PubMed

Clin Exp Hypertens. 2023 Dec 31;45(1):2177667. doi: 10.1080/10641963.2023.2177667.ABSTRACTBACKGROUND: Hypertensive intracerebral hemorrhage (HICH) is a life-threatening disease and lacks effective treatments. Previous studies have confirmed that metabolic profiles altered after ischemic stroke, but how brain metabolism changes after HICH was unclear. This study aimed to explore the metabolic profiles after HICH and the therapeutic effects of soyasaponin I on HICH.METHODS: HICH model was established first. Hematoxylin and eosin staining was used to estimate the pathological changes after HICH. Western blot and Evans blue extravasation assay were applied to determine the integrity of the blood-brain barrier (BBB). Enzyme-linked immunosorbent assay was used to detect the activation of the renin-angiotensin-aldosterone system (RAAS). Next, liquid chromatography-mass spectrometry-untargeted metabolomics was utilized to analyze the metabolic profiles of brain tissues after HICH. Finally, soyasaponin I was administered to HICH rats, and the severity of HICH and activation of the RAAS were further assessed.RESULTS: We successfully constructed HICH model. HICH significantly impaired BBB integrity and activated RAAS. HICH increased PE(14:0/24:1(15Z)), arachidonoyl serinol, PS(18:0/22:6(4Z, 7Z, 10Z, 13Z, 16Z, and 19Z)), PS(20:1(11Z)/20:5(5Z, 8Z, 11Z, 14Z, and 17Z)), glucose 1-phosphate, etc., in the brain, whereas decreased creatine, tripamide, D-N-(carboxyacetyl)alanine, N-acetylaspartate, N-acetylaspartylglutamic acid, and so on in the hemorrhagic hemisphere. Cerebral soyasaponin I was found to be downregulated after HICH and supplementation of soyasaponin I inactivated the RAAS and alleviated HICH.CONCLUSION: The metabolic profiles of the brains changed after HICH. Soyasaponin I alleviated HICH via inhibiting the RAAS and may serve as an effective drug for the treatment of HICH in the future.PMID:36809885 | DOI:10.1080/10641963.2023.2177667

Plant Commun. 2023 Feb 21:100564. doi: 10.1016/j.xplc.2023.100564. Online ahead of print.ABSTRACTEpiphytes with crassulacean acid metabolism (CAM) photosynthesis are widespread in vascular plants, with repeated evolution of CAM photosynthesis being a key innovation for micro-ecosystem adaptation. However, our understanding of the molecular regulation of CAM photosynthesis in epiphytes remains elusive. Here, we report a high-quality chromosomal-level genome assembly of a CAM epiphyte, Cymbidium mannii (Orchidaceae). The 2.88 Gb orchid genome with a contig N50 of 22.7 Mb and 27,192 annotated genes was organized into 20 pseudochromosomes, 82.8% of which were repetitive elements. Recent expansions of long terminal repeat retrotransposon families mainly contribute to the evolution of the genome size in Cymbidium orchids. We further reveal a holistic scenario of molecular regulation in metabolic physiology with high-resolution transcriptomics, proteomics, and metabolomics data across a CAM diel cycle. The patterns of rhythmically oscillated metabolites, especially CAM-related products, reflect circadian rhythmicity in metabolite accumulation in epiphytes. Genome-wide analysis of transcript and protein level regulation revealed phase shifts during the multifaceted regulation of circadian metabolism. Notably, we show the diurnal expression of several core CAM genes (especially βCA and PPC) that might temporally fix carbon sources. Our study provides a valuable resource for investigating post-transcription and translation scenarios in C. mannii, which represents a remarkable model in Orchidaceae for understanding the evolution of innovative traits in epiphytes.PMID:36809882 | DOI:10.1016/j.xplc.2023.100564

