PubMed

J Gen Virol. 2023 Feb;104(2). doi: 10.1099/jgv.0.001828.ABSTRACTPeste des petits ruminants virus (PPRV) is a highly contagious morbillivirus related to measles and canine distemper virus, mostly affecting small ruminants. The corresponding PPR disease has a high clinical impact in goats and is characterized by fever, oral and nasal erosions, diarrhoea and pneumonia. In addition, massive infection of lymphoid tissues causes lymphopaenia and immune suppression. This results in increased susceptibility to secondary bacterial infections, explaining the observed high mortality in some outbreaks. We studied the pathogenesis of PPR by experimental inoculation of Dutch domestic goats with a recombinant virulent PPRV strain modified to express EGFP and compared it to an EGFP-expressing vaccine strain of PPRV. After intratracheal inoculation with virulent PPRV, animals developed fever, viraemia and leucopaenia, and shed virus from the respiratory and gastro-intestinal tracts. Macroscopic evaluation of fluorescence at the peak of infection 7 days post-inoculation (dpi) showed prominent PPRV infection of the respiratory tract, lymphoid tissues, gastro-intestinal tract, mucosae and skin. Flow cytometry of PBMCs collected over time demonstrated a cell-associated viraemia mediated by infected lymphocytes. At 14 dpi, pathognomonic zebra stripes were detected in the mucosa of the large intestine. In contrast, vaccine strain-inoculated goats remained largely macroscopically fluorescence negative and did not present clinical signs. A low-level viraemia was detected by flow cytometry, but at necropsy no histological lesions were observed. Animals from both groups seroconverted as early as 7 dpi and sera efficiently neutralized virulent PPRV in vitro. Combined, this work presents a study of the pathogenesis of wild type- and vaccine-based PPRV in its natural host. This study shows the strength of recombinant EGFP-expressing viruses in fluorescence-guided pathogenesis studies.PMID:36757863 | DOI:10.1099/jgv.0.001828

J Gerontol A Biol Sci Med Sci. 2023 Feb 9:glad017. doi: 10.1093/gerona/glad017. Online ahead of print.ABSTRACTCalorie restriction (CR) extends lifespan by modulating the mechanisms involved in aging. We quantified the hepatic proteome of male C57BL/6 mice exposed to graded levels of CR (0% to 40% CR) for three months, and evaluated which signaling pathways were most affected. The metabolic pathways most significantly stimulated by the increase in CR, included the glycolysis/gluconeogenesis pathway, the pentose phosphate pathway, the fatty acid degradation pathway, the valine, leucine and isoleucine degradation pathway and the lysine degradation pathway. The metabolism of xenobiotics by cytochrome P450 pathway was activated and feminized by increased CR, while production in major urinary proteins (Mups) was strongly reduced, consistent with a reduced investment in reproduction as predicted by the disposable soma hypothesis. However, we found no evidence of increased somatic protection, and none of the four main pathways implied to be linked to the impact of CR on lifespan (insulin/IGF-1, NF-kB, mTOR and sirtuins) as well as pathways in cancer, were significantly changed at the protein level in relation to the increase in CR level. This was despite previous work at the transcriptome level in the same individuals indicating such changes. On the other hand, we find Aldh2, Aldh3a2 and Aldh9a1 in carnitine biosynthesis and Acsl5 in carnitine shuttle system were up-regulated by increased CR, which are consistent with our previous work on metabolome of the same individuals. Overall the patterns of protein expression were more consistent with a 'clean cupboards' than a 'disposable soma' interpretation.PMID:36757838 | DOI:10.1093/gerona/glad017

RSC Adv. 2023 Jan 31;13(6):4121. doi: 10.1039/d3ra90008h. eCollection 2023 Jan 24.ABSTRACT[This retracts the article DOI: 10.1039/C7RA08823J.].PMID:36757294 | PMC:PMC9890521 | DOI:10.1039/d3ra90008h

