PubMed

Rapid Commun Mass Spectrom. 2023 Jan 31:e9481. doi: 10.1002/rcm.9481. Online ahead of print.ABSTRACTRATIONALE: The chemical constituent of Chinese patent medicine is usually different from crude medicine because of specific preparation process. Chimonanthus nitens Oliv. leaf granule is widely used for prevention against Covid-19 in China. However, none research on chemical constituents of the granule and their variation during the preparation process is reported.METHODS: Fragmentation rules of reference compounds were investigated in electrospray ionization mass spectrometry, new gas phase reaction was rationalized via electronic and steric effect, and calculated chemistry. Then, a strategy based on new fragmentation patterns was conducted to profile aromatic constituents. Additionally, basing on untargeted metabolomics analytical workflow, comparison on chemical constituents of leaf and granule was performed.RESULTS: New fragmentation patterns related to two competing reactions, ring-opening and ring-closing reaction for coumarin have been proposed and been rationalized intensely. New established diagnostic ion at m/z 81.0331 worked powerfully in assignment of OH-7 and substituent at C-8 of coumarin. McLafferty rearrangement occurring to coumarin glycoside with sugar group at C-4 was firstly observed, and newly formed dialogue ions at m/z 147.0440, 119.0488 and 91.0543.CONCLUSIONS: Aromatic constituents of the granule were firstly profiled. A total of 114 aromatic compounds were identified, of those 85 compounds were firstly discovered. The kaempferol-7-O-neohesperidoside and its homologues were mostly enriched in the granule. Considering their reported bioactivities, these analogues possibly contribute greatly to clinical efficacy. Our present results offered new fragmentation theory for coumarins and new material basis for quality control of the granule.PMID:36721310 | DOI:10.1002/rcm.9481

Microbiome. 2023 Jan 31;11(1):19. doi: 10.1186/s40168-022-01458-x.ABSTRACTBACKGROUND: Low birth weight (LBW) is associated with intestinal inflammation and dysbiosis after birth. However, the underlying mechanism remains largely unknown.OBJECTIVE: In the present study, we aimed to investigate the metabolism, therapeutic potential, and mechanisms of action of bile acids (BAs) in LBW-induced intestinal inflammation in a piglet model.METHODS: The fecal microbiome and BA profile between LBW and normal birth weight (NBW) neonatal piglets were compared. Fecal microbiota transplantation (FMT) was employed to further confirm the linkage between microbial BA metabolism and intestinal inflammation. The therapeutic potential of ursodeoxycholic acid (UDCA), a highly differentially abundant BA between LBW and NBW piglets, in alleviating colonic inflammation was evaluated in both LBW piglets, an LBW-FMT mice model, and a DSS-induced colitis mouse model. The underlying cellular and molecular mechanisms by which UDCA suppresses intestinal inflammation were also investigated in both DSS-treated mice and a macrophage cell line. Microbiomes were analyzed by using 16S ribosomal RNA sequencing. Fecal and intestinal BA profiles were measured by using targeted BA metabolomics. Levels of farnesoid X receptor (FXR) were knocked down in J774A.1 cells with small interfering RNAs.RESULTS: We show a significant difference in both the fecal microbiome and BA profiles between LBW and normal birth weight animals in a piglet model. Transplantation of the microbiota of LBW piglets to antibiotic-treated mice leads to intestinal inflammation. Importantly, oral administration of UDCA, a major BA diminished in the intestinal tract of LBW piglets, markedly alleviates intestinal inflammation in LBW piglets, an LBW-FMT mice model, and a mouse model of colitis by inducing M2 macrophage polarization. Mechanistically, UDCA reduces inflammatory cytokine production by engaging BA receptor FXR while suppressing NF-κB activation in macrophages.CONCLUSIONS: These findings establish a causal relationship between LBW-associated intestinal abnormalities and dysbiosis, suggesting that restoring intestinal health and postnatal maldevelopment of LBW infants may be achieved by targeting intestinal microbiota and BA metabolism. Video Abstract.PMID:36721210 | DOI:10.1186/s40168-022-01458-x

