Metabolic Changes Research Articles

Bacterial and clinical metabolic signatures and their interactions in obese patients post-bariatric surgery

BackgroundObesity is a growing health concern in China, closely linked to metabolic disorders such as type 2 diabetes. Laparoscopic Sleeve Gastrectomy (LSG) is effective in promoting weight loss and improving metabolic outcomes. Emerging evidence highlights the role of gut microbiota in metabolic regulation, yet the specific alterations in gut microbiota and their association with metabolic changes post-surgery in Chinese patients remain unclear. Understanding these shifts could provide key insights into optimizing treatment strategies for metabolic improvement following bariatric surgery.MethodsStool samples and clinical data were collected from 30 obese patients before and 6 months after surgery. The composition of the gut microbiota was analyzed through 16S rRNA sequencing, and Spearman correlation analysis was used to determine the association between gut microbiota and clinical indicators.ResultsThe analysis of 30 patients showed a significant decrease in Body Mass Index (BMI) (36.75 ± 4.09 kg/m2 vs 26.37 ± 3.47 kg/m2, p < 0.0001). Glucose metabolism, including Hemoglobin A1C levels, improved significantly (6.05 ± 0.96 vs 5.05 ± 0.25, p < 0.0001), and liver function as well as serum lipid levels were also notably improved. LSG increased the richness and composition of gut microbiota in obese patients post-surgery. These changes in gut microbiota were closely associated with improved clinical metabolic parameters.ConclusionLSG not only significantly reduces body weight while also alleviating metabolic syndrome and comorbidities by altering gut microbiota.

Biochemical changes in the aetiology of floppy kid syndrome in goat kids

AbstractIn the herd, 20 of 75 goat kids born became progressively ill. Twelve affected kids, aged 4–9 days, exhibited muscle weakness, pain without fever, diarrhoea and dehydration. Their health deteriorated rapidly, and within a few hours, one kid died. The results of the blood test revealed severe metabolic acidosis, hypokalaemia and changes in urea concentrations. Floppy kid syndrome was diagnosed. Treatment was initiated to correct the acid–base balance, and all affected kids were temporarily separated from their mothers. All the treated kids recovered. Before the onset of clinical signs, elevated urea concentrations and differences in maternal blood potassium levels were observed. This is the first report on changes in potassium concentrations in periparturient dams of goat kids with and without floppy kid syndrome, as well as the first report on changes in urea concentrations in kids before the onset of clinical signs.

Multi-omics approach to reveal follicular metabolic changes and their effects on oocyte competence in PCOS patients

BackgroundPolycystic ovary syndrome (PCOS) is a common heterogeneous disorder linked with endocrine and metabolic disturbances. The underlying mechanism of PCOS, especially its effect on oocyte competence, remains unclear. The study aimed to identify abnormal follicular metabolic changes using a multi-omics approach in follicular fluid from PCOS patients and to determine their effects on oocyte competence.MethodsA total of 36 women with PCOS and 35 women without PCOS who underwent in vitro fertilization and embryo transfer were included in the study. Cumulus cells and follicular fluid samples were collected. Follicular fluid samples underwent metabolomic analysis, while cumulus cell clusters from the same patients were assessed using transcriptomic analysis. Clinical information of patients and assisted reproductive technology (ART) results were recorded. Transcriptomics and metabolomics were integrated to identify disrupted pathways, and receiver operation characteristics (ROC) analysis was conducted to identify potential diagnostic biomarkers for PCOS. Pearson correlation analysis was conducted to assess the relationship between metabolites in follicular fluid and oocyte competence (fertilization and early embryo development potential).ResultsThrough multi-omics analysis, we identified aberrantly expressed pathways at both transcriptional and metabolic levels, such as the citrate cycle (TCA cycle), oxidative phosphorylation, the cAMP signaling pathway, the mTOR signaling pathway, and steroid hormone biosynthesis. Ten candidate metabolites were identified based on metabolic profiling data from these altered pathways. Phytic acid, succinic acid, 2’-deoxyinosine triphosphate, and 4-trimethylammoniobutanoic acid in the follicular fluid exhibited high specificity and sensitivity in distinguishing PCOS. Among these metabolites, L-arginine showed a negative correlation with the 2PN fertilization rate and cleavage rate, while estrone sulfate showed a negative correlation with the high-quality embryo rate in the in-vitro fertilization (IVF) cycle.ConclusionsWe have conducted a preliminary study of a novel metabolic signature in women with PCOS using a multi-omics approach. The alterations in key metabolic pathways may enhance our understanding of the pathogenesis of PCOS.

