PubMed

Curr Res Food Sci. 2022 Dec 10;6:100409. doi: 10.1016/j.crfs.2022.100409. eCollection 2023.ABSTRACTBoiling has important effects on the texture of chicken eggs, but its effects on egg nutrients have not been systematically investigated. In this study, changes in the metabolites of egg yolks boiled under different heating intensities were quantified and compared by metabolomic analysis. A total of 797 metabolites were identified, and the abundance of 162 metabolites changed significantly after boiling. The significant reduction of L-lysine and D-fructose suggested that Maillard reactions occurred in over-boiled egg yolks. Egg yolk endogenous enzymes might induce a partial hydrolysis of proteins and phospholipids during the warm-up period of boiling, as the abundance of dipeptides, lysophospholipids, and free fatty acids was significantly increased in boiled egg yolks. Boiling increased the detectable abundance of fat-soluble vitamins, riboflavin, and biotin, possibly by altering the complex structure of protein-lipid-lipophilic compounds or denaturing vitamin-binding proteins. The results of metabolomic analyses provide important information for understanding the nutritional changes of egg yolk boiled under different heating intensities.PMID:36582447 | PMC:PMC9792406 | DOI:10.1016/j.crfs.2022.100409

Front Immunol. 2022 Dec 13;13:1095038. doi: 10.3389/fimmu.2022.1095038. eCollection 2022.ABSTRACT[This corrects the article DOI: 10.3389/fimmu.2021.811351.].PMID:36582251 | PMC:PMC9793797 | DOI:10.3389/fimmu.2022.1095038

Front Immunol. 2022 Dec 13;13:1033393. doi: 10.3389/fimmu.2022.1033393. eCollection 2022.ABSTRACTBACKGROUND: The profile of gut microbiota, serum metabolites, and lipids of type 1 diabetes (T1D) patients with different human leukocyte antigen (HLA) genotypes remains unknown. We aimed to explore gut microbiota, serum metabolites, and lipids signatures in individuals with T1D typed by HLA genotypes.METHODS: We did a cross-sectional study that included 73 T1D adult patients. Patients were categorized into two groups according to the HLA haplotypes they carried: those with any two of three susceptibility haplotypes (DR3, DR4, DR9) and without any of the protective haplotypes (DR8, DR11, DR12, DR15, DR16) were defined as high-risk HLA genotypes group (HR, n=30); those with just one or without susceptibility haplotypes as the non-high-risk HLA genotypes group (NHR, n=43). We characterized the gut microbiome profile with 16S rRNA gene amplicon sequencing and analyzed serum metabolites with liquid chromatography-mass spectrometry.RESULTS: Study individuals were 32.5 (8.18) years old, and 60.3% were female. Compared to NHR, the gut microbiota of HR patients were characterized by elevated abundances of Prevotella copri and lowered abundances of Parabacteroides distasonis. Differential serum metabolites (hypoxanthine, inosine, and guanine) which increased in HR were involved in purine metabolism. Different lipids, phosphatidylcholines and phosphatidylethanolamines, decreased in HR group. Notably, Parabacteroides distasonis was negatively associated (p ≤ 0.01) with hypoxanthine involved in purine metabolic pathways.CONCLUSIONS: The present findings enabled a better understanding of the changes in gut microbiome and serum metabolome in T1D patients with HLA risk genotypes. Alterations of the gut microbiota and serum metabolites may provide some information for distinguishing T1D patients with different HLA risk genotypes.PMID:36582242 | PMC:PMC9794034 | DOI:10.3389/fimmu.2022.1033393

