CAI) and the prediction of protein abundance (empirical data) compared to the stAI.PMID:37469707 | PMC:PMC10352787 | DOI:10.3389/fmolb.2023.1218518

Front Public Health. 2023 Jul 4;11:1217237. doi: 10.3389/fpubh.2023.1217237. eCollection 2023.ABSTRACTAIMS: Gestational diabetes mellitus (GDM) stands as a prevalent obstetric complication bearing consequential health implications for both mother and child. While existing studies have probed the alterations in acylcarnitines during GDM, an updated systematic meta-analysis is needed to consolidate these findings. Hence, this study endeavours to furnish a comprehensive systematic review and meta-analysis delineating the association between acylcarnitines and GDM, aimed at bolstering diagnostic accuracy and preventive measures against GDM.METHODS: To extract pertinent studies for this meta-analysis, we meticulously scoured databases such as PubMed, Web of Science, Embase, and Cochrane Library up until May 2023. The inclusion criteria were studies contrasting plasma metabolomics between two cohorts: women diagnosed with GDM and normoglycemic pregnant women. Weighted mean differences (SMDs) and 95% confidence intervals (CIs) were calculated using random-effects models. The I2 index was employed to quantify heterogeneity amongst the studies. All meta-analyses were executed using Stata version 12.0.RESULTS: Our meta-analysis included eight studies encompassing 878 pregnant women. The analysis disclosed that relative to normoglycemic pregnant women, women with GDM exhibited significantly elevated levels of Short-Chain Acylcarnitines (SCAC) (SMD: 0.19, 95% CI: 0.02-0.36, I2 = 71.3%). No substantial difference was discerned in fasting total carnitine levels (SMD: 0.15, 95% CI: -0.16-0.31, I2 = 68.2%), medium-chain acylcarnitines (MCAC) (SMD: 0.08, 95% CI: -0.02-0.36, I2 = 79.0%), and long-chain acylcarnitines (LCAC) (SMD: 0.04, 95% CI: -0.06-0.15, I2 = 0%). Neither funnel plot assessment nor Egger's regression and Begg's rank correlation tests indicated any evidence of publication bias.CONCLUSION: Our meta-analysis suggests that elevated levels of SCAC may heighten the risk of GDM onset. Given GDM's deleterious impact on pregnant women and their offspring, these findings underscore the clinical imperative of managing this condition. Early surveillance of plasma metabolomic profiles, particularly serum acylcarnitine concentrations, may equip clinicians with a valuable tool for timely diagnosis and intervention in GDM.PMID:37469690 | PMC:PMC10352491 | DOI:10.3389/fpubh.2023.1217237

Parkinsons Dis. 2023 Jul 10;2023:8848642. doi: 10.1155/2023/8848642. eCollection 2023.ABSTRACTOBJECTIVE: To investigate the role of aberrant Dyrk1a expression in phosphorylation modification at the α-synuclein serine 129 (Ser129) site to analyze its molecular mechanism in mediating apoptosis of PD.METHODS: The protein level of P-α-synuclein (Ser129), α-synuclein, Bcl-2, Bax, active caspase 3, GSK3β, PI3K, AKT, and cyclinD1 were detected. The mRNA transcript levels of Dyrk1a and DAT and protein levels of IL-1β, IL-6, COX-2, and TNF-α were detected.RESULTS: P-α-synuclein (Ser129), α-synuclein, Bax, active caspase 3, GSK3β, and cyclinD1 expressions were decreased in Dyrk1a-AAV-ShRNA (P < 0.05), and Bcl-2, AKT, and PI3K expressions were increased (P < 0.05). Increased TH protein expression was shown in Dyrk1a-AAV-ShRNA (P < 0.05). Dyrk1a mRNA was decreased in the Dyrk1a-AAV-ShRNA group (P < 0.05), and DAT mRNA was increased (P < 0.05). IL-1β, IL-6, COX-2, and TNF-α protein levels were decreased in Dyrk1al-AAV-Sh-RNA (P < 0.05). Transcriptome sequencing showed that Fam220a, which was expected to activate STAT family protein binding activity and participate in the negative regulation of transcription through RNA polymerase II and protein dephosphorylation showed differentially upregulated expression. The untargeted metabolome showed that the major compounds in the Dyrk1a-AAV-ShRNA group were hormones and transmission mediators and the most metabolism-related pathways. Fam220a showed differentially upregulated expression, and differentially expressed genes were enriched for the neuroactive ligand-receptor interaction, vascular smooth muscle contraction, and melanogenesis-related pathways.CONCLUSION: Abnormal Dyrk1a expression can affect α-synuclein phosphorylation modifications, and dyrk1a knockdown activates the PI3K/AKT pathway and reduces dopaminergic neuron apoptosis. It provides a theoretical basis for the group to further investigate the molecular mechanism.PMID:37469393 | PMC:PMC10352525 | DOI:10.1155/2023/8848642

