PubMed

Front Plant Sci. 2023 Feb 15;14:1132936. doi: 10.3389/fpls.2023.1132936. eCollection 2023.ABSTRACTINTRODUCTION: The bulb of Fritillaria hupehensis, a traditional cough and expectorant medicine, is usually harvested from June to September according to traditional cultivation experience, without practical scientific guidance. Although steroidal alkaloid metabolites have been identified in F. hupehensis, the dynamic changes in their levels during bulb development and their molecular regulatory mechanisms are poorly understood.METHODS: In this study, integrative analyses of the bulbus phenotype, bioactive chemical investigations, and metabolome and transcriptome profiles were performed to systematically explore the variations in steroidal alkaloid metabolite levels and identify the genes modulating their accumulation and the corresponding regulatory mechanisms.RESULTS: The results showed that weight, size, and total alkaloid content of the regenerated bulbs reached a maximum at IM03 (post-withering stage, early July), whereas peiminine content reached a maximum at IM02 (withering stage, early June). There were no significant differences between IM02 and IM03, indicating that regenerated bulbs could be harvested appropriately in early June or July. Peiminine, peimine, tortifoline, hupehenine, korseveramine, delafrine, hericenone N-oxide, korseveridine, puqiedinone, pingbeinone, puqienine B, puqienine E, pingbeimine A, jervine, and ussuriedine levels were upregulated in IM02 and IM03, compared with IM01 (vigorous growth stage, early April). The Kyoto Encyclopedia of Genes and Genomes enrichment analysis indicated that the accumulation of steroidal alkaloid metabolites mainly occurred prior to IM02. HMGR1, DXR, CAS1, CYP 90A1, and DET2 may play a positive role in peiminine, peimine, hupehenine, korseveramine, korseveridine, hericenone N-oxide, puqiedinone, delafrine, tortifoline, pingbeinone, puqienine B, puqienine E, pingbeimine A, jervine, and ussuriedine biosynthesis, whereas the downregulation of FPS1, SQE and 17-DHCR may lead to a reduction in peimisine levels. Weighted gene correlation network analysis showed that CYP 74A2-1, CYP 74A2-2, CYP 71A26-1, CYP 71A26-2, and CYP74A were negatively correlated with peiminine and pingbeimine A, whereas CYP R and CYP707A1 were positively correlated. . CYP 74A2-1 and CYP 74A2-2 may play a negative role in peimine and korseveridine biosynthesis, whereas CYP R plays a positive role. In addition, the highly expressed C2H2, HSF, AP2/ERF, HB, GRAS, C3H, NAC, MYB-related transcription factors (TFs), GARP-G2-like TFs, and WRKY may play positive roles in the accumulation of peiminine, peimine, korseveridine, and pingbeimine A.DISCUSSION: These results provide new insights into scientific harvesting of F. hupehensis.PMID:36875619 | PMC:PMC9975545 | DOI:10.3389/fpls.2023.1132936

Front Plant Sci. 2023 Feb 15;14:1120573. doi: 10.3389/fpls.2023.1120573. eCollection 2023.NO ABSTRACTPMID:36875606 | PMC:PMC9975924 | DOI:10.3389/fpls.2023.1120573

Oncoimmunology. 2023 Feb 17;12(1):2180237. doi: 10.1080/2162402X.2023.2180237. eCollection 2023.ABSTRACTAccumulating evidence indicates that Toll-like receptor (TLR) agonists proficiently (re)instore cancer immunosurveillance as immunological adjuvants. So far, three TLR agonists have been approved by regulatory agencies for use in oncological applications. Additionally, these immunotherapeutics have been extensively investigated over the past few years. Multiple clinical trials are currently evaluating the combination of TLR agonists with chemotherapy, radiotherapy, or different immunotherapies. Moreover, antibodies targeting tumor-enriched surface proteins that have been conjugated to TLR agonists are being developed to stimulate anticancer immune responses specifically within the tumor microenvironment. Solid preclinical and translational results support the favorable immune-activating effects of TLR agonists. Here, we summarize recent preclinical and clinical advances in the development of TLR agonists for anticancer immunotherapy.PMID:36875550 | PMC:PMC9980677 | DOI:10.1080/2162402X.2023.2180237