Int J Cancer. 2023 Feb 9. doi: 10.1002/ijc.34466. Online ahead of print.ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies, which is featured by systematic metabolism. Thus, a better understanding of metabolic dysregulation in PDAC is important to better characterize its etiology. Here, we performed a large metabolome-wide association study (MWAS) to systematically explore associations between genetically predicted metabolite levels in blood and PDAC risk. Using data from 881 subjects of European descent in the TwinsUK Project, comprehensive genetic models were built to predict serum metabolite levels. These prediction models were applied to the genetic data of 8,280 cases and 6,728 controls included in the PanScan (I, II, and III) and PanC4 consortia. After assessing the metabolite-PDAC risk associations by a slightly modified TWAS/FUSION framework, we identified five metabolites (including two dipeptides) showing significant associations with PDAC risk at false discovery rate (FDR)<0.05. Integrated with gut microbial information, two-sample Mendelian randomization (MR) analyses were further performed to investigate the relationship among serum metabolites, gut microbiome features, and PDAC. The flavonoid-degrading bacteria Flavonifractor sp90199495 was found to be associated with metabolite X - 21849, and it was also shown to be associated with PDAC risk. Collectively, our study identified novel candidate metabolites for PDAC risk, which could lead to new insights into the etiology of PDAC and improved treatment options.PMID:36757187 | DOI:10.1002/ijc.34466

Food Funct. 2023 Feb 9. doi: 10.1039/d2fo03975c. Online ahead of print.ABSTRACTInflammatory bowel disease (IBD) is a global health problem in which metabolite alteration plays an important pathogenic role. Bovine milk-derived extracellular vesicles (mEVs) have been shown to regulate nutrient metabolism in healthy animal models. This study investigated the effect of oral mEVs on metabolite changes in DSS-induced murine colitis. We performed metabolomic profiling on plasma samples and measured the concentrations of lipids and amino acids in both fecal samples and colonic tissues. Plasma metabolome analysis found that mEVs significantly upregulated 148 metabolite levels and downregulated 44 metabolite concentrations (VIP > 1, and p < 0.05). In the fecal samples, mEVs significantly increased the contents of acetate and butyrate and decreased the levels of tridecanoic acid (C13:0), methyl cis-10-pentadecenoate (C15:1) and cis-11-eicosenoic acid (C20:1). Moreover, the concentrations of eicosadienoic acid (C20:2), eicosapentaenoic acid (C20:5), and docosahexaenoic acid (C22:6) were decreased in colonic tissues with mEV supplementation. In addition, compared with the DSS group, mEVs significantly increased the content of L-arginine, decreased the level of L-valine in the fecal samples, and also decreased the levels of L-serine and L-glutamate in the colonic tissues. Collectively, our findings demonstrated that mEVs could recover the metabolic abnormalities caused by inflammation and provided novel insights into mEVs as a potential modulator for metabolites to prevent and treat IBD.PMID:36757176 | DOI:10.1039/d2fo03975c