Pediatr Transplant. 2022 Dec 29:e14460. doi: 10.1111/petr.14460. Online ahead of print.ABSTRACTBACKGROUND: Despite the common use of mycophenolate in pediatric renal transplantation, lack of effective therapeuic drug monitoring increases uncertainty over optimal drug exposure and risk for adverse reactions. This study aims to develop a novel urine test to estimate MPA exposure based using metabolomics.METHODS: Urine samples obtained on the same day of MPA pharmacokinetic testing from two prospective cohorts of pediatric kidney transplant recipients were assayed for 133 unique metabolites by mass spectrometry. Partial least squares (PLS) discriminate analysis was used to develop a top 10 urinary metabolite classifier that estimates MPA exposure. An independent cohort was used to test pharmacodynamic validity for allograft inflammation (urinary CXCL10 levels) and eGFR ratio (12mo/1mo eGFR) at 1 year.RESULTS: Fifty-two urine samples from separate children (36.5% female, 12.0 ± 5.3 years at transplant) were evaluated at 1.6 ± 2.5 years post-transplant. Using all detected metabolites (n = 90), the classifier exhibited strong association with MPA AUC by principal component regression (r = 0.56, p < .001) and PLS (r = 0.75, p < .001). A practical classifier (top 10 metabolites; r = 0.64, p < .001) retained similar accuracy after cross-validation (LOOCV; r = 0.52, p < .001). When applied to an independent cohort (n = 97 patients, 1053 samples), estimated mean MPA exposure over Year 1 was inversely associated with mean urinary CXCL10:Cr (r = -0.28, 95% CI -0.45, -0.08) and exhibited a trend for association with eGFR ratio (r = 0.35, p = .07), over the same time period.CONCLUSIONS: This urinary metabolite classifier can estimate MPA exposure and correlates with allograft inflammation. Future studies with larger samples are required to validate and evaluate its clinical application.PMID:36582125 | DOI:10.1111/petr.14460

J Transl Med. 2022 Dec 29;20(1):629. doi: 10.1186/s12967-022-03809-6.ABSTRACTBACKGROUND: Obesity is a major health concern for breast cancer survivors, being associated with high recurrence and reduced efficacy during cancer treatment. Metformin treatment is associated with reduced breast cancer incidence, recurrence and mortality. To better understand the underlying mechanisms through which metformin may reduce recurrence, we aimed to conduct metabolic profiling of overweight/obese breast cancer survivors before and after metformin treatment.METHODS: Fasting plasma samples from 373 overweight or obese breast cancer survivors randomly assigned to metformin (n = 194) or placebo (n = 179) administration were collected at baseline, after 6 months (Reach For Health trial), and after 12 months (MetBreCS trial). Archival samples were concurrently analyzed using three complementary methods: untargeted LC-QTOF-MS metabolomics, targeted LC-MS metabolomics (AbsoluteIDQ p180, Biocrates), and gas chromatography phospholipid fatty acid assay. Multivariable linear regression models and family-wise error correction were used to identify metabolites that significantly changed after metformin treatment.RESULTS: Participants (n = 352) with both baseline and study end point samples available were included in the analysis. After adjusting for confounders such as study center, age, body mass index and false discovery rate, we found that metformin treatment was significantly associated with decreased levels of citrulline, arginine, tyrosine, caffeine, paraxanthine, and theophylline, and increased levels of leucine, isoleucine, proline, 3-methyl-2-oxovalerate, 4-methyl-2-oxovalerate, alanine and indoxyl-sulphate. Long-chain unsaturated phosphatidylcholines (PC ae C36:4, PC ae C38:5, PC ae C36:5 and PC ae C38:6) were significantly decreased with the metformin treatment, as were phospholipid-derived long-chain n-6 fatty acids. The metabolomic profiles of metformin treatment suggest change in specific biochemical pathways known to impair cancer cell growth including activation of CYP1A2, alterations in fatty acid desaturase activity, and altered metabolism of specific amino acids, including impaired branched chain amino acid catabolism.CONCLUSIONS: Our results in overweight breast cancer survivors identify new metabolic effects of metformin treatment that may mechanistically contribute to reduced risk of recurrence in this population and reduced obesity-related cancer risk reported in observational studies.TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01302379 and EudraCT Protocol #: 2015-001001-14.PMID:36581893 | DOI:10.1186/s12967-022-03809-6