Front Cell Infect Microbiol. 2023 Feb 15;13:1013809. doi: 10.3389/fcimb.2023.1013809. eCollection 2023.ABSTRACTBACKGROUND: Differences in bronchial microbiota composition have been found to be associated with asthma; however, it is still unclear whether these findings can be applied to recurrent wheezing in infants especially with aeroallergen sensitization.OBJECTIVES: To determine the pathogenesis of atopic wheezing in infants and to identify diagnostic biomarkers, we analyzed the bronchial bacterial microbiota of infants with recurrent wheezing and with or without atopic diseases using a systems biology approach.METHODS: Bacterial communities in bronchoalveolar lavage samples from 15 atopic wheezing infants, 15 non-atopic wheezing infants, and 18 foreign body aspiration control infants were characterized using 16S rRNA gene sequencing. The bacterial composition and community-level functions inferred from between-group differences from sequence profiles were analyzed.RESULTS: Both α- and β-diversity differed significantly between the groups. Compared to non-atopic wheezing infants, atopic wheezing infants showed a significantly higher abundance in two phyla (Deinococcota and unidentified bacteria) and one genus (Haemophilus) and a significantly lower abundance in one phylum (Actinobacteria). The random forest predictive model of 10 genera based on OTU-based features suggested that airway microbiota has diagnostic value for distinguishing atopic wheezing infants from non-atopic wheezing infants. PICRUSt2 based on KEGG hierarchy (level 3) revealed that atopic wheezing-associated differences in predicted bacterial functions included cytoskeleton proteins, glutamatergic synapses, and porphyrin and chlorophyll metabolism pathways.CONCLUSION: The differential candidate biomarkers identified by microbiome analysis in our work may have reference value for the diagnosis of wheezing in infants with atopy. To confirm that, airway microbiome combined with metabolomics analysis should be further investigated in the future.PMID:36875523 | PMC:PMC9975506 | DOI:10.3389/fcimb.2023.1013809

Front Endocrinol (Lausanne). 2023 Feb 16;14:1060470. doi: 10.3389/fendo.2023.1060470. eCollection 2023.ABSTRACTOBJECTIVE: Sepsis is a life-threatening condition secondary to infection that evolves into a dysregulated host response and is associated with acute organ dysfunction. Sepsis-induced cardiac dysfunction is one of the most complex organ failures to characterize. This study performed comprehensive metabolomic profiling that distinguished between septic patients with and without cardiac dysfunction.METHOD: Plasma samples collected from 80 septic patients were analysed by untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics. Principal component analysis (PCA), partial least squares discrimination analysis (PLS-DA), and orthogonal partial least square discriminant analysis (OPLS-DA) were applied to analyse the metabolic model between septic patients with and without cardiac dysfunction. The screening criteria for potential candidate metabolites were as follows: variable importance in the projection (VIP) >1, P < 0.05, and fold change (FC) > 1.5 or < 0.7. Pathway enrichment analysis further revealed associated metabolic pathways. In addition, we constructed a subgroup metabolic analysis between the survivors and non-survivors according to 28-day mortality in the cardiac dysfunction group.RESULTS: Two metabolite markers, kynurenic acid and gluconolactone, could distinguish the cardiac dysfunction group from the normal cardiac function group. Two metabolites, kynurenic acid and galactitol, could distinguish survivors and non-survivors in the subgroup analysis. Kynurenic acid is a common differential metabolite that could be used as a candidate for both diagnosis and prognosis for septic patients with cardiac dysfunction. The main associated pathways were amino acid metabolism, glucose metabolism and bile acid metabolism.CONCLUSION: Metabolomic technology could be a promising approach for identifying diagnostic and prognostic biomarkers of sepsis-induced cardiac dysfunction.PMID:36875476 | PMC:PMC9978788 | DOI:10.3389/fendo.2023.1060470