Am J Hum Genet. 2023 Feb 10:S0002-9297(23)00046-0. doi: 10.1016/j.ajhg.2023.02.002. Online ahead of print.ABSTRACTGenome-wide association studies (GWASs) have established the contribution of common and low-frequency variants to metabolic blood measurements in the UK Biobank (UKB). To complement existing GWAS findings, we assessed the contribution of rare protein-coding variants in relation to 355 metabolic blood measurements-including 325 predominantly lipid-related nuclear magnetic resonance (NMR)-derived blood metabolite measurements (Nightingale Health Plc) and 30 clinical blood biomarkers-using 412,393 exome sequences from four genetically diverse ancestries in the UKB. Gene-level collapsing analyses were conducted to evaluate a diverse range of rare-variant architectures for the metabolic blood measurements. Altogether, we identified significant associations (p < 1 × 10-8) for 205 distinct genes that involved 1,968 significant relationships for the Nightingale blood metabolite measurements and 331 for the clinical blood biomarkers. These include associations for rare non-synonymous variants in PLIN1 and CREB3L3 with lipid metabolite measurements and SYT7 with creatinine, among others, which may not only provide insights into novel biology but also deepen our understanding of established disease mechanisms. Of the study-wide significant clinical biomarker associations, 40% were not previously detected on analyzing coding variants in a GWAS in the same cohort, reinforcing the importance of studying rare variation to fully understand the genetic architecture of metabolic blood measurements.PMID:36809768 | DOI:10.1016/j.ajhg.2023.02.002

Invest New Drugs. 2023 Feb 21. doi: 10.1007/s10637-023-01334-x. Online ahead of print.ABSTRACTBACKGROUND: New chemotherapy agents are warranted for head and neck squamous cell carcinoma (HNSCC), particularly for incidence-rising HPV-positive tumors. Based on the evidence of Notch pathway involvement in cancer promotion and progression, we aimed to gain insights into the in vitro antineoplastic effects of gamma-secretase inhibition in HPV-positive and -negative HNSCC models.METHODS: All in vitro experiments were conducted in two HPV-negative (Cal27 and FaDu) and one HPV-associated HNSCC cell line (SCC154). The influence of the gamma-secretase inhibitor PF03084014 (PF) on proliferation, migration, colony forming, and apoptosis was assessed.RESULTS: We observed significant anti-proliferative, anti-migratory, anti-clonogenic, and pro-apoptotic effects in all three HNSCC cell lines. Furthermore, synergistic effects with concomitant radiation were observable in the proliferation assay. Interestingly, effects were slightly more potent in the HPV-positive cells.CONCLUSION: We provided novel insights into the potential therapeutic relevance of gamma-secretase inhibition in HNSCC cell lines in vitro. Therefore, PF may become a viable treatment option for patients with HNSCC, particularly for patients with HPV-induced malignancy. Indeed, further in vitro and in vivo experiments should be conducted to validate our results and decipher the mechanism behind the observed anti-neoplastic effects.PMID:36809443 | DOI:10.1007/s10637-023-01334-x

Eur Radiol. 2023 Feb 21. doi: 10.1007/s00330-023-09454-x. Online ahead of print.ABSTRACTOBJECTIVE: To investigate the findings of magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and serum metabolomics for differentiating pre-eclampsia (PE) from gestational hypertension (GH).METHODS: This prospective study enrolled 176 subjects including a primary cohort with healthy non-pregnant women (HN, n = 35), healthy pregnant women (HP, n = 20), GH (n = 27), and PE (n = 39) and a validation cohort with HP (n = 22), GH (n = 22), and PE (n = 11). T1 signal intensity index (T1SI), apparent diffusion coefficient (ADC) value, and the metabolites on MRS were compared. The differentiating performances of single and combined MRI and MRS parameters for PE were evaluated. Serum liquid chromatography-mass spectrometry (LC-MS) metabolomics was investigated by sparse projection to latent structures discriminant analysis.RESULTS: Increased T1SI, lactate/creatine (Lac/Cr), and glutamine and glutamate (Glx)/Cr and decreased ADC value and myo-inositol (mI)/Cr in basal ganglia were found in PE patients. T1SI, ADC, Lac/Cr, Glx/Cr, and mI/Cr yielded an area under the curves (AUC) of 0.90, 0.80, 0.94, 0.96, and 0.94 in the primary cohort, and of 0.87, 0.81, 0.91, 0.84, and 0.83 in the validation cohort, respectively. A combination of Lac/Cr, Glx/Cr, and mI/Cr yielded the highest AUC of 0.98 in the primary cohort and 0.97 in the validation cohort. Serum metabolomics analysis showed 12 differential metabolites, which are involved in pyruvate metabolism, alanine metabolism, glycolysis, gluconeogenesis, and glutamate metabolism.CONCLUSIONS: MRS is expected to be a noninvasive and effective tool for monitoring GH patients to avoid the development of PE.KEY POINTS: • Increased T1SI and decreased ADC value in the basal ganglia were found in PE patients than in GH patients. • Increased Lac/Cr and Glx/Cr, and decreased mI/Cr in the basal ganglia were found in PE patients than in GH patients. • LC-MS metabolomics showed that the major differential metabolic pathways between PE and GH were pyruvate metabolism, alanine metabolism, glycolysis, gluconeogenesis, and glutamate metabolism.PMID:36809432 | DOI:10.1007/s00330-023-09454-x