Microbiome. 2022 Dec 30;10(1):245. doi: 10.1186/s40168-022-01437-2.ABSTRACTBACKGROUND: The early life gut microbiome is crucial in maintaining host metabolic and immune homeostasis. Though neonates with critical congenital heart disease (CCHD) are at substantial risks of malnutrition and immune imbalance, the microbial links to CCHD pathophysiology remain poorly understood. In this study, we aimed to investigate the gut microbiome in neonates with CCHD in association with metabolomic traits. Moreover, we explored the clinical implications of the host-microbe interactions in CCHD.METHODS: Deep metagenomic sequencing and metabolomic profiling of paired fecal samples from 45 neonates with CCHD and 50 healthy controls were performed. The characteristics of gut microbiome were investigated in three dimensions (microbial abundance, functionality, and genetic variation). An in-depth analysis of gut virome was conducted to elucidate the ecological interaction between gut viral and bacterial communities. Correlations between multilevel microbial features and fecal metabolites were determined using integrated association analysis. Finally, we conducted a subgroup analysis to examine whether the interactions between gut microbiota and metabolites could mediate inflammatory responses and poor surgical prognosis.RESULTS: Gut microbiota dysbiosis was observed in neonates with CCHD, characterized by the depletion of Bifidobacterium and overgrowth of Enterococcus, which was highly correlated with metabolomic perturbations. Genetic variations of Bifidobacterium and Enterococcus orchestrate the metabolomic perturbations in CCHD. A temperate core virome represented by Siphoviridae was identified to be implicated in shaping the gut bacterial composition by modifying microbial adaptation. The overgrowth of Enterococcus was correlated with systemic inflammation and poor surgical prognosis in subgroup analysis. Mediation analysis indicated that the overgrowth of Enterococcus could mediate gut barrier impairment and inflammatory responses in CCHD.CONCLUSIONS: We demonstrate for the first time that an aberrant gut microbiome associated with metabolomic perturbations is implicated in immune imbalance and adverse clinical outcomes in neonates with CCHD. Our data support the importance of reconstituting optimal gut microbiome in maintaining host metabolic and immunological homeostasis in CCHD. Video Abstract.PMID:36581858 | DOI:10.1186/s40168-022-01437-2

Clin Immunol. 2022 Dec 26:109219. doi: 10.1016/j.clim.2022.109219. Online ahead of print.ABSTRACTBACKGROUND: HLA-A29-positive birdshot chorioretinitis (BCR) is an inflammatory eye disorder that is generally assumed to be caused by an autoimmune response to HLA-A29-presented peptides from retinal arrestin (SAG), yet the epitopes recognized by CD8+ T cells from patients remain to be identified.OBJECTIVES: The identification of natural ligands of SAG presented by HLA-A29. To quantify CD8+ T cells reactive to antigenic SAG peptides presented by HLA-A29 in patients and controls.METHODS: We performed mass-spectrometry based immunopeptidomics of HLA-A29 of antigen-presenting cell lines from patients engineered to express SAG. MHC-I Dextramer technology was utilised to determine expansion of antigen-specific CD8+ T cells reactive to SAG peptides in complex with HLA-A29 in a cohort of BCR patients, HLA-A29-positive controls, and HLA-A29-negative controls.RESULTS: We report on the naturally presented antigenic SAG peptides identified by sequencing the HLA-A29 immunopeptidome of antigen-presenting cells of patients. We show that the N-terminally extended SAG peptide precursors can be trimmed in vitro by the antigen-processing aminopeptidases ERAP1 and ERAP2. Unexpectedly, no enhanced antigen engagement by CD8+ T cells upon stimulation with SAG peptides was observed in patients or HLA-A29-positive controls. Multiplexed HLA-A29-peptide dextramer profiling of a case-control cohort revealed that CD8+ T cells specific for these SAG peptides were neither detectable in peripheral blood nor in eye biopsies of patients.CONCLUSIONS: Collectively, these findings demonstrate that SAG is not a CD8+ T cell autoantigen and sharply contrast the paradigm in the pathogenesis of BCR. Therefore, the mechanism by which HLA-A29 is associated with BCR does not involve SAG.PMID:36581221 | DOI:10.1016/j.clim.2022.109219

Prog Neurobiol. 2022 Dec 26:102400. doi: 10.1016/j.pneurobio.2022.102400. Online ahead of print.ABSTRACTFrontotemporal dementia (FTD) is a heterogeneous neurodegenerative disease with multiple histopathological subtypes. FTD patients share similar symptoms with Alzheimer's disease (AD). Hence, FTD patients are commonly misdiagnosed as AD, despite the consensus clinical diagnostic criteria. It is therefore of great clinical need to identify a biomarker that can distinguish FTD from AD and control individuals, and potentially further differentiate between FTD pathological subtypes. We conducted a metabolomic analysis on post-mortem human brain tissue from three regions: cerebellum, frontal cortex and occipital cortex from control, FTLD-TDP type A, type A-C9, type C and AD. Our results indicate that the brain subdivisions responsible for different functions show different metabolic patterns. We further explored the region-specific metabolic characteristics of different FTD subtypes and AD patients. Different FTD subtypes and AD share similar metabolic phenotypes in the cerebellum, but AD exhibited distinct metabolic patterns in the frontal and occipital regions compared to FTD. The identified brain region-specific metabolite biomarkers could provide a tool for distinguishing different FTD subtypes and AD and provide the first insights into the metabolic changes of FTLD-TDP type A, type A-C9, type C and AD in different regions of the brain. The importance of protein arginine methylation in neurodegenerative disease has come to light, so we investigated whether the arginine methylation level contributes to disease pathogenesis. Our findings provide new insights into the relationship between arginine methylation and metabolic changes in FTD subtypes and AD that could be further explored, to study the molecular mechanism of pathogenesis.PMID:36581185 | DOI:10.1016/j.pneurobio.2022.102400