Front Immunol. 2023 Feb 17;14:1106881. doi: 10.3389/fimmu.2023.1106881. eCollection 2023.ABSTRACTThe complex mechanism of immune-system damage in HIV infection is incompletely understood. HIV-infected "rapid progressors" (RPs) have severe damage to the immune system early in HIV infection, which provides a "magnified" opportunity to study the interaction between HIV and the immune system. In this study, forty-four early HIV-infected patients (documented HIV acquisition within the previous 6 months) were enrolled. By study the plasma of 23 RPs (CD4+ T-cell count < 350 cells/µl within 1 year of infection) and 21 "normal progressors" (NPs; CD4+ T-cell count > 500 cells/μl after 1 year of infection), eleven lipid metabolites were identified that could distinguish most of the RPs from NPs using an unsupervised clustering method. Among them, the long chain fatty acid eicosenoate significantly inhibited the proliferation and secretion of cytokines and induced TIM-3 expression in CD4+ and CD8+ T cells. Eicosenoate also increased levels of reactive oxygen species (ROS) and decreased oxygen consumption rate (OCR) and mitochondrial mass in T cells, indicating impairment in mitochondrial function. In addition, we found that eicosenoate induced p53 expression in T cells, and inhibition of p53 effectively decreased mitochondrial ROS in T cells. More importantly, treatment of T cells with the mitochondrial-targeting antioxidant mito-TEMPO restored eicosenoate-induced T-cell functional impairment. These data suggest that the lipid metabolite eicosenoate inhibits immune T-cell function by increasing mitochondrial ROS by inducing p53 transcription. Our results provide a new mechanism of metabolite regulation of effector T-cell function and provides a potential therapeutic target for restoring T-cell function during HIV infection.PMID:36875092 | PMC:PMC9981933 | DOI:10.3389/fimmu.2023.1106881

Bioact Mater. 2023 Feb 24;26:102-115. doi: 10.1016/j.bioactmat.2023.02.015. eCollection 2023 Aug.ABSTRACTCancer cells could be eradicated by promoting generation of excessive intracellular reactive oxygen species (ROS) via emerging nanomedicines. However, tumor heterogeneity and poor penetration of nanomedicines often lead to diverse levels of ROS production in the tumor site, and ROS at a low level promote tumor cell growth, thus diminishing the therapeutic effect of these nanomedicines. Herein, we construct an amphiphilic and block polymer-dendron conjugate-derived nanomedicine (Lap@pOEGMA-b-p(GFLG-Dendron-Ppa), GFLG-DP/Lap NPs) that incorporates a photosensitizer, Pyropheophorbide a (Ppa), for ROS therapy and Lapatinib (Lap) for molecular targeted therapy. Lap, an epidermal growth factor receptor (EGFR) inhibitor that plays a role in inhibiting cell growth and proliferation, is hypothesized to synergize with ROS therapy for effectively killing cancer cells. Our results suggest that the enzyme-sensitive polymeric conjugate, pOEGMA-b-p(GFLG-Dendron-Ppa) (GFLG-DP), releases in response to cathepsin B (CTSB) after entering the tumor tissue. Dendritic-Ppa has a strong adsorption capacity to tumor cell membranes, which promotes efficient penetration and long-term retention. Lap can also be efficiently delivered to internal tumor cells to play its role due to the increased vesicle activity. Laser irradiation of Ppa-containing tumor cells results in production of intracellular ROS that is sufficient for inducing cell apoptosis. Meanwhile, Lap efficiently inhibits proliferation of remaining viable cells even in deep tumor regions, thus generating a significant synergistic anti-tumor therapeutic effect. This novel strategy can be extended to the development of efficient membrane lipid-based therapies to effectively combat tumors.PMID:36875053 | PMC:PMC9974368 | DOI:10.1016/j.bioactmat.2023.02.015

Front Physiol. 2023 Feb 15;14:1136574. doi: 10.3389/fphys.2023.1136574. eCollection 2023.ABSTRACTThe goal of this paper is to elucidate the effects of sodium restriction on hypertension and left ventricular (LV) hypertrophy in a mouse model with primary aldosteronism (PA). Mice with genetic deletion of TWIK-related acid-sensitive K (TASK)-1 and TASK-3 channels (TASK-/-) were used as the animal model of PA. Parameters of the LV were assessed using echocardiography and histomorphology analysis. Untargeted metabolomics analysis was conducted to reveal the mechanisms underlying the hypertrophic changes in the TASK-/- mice. The TASK-/- adult male mice exhibited the hallmarks of PA, including hypertension, hyperaldosteronism, hypernatremia, hypokalemia, and mild acid-base balance disorders. Two weeks of low sodium intake significantly reduced the 24-h average systolic and diastolic BP in TASK-/- but not TASK+/+ mice. In addition, TASK-/- mice showed increasing LV hypertrophy with age, and 2 weeks of the low-sodium diet significantly reversed the increased BP and LV wall thickness in adult TASK-/- mice. Furthermore, a low-sodium diet beginning at 4 weeks of age protected TASK-/- mice from LV hypertrophy at 8-12 weeks of age. Untargeted metabolomics demonstrated that the disturbances in heart metabolism in the TASK-/- mice (e.g., Glutathione metabolism; biosynthesis of unsaturated fatty acids; amino sugar and nucleotide sugar metabolism; pantothenate and CoA biosynthesis; D-glutamine and D-glutamate metabolism), some of which were reversed after sodium restriction, might be involved in the development of LV hypertrophy. In conclusion, adult male TASK-/- mice exhibit spontaneous hypertension and LV hypertrophy, which are ameliorated by a low-sodium intake.PMID:36875038 | PMC:PMC9974669 | DOI:10.3389/fphys.2023.1136574