Front Microbiomes. 2022;1:986951. doi: 10.3389/frmbi.2022.986951. Epub 2022 Nov 30.ABSTRACTINTRODUCTION: Mild traumatic brain injury (mTBI) has been shown to negatively alter bacterial diversity and composition within the gut, known as dysbiosis, in rodents and humans. These changes cause secondary consequences systemically through decreased bacterial metabolites such as short chain fatty acids (SCFAs) which play a role in inflammation and metabolism. The goal of the study was to identify if giving prebiotic inulin prior to closed head injury (CHI) could mitigate gut dysbiosis, increase SCFAs, and improve recovery outcomes, including protecting cerebral blood flow (CBF) and white matter integrity (WMI) in young mice.METHODS: We fed mice at 2 months of age with either inulin or control diet (with cellulose as fiber source) for two months before the CHI and continued till the end of the study. We analyzed gut microbiome composition and diversity, determined SCFAs levels, and measured CBF and WMI using MRI. We compared the results with Naïve and Sham-injury mice at 24 hours, 1.5 months, and 3-4 months post-injury.RESULTS: We found that both CHI and Sham mice had time-dependent changes in gut composition and diversity after surgery. Inulin significantly reduced the abundance of pathobiont bacteria, such as E. coli, Desulfovibrio spp and Pseudomonas aeruginosa, in Sham and CHI mice compared to mice fed with control diet. On the other hand, inulin increased SCFAs-producing bacteria, such as Bifidobacterium spp and Lactobacillus spp, increased levels of SCFAs, including butyrate and propionate, and significantly altered beta diversity as early as 24 hours post-injury, which lasted up to 3-4 months post-injury. The mitigation of dysbiosis is associated with protection of WMI in fimbria, internal and external capsule, and CBF in the right hippocampus of CHI mice, suggesting protection of memory and cognitive functions.DISCUSSION: The results indicate that giving inulin prior to CHI could promote recovery outcome through gut microbiome modulation. As inulin, microbiome analysis, and MRI are readily to be used in humans, the findings from the study may pave a way for a cost-effective, accessible intervention for those at risk of sustaining a head injury, such as military personnel or athletes in contact sports.PMID:36756543 | PMC:PMC9903356 | DOI:10.3389/frmbi.2022.986951

Afr J Infect Dis. 2022 Dec 22;17(1):60-73. doi: 10.21010/Ajidv17i1.6. eCollection 2023.ABSTRACTBACKGROUND: Despite the available treatment options, pulmonary tuberculosis (TB) remains a leading cause of disease-related deaths worldwide. Treatment non-adherence/lost to follow-up (LTFU), particularly in developing countries, is a continuous concern. LTFU prolongs TB infectiousness and contributes to TB treatment failure, relapse, and death. Furthermore, LTFU also delays global TB eradication by promoting TB spread and drug-resistant TB strain development.[1] The purpose of this paper is to give an overview of the commonly observed risk factors associated with TB treatment LTFU in developing countries.MATERIALS AND METHODS: A literature survey was done of studies published in the past decade, which evaluated the risk factors for LTFU in TB patients, specifically in developing countries. Furthermore, some prospective TB treatment adherence initiatives and the feasibility of these initiatives within developing countries were assessed.[3].RESULTS: Several variables, including socio-demographic, patient-related, TB disease and other health-related-factors, healthcare and system determinants, as well as treatment-related factors, were identified to increase the risk of TB treatment LTFU. More recently applied adherence interventions in developing countries, show potential for implementation on a larger scale.CONCLUSION: Successful TB treatment is contingent on treatment adherence, and by addressing these persisting LTFU risk factors, treatment adherence in developing countries may be improved.PMID:36756489 | PMC:PMC9885020 | DOI:10.21010/Ajidv17i1.6

iScience. 2023 Jan 14;26(2):105987. doi: 10.1016/j.isci.2023.105987. eCollection 2023 Feb 17.ABSTRACTMethionine adenosyltransferase 1a (MAT1A) is responsible for hepatic S-adenosyl-L-methionine (SAMe) biosynthesis. Mat1a -/- mice have hepatic SAMe depletion, develop nonalcoholic steatohepatitis (NASH) which is reversed with SAMe administration. We examined temporal alterations in the proteome/phosphoproteome in pre-disease and NASH Mat1a -/- mice, effects of SAMe administration, and compared to human nonalcoholic fatty liver disease (NAFLD). Mitochondrial and peroxisomal lipid metabolism proteins were altered in pre-disease mice and persisted in NASH Mat1a -/- mice, which exhibited more progressive alterations in cytoplasmic ribosomes, ER, and nuclear proteins. A common mechanism found in both pre-disease and NASH livers was a hyperphosphorylation signature consistent with casein kinase 2α (CK2α) and AKT1 activation, which was normalized by SAMe administration. This was mimicked in human NAFLD with a metabolomic signature (M-subtype) resembling Mat1a -/- mice. In conclusion, we have identified a common proteome/phosphoproteome signature between Mat1a -/- mice and human NAFLD M-subtype that may have pathophysiological and therapeutic implications.PMID:36756374 | PMC:PMC9900401 | DOI:10.1016/j.isci.2023.105987