BMC Plant Biol. 2023 Feb 1;23(1):65. doi: 10.1186/s12870-023-04076-3.ABSTRACTBACKGROUND: The desert shrub Nitraria tangutorum Bobr. is important for its resistance to salt and alkali in Northwest China. It is an ecologically important species in this region and provides edible and medicinal berries. This study showed a mutant of N. tangutorum (named Jincan, JC) that has a strong yellow pericarp vs red in a wild type (represented by NT).RESULTS: In this study, the secondary metabolic and molecular mechanisms responsible for Nitraria fruit coloration were investigated using LC-MS-based widely targeted metabolomics and transcriptomics data. As a result of our study, 122 and 104 flavonoid metabolites were differentially expressed throughout the mature and transition stages between JC and NT, respectively. Furthermore, two cyanidin derivatives (cyanidin 3-O-glucoside and cyanidin-3-O-(2''-O-glucosyl) glucoside) and one pelargonidin derivative (pelargonidin-3-O-glucoside) were identified only in the NT phenotype. The functional genes F3H (flavanone 3-hydroxylase), F3'H (flavonoid 3'-hydroxylase) and UFGT (flavonoid 3-O-glucosyltransferase) and the transcription factors MYB, bHLH, NAC and bZIP were significantly downregulated in JC. Meanwhile, the activity of UFGT was extremely low in both periods of JC, with a five-fold higher enzymatic activity of UFGT in RT than in YT. In summary, due to the lack of catalysis of UGFT, yellow fruit of JC could not accumulate sufficient cyanidin and pelargonidin derivatives during fruit ripening.CONCLUSION: Taken together, our data provide insights into the mechanism for the regulation of anthocyanin synthesis and N. tangutorum fruit coloration and provide a theoretical basis to develop new strategies for developing bioactive compounds from N. tangutorum fruits.PMID:36721098 | DOI:10.1186/s12870-023-04076-3

Nat Rev Clin Oncol. 2023 Jan 31. doi: 10.1038/s41571-023-00729-2. Online ahead of print.ABSTRACTDespite the notable success of chimeric antigen receptor (CAR) T cell therapies in the treatment of certain haematological malignancies, challenges remain in optimizing CAR designs and cell products, improving response rates, extending the durability of remissions, reducing toxicity and broadening the utility of this therapeutic modality to other cancer types. Data from multidimensional omics analyses, including genomics, epigenomics, transcriptomics, T cell receptor-repertoire profiling, proteomics, metabolomics and/or microbiomics, provide unique opportunities to dissect the complex and dynamic multifactorial phenotypes, processes and responses of CAR T cells as well as to discover novel tumour targets and pathways of resistance. In this Review, we summarize the multidimensional cellular and molecular profiling technologies that have been used to advance our mechanistic understanding of CAR T cell therapies. In addition, we discuss current applications and potential strategies leveraging multi-omics data to identify optimal target antigens and other molecular features that could be exploited to enhance the antitumour activity and minimize the toxicity of CAR T cell therapy. Indeed, fully utilizing multi-omics data will provide new insights into the biology of CAR T cell therapy, further accelerate the development of products with improved efficacy and safety profiles, and enable clinicians to better predict and monitor patient responses.PMID:36721024 | DOI:10.1038/s41571-023-00729-2