JCI Insight. 2023 Feb 21:e164296. doi: 10.1172/jci.insight.164296. Online ahead of print.ABSTRACTDiabetes is associated with increased risk for kidney and liver diseases, congestive heart failure, and mortality. Urinary glucose excretion using sodium-glucose cotransporter 2 (SGLT2) inhibitors prevents these adverse outcomes. We performed in vivo metabolic labeling with 13C-glucose in normoglycemic and diabetic mice treated with or without the SGLT2 inhibitor dapagliflozin, followed by simultaneous metabolomics and metabolic flux analyses in different organs and the plasma. We found that in diabetes, glycolysis and glucose oxidation are impaired in the kidney, liver, and heart. Treatment with dapagliflozin failed to rescue glycolysis and further inhibited pyruvate kinase activity in the liver. SGLT2 inhibition increased glucose oxidation in all organs; in the kidney, this effect was associated with modulation of the redox state, which may protect against oxidative stress. In addition, diabetes was associated with altered methionine cycle metabolism, evident by decreased betaine and methionine levels, whereas treatment with SGLT2i increased hepatic betaine along with decreased homocysteine levels. mTORC1 activity was inhibited by SGLT2i along with stimulation of AMPK in both normoglycemic and diabetic animals, possibly explaining the protective effects against kidney, liver, and heart diseases. Collectively, our findings suggest that SGLT2i induces metabolic reprogramming orchestrated by AMPK-mTORC1 signaling with common and distinct effects in various tissues with implications for diabetes and aging.PMID:36809274 | DOI:10.1172/jci.insight.164296

PLoS Negl Trop Dis. 2023 Feb 21;17(2):e0011119. doi: 10.1371/journal.pntd.0011119. eCollection 2023 Feb.ABSTRACTBACKGROUND: Trichinellosis, caused by a parasitic nematode of the genus Trichinella, is a zoonosis that affects people worldwide. After ingesting raw meat containing Trichinella spp. larvae, patients show signs of myalgia, headaches, and facial and periorbital edema, and severe cases may die from myocarditis and heart failure. The molecular mechanisms of trichinellosis are unclear, and the sensitivity of the diagnostic methods used for this disease are unsatisfactory. Metabolomics is an excellent tool for studying disease progression and biomarkers; however, it has never been applied to trichinellosis. We aimed to elucidate the impacts of Trichinella infection on the host body and identify potential biomarkers using metabolomics.METHODOLOGY/PRINCIPAL FINDINGS: Mice were infected with T. spiralis larvae, and sera were collected before and 2, 4, and 8 weeks after infection. Metabolites in the sera were extracted and identified using untargeted mass spectrometry. Metabolomic data were annotated via the XCMS online platform and analyzed with Metaboanalyst version 5.0. A total of 10,221 metabolomic features were identified, and the levels of 566, 330, and 418 features were significantly changed at 2-, 4-, and 8-weeks post-infection, respectively. The altered metabolites were used for further pathway analysis and biomarker selection. A major pathway affected by Trichinella infection was glycerophospholipid metabolism, and glycerophospholipids comprised the main metabolite class identified. Receiver operating characteristic revealed 244 molecules with diagnostic power for trichinellosis, with phosphatidylserines (PS) being the primary lipid class. Some lipid molecules, e.g., PS (18:0/19:0)[U] and PA (O-16:0/21:0), were not present in metabolome databases of humans and mice, thus they may have been secreted by the parasites.CONCLUSIONS/SIGNIFICANCE: Our study highlighted glycerophospholipid metabolism as the major pathway affected by trichinellosis, hence glycerophospholipid species are potential markers of trichinellosis. The findings of this study represent the initial steps in biomarker discovery that may benefit future trichinellosis diagnosis.PMID:36809241 | DOI:10.1371/journal.pntd.0011119