Front Plant Sci. 2023 Jan 13;13:1083971. doi: 10.3389/fpls.2022.1083971. eCollection 2022.ABSTRACTHeat stress drastically affects anther tissues resulting in poor plant fertility, necessitating an urgent need to determine the key proteome regulation associated with mature anther in response to heat stress. We identified several genotype - specific protein alterations in rice anthers of Moroberekan (Japonica, heat sensitive), IR64 (Indica, moderately heat tolerant), and Nagina22 (Aus, heat tolerant) in the short-term (ST_HS; one cycle of 42°C, 4 hours before anthesis) and long-term (LT_HS; 6 cycles of 38°C, 6 hours before anthesis) heat stress. The proteins upregulated in long-term heat stress in Nagina22 were enriched in biological processes related to unfolded protein binding and carboxylic acid metabolism, including amino acid metabolism. In short-term heat stress, Nagina22 anthers were enriched in proteins associated with vitamin E biosynthesis and GTPase activator activity. In contrast, downregulated proteins were related to ribosomal proteins. The expression of different Hsp20 and DnaJ was genotype specific. Overall, the heat response in Nagina22 was associated with its capacity for adequate metabolic control and cellular homeostasis, which may be critical for its higher reproductive thermotolerance. This study improves our understanding of thermotolerance mechanisms in rice anthers during anthesis and lays a foundation for breeding thermotolerant varieties via molecular breeding.PMID:36756226 | PMC:PMC9901367 | DOI:10.3389/fpls.2022.1083971

Front Oncol. 2023 Jan 23;13:1082841. doi: 10.3389/fonc.2023.1082841. eCollection 2023.ABSTRACTINTRODUCTION: The goal of this study was to establish an optimized metabolic panel by combining serum and urine biomarkers that could reflect the malignancy of cancer tissues to improve the non-invasive diagnosis of esophageal squamous cell cancer (ESCC).METHODS: Urine and serum specimens representing the healthy and ESCC individuals, together with the paralleled ESCC cancer tissues and corresponding distant non-cancerous tissues were investigated in this study using the high-resolution 600 MHz 1H-NMR technique.RESULTS: We identified distinct 1H NMR-based serum and urine metabolic signatures respectively, which were linked to the metabolic profiles of esophageal-cancerous tissues. Creatine and glycine in both serum and urine were selected as the optimal biofluids biomarker panel for ESCC detection, as they were the overlapping discriminative metabolites across serum, urine and cancer tissues in ESCC patients. Also, the were the major metabolites involved in the perturbation of "glycine, serine, and threonine metabolism", the significant pathway alteration associated with ESCC progression. Then a visual predictive nomogram was constructed by combining creatine and glycine in both serum and urine, which exhibited superior diagnostic efficiency (with an AUC of 0.930) than any diagnostic model constructed by a single urine or serum metabolic biomarkers.DISCUSSION: Overall, this study highlighted that NMR-based biofluids metabolomics fingerprinting, as a non-invasive predictor, has the potential utility for ESCC detection. Further studies based on a lager number size and in combination with other omics or molecular biological approaches are needed to validate the metabolic pathway disturbances in ESCC patients.PMID:36756157 | PMC:PMC9900168 | DOI:10.3389/fonc.2023.1082841