Adv Sci (Weinh). 2023 Jul 19:e2301190. doi: 10.1002/advs.202301190. Online ahead of print.ABSTRACTRNA-binding proteins (RBPs) play essential roles in tumorigenesis and progression, but their functions in gastric cancer (GC) remain largely elusive. Here, it is reported that Pumilio 1 (PUM1), an RBP, induces metabolic reprogramming through post-transcriptional regulation of DEP domain-containing mammalian target of rapamycin (mTOR)-interacting protein (DEPTOR) in GC. In clinical samples, elevated expression of PUM1 is associated with recurrence, metastasis, and poor survival. In vitro and in vivo experiments demonstrate that knockdown of PUM1 inhibits the proliferation and metastasis of GC cells. In addition, RNA-sequencing and bioinformatics analyses show that PUM1 is enriched in the glycolysis gene signature. Metabolomics studies confirm that PUM1 deficiency suppresses glycolytic metabolism. Mechanistically, PUM1 binds directly to DEPTOR mRNA pumilio response element to maintain the stability of the transcript and prevent DEPTOR degradation through post-transcriptional pathway. PUM1-mediated DEPTOR upregulation inhibits mTORC1 and alleviates the inhibitory feedback signal transmitted from mTORC1 to PI3K under normal conditions, thus activating the PI3K-Akt signal and glycolysis continuously. Collectively, these results reveal the critical epigenetic role of PUM1 in modulating DEPTOR-dependent GC progression. These conclusions support further clinical investigation of PUM1 inhibitors as a metabolic-targeting treatment strategy for GC.PMID:37469018 | DOI:10.1002/advs.202301190

J Ren Nutr. 2023 Jul 17:S1051-2276(23)00110-3. doi: 10.1053/j.jrn.2023.06.011. Online ahead of print.ABSTRACTOBJECTIVE: To determine serum and urine concentrations of the uremic retention solutes (URS), indoxyl sulfate (IS), p-cresol sulfate (PCS), and trimethylamine N-oxide (TMAO), and gut microbiota composition in individuals with moderate chronic kidney disease (CKD) compared with matched adults without CKD in a 6-day controlled feeding study.DESIGN: Methods, Participants, and Setting: This study was a secondary analysis in which 8 adults with moderate CKD were matched for age, sex, and race with 8 adults without CKD in a parallel-arm, 6-day controlled feeding study. IS, PCS, and TMAO were quantified using liquid chromatography-mass spectrometry (LC-MS) in fecal samples, fasting serum, and fasting spot urine samples collected at the end of the feeding period.RESULTS: Fasting serum URS concentrations were 2.8 to 4.9x higher in CKD compared to controls (all p<0.05). No differences were found in the composition of the gut microbiota between patients with and without CKD when analyzing samples for α-diversity, β-diversity, and only minor abundance differences across taxa were apparent. Estimated glomerular filtration rate (eGFR) was inversely related to each serum URS in the whole cohort (all p<0.01). However, within groups the relationships between eGFR and serum URS remained strong for CKD patients for IS and TMAO (both p<0.05) but weakened for PCS (p=0.10). eGFR was only correlated with urine PCS in the whole cohort (p=0.03); within groups, no correlation for eGFR with any urine URS was observed. Only urine TMAO was higher in CKD compared to controls (p<0.05).CONCLUSION: Serum URS concentrations are elevated in adults with CKD compared to matched non-CKD adults without differences in gut microbiota composition after consuming the same controlled study diet for 6 days. Future studies are needed to determine if specific dietary components may differentially alter the microbiota and URS.PMID:37468049 | DOI:10.1053/j.jrn.2023.06.011