Microbiol Spectr. 2023 Feb 21:e0366122. doi: 10.1128/spectrum.03661-22. Online ahead of print.ABSTRACTIn this study, a novel actinomycete strain, DSD3025T, isolated from the underexplored marine sediments in Tubbataha Reefs Natural Park, Sulu Sea, Philippines, with the proposed name Streptomyces tubbatahanensis sp. nov., was described using polyphasic approaches and characterized using whole-genome sequencing. Its specialized metabolites were profiled using mass spectrometry and nuclear magnetic resonance analyses, followed by antibacterial, anticancer, and toxicity screening. The S. tubbatahanensis DSD3025T genome was comprised of 7.76 Mbp with a 72.3% G+C content. The average nucleotide identity and digital DNA-DNA hybridization values were 96.5% and 64.1%, respectively, compared with its closest related species, thus delineating the novelty of Streptomyces species. The genome encoded 29 putative biosynthetic gene clusters (BGCs), including a BGC region containing tryptophan halogenase and its associated flavin reductase, which were not found in its close Streptomyces relatives. The metabolite profiling unfolded six rare halogenated carbazole alkaloids, with chlocarbazomycin A as the major compound. A biosynthetic pathway for chlocarbazomycin A was proposed using genome mining, metabolomics, and bioinformatics platforms. Chlocarbazomycin A produced by S. tubbatahanensis DSD3025T has antibacterial activities against Staphylococcus aureus ATCC BAA-44 and Streptococcus pyogenes and showed antiproliferative activity against colon (HCT-116) and ovarian (A2780) human cancer cell lines. Chlocarbazomycin A exhibited no toxicity to liver cells but moderate and high toxicity to kidney and cardiac cell lines, respectively. IMPORTANCE Streptomyces tubbatahanensis DSD3025T is a novel actinomycete with antibiotic and anticancer activities from Tubbataha Reefs Natural Park, a United Nations Educational, Scientific and Cultural Organization World Heritage Site in Sulu Sea and considered one of the Philippines' oldest and most-well-protected marine ecosystems. In silico genome mining tools were used to identify putative BGCs that led to the discovery of genes involved in the production of halogenated carbazole alkaloids and new natural products. By integrating bioinformatics-driven genome mining and metabolomics, we unearthed the hidden biosynthetic richness and mined the associated chemical entities from the novel Streptomyces species. The bioprospecting of novel Streptomyces species from marine sediments of underexplored ecological niches serves as an important source of antibiotic and anticancer drug leads with unique chemical scaffolds.PMID:36809153 | DOI:10.1128/spectrum.03661-22

J Agric Food Chem. 2023 Feb 21. doi: 10.1021/acs.jafc.2c08067. Online ahead of print.ABSTRACTSevere allergic reactions to certain types of meat following tick bites have been reported in geographic regions which are endemic with ticks. This immune response is directed to a carbohydrate antigen (galactose-α-1,3-galactose or α-Gal), which is present in glycoproteins of mammalian meats. At the moment, asparagine-linked complex carbohydrates (N-glycans) with α-Gal motifs in meat glycoproteins and in which cell types or tissue morphologies these α-Gal moieties are present in mammalian meats are still unclear. In this study, we analyzed α-Gal-containing N-glycans in beef, mutton, and pork tenderloin and provided for the first time the spatial distribution of these types of N-glycans in various meat samples. Terminal α-Gal-modified N-glycans were found to be highly abundant in all analyzed samples (55, 45, and 36% of N-glycome in beef, mutton, and pork, respectively). Visualizations of the N-glycans with α-Gal modification revealed that this motif was mainly present in the fibroconnective tissue. To conclude, this study contributes to a better understanding of the glycosylation biology of meat samples and provides guidance for processed meat products, in which only meat fibers are required as an ingredient (i.e., sausages or canned meat).PMID:36809004 | DOI:10.1021/acs.jafc.2c08067