JACC Adv. 2023 Jan;2(1):100169. doi: 10.1016/j.jacadv.2022.100169. Epub 2023 Jan 27.ABSTRACTBACKGROUND: Infants with SVHD experience morbidity related to pulmonary vascular inadequacy. Metabolomic analysis involves a systems biology approach to identifying novel biomarkers and pathways in complex diseases. The metabolome of infants with SVHD is not well understood and no prior study has evaluated the relationship between serum metabolite patterns and pulmonary vascular readiness for staged SVHD palliation.OBJECTIVES: The purpose of this study was to evaluate the circulating metabolome of interstage infants with single ventricle heart disease (SVHD) and determine whether metabolite levels were associated with pulmonary vascular inadequacy.METHODS: This was a prospective cohort study of 52 infants with SVHD undergoing Stage 2 palliation and 48 healthy infants. Targeted metabolomic phenotyping (175 metabolites) was performed by tandem mass spectrometry on SVHD pre-Stage 2, post-Stage 2, and control serum samples. Clinical variables were extracted from the medical record.RESULTS: Random forest analysis readily distinguished between cases and controls and preoperative and postoperative samples. Seventy-four of 175 metabolites differed between SVHD and controls. Twenty-seven of 39 metabolic pathways were altered including pentose phosphate and arginine metabolism. Seventy-one metabolites differed in SVHD patients between timepoints. Thirty-three of 39 pathways were altered postoperatively including arginine and tryptophan metabolism. We found trends toward increased preoperative methionine metabolites in patients with higher pulmonary vascular resistance and higher postoperative tryptophan metabolites in patients with greater postoperative hypoxemia.CONCLUSIONS: The circulating metabolome of interstage SVHD infants differs significantly from controls and is further disrupted after Stage 2. Several metabolites showed trends toward association with adverse outcomes. Metabolic dysregulation may be an important factor in early SVHD pathobiology.PMID:36875009 | PMC:PMC9979841 | DOI:10.1016/j.jacadv.2022.100169

Open Life Sci. 2023 Feb 28;18(1):20220572. doi: 10.1515/biol-2022-0572. eCollection 2023.ABSTRACTThis study set out to determine the key metabolite changes underlying the pathophysiology of severe preeclampsia (PE) using metabolic analysis. We collected sera from 10 patients with severe PE and from 10 healthy pregnant women of the same trimester and analyzed them using liquid chromatography mass spectrometry. A total of 3,138 differential metabolites were screened, resulting in the identification of 124 differential metabolites. Kyoto encyclopedia of genes and genomes pathway analysis revealed that they were mainly enriched in the following metabolic pathways: central carbon metabolism in cancer; protein digestion and absorption; aminoacyl-transfer RNA biosynthesis; mineral absorption; alanine, aspartate, and glutamate metabolism; and prostate cancer. After analysis of 124 differential metabolites, 2-hydroxybutyric acid was found to be the most critical differential metabolite, and its use allowed the differentiation of women with severe PE from healthy pregnant women. In summary, our analysis revealed that 2-hydroxybutyric acid is a potential key metabolite for distinguishing severe PE from healthy controls and is also a marker for the early diagnosis of severe PE, thus allowing early intervention.PMID:36874628 | PMC:PMC9975955 | DOI:10.1515/biol-2022-0572