Sci Total Environ. 2023 Jul 17:165521. doi: 10.1016/j.scitotenv.2023.165521. Online ahead of print.ABSTRACTThe molecular and metabolic mechanisms of foliar selenium (Se) nanoparticles (SeNPs) application in mitigating cadmium (Cd) toxicity in crops have not been well studied. Herein, hydroponically cultured maize seedlings were exposed to Cd (20 μM) and treated without and with foliar SeNPs application. Effects of SeNPs on Cd transporter genes and plant metabolism were also explored. Results showed that compared to control plants without Cd exposure, Cd exposure decreased shoot height (16.8 %), root length (17.7 %), and fresh weight of root (24.2 %), stem (28.8 %), and foliar-applied leaves (Se-leaves) (15.0 %) via oxidative damage. Compared to Cd exposure alone, foliar SeNPs application at 20 mg/L (0.25 mg/plant) significantly alleviated the Cd toxicity by promoting photosynthesis and antioxidant capacity and fixing Cd in cell wall. Meanwhile, the mineral concentration of Ca (26.0 %), Fe (55.4 %), Mg (27.0 %), Na (28.6 %), and Zn (10.1 %) in Se-leaves was improved via foliar SeNPs application at 20 mg/L. QRT-PCR analysis further revealed that down- and up-regulation of the expression of ZmHMA2 and ZmHMA3 gene in Se-leaves contributed to reduced translocation of Cd in plants and enhanced Cd sequestration in the vacuole, respectively. Metabolomic results further indicated that metabolic pathways including carbohydrate metabolism, membrane transport, translation, amino acid metabolism, and energy metabolism were significantly affected by foliar SeNPs application. In conclusion, foliar SeNPs application at 20 mg/L could be a prospective strategy to mitigate Cd toxicity in maize.PMID:37467994 | DOI:10.1016/j.scitotenv.2023.165521

Mol Metab. 2023 Jul 17:101779. doi: 10.1016/j.molmet.2023.101779. Online ahead of print.ABSTRACTOBJECTIVE: Both obesity and exposure to chemicals may induce non-alcoholic fatty liver disease (NAFLD). Pregnane X Receptor (PXR) is a central target of metabolism disrupting chemicals and disturbs hepatic glucose and lipid metabolism. We hypothesized that the metabolic consequences of PXR activation may be modified by existing obesity and associated metabolic dysfunction.METHODS: Wildtype and PXR knockout male mice were fed high-fat diet to induce obesity and metabolic dysfunction. PXR was activated with pregnenolone-16α-carbonitrile. Glucose metabolism, hepatosteatosis, insulin signaling, glucose uptake, liver glycogen, plasma and liver metabolomics, and liver, white adipose tissue, and muscle transcriptomics were investigated.RESULTS: PXR activation aggravated obesity-induced liver steatosis by promoting lipogenesis and inhibiting fatty acid disposal. Accordingly, hepatic insulin sensitivity was impaired and circulating alanine aminotransferase level increased. Lipid synthesis was facilitated by increased liver glucose uptake and utilization of glycogen reserves resulting in dissociation of hepatosteatosis and hepatic insulin resistance from the systemic glucose tolerance and insulin sensitivity. Furthermore, glucagon-induced hepatic glucose production was impaired. PXR deficiency did not protect from the metabolic manifestations of obesity, but the liver transcriptomics and metabolomics profiling suggest diminished activation of inflammation and less prominent changes in the overall metabolite profile.CONCLUSIONS: Obesity and PXR activation by chemical exposure have a synergistic effect on NAFLD development. To support liver fat accumulation the PXR activation reorganizes glucose metabolism that seemingly improves systemic glucose metabolism. This implies that obese individuals, already predisposed to metabolic diseases, may be more susceptible to harmful metabolic effects of PXR-activating drugs and environmental chemicals.PMID:37467962 | DOI:10.1016/j.molmet.2023.101779

J Lipid Res. 2023 Jul 17:100416. doi: 10.1016/j.jlr.2023.100416. Online ahead of print.ABSTRACTAcute kidney injury (AKI) is a global public health concern with high mortality and morbidity. In ischemic reperfusion injury (IRI), a main cause of AKI, the brush border membrane of S3 proximal tubules (PT) is lost to the tubular lumen. How injured tubules reconstitute lost membrane lipids during renal recovery is not known. Here, we identified Mfsd2a, a sodium-dependent lysophosphatidylcholine (LPC) transporter, to be expressed specifically in the basolateral membrane of S3 PT. Using an in vivo activity probe for Mfsd2a, transport activity was found to be specific to the S3 PT. Mice with haploinsufficiency of Mfsd2a exhibited delayed recovery of renal function after acute IRI, with depressed urine osmolality and elevated levels of histological markers of damage, fibrosis and inflammation, findings corroborated by transcriptomic analysis. Lipidomics revealed deficiency in docosahexaenoic acid (DHA) containing phospholipids in Mfsd2a haploinsufficiency. Treatment of Mfsd2a haploinsufficient mice with LPC-DHA improved renal function and reduced markers of injury, fibrosis and inflammation. Additionally, LPC-DHA treatment restored S3 brush border membrane architecture, and normalized DHA containing phospholipid content. These findings indicate that Mfsd2a mediated transport of LPC-DHA is limiting for renal recovery after AKI and suggest that LPC-DHA could be a promising dietary supplement for improving recovery following AKI.PMID:37467896 | DOI:10.1016/j.jlr.2023.100416