J Ethnopharmacol. 2022 Dec 26:116112. doi: 10.1016/j.jep.2022.116112. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Buyang Huanwu Decoction (BYHW) is a classic representative formula for treating qi deficiency and the blood stasis syndrome of stroke in the Qing Dynasty physician Wang Qingren's Correction on the Errors of Medical Works. However, the research on the mechanism of BYHW in the treatment of stroke is not systematic and comprehensive.AIM OF THE STUDY: Combined with multi-omics analysis methods to explore the potential targets of BYHW in the treatment of cerebral ischemia-reperfusion (I/R).MATERIALS AND METHODS: The rat middle cerebral artery occlusion (MCAO) model was established to study the effect of BYHW on cerebral I/R injury in rats. Then, the potential targets and pathways of BYHW in the treatment of cerebral I/R injury were analyzed by proteomic, transcriptomic, and metabolomic methods. Finally, 4D-PRM was used to validate potential targets.RESULTS: BYHW effectively improved the neurological function scores of MCAO rats and significantly reduced the rate of cerebral infarction in MCAO rats. Multi-omics analysis had identified 15 potential targets and 4 potential signaling pathways. The results of 4D-PRM targeted proteomics verification showed that Pde1b was reversed up-regulated, and Aprt, Gpd1, Glb1, HEXA, and HEXB were reversed down-regulated.CONCLUSION: BYHW may improve cerebral I/R through Aprt, Pde1b, Gpd1, Glb1, HEXA and HEXB targets, and Glycerophospholipid metabolism, Purine metabolism and Glycosphingolipid biosynthesis - globoseries pathway.PMID:36581164 | DOI:10.1016/j.jep.2022.116112

J Ethnopharmacol. 2022 Dec 26:116082. doi: 10.1016/j.jep.2022.116082. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Terminalia bellirica (Gaertn.) Roxb. (TB) is a traditional Tibetan medicine used to treat hepatobiliary diseases. However, modern pharmacological evidence of the activities and potential mechanisms of TB against nonalcoholic fatty liver disease (NAFLD) are still unknown.AIM OF THE STUDY: This study aimed to evaluate the anti-NAFLD effect of ethanol extract of TB (ETB) and investigate whether its ameliorative effects are associated with the regulation of intestinal microecology.MATERIALS AND METHODS: In this study, the curative effects of ETB on NAFLD were evaluated in mice fed a choline-deficient, L-amino acid defined, high fat diet (CDAHFD). Biochemical markers and hepatic histological alterations were detected. Gut microbiota and faecal metabolites were analyzed by 16S rRNA gene sequencing and liquid chromatograph mass spectrometer (LC‒MS) profiling.RESULTS: The results showed that oral treatment with middle- and high-dose ETB significantly improved features of NAFLD, reducing the levels of TG, LDL-C, ALT and AST, and increasing the level of HDL-C. Liver histopathologic examination demonstrated that ETB attenuated lipid accumulation and hepatocellular necrosis. ETB treatment restored the structural disturbances of gut microbiota induced by CDAHFD, reduced the levels of Intestinimonas, Lachnoclostridium, and Lachnospirace-ae_FCS020_group, and increased Akkermansia and Bifidobacterium. Moreover, untargeted metabolomics analysis revealed that ETB could restore the disrupted taurine and hypotaurine metabolism, glycine, serine and threonine metabolism, and glutathione metabolism of the intestinal bacterial community in NAFLD mice.CONCLUSIONS: ETB was effective in ameliorating the NAFLD, possibly by remodelling the gut microbiota composition and modulating the faecal metabolism metabolites of the host, highlighting the potential of TB as a resource for the development of anti-NAFLD drugs.PMID:36581163 | DOI:10.1016/j.jep.2022.116082