Open Med (Wars). 2023 Mar 1;18(1):20230658. doi: 10.1515/med-2023-0658. eCollection 2023.ABSTRACTVitamin D is a fat-soluble vitamin with multiple functions. However, the metabolism of people with different vitamin D concentrations is still unclear. Herein, we collected clinical data and analysed the serum metabolome of people with 25-hydroxyvitamin D (25[OH]D) ≥40 ng/mL (A), 30 ng/mL ≤25(OH)D <40 ng/mL (B) and 25(OH)D <30 ng/mL (C) by the ultra-high-performance liquid chromatography-tandem mass spectrometry method. We found that haemoglobin A1c, fasting blood glucose, fasting insulin, homeostasis model assessment of insulin resistance and thioredoxin interaction protein were enhanced, while HOMA-β was reduced with the decrease of 25(OH)D concentration. In addition, people in the C group were diagnosed with prediabetes or diabetes. Metabolomics analysis showed that seven, thirty-four and nine differential metabolites were identified in the groups B vs A, C vs A and C vs B, respectively. Metabolites associated with cholesterol metabolism and bile acid biosynthesis, such as 7-ketolithocholic acid, 12-ketolithocholic acid, apocholic acid, N-arachidene glycine and d-mannose 6-phosphate, were significantly upregulated in the C group compared with the A or B groups. In conclusion, the disorder of vitamin D metabolism may be related to cholesterol metabolism and bile acid biosynthesis. This study provided a basis for exploring the possible mechanism leading to abnormal vitamin D metabolism.PMID:36874363 | PMC:PMC9979004 | DOI:10.1515/med-2023-0658

bioRxiv. 2023 Feb 16:2023.02.15.528756. doi: 10.1101/2023.02.15.528756. Preprint.ABSTRACTChanges in an organism's environment, genome, or gene expression patterns ultimately lead to changes in its metabolome. The metabolic phenotype can be under selection and is known to contribute to adaptation. However, the networked and convoluted nature of the metabolome makes relating mutations, metabolic changes, and effects on fitness challenging. To overcome this challenge, we use the Long Term Evolution Experiment (LTEE) as a model to understand how mutations can transduce themselves through a cellular network, eventually affecting metabolism and perhaps fitness. We used mass-spectrometry to broadly survey the metabolomes of both ancestors and all 12 evolved lines and combined this with genomic and expression data to suggest how mutations that alter specific reaction pathways, such as the biosynthesis of nicotinamide adenine dinucleotide, might increase fitness in the system. Our work brings the field closer to a complete genotype-phenotype map for the LTEE and a better understanding of how mutations might affect fitness through the metabolome.PMID:36874203 | PMC:PMC9985142 | DOI:10.1101/2023.02.15.528756

Comput Struct Biotechnol J. 2023 Feb 13;21:1606-1620. doi: 10.1016/j.csbj.2023.02.022. eCollection 2023.ABSTRACTShort-chain fatty acids (SCFAs) exhibit anticancer activity in cellular and animal models of colon cancer. Acetate, propionate, and butyrate are the three major SCFAs produced from dietary fiber by gut microbiota fermentation and have beneficial effects on human health. Most previous studies on the antitumor mechanisms of SCFAs have focused on specific metabolites or genes involved in antitumor pathways, such as reactive oxygen species (ROS) biosynthesis. In this study, we performed a systematic and unbiased analysis of the effects of acetate, propionate, and butyrate on ROS levels and metabolic and transcriptomic signatures at physiological concentrations in human colorectal adenocarcinoma cells. We observed significantly elevated levels of ROS in the treated cells. Furthermore, significantly regulated signatures were involved in overlapping pathways at metabolic and transcriptomic levels, including ROS response and metabolism, fatty acid transport and metabolism, glucose response and metabolism, mitochondrial transport and respiratory chain complex, one-carbon metabolism, amino acid transport and metabolism, and glutaminolysis, which are directly or indirectly linked to ROS production. Additionally, metabolic and transcriptomic regulation occurred in a SCFAs types-dependent manner, with an increasing degree from acetate to propionate and then to butyrate. This study provides a comprehensive analysis of how SCFAs induce ROS production and modulate metabolic and transcriptomic levels in colon cancer cells, which is vital for understanding the mechanisms of the effects of SCFAs on antitumor activity in colon cancer.PMID:36874158 | PMC:PMC9975252 | DOI:10.1016/j.csbj.2023.02.022