ACS Chem Neurosci. 2023 Feb 21. doi: 10.1021/acschemneuro.2c00735. Online ahead of print.ABSTRACTAutism spectrum disorder (ASD) is a complex neurodevelopmental condition that is characterized by patients displaying at least two out of the classical symptoms, such as impaired social communication, impaired interactions, and restricted repetitive behavior. Early parent-mediated interventions, such as video modeling for parental training, were demonstrated to be a successful low-cost way to deliver care for children with ASD. Nuclear magnetic resonance (NMR)-based metabolomics/lipidomics has been successfully employed in several mental disorder studies. Metabolomics and lipidomics of 37 ASD patients (children, aged 3-8 years), who were divided into two groups, one control group with no parental-training intervention (N = 18) and the other in which the parents were trained by a video modeling intervention (ASD parental training, N = 19), were analyzed by proton NMR spectroscopy. Patients in the ASD parental-training group sera were seen to have increased glucose, myo-inositol, malonate, proline, phenylalanine, and gangliosides in their blood serum, while cholesterol, choline, and lipids were decreased, compared to the control group, who received no parental-training. Taken together, we demonstrated here significant changes in serum metabolites and lipids in ASD children, previously demonstrated to show clinical positive effects following a parental training intervention based on video modeling, delivered over 22 weeks. We demonstrate the value of applying metabolomics and lipidomics to identify potential biomarkers for clinical interventions follow-up in ASD.PMID:36808953 | DOI:10.1021/acschemneuro.2c00735

Biochemistry. 2023 Feb 21. doi: 10.1021/acs.biochem.2c00656. Online ahead of print.ABSTRACTAccelerated spontaneous deamidation of asparagine 373 and subsequent conversion into an isoaspartate has been shown to attenuate the binding of histo blood group antigens (HBGAs) to the protruding domain (P-domain) of the capsid protein of a prevalent norovirus strain (GII.4). Here, we link an unusual backbone conformation of asparagine 373 to its fast site-specific deamidation. NMR spectroscopy and ion exchange chromatography have been used to monitor the deamidation reaction of P-domains of two closely related GII.4 norovirus strains, specific point mutants, and control peptides. MD simulations over several microseconds have been instrumental to rationalize the experimental findings. While conventional descriptors such as available surface area, root-mean-square fluctuations, or nucleophilic attack distance fail as explanations, the population of a rare syn-backbone conformation distinguishes asparagine 373 from all other asparagine residues. We suggest that stabilization of this unusual conformation enhances the nucleophilicity of the backbone nitrogen of aspartate 374, in turn accelerating the deamidation of asparagine 373. This finding should be relevant to the development of reliable prediction algorithms for sites of rapid asparagine deamidation in proteins.PMID:36808948 | DOI:10.1021/acs.biochem.2c00656

Physiol Rep. 2023 Feb;11(4):e15603. doi: 10.14814/phy2.15603.ABSTRACTAlterations in perioperative metabolic function, particularly hyperglycemia, are associated with increased post-operative complications, even in patients without preexisting metabolic abnormalities. Anesthetic medications and the neuroendocrine stress response to surgery may both contribute to altered energy metabolism through impaired glucose and insulin homeostasis but the discrete pathways involved are unclear. Prior human studies, though informative, have been limited by analytic sensitivity or technique, preventing resolution of underlying mechanisms. We hypothesized that general anesthesia with a volatile agent would suppress basal insulin secretion without altering hepatic insulin extraction, and that surgical stress would promote hyperglycemia through gluconeogenesis, lipid oxidation, and insulin resistance. In order to address these hypotheses, we conducted an observational study of subjects undergoing multi-level lumbar surgery with an inhaled anesthetic agent. We measured circulating glucose, insulin, c-peptide, and cortisol frequently throughout the perioperative period and analyzed the circulating metabolome in a subset of these samples. We found volatile anesthetic agents suppress basal insulin secretion and uncouple glucose-stimulated insulin secretion. Following surgical stimulus, this inhibition disappeared and there was gluconeogenesis with selective amino acid metabolism. No robust evidence of lipid metabolism or insulin resistance was observed. These results show that volatile anesthetic agents suppress basal insulin secretion, which results in reduced glucose metabolism. The neuroendocrine stress response to surgery ameliorates the inhibitory effect of the volatile agent on insulin secretion and glucose metabolism, promoting catabolic gluconeogenesis. A better understanding of the complex metabolic interaction between anesthetic medications and surgical stress is needed to inform design of clinical pathways aimed at improving perioperative metabolic function.PMID:36808704 | DOI:10.14814/phy2.15603