J Proteomics. 2023 Jul 17:104972. doi: 10.1016/j.jprot.2023.104972. Online ahead of print.ABSTRACTCongenital cataracts are a threat to visual development in children, and the visual impairment persists after surgical treatment; however, the mechanisms involved remain unclear. Previous clinical studies have identified the effect of congenital cataracts on retinal morphology and function. To further understand the molecular mechanisms by which congenital cataracts affect retinal development, we analyzed retina samples from 7-week-old GJA8-knockout rabbits with congenital cataracts and controls by four-dimensional label-free quantification proteomics and untargeted metabolomics. Bioinformatics analysis of proteomic data showed that retinol metabolism, oxidative phosphorylation, and fatty acid degradation pathways were downregulated in the retinas of rabbits with congenital cataracts, indicating that their visual cycle and mitochondrial function were affected. Additional validation of differentially abundant proteins related to the visual cycle and mitochondrial function was performed using Parallel reaction monitoring and western blot experiments. Untargeted metabolome analysis showed significant upregulation of the antioxidant glutathione and ascorbic acid in the retinas of rabbits with congenital cataracts, indicating that their oxidative stress balance was not dysregulated. SIGNIFICANCE: Congenital cataracts in children can alter retinal structure and function, yet the mechanisms are uncertain. Here is the first study to use proteomics and metabolomics approaches to investigate the effects of congenital cataracts on retinal development in the early postnatal period. Our findings suggest that congenital cataracts have an impact on the retinal visual cycle and mitochondrial function. These findings give insight on the molecular pathways behind congenital cataract-induced visual function impairment in the early postnatal period.PMID:37467890 | DOI:10.1016/j.jprot.2023.104972

J Ethnopharmacol. 2023 Jul 17:116925. doi: 10.1016/j.jep.2023.116925. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Sijunzi decoction (SJZD), a traditional Chinese medicine formula, is commonly used in clinical practice for the treatment of gastric precancerous lesions (GPL). However, the mechanism of gastric protection is not fully understood.AIMS OF THE STUDY: The purpose of this study was to systematically evaluate the efficacy of SJZD in blocking the development of GPL and to reveal the underlying mechanism.METHODS: First, we established a rat model of GPL, which was induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) combined with an irregular diet and 40% ethanol. The efficacy of SJZD was evaluated based on pathological sections and serum biochemical indices. Then, the pharmacodynamic mechanism of SJZD was revealed by quantitative proteomics based on stable isotope dimethyl labeling. At the same time, the pharmacodynamic mechanism was verified by quantitative metabolomics. In addition, the anti-gastritis effect of SJZD was confirmed by a serum pharmacology method in a cell model, and the functional mechanism was further verified.RESULTS: We demonstrated that SJZD could block the development of GPL in the animal model. Proteomics and metabolomics revealed that SJZD blocks GPL development by regulating oxidative phosphorylation (OXPHOS). In addition, the serum pharmacology results showed that SJZD-containing serum (SJZD-CS) could inhibit apoptosis in MNNG-induced GES-1 cells. OXPHOS inhibitors could significantly reduce the protective effect of SJZD-CS.CONCLUSION: SJZD effectively ameliorates GPL, and proteomics and metabolomics revealed that its protective effects are closely related to OXPHOS.PMID:37467821 | DOI:10.1016/j.jep.2023.116925

Cell Chem Biol. 2023 Jul 3:S2451-9456(23)00194-0. doi: 10.1016/j.chembiol.2023.06.016. Online ahead of print.ABSTRACTThe immune checkpoint protein PD-L1 plays critical roles in both immune system homeostasis and tumor progression. Impaired PD-1/PD-L1 function promotes autoimmunity and PD-L1 expression within tumors promotes immune evasion. If and how changes in metabolism or defined metabolites regulate PD-L1 expression is not fully understood. Here, using a metabolomics activity screening-based approach, we have determined that hydroxyproline (Hyp) significantly and directly enhances adaptive (i.e., IFN-γ-induced) PD-L1 expression in multiple relevant myeloid and cancer cell types. Mechanistic studies reveal that Hyp acts as an inhibitor of autophagic flux, which allows it to regulate this negative feedback mechanism, thereby contributing to its overall effect on PD-L1 expression. Due to its prevalence in fibrotic tumors, these findings suggest that hydroxyproline could contribute to the establishment of an immunosuppressive tumor microenvironment and that Hyp metabolism could be targeted to pharmacologically control PD-L1 expression for the treatment of cancer or autoimmune diseases.PMID:37467751 | DOI:10.1016/j.chembiol.2023.06.016