Heliyon. 2023 Feb 17;9(3):e13828. doi: 10.1016/j.heliyon.2023.e13828. eCollection 2023 Mar.ABSTRACTThe acquisition of carotenoids and polyunsaturated fatty acids (PUFAs) from plants and animals for use as functional ingredients raises concerns regarding productivity and cost; utilization of microorganisms as alternative sources is an option. We proposed to evaluate the production of carotenoids and PUFAs by Rhodopseudomonas faecalis PA2 using different vegetable oils (rice bran oil, palm oil, coconut oil, and soybean oil) as carbon source, different concentrations of yeast extract as nitrogen source at different cultivation time to ensure the best production. Cultivation with soybean oil as source of carbon led to the most significant changes in the fatty acid profile. Compared to the initial condition, the strain cultivated in the optimal conditions (4% soybean oil, 0.35% yeast extract, and 14 days of incubation) showed an increase in μmax, biomass, carotenoid productivity, and microbial lipids by 102.5%, 52.7%, 33.82%, and 34.78%, respectively. The unsaturated fatty acids content was raised with additional types of PUFAs; omega-3 [alpha-linolenic acid and eicosapentaenoic acid] and omega-6 [linoleic acid and eicosatrienoic acid] fatty acids were identified. The results of ultra high-performance liquid chromatography-electrospray ionization-quadrupole time of flight-mass spectrometry (UHPLC-ESI-QTOF-MS/MS) indicated the molecular formula and mass of bacterial metabolites were identical to those of lycopene and beta-carotene. The untargeted metabolomics revealed functional lipids and several physiologically bioactive compounds. The outcome provides scientific reference regarding carotenoids, PUFAs, and useful metabolites that have not yet been reported in the species Rhodopseudomonas faecalis for further use as a microbial-based functional ingredient.PMID:36873505 | PMC:PMC9981927 | DOI:10.1016/j.heliyon.2023.e13828

Heliyon. 2023 Mar;9(3):e14161. doi: 10.1016/j.heliyon.2023.e14161. Epub 2023 Feb 28.ABSTRACTBACKGROUND: Since the state of alarm was declared due to the COVID-19 pandemic, hospitals have been the main ones in charge of registering the therapeutic follow-up of affected people. The analysis of these data has allowed those different biochemical markers have been identified as predictors of the severity of the disease, but most of the published studies tend to be eminently descriptive and do not propose a biochemical hypothesis to explain the alteration of the results they are showing. Our objective is to recognize the main metabolic processes that are occurring in COVID-19 patients, as well as the identification of clinical parameters that are decisive to predict the severity of the disease.METHODS: A multivariate analysis was carried out from the clinical parameters collected in the database of the HM hospitals in Madrid, to determine the most relevant variables to predict the severity of the disease. Chemometric methods allow these variables to be obtained by applying a classification strategy with PLS-LDA.FINDINGS AND INTERPRETATION: The variables that most contribute to separation are age in men and, in both sexes, the concentration of lactate dehydrogenase, urea and C-reactive protein.Oxygen deficiency in the tissues, due to the loss of functionality of the lungs, could be affecting the muscle tissue with special severity. Inflammation and tissue damage is related to increased LDH and CRP. The loss of muscle mass and the increase in the concentration of urea and LDH is explained by the adaptation of muscle metabolism to this oxygen deficiency.FUNDING: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profits sectors.PMID:36873473 | PMC:PMC9972677 | DOI:10.1016/j.heliyon.2023.e14161