J Ethnopharmacol. 2022 Dec 26:116110. doi: 10.1016/j.jep.2022.116110. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Hyperlipidemia is the systemic manifestation of abnormal lipid metabolism, characterized by elevated circulating levels of cholesterol and triglyceride and a high risk of cardiovascular events. Radix Bupleuri (RB) is a traditional Chinese herbal product used to treat liver diseases. Our previous study demonstrated that Saikosaponins (SSs), the most potent bioactive ingredients in RB, ameliorate hepatic steatosis. However, whether SSs have anti-hyperlipidemia effects and plausible underlying mechanisms remain elusive.AIM OF THE STUDY: To comprehensively evaluate the lipid-lowering potential of SSs against hyperlipidemia in rats.MATERIALS AND METHODS: RNA sequencing and untargeted metabolomics approaches were applied to analyze the changes in the liver transcriptome and serum lipid profile in long-term high-fat diet feeding-induced hyperlipidemia rats in response to SSs or positive drug simvastatin (SIM) intervention.RESULTS: Our data revealed that SSs significantly alleviated HFD-induced hypertriglyceridemia and hypercholesterolemia. Combined with the analysis of gene ontology enrichment analysis and gene set enrichment analysis, we found that SSs remarkably repaired the unbalanced blood lipid metabolic spectrum in a dose-dependent manner by increasing the hepatic uptake of circulating fatty acids and facilitating mitochondrial respiration in fatty acid oxidation, comparable to SIM group. In addition, SSs markedly modulated cholesterol clearance by promoting intracellular cholesterol efflux, HDL remodeling, LDL particle clearance, and bile acid synthesis. SSs also efficiently protected the liver from lipid overload-related oxidative stress and lipid peroxidation, as well as substantially exaggerated inflammatory response.CONCLUSION: Our research not only unraveled the intricate mechanisms underlying the lipid-lowering functions of SSs but also provided novel perspectives on developing an SSs-based therapeutic strategy for the treatment of hyperlipidemia.CLASSIFICATION: Metabolism.PMID:36581162 | DOI:10.1016/j.jep.2022.116110

J Ethnopharmacol. 2022 Dec 26:116095. doi: 10.1016/j.jep.2022.116095. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Baitouweng decoction (BTW) has been used for hundreds of years to treat ulcerative colitis (UC) in China and has produced remarkable clinical results. However, the knowledge in protective mechanism of BTW against UC is still unclear.AIM OF THE STUDY: The present study was designed to investigate the anti-UC effects of BTW and the underlying mechanisms involved.METHODS: 3.5% dextran sulfate sodium (DSS)-induced experimental colitis was used to simulate human UC and the mice were treated with BTW (6.83 g/kg), leucine (200 mg/kg, Leu) or rapamycin (2 mg/kg, RAPA) as a positive control for 7 days. The clinical symptoms, serum myeloperoxidase (MPO) and malondialdehyde (MDA) levels were evaluated. Biological samples were collected to detect the effects of BTW on mechanistic target of rapamycin complex 1 (mTORC1) pathway and Leu metabolism.RESULTS: In our study, BTW notably improved the clinical symptoms and histopathological tissue damage and reduced the release of proinflammatory cytokines, including IL-6, IL-1β and TNF-α in UC mice. BTW also alleviated oxidative stress by decreasing serum MPO and MDA levels. Additionally, BTW significantly suppressed mTORC1 activity in the colon tissues of UC mice. Serum metabolomics analysis revealed that the mice receiving BTW had lower Leu levels, which was in line with the decreased expression of branched-chain α-keto acid dehydrogenase kinase (BCKDK) in the colon tissues. Furthermore, oral administration of Leu aggravated DSS-induced acute colitis and enhanced mTORC1 activity in the colon.CONCLUSION: These data strongly demonstrated that BTW could ameliorate DSS-induced UC by regulating the Leu-related mTORC1 pathway and reducing oxidative stress.PMID:36581160 | DOI:10.1016/j.jep.2022.116095