Sci Rep. 2023 Jan 31;13(1):1789. doi: 10.1038/s41598-023-27827-6.ABSTRACTContamination of microalgae cultures can reduce their productivity and affect the quality of biomass and valuable bioproducts. In this article, after having isolated and identified for the first time the filamentous fungus Penicillium citrinum from heterotrophic cultures of the red polyextremophilic microalga Galdieria sulphuraria, we investigated the biological and metabolic significance of this alga-fungus association. In the same medium, both organisms grow better in each other's presence than separately. Both cell density and cell size of G. sulphuraria increase in co-cultures compared to pure alga cultures. In co-cultures, despite very severe growth conditions, the load of P. citrinum increases compared to pure fungus cultures. Optical microscope images have shown physical contact between cells of P. citrinum hyphae and G. sulphuraria which, however, retain their morphology and cell wall intact. GC-MS-based metabolomics analysis of metabolites excreted in the culture medium shows that pure cultures of the fungus and alga and co-cultures of alga plus fungus can be easily differentiated based on their metabolic products. Indeed, a richer assortment of extracellular metabolites (comprising both products of primary and secondary metabolism) is a distinct feature of co-cultures compared to both pure alga and pure fungus cultures.PMID:36720953 | DOI:10.1038/s41598-023-27827-6

Sci Rep. 2023 Jan 31;13(1):1802. doi: 10.1038/s41598-023-28816-5.ABSTRACTThree years after the pandemic, we still have an imprecise comprehension of the pathogen landscape and we are left with an urgent need for early detection methods and effective therapy for severe COVID-19 patients. The implications of infection go beyond pulmonary damage since the virus hijacks the host's cellular machinery and consumes its resources. Here, we profiled the plasma proteome and metabolome of a cohort of 57 control and severe COVID-19 cases using high-resolution mass spectrometry. We analyzed their proteome and metabolome profiles with multiple depths and methodologies as conventional single omics analysis and other multi-omics integrative methods to obtain the most comprehensive method that portrays an in-depth molecular landscape of the disease. Our findings revealed that integrating the knowledge-based and statistical-based techniques (knowledge-statistical network) outperformed other methods not only on the pathway detection level but even on the number of features detected within pathways. The versatile usage of this approach could provide us with a better understanding of the molecular mechanisms behind any biological system and provide multi-dimensional therapeutic solutions by simultaneously targeting more than one pathogenic factor.PMID:36720931 | DOI:10.1038/s41598-023-28816-5

Nat Commun. 2023 Jan 31;14(1):512. doi: 10.1038/s41467-023-36138-3.ABSTRACTThe human gut microbiota produces dozens of small molecules that circulate in blood, accumulate to comparable levels as pharmaceutical drugs, and influence host physiology. Despite the importance of these metabolites to human health and disease, the origin of most microbially-produced molecules and their fate in the host remains largely unknown. Here, we uncover a host-microbe co-metabolic pathway for generation of hippuric acid, one of the most abundant organic acids in mammalian urine. Combining stable isotope tracing with bacterial and host genetics, we demonstrate reduction of phenylalanine to phenylpropionic acid by gut bacteria; the host re-oxidizes phenylpropionic acid involving medium-chain acyl-CoA dehydrogenase (MCAD). Generation of germ-free male and female MCAD-/- mice enabled gnotobiotic colonization combined with untargeted metabolomics to identify additional microbial metabolites processed by MCAD in host circulation. Our findings uncover a host-microbe pathway for the abundant, non-toxic phenylalanine metabolite hippurate and identify β-oxidation via MCAD as a novel mechanism by which mammals metabolize microbiota-derived metabolites.PMID:36720857 | DOI:10.1038/s41467-023-36138-3