Front Immunol. 2023 Jan 23;14:1099186. doi: 10.3389/fimmu.2023.1099186. eCollection 2023.ABSTRACTThe mitigation and prevention of acute immune stress are essential for livestock production. Clostridium butyricum (C. butyricum) has shown positive effects in stabilizing intestinal microbiota disorders, improving immune function and inhibiting disease development, but its effects on ruminants are unclear. Therefore, the current trial hypothesized that C. butyricum could improve goats' immune function and antioxidant capacity by regulating bacterial communities and blood metabolism and effectively alleviating the acute immune stress induced by Lipopolysaccharides (LPS). Sixteen healthy goats were fed C. butyricum for 70 days, and the goats were challenged with LPS on day 71. Blood and feces were collected at 0 h and 6 h after the challenge to evaluate the effects of C. butyricum on their intestinal microbiota, immune function, antioxidant function, and plasma metabolites. The results showed that C. butyricum had no significant effect on plasma biochemical parameters at the beginning of the LPS challenge. However, supplementation with C. butyricum increased plasma levels of IgA, IgG, T-SOD, and T-AOC (P < 0.05), but TNF-α, IL-6, and MDA were decreased (P < 0.05). In contrast, IL-10 showed an increasing trend (P < 0.10). Rectal microbiota analysis showed that C. butyricum significantly increased the relative abundance of Epsilonbacteraeota at the phylum level of goats; at the genus level, the relative abundances of Campylobacter and Anaerorhabdus]_furcosa_group were also significantly increased (P < 0.05). Christensenellaceae_R-7_group as the dominant microbiota also showed a significant increase in their abundance values, while Clostridium and Lachnospiraceae_UCG-001 were significantly lower (P < 0.05). When the LPS challenge continued up to 6 h, dietary supplementation with C. butyricum still resulted in significantly higher plasma concentrations of IgA, IL-10, and T-SOD in goats than in the control group, reducing TNF-α levels (P < 0.05). In addition, plasma levels of T-CHOL and LDL were significantly reduced, and the expression of d-proline was significantly upregulated according to metabolomic analysis (P < 0.05). In conclusion, dietary supplementation with C. butyricum helped optimize the expression of bacterial communities and plasma metabolites to enhance the ability of goats to alleviate acute immune stress.PMID:36756118 | PMC:PMC9899838 | DOI:10.3389/fimmu.2023.1099186

Front Nutr. 2023 Jan 23;10:1118113. doi: 10.3389/fnut.2023.1118113. eCollection 2023.ABSTRACTAIM: Evidence linking dietary patterns and the risk of gastric cancer was limited, especially in Chinese populations. This study aimed to explore the association between dietary patterns and the risk of gastric cancer in residents of the Huaihe River Basin, China.METHODS: The association between dietary patterns and the risk of gastric cancer was investigated through a case-control study. Dietary patterns were identified with factor analysis based on responses to a food frequency questionnaire (FFQ). Gastric cancer was diagnosed according to the International Classification of Diseases, 10th Revision (ICD 10). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated across the tertiles of dietary pattern scores using unconditional logistic regression models.RESULTS: A total of 2,468 participants were included in this study. Six main dietary patterns were extracted, and those patterns explained 57.09% of the total variation in food intake. After adjusting for demographic characteristics, lifestyle factors, individual disease history, family history of cancer and Helicobacter. Pylori (H. pylori) infection, comparing the highest with the lowest tertiles of dietary pattern scores, the multivariable ORs (95% CIs) were 0.786 (0.488, 1.265; P trend < 0.001) for the flavors, garlic and protein pattern, 2.133 (1.299, 3.502; P trend < 0.001) for the fast food pattern, 1.050 (0.682, 1.617; P trend < 0.001) for the vegetable and fruit pattern, 0.919 (0.659, 1.282; P trend < 0.001) for the pickled food, processed meat products and soy products pattern, 1.149 (0.804, 1.642; P trend < 0.001) for the non-staple food pattern and 0.690 (0.481, 0.989; P trend < 0.001) for the coffee and dairy pattern.CONCLUSIONS: The specific dietary patterns were associated with the risk of gastric cancer. This study has implications for the prevention of gastric cancer.PMID:36755993 | PMC:PMC9899829 | DOI:10.3389/fnut.2023.1118113