Int J Biol Macromol. 2022 Dec 26:S0141-8130(22)03155-5. doi: 10.1016/j.ijbiomac.2022.12.244. Online ahead of print.ABSTRACTSpirulina polysaccharides (PSP) possess significant biological properties. However, it is still a lack of investigation on the anti-colorectal cancer effect and mechanism. In this study, PSP showed significant effects on LoVo cell spheroids with an IC50 value of 0.1943 mg/mL. The analysis of transcriptomics and metabolomics indicated the impact of PSP on LoVo spheroid cells through involvement in the two pathways of "glycine, serine, and threonine metabolism" and "ABC transporters". And, the q-PCR data further verified the pointed mechanism of PSP on colon cancer (CC) by regulating the expression levels of relevant genes in the synthesis pathways of serine and glycine in tumor cells. Furthermore, the anti-colon cancer effects of PSP were verified via other human colon cancer cell lines HCT116 and HT29 spheroids (IC50 = 0.0646 mg/mL and 0.2213 mg/mL, respectively), and three patient-derived organoids (PDOs) with IC50 values ranging from 3.807 to 7.788 mg/mL. In addition, this study found that a mild concentration of PSP cannot enhance the anti-tumor effect of 5-Fu. And a significant inhibition was found of PSP in 5-Fu resistance organoids. These results illustrated that PSP could be a treatment or supplement for 5-Fu resistant colorectal cancer (CRC).PMID:36581031 | DOI:10.1016/j.ijbiomac.2022.12.244

Environ Res. 2022 Dec 26:115161. doi: 10.1016/j.envres.2022.115161. Online ahead of print.ABSTRACTSoluble extracellular metabolites (SEM) produced by microorganisms might significantly change during sludge bulking, which is a major operational problem caused by the excessive growth of filamentous bacteria. However, knowledge remains limited about the dynamics and potential role of SEM in the bulking of sludge. In this study, filamentous bulking was simulated in a laboratory-scale reactor and changes to SEM characteristics during the bulking process were investigated using excitation-emission matrix spectroscopy and ultrahigh-performance liquid chromatography-mass spectrometry. SEM components changed significantly at different phases of sludge bulking. Changes in SEM were closely correlated with the structure of the bacterial community. Based on the EEM profiles, significant increases in fulvic acid-like and humic acid-like substances in SEM were observed with the development of filamentous bulking. The degree of humification in SEM showed a clear increasing trend. Untargeted extracellular metabolomic analysis showed that the intensity of berberine and isorhamnetin in SEM increased significantly during the bulking phase, which might synergistically facilitate the development of filamentous bulking.PMID:36580981 | DOI:10.1016/j.envres.2022.115161

Biosens Bioelectron. 2022 Dec 16;223:114966. doi: 10.1016/j.bios.2022.114966. Online ahead of print.ABSTRACTEffective isolation and in-depth analysis of Circulating Tumour Cells (CTCs) are greatly needed in diagnosis, prognosis and monitoring of the therapeutic response of cancer patients but have not been completely fulfilled by conventional approaches. The rarity of CTCs and the lack of reliable biomarkers to distinguish them from peripheral blood cells have remained outstanding challenges for their clinical implementation. Herein, we developed a high throughput Static Droplet Microfluidic (SDM) device with 38,400 chambers, capable of isolating and classifying the number of metabolically active CTCs in peripheral blood at single-cell resolution. Owing to the miniaturisation and compartmentalisation capability of our device, we first demonstrated the ability to precisely measure the lactate production of different types of cancer cells inside 125 pL droplets at single-cell resolution. Furthermore, we compared the metabolomic activity of leukocytes from healthy donors to cancer cells and showed the ability to differentiate them. To further prove the clinical relevance, we spiked cancer cell lines in human healthy blood and showed the possibility to detect the cancer cells from leukocytes. Lastly, we tested the workflow on 8 preclinical mammary mouse models including syngeneic 67NR (non-metastatic) and 4T1.2 (metastatic) models with Triple-Negative Breast Cancer (TNBC) as well as transgenic mouses (12-week-old MMTV-PyMT). The results have shown the ability to precisely distinguish metabolically active CTCs from the blood using the proposed SDM device. The workflow is simple and robust which can eliminate the need for specialised equipment and expertise required for single-cell analysis of CTCs and facilitate on-site metabolic screening of cancer cells.PMID:36580816 | DOI:10.1016/j.bios.2022.114966