Associations between plasma markers and symptoms of anxiety and depression in patients with breast cancer

Background and purposeAmong patients with solid tumors, those with breast cancer (BC) experience the most severe psychological issues, exhibiting a high global prevalence of depression that negatively impacts prognosis. Depression can be easily missed, and clinical markers for its diagnosis are lacking. Therefore, this study in order to investigate the diagnostic markers for BC patients with depression and anxiety and explore the specific changes of metabolism.Method and resultsThirty-eight BC patients and thirty-six matched healthy controls were included in the study. The anxiety and depression symptoms of the participants were evaluated by the 17-item Hamilton Depression Scale (HAMD-17) and Hamilton Anxiety Scale (HAMA). Plasma levels of glial fibrillary acidic protein (GFAP) and lipocalin-2 (LCN2) were evaluated using enzyme linked immunosorbent assay, and plasma lactate levels and metabolic characteristics were analyzed.ConclusionThis study revealed that GFAP and LCN2 may be good diagnostic markers for anxiety or depression in patients with BC and that plasma lactate levels are also a good diagnostic marker for anxiety. In addition, specific changes in metabolism in patients with BC were preliminarily explored.

Targeted metabolomic profiling of acute ST-segment elevation myocardial infarction

Myocardial infarction is a major cause of morbidity and mortality worldwide. Metabolomic investigations may be useful for understanding the pathogenesis of ST-segment elevation myocardial infarction (STEMI). STEMI patients were comprehensively examined via targeted metabolomic profiling, machine learning and weighted correlation network analysis. A total of 195 subjects, including 68 STEMI patients, 84 patients with stable angina pectoris (SAP) and 43 non-CVD patients, were enrolled in the study. Metabolomic profiling involving the quantitative analysis of 87 endogenous metabolites in plasma was conducted. This study is the first to perform targeted metabolomic profiling in patients with STEMI. We identified 36 significantly altered metabolites in STEMI patients. Increased levels of four amino acids, eight acylcarnitines, six metabolites of the NO–urea cycle and neurotransmitters, and three intermediates of tryptophan metabolism were detected. The following metabolites exhibited decreased levels: six amino acids, three acylcarnitines, three components of the NO–urea cycle and neurotransmitters, and three intermediates of tryptophan metabolism. We found that the significant changes in tryptophan metabolism observed in STEMI patients—the increase in anthranilic acid and tryptophol and decrease in xanthurenic acid and 3-OH-kynurenine—may play important roles in STEMI pathogenesis. On the basis of the differences in the constructed weighted correlation networks, new significant metabolite ratios were identified. Among the 22 significantly altered metabolite ratios identified, 13 were between STEMI patients and non-CVD patients, and 17 were between STEMI patients and SAP patients. Seven of these ratios were common to both comparisons (STEMI patients vs. non-CVD patients and STEMI patients vs. SAP patients). Additionally, two ratios were consistently observed among the STEMI, SAP and non-CVD groups (anthranilic acid: aspartic acid and GSG (glutamine: serine + glycine)). These findings provide new insight into the diagnosis and pathogenesis of STEMI.

How lactate affects immune strategies in lymphoma

Tumor cells undergo metabolic reprogramming through shared pathways, resulting in a hypoxic, acidic, and highly permeable internal tumor microenvironment (TME). Lactate, once only regarded as a waste product of glycolysis, has an inseparable dual role with tumor immunity. It can not only provide a carbon source for immune cells to enhance immunity but also help the immune escape through a variety of ways. Lymphoma also depends on the proliferation signal of TME. This review focuses on the dynamic process of lactate metabolism and immune function changes in lymphoma and aims to comprehensively summarize and explore which genes, transcription factors, and pathways affect the biological changes and functions of immune cells. To deeply understand the complex and multifaceted role of lactate metabolism and immunity in lymphoma, the combination of lactate targeted therapy and classical immunotherapy will be a promising development direction in the future.