J Mol Med (Berl). 2023 Feb 19. doi: 10.1007/s00109-023-02296-6. Online ahead of print.ABSTRACTIschemia-induced metabolic remodeling plays a critical role in the pathogenesis of adverse cardiac remodeling and heart failure however, the underlying molecular mechanism is largely unknown. Here, we assess the potential roles of nicotinamide riboside kinase-2 (NRK-2), a muscle-specific protein, in ischemia-induced metabolic switch and heart failure through employing transcriptomic and metabolomic approaches in ischemic NRK-2 knockout mice. The investigations revealed NRK-2 as a novel regulator of several metabolic processes in the ischemic heart. Cardiac metabolism and mitochondrial function and fibrosis were identified as top dysregulated cellular processes in the KO hearts post-MI. Several genes linked to mitochondrial function, metabolism, and cardiomyocyte structural proteins were severely downregulated in the ischemic NRK-2 KO hearts. Analysis revealed significantly upregulated ECM-related pathways which was accompanied by the upregulation of several key cell signaling pathways including SMAD, MAPK, cGMP, integrin, and Akt in the KO heart post-MI. Metabolomic studies identified profound upregulation of metabolites mevalonic acid, 3,4-dihydroxyphenylglycol, 2-penylbutyric acid, and uridine. However, other metabolites stearic acid, 8,11,14-eicosatrienoic acid, and 2-pyrrolidinone were significantly downregulated in the ischemic KO hearts. Taken together, these findings suggest that NRK-2 promotes metabolic adaptation in the ischemic heart. The aberrant metabolism in the ischemic NRK-2 KO heart is largely driven by dysregulated cGMP and Akt and mitochondrial pathways. KEY MESSAGES: Post-myocardial infarction metabolic switch critically regulates the pathogenesis of adverse cardiac remodeling and heart failure. Here, we report NRK-2 as a novel regulator of several cellular processes including metabolism and mitochondrial function post-MI. NRK-2 deficiency leads to downregulation of genes important for mitochondrial pathway, metabolism, and cardiomyocyte structural proteins in the ischemic heart. It was accompanied by upregulation of several key cell signaling pathways including SMAD, MAPK, cGMP, integrin, and Akt and dysregulation of numerous metabolites essential for cardiac bioenergetics. Taken together, these findings suggest that NRK-2 is critical for metabolic adaptation of the ischemic heart.PMID:36808555 | DOI:10.1007/s00109-023-02296-6

Epilepsia Open. 2023 Feb 20. doi: 10.1002/epi4.12712. Online ahead of print.ABSTRACTOBJECTIVE: The drug-refractory epilepsy (DRE) in children is commonly observed but the underlying mechanisms remain elusive. We examined whether fatty acids (FAs) and lipids are potentially associated with the pharmacoresistance to valproic acid (VPA) therapy.METHODS: This single-center, retrospective cohort study was conducted using data from pediatric patients collected between May 2019 and December 2019 at the Children's Hospital of Nanjing Medical University. 90 plasma samples from 53 responders with VPA monotherapy (RE group) and 37 non-responders with VPA polytherapy (NR group) were collected. Non-targeted metabolomics and lipidomics analysis for those plasma samples were performed to compare the potential differences of small metabolites and lipids between the two groups. Plasma metabolites and lipids passing the threshold of variable importance in projection value > 1, fold change > 1.2 or < 0.8, and p-value < 0.05 were regarded as statistically different substances.RESULTS: A total of 204 small metabolites and 433 lipids comprising 16 different lipid subclasses were identified. The well-established Partial Least-squares-Discriminant Analysis (PLS-DA) revealed a good separation of RE from NR group. The FAs and glycerophospholipids status were significantly decreased in the NR group, but their triglycerides (TG) levels were significantly increased. The trend of TG levels in routine lab tests was in line with the lipidomics analysis. Meanwhile, cases from the NR group were characterized by a decreased level of citric acid and L-thyroxine, but an increased level of glucose and 2-oxoglutarate. The most two enriched metabolic pathways, biosynthesis of unsaturated FAs and linoleic acid metabolism, were involved in the DRE condition.SIGNIFICANCE: The results of this study suggested an association between FAs metabolism and the medically intractable epilepsy. Such novel findings might propose a potential mechanism linked to the energy metabolism. Ketogenic acid and FAs supplementation might therefore be high priority strategies for DRE management efforts.PMID:36808532 | DOI:10.1002/epi4.12712