Proc Natl Acad Sci U S A. 2023 Jan 3;120(1):e2208525120. doi: 10.1073/pnas.2211155120. Epub 2022 Dec 29.ABSTRACTDimethylated histone H3 Lys9 (H3K9me2) is a conserved heterochromatic mark catalyzed by SUPPRESSOR OF VARIEGATION 3-9 HOMOLOG (SUVH) methyltransferases in plants. However, the mechanism underlying the locus specificity of SUVH enzymes has long been elusive. Here, we show that a conserved N-terminal motif is essential for SUVH6-mediated H3K9me2 deposition in planta. The SUVH6 N-terminal peptide can be recognized by the bromo-adjacent homology (BAH) domain of the RNA- and chromatin-binding protein ANTI-SILENCING 1 (ASI1), which has been shown to function in a complex to confer gene expression regulation. Structural data indicate that a classic aromatic cage of ASI1-BAH domain specifically recognizes an arginine residue of SUVH6 through extensive hydrogen bonding interactions. A classic aromatic cage of ASI1 specifically recognizes an arginine residue of SUVH6 through extensive cation-π interactions, playing a key role in recognition. The SUVH6-ASI1 module confers locus-specific H3K9me2 deposition at most SUVH6 target loci and gives rise to distinct regulation of gene expression depending on the target loci, either conferring transcriptional silencing or posttranscriptional processing of mRNA. More importantly, such mechanism is conserved in multiple plant species, indicating a coordinated evolutionary process between SUVH6 and ASI1. In summary, our findings uncover a conserved mechanism for the locus specificity of H3K9 methylation in planta. These findings provide mechanistic insights into the delicate regulation of H3K9 methylation homeostasis in plants.PMID:36580600 | DOI:10.1073/pnas.2211155120

J Gerontol A Biol Sci Med Sci. 2022 Dec 29;77(12):2367-2372. doi: 10.1093/gerona/glab315.ABSTRACTDysregulation of energy producing metabolic pathways has been observed in older adults with frailty. In this study, we used liquid chromatography-mass spectrometry technology to identify aging- and frailty-related differences in metabolites involved in glycolysis, the tricarboxylic (TCA) cycle, and other energy metabolism-related pathways in the serum of a cohort of community-dwelling adults aged 20-97 (n = 146). We also examined the relationship between serum levels of metabolites and functional measures, physical frailty, and risk status for adverse health outcomes. We observed elevated levels of TCA cycle and glycolytic intermediates in frail subjects; however, the differences in the levels of ATP and other energy metabolites between young, nonfrail, and frail adults were not significant. Instead, we found that serum levels of neurotransmitters N-acetyl-aspartyl-glutamate, glutamate, and γ-aminobutyric acid were significantly elevated in older adults with frailty. These elevations of glycolytic and TCA cycle intermediates, and neurotransmitters may be part of the biological signature of frailty.PMID:36580380 | DOI:10.1093/gerona/glab315

Autophagy. 2022 Dec 29:1-4. doi: 10.1080/15548627.2022.2160565. Online ahead of print.ABSTRACTDBI/ACBP (diazepam binding inhibitor, acyl-CoA binding protein) is a phylogenetically conserved paracrine inhibitor of macroautophagy/autophagy. As such, DBI/ACBP acts as a pro-aging molecule. Indeed, we observed that the knockout of ACB1 (the yeast equivalent of human DBI/ACBP) induces autophagy and prolongs lifespan in an autophagy-dependent fashion in chronological lifespan experiments. Intriguingly, circulating DBI/ACBP protein augments with age in humans, and this increase occurs independently from the known correlation of DBI/ACBP with body mass index (BMI). A supraphysiological DBI/ACBP level announces future cardiovascular disease (such as heart surgery, myocardial infarction and stroke) in still healthy individuals, suggesting that, beyond its correlation with chronological age, DBI/ACBP is a biomarker of biological age. Plasma DBI/ACBP concentrations correlate with triglycerides and anticorrelate with high-density lipoprotein. Of note, these associations with cardiovascular risk factors are independent from age and BMI in a multivariate regression model. In mice, we found that antibody-mediated neutralization of DBI/ACBP reduces signs of anthracycline-accelerated cardiac aging including the upregulation of the senescence marker CDKN2A/p16 (cyclin dependent kinase inhibitor 2A) and the functional decline of the heart. In conclusion, it appears that extracellular DBI/ACBP can be targeted to combat age-associated cardiovascular disease.Abbreviations: BMI: body mass index; CDKN2A/p16: cyclin dependent kinase inhibitor 2A; CVD: cardiovascular disease; DBI/ACBP: diazepam binding inhibitor, acyl-CoA binding protein; ELISA: enzyme-linked immunosorbent assay; GABA: gamma-aminobutyric acid; GABR: gamma-aminobutyric acid type A receptor.PMID:36579946 | DOI:10.1080/15548627.2022.2160565