J Proteome Res. 2023 Jan 31. doi: 10.1021/acs.jproteome.2c00460. Online ahead of print.ABSTRACTThe progressive forms of multiple sclerosis (MS) primary progressive MS (PPMS) and secondary progressive MS (SPMS) are clinically distinguished by the rate at which symptoms worsen. Little is however known about the pathological mechanisms underlying the differential rate of accumulation of pathological changes. In this study, 1H NMR spectroscopy was used to measure low-molecular-weight metabolites in paired cerebrospinal fluid (CSF) and serum of PPMS, SPMS, and control patients, as well as to determine lipoproteins and glycoproteins in serum samples. Additionally, neurodegenerative and inflammatory markers, neurofilament light (NFL) and chitinase-3-like protein 1 (CHI3L1), and the concentration of seven metal elements, Mg, Mn, Cu, Fe, Pb, Zn, and Ca, were also determined in both CSF and serum. The results indicate that the pathological changes associated with progressive MS are mainly localized in the central nervous system (CNS). More so, PPMS and SPMS patients with comparable disability status are pathologically similar in relation to neurodegeneration, neuroinflammation, and some metabolites that distinguish them from controls. However, the rapid progression of PPMS from the onset may be driven by a combination of neurotoxicity induced by heavy metals coupled with diminished CNS antioxidative capacity associated with differential intrathecal ascorbate retention and imbalance of Mg and Cu.PMID:36720471 | DOI:10.1021/acs.jproteome.2c00460

J Agric Food Chem. 2023 Jan 31. doi: 10.1021/acs.jafc.2c07498. Online ahead of print.ABSTRACTStorage is a critical step in the post-harvest processing of hazelnuts, as it can lead to mold, rancidity, and off-flavor. However, there is a lack of analytical methods to detect improper or extended storage. To comprehensively investigate the effects of hazelnut storage, samples were stored under five different conditions for up to 18 months. Subsequently, the polar and nonpolar metabolome were analyzed by 1H NMR spectroscopy and chemometric approaches for classification as well as variable selection. Increases in hexanoic, octanoic, and nonanoic acid, all products of lipid oxidation and responsible for quality defects, were found across all conditions. Furthermore, the concentration of free long-chain fatty acids increased in samples stored at high temperatures. Harsh short-term storage resulted in an increase in fumaric and lactic acid, glucose, fructose, and choline and a decrease in acetic acid.PMID:36720100 | DOI:10.1021/acs.jafc.2c07498

Microbiol Spectr. 2023 Jan 31:e0348922. doi: 10.1128/spectrum.03489-22. Online ahead of print.ABSTRACTThe Actinomycetia isolate PBR11 was isolated from the forest rhizosphere soil of Pobitora Wildlife Sanctuary (PWS), Assam, India. The isolate was identified as Streptomyces sp. with 92.91% sequence similarity to their closest type strain, Streptomyces atrovirens NRRL B-16357 DQ026672. The strain demonstrated significant antimicrobial activity against 19 test pathogens, including multidrug-resistant (MDR) clinical isolates and dermatophytes. Phenol, 2,5-bis(1,1-dimethylethyl), is the major chemical compound detected by gas chromatography-mass spectrometry in the ethyl acetate extract of PBR11 (EtAc-PBR11). The presence of the PKS type II gene (type II polyketide synthases) and chitinase gene suggested that it has been involved in the production of antimicrobial compounds. Metabolic profiling of the EtAc-PBR11 was performed by thin-layer chromatography and flash chromatography resulted in the extraction of two bioactive fractions, namely, PBR11Fr-1 and PBR11Fr-2. Liquid chromatography-tandem mass spectrometry analysis of both the fractions demonstrated the presence of significant antimicrobial compounds, including ethambutol. This is the first report on the detection of antituberculosis drug in the bioactive fractions of Streptomyces sp. PBR11. EtAc-PBR11 and PBR11Fr-1 showed the lowest MIC values (>0.097 and >0.048 μg/mL, respectively) against Candida albicans MTCC 227, whereas they showed the highest MIC values (>0.390 and >0.195 μg/mL, respectively) against Escherichia coli ATCC BAA-2469. The effects of PBR11Fr-1 were investigated on the pathogens by using a scanning electron microscope. The results indicated major morphological alterations in the cytoplasmic membrane. PBR11Fr-1 exhibited low cytotoxicity on normal hepatocyte cell line (CC-1) and the percent cell viability started to decline as the concentration increased from 50 μg/mL (87.07% ± 3.22%) to 100 μg/mL (81.26% ± 2.99%). IMPORTANCE Novel antibiotic breakthroughs are urgently required to combat antimicrobial resistance. Actinomycetia are the principal producers of antibiotics. The present study demonstrated the broad-spectrum antimicrobial potential of an Actinomycetia strain Streptomyces sp. strain PBR11 isolated from the PWS of Assam, India, which represents diverse, poorly screened habitats for novel microorganisms. The strain displayed 92.4% sequence similarity with genes of the closest type strain, indicating that the strain may represent a novel taxon within the phylum Actinomycetota. The metabolomics studies of EtAc-PBR11 revealed structurally diverse antimicrobial agents, including the detection of the antituberculosis drug ethambutol, in the bioactive fraction of Streptomyces sp. PBR11 for the first time. The PBR11 strain also yielded positive results for the antibiotic synthesis gene and the chitinase gene, both of which are responsible for broad-spectrum antimicrobial activity. This suggests that the untouched forest ecosystems have a tremendous potential to harbor potent actinomycetia for future drug discovery.PMID:36719230 | DOI:10.1128/spectrum.03489-22