Anal Bioanal Chem. 2023 Feb 18. doi: 10.1007/s00216-023-04572-3. Online ahead of print.NO ABSTRACTPMID:36808274 | DOI:10.1007/s00216-023-04572-3

Thorax. 2023 Feb 20:thorax-2022-219557. doi: 10.1136/thorax-2022-219557. Online ahead of print.ABSTRACTBACKGROUND: Tracheostomies in children are associated with significant morbidity, poor quality of life, excess healthcare costs and excess mortality. The underlying mechanisms facilitating adverse respiratory outcomes in tracheostomised children are poorly understood. We aimed to characterise airway host defence in tracheostomised children using serial molecular analyses.METHODS: Tracheal aspirates, tracheal cytology brushings and nasal swabs were prospectively collected from children with a tracheostomy and controls. Transcriptomic, proteomic and metabolomic methods were applied to characterise the impact of tracheostomy on host immune response and the airway microbiome.RESULTS: Children followed up serially from the time of tracheostomy up to 3 months postprocedure (n=9) were studied. A further cohort of children with a long-term tracheostomy were also enrolled (n=24). Controls (n=13) comprised children without a tracheostomy undergoing bronchoscopy. Long-term tracheostomy was associated with airway neutrophilic inflammation, superoxide production and evidence of proteolysis when compared with controls. Reduced airway microbial diversity was established pre-tracheostomy and sustained thereafter.CONCLUSIONS: Long-term childhood tracheostomy is associated with a inflammatory tracheal phenotype characterised by neutrophilic inflammation and the ongoing presence of potential respiratory pathogens. These findings suggest neutrophil recruitment and activation as potential exploratory targets in seeking to prevent recurrent airway complications in this vulnerable group of patients.PMID:36808087 | DOI:10.1136/thorax-2022-219557

AMB Express. 2023 Feb 20;13(1):20. doi: 10.1186/s13568-023-01523-0.ABSTRACTThe prevalence of antibiotic resistance in Pseudomonas aeruginosa places a heavy burden on the health care sectors urging the need to find alternative, non-antibiotic strategies. The interference with the P. aeruginosa quorum sensing (QS) system represents a promising alternative strategy to attenuate the bacterial virulency and its ability to form biofilms. Micafungin has been reported to impede the pseudomonal biofilm formation. However, the influences of micafungin on the biochemical composition and metabolites levels of P. aeruginosa have not been explored. In this study, the effect of micafungin (100 µg/mL) on the virulence factors, QS signal molecules and the metabolome of P. aeruginosa was studied using exofactor assay and mass spectrometry-based metabolomics approaches. Furthermore, confocal laser scanning microscopy (CLSM) using the fluorescent dyes ConA-FITC and SYPRO® Ruby was used to visualize micafungin disturbing effects on the pseudomonal glycocalyx and protein biofilm-constituents, respectively. Our findings showed that micafungin significantly decreased the production of various QS-controlled virulence factors (pyocyanin, pyoverdine, pyochelin and rhamnolipid), along with a dysregulation in the level of various metabolites involved in QS system, lysine degradation, tryptophan biosynthesis, TCA cycle, and biotin metabolism. In addition, the CLSM examination showed an altered matrix distribution. The presented findings highlight the promising role of micafungin as a potential quorum sensing inhibitor (QSI) and anti-biofilm agent to attenuate P. aeruginosa pathogenicity. In addition, they point to the promising role of metabolomics study in investigating the altered biochemical pathways in P. aeruginosa.PMID:36807839 | DOI:10.1186/s13568-023-01523-0