Eur J Clin Invest. 2022 Dec 28:e13943. doi: 10.1111/eci.13943. Online ahead of print.ABSTRACTBACKGROUND: The HIV viral protein R (Vpr) is a multifunction protein involved in the pathophysiology of HIV-1. Recent evidence has suggested that Vpr amino acid substitutions influence the pathophysiology of HIV-1 and clinical outcomes in people living with HIV (PLWH). Several studies have linked Vpr amino acid substitutions to clinical outcomes in PLWH, however, there is no clear consensus as to which amino acids or amino acid substitutions are most important in the pathophysiology and clinical outcomes in PLWH. We, therefore, conducted a systematic review of studies investigating Vpr amino acid substitutions and clinical outcomes in PLWH.METHODS: PubMed, Scopus, and Web of Science databases were searched according to PRISMA guidelines using a search protocol designed specifically for this study.RESULTS: A total of twenty-two studies were included for data extraction, comprising fourteen cross-sectional and eight longitudinal studies. Results indicated that Vpr amino acid substitutions were associated with specific clinical outcomes including disease progressions, neurological outcomes, treatment status, and other clinical manifestations. Studies consistently showed that the Vpr substitution 63T was associated with slower disease progression, whereas 77H and 85P were associated with no significant contribution to disease progression.CONCLUSIONS: Vpr-specific amino acid substitutions may be contributors to clinical outcomes in PLWH, and future studies should consider investigating the Vpr amino acid substitutions highlighted in this review.PMID:36579370 | DOI:10.1111/eci.13943

Front Genet. 2022 Dec 12;13:1046192. doi: 10.3389/fgene.2022.1046192. eCollection 2022.ABSTRACTBovine respiratory disease (BRD) is the most common and costly infectious disease affecting the wellbeing and productivity of beef cattle in North America. BRD is a complex disease whose development is dependent on environmental factors and host genetics. Due to the polymicrobial nature of BRD, our understanding of the genetic and molecular mechanisms underlying the disease is still limited. This knowledge would augment the development of better genetic/genomic selection strategies and more accurate diagnostic tools to reduce BRD prevalence. Therefore, this study aimed to utilize multi-omics data (genomics, transcriptomics, and metabolomics) analyses to study the genetic and molecular mechanisms of BRD infection. Blood samples of 143 cattle (80 BRD; 63 non-BRD animals) were collected for genotyping, RNA sequencing, and metabolite profiling. Firstly, a genome-wide association study (GWAS) was performed for BRD susceptibility using 207,038 SNPs. Two SNPs (Chr5:25858264 and BovineHD1800016801) were identified as associated (p-value <1 × 10-5) with BRD susceptibility. Secondly, differential gene expression between BRD and non-BRD animals was studied. At the significance threshold used (log2FC>2, logCPM>2, and FDR<0.01), 101 differentially expressed (DE) genes were identified. These DE genes significantly (p-value <0.05) enriched several immune responses related functions such as inflammatory response. Additionally, we performed expression quantitative trait loci (eQTL) analysis and identified 420 cis-eQTLs and 144 trans-eQTLs significantly (FDR <0.05) associated with the expression of DE genes. Interestingly, eQTL results indicated the most significant SNP (Chr5:25858264) identified via GWAS was a cis-eQTL for DE gene GPR84. This analysis also demonstrated that an important SNP (rs209419196) located in the promoter region of the DE gene BPI significantly influenced the expression of this gene. Finally, the abundance of 31 metabolites was significantly (FDR <0.05) different between BRD and non-BRD animals, and 17 of them showed correlations with multiple DE genes, which shed light on the interactions between immune response and metabolism. This study identified associations between genome, transcriptome, metabolome, and BRD phenotype of feedlot crossbred cattle. The findings may be useful for the development of genomic selection strategies for BRD susceptibility, and for the development of new diagnostic and therapeutic tools.PMID:36579334 | PMC:PMC9790935 | DOI:10.3389/fgene.2022.1046192