Microbiol Spectr. 2023 Jan 31:e0469822. doi: 10.1128/spectrum.04698-22. Online ahead of print.ABSTRACTEnvironmental (restraint stress) and dietary (high fructose) factors are key triggers for flares of inflammatory bowel disease; however, the mechanisms involved in this phenomenon are not fully elucidated. This study aimed to investigate the mechanisms by which restraint stress and high fructose damage the intestinal mucosal immune barrier. The feces of C57BL/6J mice were subjected to 16S rRNA and untargeted metabolome sequencing, and the intestinal histological structure was analyzed by immunohistochemistry and immunofluorescence staining. The mRNA and protein levels of the intestinal protein were analyzed by reverse transcription-PCR (RT-PCR), Western blotting, and enzyme-linked immunosorbent assay (ELISA). The metabolites of the microbiota were tested in vitro, and Akkermansia muciniphila was used for colonization in vivo. Dietary fructose exacerbated the development of restraint stress, with an extensive change in the composition of the gut microbiota and microbial metabolites. The disturbance of the microbiota composition led to an increase in the abundance of histamine and a decrease in the abundance of taurine, which inhibited the expression of tight junction and MUC2 proteins, destroyed the function of NLRP6, and reduced intestinal autophagy level; this in turn disrupted the function of colonic goblet cells to secrete mucus, leading to defects in the intestinal mucosal barrier, which ultimately codrives colon autoinflammation. However, A. muciniphila supplementation counteracted damage to the intestinal mucosal barrier by high fructose and restraint stress. Therefore, the gut microbiota and microbiota metabolites play an important role in maintaining microenvironment homeostasis of the intestinal mucosal barrier. IMPORTANCE A high-fructose diet aggravated restraint stress-induced changes in the composition of the intestinal microbiome, in which the abundance of A. muciniphila was significantly increased. The high-fructose diet exacerbated restraint stress-induced the changes in the composition of the microbial metabolites, with taurine abundance being downregulated and histamine abundance upregulated. High fructose and restraint stress induced colonic mucosal immune barrier damage, possibly due to changes in the abundance of the microbial metabolites taurine and histamine. Colonization with A. muciniphila stimulated the expression of the NLRP6 inflammasome and activated autophagy in goblet cells, thereby producing more new mucins, which could protect the intestinal mucosal barrier.PMID:36719201 | DOI:10.1128/spectrum.04698-22