Physiological and metabolomic analyses reveal the mechanism by which exogenous spermine improves drought resistance in alfalfa leaves (Medicago sativa L.)

IntroductionAlfalfa (Medicago sativa L.) is a globally important legume crop with high nutritional and ecological value. Drought poses a serious threat to alfalfa acreage and yields. Spermine (Spm) has been shown to protect plants from drought damage. The aim of this study was to clarify the mechanism of exogenous Spm to improve drought resistance of alfalfa. MethodsIn this study, we root applied 0.1, 0.5, and 1 mM Spm to Gannong No. 3 (G3) alfalfa under drought stress, and then determined their physiological and metabolic changes. ResultsThe results showed that exogenous Spm increased chlorophyll content, chlorophyll fluorescence parameters and gas exchange parameters, enhanced antioxidant enzymes activity, improved ascorbic acid-glutathione (AsA-GSH) cycle, increased osmoregulatory substances content, reduced hydrogen peroxide and superoxide anion levels, and inhibited malondialdehyde accumulation in alfalfa under drought stress, thereby increasing plant height and leaf relative water content and enhancing drought tolerance of alfalfa. The redundancy analysis of the above physiological indicators showed that the addition of the optimal Spm to improve drought tolerance of alfalfa under drought stress was mainly achieved by increasing catalase activity and improving the ASA-GSH cycle. In addition, metabolomics analysis revealed that exogenous Spm increased the content of oxobutanedioic acid, citric acid, fumaric acid and malic acid to enhance the tricarboxylic acid cycle. Meanwhile, exogenous Spm increased endogenous Spm and proline (Pro) content to resist drought stress by enhancing Spm and Pro metabolism. Moreover, exogenous Spm increased the accumulation of the signaling substance abscisic acid. DiscussionIn conclusion, exogenous Spm enhanced drought resistance of alfalfa leaves under drought stress.

Systematic preoperative approach for bariatric surgery, perioperative results, and economic impact

IntroductionObesity is a complex systemic condition, involving numerous anatomical and metabolic changes. Therefore, a comprehensive preoperative assessment is essential for each patient contemplating bariatric surgery.ObjetiveThis study presents the findings of a proposed protocol designed to streamline the pre-anesthesia consultation process. Our aim was to compare the efficiency and costs of consultations guided by the protocol with those conducted without a specific strategy. The secondary outcomes assessed included postoperative (PO) length of hospital stay and surgical duration.Matherial and methodsWe conducted a retrospective cross-sectional analysis involving 206 clinical cases. Statistical analyses, including the chi-squared test, Student’s t-test, and Mann–Whitney U test, were utilized based on the type of variables.ResultsThe results showed a significant reduction in the costs, pre-anesthesia consultation duration, time spent in the recovery unit, and the need for referrals. However, no statistically significant differences were observed in the delay before surgery and length of hospital stays, measured in days.ConclusionThis algorithm offers a promising approach for optimizing perioperative management in bariatric surgery, demonstrating its effectiveness in cutting costs and reducing the need for referrals.

Pediatric migraine is characterized by traits of ecological and metabolic dysbiosis and inflammation.

Recently, there has been increasing interest in the possible role of the gut microbiota (GM) in the onset of migraine. Our aim was to verify whether bacterial populations associated with intestinal dysbiosis are found in pediatric patients with migraine. We looked for which metabolic pathways, these bacteria were involved and whether they might be associated with gut inflammation and increased intestinal permeability. Patients aged between 6 and 17years were recruited. The GM profiling was performed by the 16S rRNA metataxonomics of faecal samples from 98 patients with migraine and 98 healthy subjects. Alpha and beta diversity analyses and multivariate and univariate analyses were applied to compare the gut microbiota profiles between the two group. To predict functional metabolic pathways, we used phylogenetic analysis of communities. The level of indican in urine was analyzed to investigate the presence of metabolic dysbiosis. To assess gut inflammation, increased intestinal permeability and the mucosal immune activation, we measured the plasmatic levels of lipopolysaccharide, occludin and IgA, respectively. The α-diversity analysis revealed a significant increase of bacterial richness in the migraine group. The β-diversity analysis showed significant differences between the two groups indicating gut dysbiosis in patients with migraine. Thirty-seven metabolic pathways were increased in the migraine group, which includes changes in tryptophan and phenylalanine metabolism. The presence of metabolic dysbiosis was confirmed by the increased level of indican in urine. Increased levels of plasmatic occludin and IgA indicated the presence of intestinal permeability and mucosal immune activation. The plasmatic LPS levels showed a low intestinal inflammation in patients with migraine. Pediatric patients with migraine present GM profiles different from healthy subjects, associated with metabolic pathways important in migraine.