Pulm Circ. 2023 Mar 1;13(1):e12205. doi: 10.1002/pul2.12205. eCollection 2023 Jan.ABSTRACTIn pulmonary artery hypertension (PAH), emerging evidence suggests that metabolic abnormalities may be contributing to cellular dysfunction in PAH. Metabolic abnormalities such as glycolytic shift have been observed intracellularly in several cell types in PAH, including microvacular endothelial cells (MVECs). Concurrently, metabolomics of human PAH samples has also revealed a variety of metabolic abnormalities; however the relationship between the intracellular metabolic abnormalities and the serum metabolome in PAH remains under investigation. In this study, we utilize the sugen/hypoxia (SuHx) rodent model of PAH to examine the RV, LV and MVEC intracellular metabolome (using targeted metabolomics) in normoxic and SuHx rats. We additionally validate key findings from our metabolomics experiments with data obtained from cell culture of normoxic and SuHx MVECs, as well as metabolomics of human serum samples from two different PAH patient cohorts. Taken together, our data, spanning rat serum, human serum and primary isolated rat MVECs reveal that: (1) key classes of amino acids (specifically, branched chain amino acids-BCAA) are lower in the pre-capillary (i.e., RV) serum of SuHx rats (and humans); (2) intracellular amino acid levels (in particular BCAAs) are increased in SuHx-MVECs; (3) there may be secretion rather than utilization of amino acids across the pulmonary microvasculature in PAH and (4) an oxidized glutathione gradient is present across the pulmonary vasculature, suggesting a novel fate for increased glutamine uptake (i.e., as a source of glutathione). in MVECs in PAH. In summary, these data reveal new insight into the shifts in amino acid metabolism occurring across the pulmonary circulation in PAH.PMID:36873460 | PMC:PMC9978170 | DOI:10.1002/pul2.12205

EClinicalMedicine. 2023 Apr;58:101884. doi: 10.1016/j.eclinm.2023.101884. Epub 2023 Feb 27.ABSTRACTBACKGROUND: We aimed to characterise the long-term health outcomes of survivors of severe acute respiratory syndrome (SARS) and determine their recovery status and possible immunological basis.METHODS: We performed a clinical observational study on 14 health workers who survived SARS coronavirus infection between Apr 20, 2003 and Jun 6, 2003 in Haihe Hospital (Tianjin, China). Eighteen years after discharge, SARS survivors were interviewed using questionnaires on symptoms and quality of life, and received physical examination, laboratory tests, pulmonary function tests, arterial blood gas analysis, and chest imaging. Plasma samples were collected for metabolomic, proteomic, and single-cell transcriptomic analyses. The health outcomes were compared 18 and 12 years after discharge. Control individuals were also health workers from the same hospital but did not infect with SARS coronavirus.FINDINGS: Fatigue was the most common symptom in SARS survivors 18 years after discharge, with osteoporosis and necrosis of the femoral head being the main sequelae. The respiratory function and hip function scores of the SARS survivors were significantly lower than those of the controls. Physical and social functioning at 18 years was improved compared to that after 12 years but still worse than the controls. Emotional and mental health were fully recovered. Lung lesions on CT scans remained consistent at 18 years, especially in the right upper lobe and left lower lobe lesions. Plasma multiomics analysis indicated an abnormal metabolism of amino acids and lipids, promoted host defense immune responses to bacteria and external stimuli, B-cell activation, and enhanced cytotoxicity of CD8+ T cells but impaired antigen presentation capacity of CD4+ T cells.INTERPRETATION: Although health outcomes continued to improve, our study suggested that SARS survivors still suffered from physical fatigue, osteoporosis, and necrosis of the femoral head 18 years after discharge, possibly related to plasma metabolic disorders and immunological alterations.FUNDING: This study was funded by the Tianjin Haihe Hospital Science and Technology Fund (HHYY-202012) and Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-063B, TJYXZDXK-067C).PMID:36873427 | PMC:PMC9969173 | DOI:10.1016/j.eclinm.2023.101884

Front Bioeng Biotechnol. 2023 Feb 17;11:1006246. doi: 10.3389/fbioe.2023.1006246. eCollection 2023.ABSTRACTBackground: With the development of chronic kidney disease (CKD), there are various changes in metabolites. However, the effect of these metabolites on the etiology, progression and prognosis of CKD remains unclear. Objective: We aimed to identify significant metabolic pathways in CKD progression by screening metabolites through metabolic profiling, thus identifying potential targets for CKD treatment. Methods: Clinical data were collected from 145 CKD participants. GFR (mGFR) was measured by the iohexol method and participants were divided into four groups according to their mGFR. Untargeted metabolomics analysis was performed via UPLC-MS/MSUPLC-MSMS/MS assays. Metabolomic data were analyzed by MetaboAnalyst 5.0, one-way ANOVA, principal component analysis (PCA), and partial least squares discriminant analysis (PLS-DA) to identify differential metabolites for further analysis. The open database sources of MBRole2.0, including KEGG and HMDB, were used to identify significant metabolic pathways in CKD progression. Results: Four metabolic pathways were classified as important in CKD progression, among which the most significant was caffeine metabolism. A total of 12 differential metabolites were enriched in caffeine metabolism, four of which decreased with the deterioration of the CKD stage, and two of which increased with the deterioration of the CKD stage. Of the four decreased metabolites, the most important was caffeine. Conclusion: Caffeine metabolism appears to be the most important pathway in the progression of CKD as identified by metabolic profiling. Caffeine is the most important metabolite that decreases with the deterioration of the CKD stage.PMID:36873366 | PMC:PMC9981652 | DOI:10.3389/fbioe.2023.1006246