Front Pharmacol. 2023 Jan 23;14:1104403. doi: 10.3389/fphar.2023.1104403. eCollection 2023.ABSTRACTObjective: Leonurine is a bioactive alkaloid compound extracted from Leonurus japonicus Houtt, which potentially has immunomodulatory effects. The immunomodulatory effect and mechanism of leonurine on monocyte derived dendritic cells (moDCs) from healthy donors (HDs) and multiple myeloma (MM) patients were investigated for the first time. Methods: Peripheral blood from HDs and MM patients was isolated for peripheral blood mononuclear cells (PBMCs). The generation of moDCs was conducted by the incubation of monocytes from PBMCs in the medium consisting of RPMI 1640 medium, 2 mmol/L L-glutamine, 5% human serum, 800 U/mL GM-CSF, 500 U/mL IL-4, 100 U/mL penicillin and 0.1 mg/mL streptomycin. During the incubation of 7 days, the cells were administrated with 1 μM leonurine or 1 × PBS as the control group. On the 8th day, cells were harvested. The expression of maturation associated surface markers CD40, CD83, and HLA-DR on moDCs was analyzed by flow cytometry. Moreover, moDCs with or without 1 μM leonurine administration were evaluated by LC-MS/MS for metabolomics which was further analyzed for the potential mechanism of leonurine on moDCs. Results: The proportion of moDCs in the harvested cells was significantly higher in the HD group (n = 14) than in the MM patient group (n = 11) (p = 0.000). Leonurine significantly enhanced the median fluorescence intensity of CD83, HLA-DR and CD40 expression on HD-moDCs (n = 14; p = 0.042, p = 0.013, p = 0.084) as well as MM paitent-moDCs (n = 11; p = 0.020, p = 0.006, p = 0.025). The metabolomics data showed that in moDCs (HD, n = 15), 18 metabolites in the pathway of arachidonic acid metabolism showed significant differences between the leonurine group and the control group (VIP all >1 and P all <0.05). To be specific, 6-Keto-PGE1, 8,9-DHET, 11 (R)-HETE, 12-Keto-LTB4, 12-OxoETE, 15 (S)-HETE, 15-Deoxy-Delta12,14-PGJ2, 15-Keto-PGF2a, 20-COOH-LTB4, Lecithin, PGA2, PGB2, PGE2, PGF2a, PGG2, Prostacyclin were significantly upregulated in the leonurine group than in the control group, while Arachidonic Acid and TXB2 were significantly downregulated in the leonurine group than in the control group. Conclusion: Leonurine significantly promotes the maturation of moDCs derived from HDs and MM patients, the mechanism of which is related to arachidonic acid metabolism.PMID:36755947 | PMC:PMC9899801 | DOI:10.3389/fphar.2023.1104403

Nat Protoc. 2023 Feb 8. doi: 10.1038/s41596-023-00803-0. Online ahead of print.ABSTRACTAnalytical techniques with high sensitivity and selectivity are essential to the quantitative analysis of clinical samples. Liquid chromatography coupled to tandem mass spectrometry is the gold standard in clinical chemistry. However, tandem mass spectrometers come at high capital expenditure and maintenance costs. We recently showed that it is possible to generate very similar results using a much simpler single mass spectrometry detector by performing enhanced in-source fragmentation/annotation (EISA) combined with correlated ion monitoring. Here we provide a step-by-step protocol for optimizing the analytical conditions for EISA, so anyone properly trained in liquid chromatography-mass spectrometry can follow and apply this technique for any given analyte. We exemplify the approach by using 2-hydroxyglutarate (2-HG) which is a clinically relevant metabolite whose D-enantiomer is considered an 'oncometabolite', characteristic of cancers associated with mutated isocitrate dehydrogenases 1 or 2 (IDH1/2). We include procedures for determining quantitative robustness, and show results of these relating to the analysis of DL-2-hydroxyglutarate in cells, as well as in serum samples from patients with acute myeloid leukemia that contain the IDH1/2 mutation. This EISA-mass spectrometry protocol is a broadly applicable and low-cost approach for the quantification of small molecules that has been developed to work well for both single-quadrupole and time-of-flight mass analyzers.PMID:36755131 | DOI:10.1038/s41596-023-00803-0