Am J Physiol Lung Cell Mol Physiol. 2023 Jan 31. doi: 10.1152/ajplung.00522.2021. Online ahead of print.ABSTRACTSupplemental oxygen is a lifesaving measure in infants born premature to facilitate oxygenation that may lead to alveolar simplification and loss of proximal airway epithelial cilia. Little is known about the mechanism of hyperoxic ciliary dysfunction in the proximal respiratory tract. We hypothesized that hyperoxia causes intraflagellar transport (IFT) dysfunction with resultant decreased cilia length. Differentiated basal human airway epithelial cells (HAEC) were exposed to hyperoxia or air for up to 48 h. Neonatal mice (<12 h old) were exposed to hyperoxia for 72 h and recovered in air until postnatal day (PND) 60. Cilia length was measured from scanning electron microscopy images using a MATLAB derived program. Proteomics and metabolomics were carried out in cells after hyperoxia. There was a significant time-dependent reduction in cilia length after hyperoxia in HAEC. Proteomic analysis showed decreased abundance of multiple proteins related to IFT including dynein motor proteins after hyperoxia. In neonatal mice exposed to hyperoxia, there was a significant decrease in acetylated α tubulin at PND10 with recovery to normal levels at PND60. In HAEC, abundance of multiple proteins associated with complex I of the electron transport chain were decreased by hyperoxia. Additionally, in HAEC, hyperoxia increased levels of malate, fumarate, and citrate, and reduced the ATP/ADP ratio at 24 h with a subsequent increase at 36 h. Exposure to hyperoxia reduces cilia length, which is associated with aberrant IFT protein expression and dysregulated metabolism. This delineates potential aberrant IFT protein expression upon hyperoxic exposure on the respiratory epithelium.PMID:36719084 | DOI:10.1152/ajplung.00522.2021

Electrophoresis. 2023 Jan 31. doi: 10.1002/elps.202200251. Online ahead of print.ABSTRACTTryptophan (TRP) is an essential amino acid catabolized mainly through the kynurenine pathway (KP), and part of it is catabolized in the brain. The abnormal depletion of TRP and production of kynurenine (KYN) by two enzymes, tryptophan 2, 3-dioxygenase (TDO) and indolamine 2, 3-dioxygenase (IDO), have been linked to various neurological diseases. The ratio of TRP/KYN in plasma is a valuable measure for IDO/TDO activity and the prognosis of disease conditions. The vinylphenyl boronic acid (4-VPBA) was evaluated as a novel stationary phase for OT-CEC-MS/MS. TRP, KYN, and 3-hydroxykynurenine (3-OHKYN) were separated using optimum conditions of 15 mM (NH4 )2 CO3 at pH 8 as a BGE and 25 kV separation voltage on a 90 cm column. The usefulness of the 4-VPBA column for simple, fast, repeatable, and sensitive CEC-ESI-MS/MS application was demonstrated for the quantitation of TRP and KYN in the plasma of healthy human subjects and neuroinflammation subjects. The plasma sample was extracted on a zirconia-based ion-exchange cartridge for simultaneous protein precipita-tion and phospholipid removal. The method of standard addition, in combination with the internal standards approach, was used to prepare the calibration curve to overcome matrix matching and eliminate procedural errors. The developed quantitation method was validated according to FDA guidelines for sensitivity, accuracy, precision, and extraction recovery. The measured plasma level of TRP and KYN in healthy humans is aligned with the human metabolome database for the same two metabolites. This article is protected by copyright. All rights reserved.PMID:36718859 | DOI:10.1002/elps.202200251