Cell Rep Med. 2023 Jul 18;4(7):101109. doi: 10.1016/j.xcrm.2023.101109.ABSTRACTDirect diagnosis and accurate assessment of metabolic syndrome (MetS) allow for prompt clinical interventions. However, traditional diagnostic strategies overlook the complex heterogeneity of MetS. Here, we perform metabolomic analysis in 13,554 participants from the natural cohort and identify 26 hub plasma metabolic fingerprints (PMFs) associated with MetS and its early identification (pre-MetS). By leveraging machine-learning algorithms, we develop robust diagnostic models for pre-MetS and MetS with convincing performance through independent validation. We utilize these PMFs to assess the relative contributions of the four major MetS risk factors in the general population, ranked as follows: hyperglycemia, hypertension, dyslipidemia, and obesity. Furthermore, we devise a personalized three-dimensional plasma metabolic risk (PMR) stratification, revealing three distinct risk patterns. In summary, our study offers effective screening tools for identifying pre-MetS and MetS patients in the general community, while defining the heterogeneous risk stratification of metabolic phenotypes in real-world settings.PMID:37467725 | DOI:10.1016/j.xcrm.2023.101109

Cell Rep Med. 2023 Jul 18;4(7):101077. doi: 10.1016/j.xcrm.2023.101077.ABSTRACTIn this issue of Cell Reports Medicine, Han et al.1 conducted a multi-ancestry genetic and metabolomic analysis to investigate the causal relationships between age-related macular degeneration and plasma and urine metabolites.PMID:37467724 | DOI:10.1016/j.xcrm.2023.101077

Food Chem. 2023 Jul 1;428:136785. doi: 10.1016/j.foodchem.2023.136785. Online ahead of print.ABSTRACTIn this study, an optimized yellowing process for yellow tea (YT) was developed by response surface methodology. The results showed that increasing the yellowing temperature from 20 °C to 34 °C, increasing the relative humidity from 55% to 67%, and reducing the yellowing time from 48 h to 16 h, caused a 40.5% and 43.2% increase in the yellowness and sweetness of YT, respectively, and improved the consumer acceptability by 36.8%. Moreover, metabolomics was used to explore the involved mechanisms that resulted in the improved YT quality. The optimized yellowing promoted the hydrolysis of 5 gallated catechins, 6 flavonoid glycosides, theogallin and digalloylglucose, resulting in the accumulation of 5 soluble sugars and gallic acid. Meanwhile, it promoted the oxidative polymerization of catechins (e.g., theaflagallin, δ-type dehydrodicatechin and theasinensin A), but decelerated the degradation of chlorophylls. Overall, this optimized yellowing process could serve as a guide to a shorter yellowing cycle.PMID:37467693 | DOI:10.1016/j.foodchem.2023.136785