Expo Health. 2023;15(1):33-51. doi: 10.1007/s12403-022-00470-8. Epub 2022 Mar 22.ABSTRACTMicro- and nanoplastics (MNPs) are recognized as emerging contaminants, especially in food, with unknown health significance. MNPs passing through the gastrointestinal tract have been brought in context with disruption of the gut microbiome. Several molecular mechanisms have been described to facilitate tissue uptake of MNPs, which then are involved in local inflammatory and immune responses. Furthermore, MNPs can act as potential transporters ("vectors") of contaminants and as chemosensitizers for toxic substances ("Trojan Horse effect"). In this review, we summarize current multidisciplinary knowledge of ingested MNPs and their potential adverse health effects. We discuss new insights into analytical and molecular modeling tools to help us better understand the local deposition and uptake of MNPs that might drive carcinogenic signaling. We present bioethical insights to basically re-consider the "culture of consumerism." Finally, we map out prominent research questions in accordance with the Sustainable Development Goals of the United Nations.PMID:36873245 | PMC:PMC9971145 | DOI:10.1007/s12403-022-00470-8

ACS Omega. 2023 Feb 16;8(8):7722-7737. doi: 10.1021/acsomega.2c06469. eCollection 2023 Feb 28.ABSTRACTChronic kidney disease (CKD) is the end point of a number of systemic chronic diseases. The prevalence of CKD is increasing worldwide and recent epidemiological studies are showing the high prevalence of renal failure in CKD patients using complementary and alternative medicines (CAMs). Clinicians believe that biochemical profiles of CKD patients using CAM (referred here to as CAM-CKD) may be different compared to those on standard clinical treatment and should be managed differently. The present study aims to explore the potential of the NMR-based metabolomics approach to reveal the serum metabolic disparity between CKD and CAM-CKD patients with respect to normal control (NC) subjects and if the differential metabolic patterns can provide rationale for the efficacy and safety of standard and/or alternative therapies. Serum samples were obtained from 30 CKD patients, 43 CAM-CKD patients, and 47 NC subjects. The quantitative serum metabolic profiles were measured using 1D 1H CPMG NMR experiments performed at 800 MHz NMR spectrometer. The serum metabolic profiles were compared using various multivariate statistical analysis tools available on MetaboAnalyst (freely available web-based software) such as partial least-squares discriminant analysis (PLS-DA) and random forest (a machine learning) classification method. The discriminatory metabolites were identified based on variable importance in projection (VIP) statistics and further evaluated for statistical significance (i.e., p < 0.05) using either Student t-test or ANOVA statistics. PLS-DA models were capable of clustering CKD and CAM-CKD with considerably high values of Q 2 and R 2. Compared to CAM-CKD patients, the sera of CKD patients were characterized by (a) elevated levels of urea, creatinine, citrate, glucose, glycerol, and phenylalanine and phenylalanine-to-tyrosine ratio (PTR) and (b) decreased levels of various amino acids (such leucine, isoleucine, valine, and alanine), high-density lipoproteins, lactate, and acetate. These changes suggested that CKD patients manifest severe oxidative stress, hyperglycemia (with dampened glycolysis), increased protein energy wasting, and reduced lipid/membrane metabolism. Statistically significant and strong positive correlation of PTR with serum creatinine levels suggested the role of oxidative stress in the progression of kidney disease. Significant differences in metabolic patterns between CKD and CAM-CKD patients were observed. With respect to NC subjects, the serum metabolic changes were more aberrant in CKD patients compared to CAM-CKD patients. The aberrant metabolic changes in CKD patients with manifestations of higher oxidative stress compared to CAM-CKD patients could explain clinical discrepancies between CKD and CAM-CKD patients and further advocate the use of different treatment strategies for CKD and CAM-CKD patients.PMID:36872986 | PMC:PMC9979328 | DOI:10.1021/acsomega.2c06469