J Clin Endocrinol Metab. 2023 Jan 31:dgad034. doi: 10.1210/clinem/dgad034. Online ahead of print.ABSTRACTCONTEXT: Nearly 20% patients with Tumor-induced osteomalacia (TIO) experienced recurrence or nonrecovery after surgery. Serum FGF23 and phosphate concentrations are not capable for prognosis in such cases. Despite its importance for understanding of prognosis and underlying pathogenesis, the alteration of systemic metabolism in refractory TIO remains unclear.OBJECTIVE: We aimed to find the metabolomic characteristics of refractory TIO, and establish a novel predictive model for early discriminating refractory TIO based on their serum metabolomics.DESIGN AND SETTING: Cross-section study for comparison of metabolomic profile between TIO and normal control, and longitudinal study for identifying prognostic model.METHODS: Based on liquid chromatography-tandem mass spectrometry, we analyzed the global metabolomes of preoperative sera from 86 samples (32 TIO recovery patients, 11 non-remission patients and 43 matched controls). Statistical analyses, pathway enrichment and receiver operating characteristic analysis were performed to identified and evaluate potential markers.RESULTS: Sparse partial least squares discriminant analysis indicated a clear separation of metabolomic profiles between Healthy controls and TIO patients. The serum metabolites altered in different prognostic groups. L-Pipecolic acid, 2-Dodecylbenzenesulfonic acid and 2-Deoxygalactopyranose were the top 3 metabolites that were significantly perturbed. A combination of L-Pipecolic acid and 2-Dodecylbenzenesulfonic acid demonstrated a high-performance panel for TIO prognosis evaluated by random forest algorithm (AUC=0.921, 95% confidence interval of 0.787-0.995).CONCLUSIONS: We investigate the global metabolomes of refractory TIO and identify potential prognostic biomarkers preliminarily. A high sensitivity and specificity panel were identified as promising discriminating predictor, which need to be verified in more patients. This work may demonstrate novel insights into TIO prognosis and pathogenesis.PMID:36718510 | DOI:10.1210/clinem/dgad034

Expert Rev Hematol. 2023 Jan 30. doi: 10.1080/17474086.2023.2174521. Online ahead of print.ABSTRACTINTRODUCTION: The past decade has seen a sea change in the AML landscape with vastly improved cognizance of molecular pathogenesis, clonal evolution, importance of measurable residual disease and most importantly, approval of novel therapies in the frontline and relapsed/refractory management settings based on fitness and genomic markers. The year 2017 marks a cornerstone in the treatment landscape of AML with the approval of midostaurin in the United States for newly diagnosed fit adults with FLT3 mutated AML. Subsequently, the therapeutic armamentarium of AML considerably expanded with the approval of enasidenib, ivosidenib, gilteritinib, and venetoclax in combination with hypomethylating agents and others. Nevertheless, relapse and treatment refractoriness remain the insurmountable challenges in AML therapy. This has galvanized the leukemic research community leading to the discovery and development of agents that specifically target gene mutations, molecularly agnostic therapies that exploit immune environment, apoptotic pathways, leukemic cell surface antigens and so forth.AREAS COVERED: : This article provides an overview of the pathophysiology of AML in the context of non-cellular immune and molecularly targeted and agnostic therapies that are in clinical trial development in AML.EXPERT COMMENTARY: Ever growing understanding of the molecular pathogenesis and metabolomics in AML has allowed the researchers to identify targets directed at specific genes and metabolic pathways. As a result, AML therapy is constantly evolving and so are the escape mechanisms leading to disease relapse. Therefore, it is of paramount importance to sequentially evaluate the patient during the course of AML treatment and intervene at the right time.PMID:36718500 | DOI:10.1080/17474086.2023.2174521

Chromatographia. 2023 Jan 25:1-9. doi: 10.1007/s10337-022-04222-3. Online ahead of print.ABSTRACTSARS-CoV-2 infection in the human body induces a severe storm of inflammatory factors. However, its specific mechanism is still not clear. Gas chromatography-mass spectrometry (GC-MS) technology is expected to explain the possible mechanism of the disease by detecting differential metabolites. 15 COVID-19 patients and healthy controls were included in this study. Immune indicators such as hs CRP and cytokines were detected to reflect the level of inflammation in patients with COVID-19. The distribution of lymphocytes and subpopulations in peripheral whole blood were detected using flow cytometry to assess the immune function of COVID-19 patients. The expression of differential metabolites in serum was analyzed using GC-MS non-targeted metabolomics. The results showed that hs CRP, IL-5/6/8/10 and IFN-α in the serum of COVID-19 patients increased to varying degrees, and CD3/4/8+ T lymphocytes decreased. Additionally, 53 metabolites in the serum of COVID-19 patients were up regulated, 18 metabolites were down regulated, and 8 metabolites remained unchanged. Increased Cholesterol, Lactic Acid and 1-Monopalmitin may be the mechanism that causes excessive inflammation in COVID-19 patients. The increase of D-Allose may be involved in the process of lymphocyte decrease. In conclusion, the significance of our study is to reveal the possible mechanism of inflammatory response in patients with COVID-19 from the perspective of metabolomics. This provided a new idea for the treatment of COVID-19.PMID:36718226 | PMC:PMC9876404 | DOI:10.1007/s10337-022-04222-3