NPJ Biofilms Microbiomes. 2023 Feb 8;9(1):8. doi: 10.1038/s41522-023-00374-8.ABSTRACTAlthough emerging evidence shows that gut microbiota-mediated metabolic changes regulate intestinal pathogen invasions, little is known about whether and how gut microbiota-mediated metabolites affect pathogen infection in the distal organs. In this study, untargeted metabolomics was performed to identify the metabolic changes in a subacute ruminal acidosis (SARA)-associated mastitis model, a mastitis model with increased susceptibility to Staphylococcus aureus (S. aureus). The results showed that cows with SARA had reduced cholic acid (CA) and deoxycholic acid (DCA) levels compared to healthy cows. Treatment of mice with DCA, but not CA, alleviated S. aureus-induced mastitis by improving inflammation and the blood-milk barrier integrity in mice. DCA inhibited the activation of NF-κB and NLRP3 signatures caused by S. aureus in the mouse mammary epithelial cells, which was involved in the activation of TGR5. DCA-mediated TGR5 activation inhibited the NF-κB and NLRP3 pathways and mastitis caused by S. aureus via activating cAMP and PKA. Moreover, gut-dysbiotic mice had impaired TGR5 activation and aggravated S. aureus-induced mastitis, while restoring TGR5 activation by spore-forming bacteria reversed these changes. Furthermore, supplementation of mice with secondary bile acids producer Clostridium scindens also activated TGR5 and alleviated S. aureus-induced mastitis in mice. These results suggest that impaired secondary bile acid production by gut dysbiosis facilitates the development of S. aureus-induced mastitis and highlight a potential strategy for the intervention of distal infection by regulating gut microbial metabolism.PMID:36755021 | DOI:10.1038/s41522-023-00374-8

Nat Commun. 2023 Feb 8;14(1):697. doi: 10.1038/s41467-023-36368-5.ABSTRACTHuman acetyltransferases MOZ and MORF are implicated in chromosomal translocations associated with aggressive leukemias. Oncogenic translocations involve the far amino terminus of MOZ/MORF, the function of which remains unclear. Here, we identified and characterized two structured winged helix (WH) domains, WH1 and WH2, in MORF and MOZ. WHs bind DNA in a cooperative manner, with WH1 specifically recognizing unmethylated CpG sequences. Structural and genomic analyses show that the DNA binding function of WHs targets MORF/MOZ to gene promoters, stimulating transcription and H3K23 acetylation, and WH1 recruits oncogenic fusions to HOXA genes that trigger leukemogenesis. Cryo-EM, NMR, mass spectrometry and mutagenesis studies provide mechanistic insight into the DNA-binding mechanism, which includes the association of WH1 with the CpG-containing linker DNA and binding of WH2 to the dyad of the nucleosome. The discovery of WHs in MORF and MOZ and their DNA binding functions could open an avenue in developing therapeutics to treat diseases associated with aberrant MOZ/MORF acetyltransferase activities.PMID:36754959 | DOI:10.1038/s41467-023-36368-5

Gut. 2023 Feb 8:gutjnl-2022-329297. doi: 10.1136/gutjnl-2022-329297. Online ahead of print.NO ABSTRACTPMID:36754608 | DOI:10.1136/gutjnl-2022-329297