J Integr Plant Biol. 2023 Feb 21. doi: 10.1111/jipb.13469. Online ahead of print.ABSTRACTPlants accumulate a vast array of secondary metabolites, which constitute a natural resource for pharmaceuticals. Oldenlandia corymbosa belongs to the Rubiaceae family, and has been used in traditional medicine to treat different diseases, including cancer. However, the active metabolites of the plant, their biosynthetic pathway and mode of action in cancer are unknown. To fill these gaps, we exposed this plant to eight different stress conditions and combined different omics data capturing gene expression, metabolic profiles and anti-cancer activity. Our results show that O. corymbosa extracts are active against breast cancer cell lines and that ursolic acid is responsible for this activity. Moreover, we assembled a high-quality genome and uncovered two genes involved in the biosynthesis of ursolic acid. Finally, we also revealed that ursolic acid causes mitotic catastrophe in cancer cells and identified three high-confidence protein binding targets by Cellular Thermal Shift Assay (CETSA) and reverse docking. Altogether, these results constitute a valuable resource to further characterize the biosynthesis of active metabolites in the Oldenlandia group, while the mode of action of ursolic acid will allow us to further develop this valuable compound. This article is protected by copyright. All rights reserved.PMID:36807520 | DOI:10.1111/jipb.13469

Chemosphere. 2023 Feb 18:138173. doi: 10.1016/j.chemosphere.2023.138173. Online ahead of print.ABSTRACTTo alleviate the arsenic (As) toxicity in aromatic rice, a hydroponic experiment of two As concentrations (0 and 100 μM sodium arsenite: A0, A1), three glutamic acid (Glu) concentrations (0, 100, and 500 μM l-glutamic acid: G0, G1, and G2) with Xiangyaxiangzhan and Meixiangzhan 2 was conducted. Results showed that the root As content were increased under A1G2 but reduced under A1G1 for Xiangyaxiangzhan as compared with A1G0. A decrement of As was transported from root to shoot caused by up-regulated OsABCC1 relative expression in Meixiangzhan 2. Likewise, As stress enhanced the H2O2 and malondialdehyde content, resulting in the impaired cell wall observed by transmission electron microscopy. However, compared with A1G0, the superoxide dismutase activity, ascorbic acid, glutathione, proline, and soluble sugar content were increased under A1G1. Additionally, arsenate reductase, monodehydroascorbate reductase activity, Glu, proline, and soluble sugar content were found positively associated with the As accumulation. Further, the metabolome analysis indicated that the pathway of amino acid and arginine biosynthesis were notably enriched after Glu application. Generally, 100 μM Glu application was the better treatment to enhance As tolerance in aromatic rice through up-regulating amino acid biosynthesis with increasing antioxidants and osmolytes to scavenge excessive reactive oxygen species.PMID:36806810 | DOI:10.1016/j.chemosphere.2023.138173

J Lipid Res. 2023 Feb 18:100349. doi: 10.1016/j.jlr.2023.100349. Online ahead of print.ABSTRACTWe previously demonstrated that antisense oligonucleotide (ASO)-mediated knockdown of Mboat7, the gene encoding Membrane Bound O-Acyltransferase 7, in the liver and adipose tissue of mice promoted high fat diet-induced hepatic steatosis, hyperinsulinemia, and systemic insulin resistance. Thereafter, other groups showed that hepatocyte-specific genetic deletion of Mboat7 promoted striking fatty liver and NAFLD progression in mice but does not alter insulin sensitivity, suggesting the potential for cell autonomous roles. Here, we show that MBOAT7 function in adipocytes contributes to diet-induced metabolic disturbances including hyperinsulinemia and systemic insulin resistance. We generated floxed Mboat7 mice and created hepatocyte- and adipocyte-specific knockout mice using Cre-recombinase mice under the control of the albumin and adiponectin promoter, respectively. After chow and high fat diet feeding (60% kCal fat), mice were subjected to metabolic phenotyping and tissues to molecular workup and analysis. Here, we show that MBOAT7 function in adipocytes contributes to diet-induced metabolic disturbances including hyperinsulinemia and systemic insulin resistance. The expression of Mboat7 in white adipose tissue closely correlates with diet-induced obesity across a panel of ∼100 inbred strains of mice fed a high fat/high sucrose diet. Moreover, we found that adipocyte-specific genetic deletion of Mboat7 is sufficient to promote hyperinsulinemia, systemic insulin resistance, and mild fatty liver. Unlike in the liver, where Mboat7 plays a relatively minor role in maintaining arachidonic acid (AA)-containing PI pools, Mboat7 is the major source of AA-containing PI pools in adipose tissue. Our data demonstrate that MBOAT7 is a critical regulator of adipose tissue PI homeostasis, and adipocyte MBOAT7-driven PI biosynthesis is closely linked to hyperinsulinemia and insulin resistance in mice.PMID:36806709 | DOI:10.1016/j.jlr.2023.100349