Circulation. 2023 Jan 31;147(5):e70-e71. doi: 10.1161/CIRCULATIONAHA.122.062095. Epub 2023 Jan 30.NO ABSTRACTPMID:36716256 | DOI:10.1161/CIRCULATIONAHA.122.062095

Circulation. 2023 Jan 31;147(5):e72. doi: 10.1161/CIRCULATIONAHA.122.062689. Epub 2023 Jan 30.NO ABSTRACTPMID:36716251 | DOI:10.1161/CIRCULATIONAHA.122.062689

Nat Metab. 2023 Jan;5(1):80-95. doi: 10.1038/s42255-022-00720-8. Epub 2023 Jan 26.ABSTRACTMethylmalonic aciduria (MMA) is an inborn error of metabolism with multiple monogenic causes and a poorly understood pathogenesis, leading to the absence of effective causal treatments. Here we employ multi-layered omics profiling combined with biochemical and clinical features of individuals with MMA to reveal a molecular diagnosis for 177 out of 210 (84%) cases, the majority (148) of whom display pathogenic variants in methylmalonyl-CoA mutase (MMUT). Stratification of these data layers by disease severity shows dysregulation of the tricarboxylic acid cycle and its replenishment (anaplerosis) by glutamine. The relevance of these disturbances is evidenced by multi-organ metabolomics of a hemizygous Mmut mouse model as well as through identification of physical interactions between MMUT and glutamine anaplerotic enzymes. Using stable-isotope tracing, we find that treatment with dimethyl-oxoglutarate restores deficient tricarboxylic acid cycling. Our work highlights glutamine anaplerosis as a potential therapeutic intervention point in MMA.PMID:36717752 | DOI:10.1038/s42255-022-00720-8

Funct Integr Genomics. 2023 Jan 31;23(1):53. doi: 10.1007/s10142-023-00980-x.ABSTRACTOlverembatinib represents the third-generation breakpoint cluster region protein-Abelson-murine leukemia 1 (BCR-ABL1) tyrosine kinase inhibitor with oral bioavailability, which can be used to overcome the T315I mutation in Philadelphia chromosome-positive (Ph +) leukemia. BCR-ABL-independent resistance to olverembatinib has been reported among patients in various clinical cases. However, the mechanism of olverembatinib resistance has rarely been reported. This study has illustrated bone marrow cell transcriptome and metabolome profiles among Ph + acute lymphoblastic leukemias (ALL) cases pre- and post-olverembatinib resistance. The transcriptome studies demonstrated that PI3K/AKT, purine metabolism, and other signaling pathways could play a vital role in olverembatinib resistance. As suggested by metabolomics, olverembatinib resistance in Ph + ALL was associated with purine metabolism alterations. Subsequently, high-performance liquid chromatography along with real-time quantitative PCR was utilized to measure purine metabolism-related mRNA levels and metabolism expression levels between olverembatinib resistance and sensitive cell lines. Our results elucidate the mechanism of olverembatinib resistance in Ph + ALL at transcriptome and metabolome levels, which facilitate a better understanding of olverembatinib resistance and hence may prove crucial in identifying novel drugs to tackle this conundrum.PMID:36717477 | DOI:10.1007/s10142-023-00980-x