BMC Med. 2023 Jul 19;21(1):264. doi: 10.1186/s12916-023-02972-x.ABSTRACTBACKGROUND: Since the coronavirus disease 2019 (COVID-19) outbreak, many COVID-19 variants have emerged, causing several waves of pandemics and many infections. Long COVID-19, or long-term sequelae after recovery from COVID-19, has aroused worldwide concern because it reduces patient quality of life after rehabilitation. We aimed to characterize the functional differential profile of the oral and gut microbiomes and serum metabolites in patients with gastrointestinal symptoms associated with long COVID-19.METHODS: We prospectively collected oral, fecal, and serum samples from 983 antibiotic-naïve patients with mild COVID-19 and performed a 3-month follow-up postdischarge. Forty-five fecal and saliva samples, and 25 paired serum samples were collected from patients with gastrointestinal symptoms of long COVID-19 at follow-up and from healthy controls, respectively. Eight fecal and saliva samples were collected without gastrointestinal symptoms of long COVID-19 at follow-up. Shotgun metagenomic sequencing of fecal samples and 2bRAD-M sequencing of saliva samples were performed on these paired samples. Two published COVID-19 gut microbiota cohorts were analyzed for comparison. Paired serum samples were analyzed using widely targeted metabolomics.RESULTS: Mild COVID-19 patients without gastrointestinal symptoms of long COVID-19 showed little difference in the gut and oral microbiota during hospitalization and at follow-up from healthy controls. The baseline and 3-month samples collected from patients with gastrointestinal symptoms associated with long COVID-19 showed significant differences, and ectopic colonization of the oral cavity by gut microbes including 27 common differentially abundant genera in the Proteobacteria phylum, was observed at the 3-month timepoint. Some of these bacteria, including Neisseria, Lautropia, and Agrobacterium, were highly related to differentially expressed serum metabolites with potential toxicity, such as 4-chlorophenylacetic acid, 5-sulfoxymethylfurfural, and estradiol valerate.CONCLUSIONS: Our study characterized the changes in and correlations between the oral and gut microbiomes and serum metabolites in patients with gastrointestinal symptoms associated with long COVID-19. Additionally, our findings reveal that ectopically colonized bacteria from the gut to the oral cavity could exist in long COVID-19 patients with gastrointestinal symptoms, with a strong correlation to some potential harmful metabolites in serum.PMID:37468867 | DOI:10.1186/s12916-023-02972-x

Cell Mol Life Sci. 2023 Jul 19;80(8):217. doi: 10.1007/s00018-023-04872-y.ABSTRACTSpermatogenesis is a complicated process of germ cell differentiation that occurs within the seminiferous tubule in the testis. Peritubular myoid cells (PTMCs) produce major components of the basement membrane that separates and ensures the structural integrity of seminiferous tubules. These cells secrete niche factors to promote spermatogonial stem cell (SSC) maintenance and mediate androgen signals to direct spermatid development. However, the regulatory mechanisms underlying the identity and function of PTMCs have not been fully elucidated. In the present study, we showed that the expression of pancreatic lipase-related protein 2 (Pnliprp2) was restricted in PTMCs in the testis and that its genetic ablation caused age-dependent defects in spermatogenesis. The fertility of Pnliprp2 knockout animals (Pnliprp2-/-) was normal at a young age but declined sharply beginning at 9 months. Pnliprp2 deletion impaired the homeostasis of undifferentiated spermatogonia and severely disrupted the development and function of spermatids. Integrated analyses of single-cell RNA-seq and metabolomics data revealed that glyceride metabolism was changed in PTMCs from Pnliprp2-/- mice. Further analysis found that 60 metabolites were altered in the sperm of the Pnliprp2-/- animals; notably, lipid metabolism was significantly dysregulated. Collectively, these results revealed that Pnliprp2 was exclusively expressed in PTMCs in the testis and played a novel role in supporting continual spermatogenesis in mice. The outcomes of these findings highlight the function of lipid metabolism in reproduction and provide new insights into the regulation of PTMCs in mammals.PMID:37468762 | DOI:10.1007/s00018-023-04872-y

Anal Bioanal Chem. 2023 Jul 19. doi: 10.1007/s00216-023-04851-z. Online ahead of print.ABSTRACTLipidomics investigates the composition and function of lipids, typically employing blood or tissue samples as the primary study matrices. Hair has recently emerged as a potential complementary sample type to identify biomarkers in early disease stages and retrospectively document an individual's metabolic status due to its long detection window of up to several months prior to the time of sampling. However, the limited coverage of lipid profiling presented in previous studies has hindered its exploitation. This study aimed to evaluate the lipid coverage of hair using an untargeted liquid chromatography-high-resolution mass spectrometry lipidomics platform. Two distinct three-step exhaustive extraction experiments were performed using a hair metabolomics one-phase extraction technique that has been recently optimized, and the two-phase Folch extraction method which is recognized as the gold standard for lipid extraction in biological matrices. The applied lipidomics workflow improved hair lipid coverage, as only 99 species could be annotated using the one-phase extraction method, while 297 lipid species across six categories were annotated with the Folch method. Several lipids in hair were reported for the first time, including N-acyl amino acids, diradylglycerols, and coenzyme Q10. The study suggests that hair lipids are not solely derived from de novo synthesis in hair, but are also incorporated from sebum and blood, making hair a valuable matrix for clinical, forensic, and dermatological research. The improved understanding of the lipid composition and analytical considerations for retrospective analysis offers valuable insights to contextualize untargeted hair lipidomic analysis and facilitate the use of hair in translational studies.PMID:37468753 | DOI:10.1007/s00216-023-04851-z