Sci Total Environ. 2023 Feb 6:162042. doi: 10.1016/j.scitotenv.2023.162042. Online ahead of print.ABSTRACTWater quality and phytoplankton community composition are important factors that can indicate freshwater ecosystem health. We combined water quality, phytoplankton community, and metabolomic data from algae and water sampled from two embayments in Lake Ontario, Hamilton Harbour and the Bay of Quinte, over ten weeks from August to October in the year 2020. Metabolomics was performed using liquid chromatography tandem mass spectroscopy (LC-MS/MS) to identify changes in intracellular metabolites within algae communities over time, and Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) was used to characterize putative isomers of extracellular metabolites at sub-ppb mass accuracy. Results from this study indicate that Hamilton Harbour and the Bay of Quinte are two very different ecosystems with respect to water quality, phytoplankton metabolites, and phytoplankton community composition. Community composition is strongly driven by conductivity and nitrates in Hamilton Harbour, while the opposite is true in the Bay of Quinte. Metabolites including α-aminobutyric acid and glycine were found in larger abundance within algal communities at both locations, while taurine was more predominant in algal communities from the Bay of Quinte. These metabolic profiles could reflect the different communities of phytoplankton, and be alternative indicators of algal bloom growth.PMID:36754333 | DOI:10.1016/j.scitotenv.2023.162042

Biomed Chromatogr. 2023 Feb 8:e5598. doi: 10.1002/bmc.5598. Online ahead of print.ABSTRACTOBJECTIVE: This study aimed to investigate the effect of Pikang oral liquid (PK) on psoriasis and analyze its possible mechanism from the perspective of metabolism.METHODS: A psoriasis-form mouse model established using imiquimod (IMQ) was used to evaluate the anti-psoriatic effects of PK. The serum samples were analyzed by high-resolution nuclear magnetic resonance (1 H NMR) based metabonomics. Nine amino acids were furthere quantitatively analyzed by ultraperformance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS).RESULTS: This study suggested that PK treatment markedly attenuated IMQ-induced psoriasis in a dose-dependent manner. 1 HNMR based multivariate trajectory analysis revealed that PK had a certain regression effect on eight differential metabolites. The quantitative results showed that PK could regulate significantly the serum levels of alanine, histidine and arginine to the healthy control levels.CONCLUSIONS: The mechanism of PK on anti-psoriasis may be associated with the restoration of the disturbance in the amino acid metabolism, energy metabolism, and lipid metabolism and so on. Quantitative results further confirmed that amino acid metabolism play an key role in the pathogenesis of psoriasis. Our investigation provided a holistic view of PK for intervention psoriasis and provided the scientific information in vivo about a clinical value of PK for psoriasis.PMID:36754046 | DOI:10.1002/bmc.5598

Cell Metab. 2023 Feb 7;35(2):299-315.e8. doi: 10.1016/j.cmet.2023.01.009.ABSTRACTFOXP3+ regulatory T cells (Tregs) are central for peripheral tolerance, and their deregulation is associated with autoimmunity. Dysfunctional autoimmune Tregs display pro-inflammatory features and altered mitochondrial metabolism, but contributing factors remain elusive. High salt (HS) has been identified to alter immune function and to promote autoimmunity. By investigating longitudinal transcriptional changes of human Tregs, we identified that HS induces metabolic reprogramming, recapitulating features of autoimmune Tregs. Mechanistically, extracellular HS raises intracellular Na+, perturbing mitochondrial respiration by interfering with the electron transport chain (ETC). Metabolic disturbance by a temporary HS encounter or complex III blockade rapidly induces a pro-inflammatory signature and FOXP3 downregulation, leading to long-term dysfunction in vitro and in vivo. The HS-induced effect could be reversed by inhibition of mitochondrial Na+/Ca2+ exchanger (NCLX). Our results indicate that salt could contribute to metabolic reprogramming and that short-term HS encounter perturb metabolic fitness and long-term function of human Tregs with important implications for autoimmunity.PMID:36754020 | DOI:10.1016/j.cmet.2023.01.009