NURSING PERFORMANCE IN PATIENTS WITH CHRONIC RENAL FAILURE AND DIABETES MELLITUS

The goal was to identify the importance of nursing care to the patient with renal impairment and diabetes mellitus. As for the methodology, we opted for a bibliographic review by searching in Latin American and Caribbean Health Sciences (Lilacs), Scientific Eletronic Library Online (Scielo) and Nursing Database (BDEF). and Discussion: It was observed that diabetes is a chronic disease that is characterized by changes in glucose metabolism, whether by poor insulin production-type 1, or by resistance to its action, as it has happened in type 2. That the performance of nursing in the care of patients with diabetes mellitus and chronic renal failure is critical, where the professional employs a systematization of nursing care ensuring the patient a whole and individualized care. It is concluded that the nursing team should act in the promotion of health and/or prevention of diseases such as diabetes and their comorbidities. Also, it was observed in this review that the actions of permanent education and orientation of patients for self-care should be intensely promoted by nurses, among this population who, because they have diabetes mellitus, are pre-discredted the risk factors for development of chronic renal failure.

Multi-scale phenotyping of senescence-related changes in roots of Rapeseed in response to nitrate limitation.

Root senescence remains largely unexplored. In this study, the temporality of the morphological, metabolic, and proteomic changes occurring with root aging were investigated, providing a comprehensive picture of the root senescence program. We found novel senescence-related markers for the characterization of the developmental stage of root tissues. The rapeseed root system is unique in that it consists of the taproot and lateral roots. Our study confirms that the taproot, which transiently accumulates large quantities of starch and proteins, is specifically dedicated to nutrient storage and remobilization, while the lateral roots are mainly dedicated to nutrient uptake. Proteomic data from the taproot and lateral roots highlight the different senescence-related events that control nutrient remobilization and nutrient uptake capacities. Both the proteome and enzyme activities revealed senescence-induced proteases and nucleotide catabolic enzymes that deserve attention as they may play important roles in nutrient remobilization efficiency in rapeseed roots. Taking advantage of publicly available transcriptomic and proteomic data on senescent Arabidopsis leaves, we have highlighted new lists of senescence-related proteins specific or common to root organs and/or leaves.

The use of 7T MRI in multiple sclerosis: review and consensus statement from the North American imaging in multiple sclerosis cooperative

Abstract The use of ultra-high field 7 Tesla (7T) MRI in multiple sclerosis (MS) research has grown significantly over the past two decades. With recent regulatory approvals of 7T scanners for clinical use in 2017 and 2020, the use of this technology for routine care is poised to continue to increase in the coming years. In this context, the North American Imaging in MS Cooperative (NAIMS) convened a workshop in February 2023 to review the previous and current use of 7T technology for MS research, and potential future research and clinical applications. In this workshop, experts were tasked with reviewing the current literature and proposing a series of consensus statements, which were reviewed and approved by NAIMS. In this review and consensus paper, we provide background on the use of 7T MRI in MS research, highlighting this technology’s promise for identification and quantification of aspects of MS pathology that are more difficult to visualize with lower field MRI, such as gray matter lesions, paramagnetic rim lesions, leptomeningeal enhancement, and the central vein sign. We also review the promise of 7T MRI to study metabolic and functional changes to the brain in MS. NAIMS provides a series of consensus statements regarding what is currently known about the use of 7T MRI in MS, and additional statements intended to provide guidance as to what work is necessary going forward to accelerate 7T MRI research in MS and translate this technology for use in clinical practice and clinical trials. This includes guidance on technical development, proposals for a universal acquisition protocol, and suggestions for research geared towards assessing the utility of 7T MRI to improve MS diagnostics, prognostics, and therapeutic efficacy monitoring. NAIMS expects that this article will provide a roadmap for future use of 7T MRI in MS.

Glutamine Oxidation in Mouse Dorsal Root Ganglia Regulates Pain Resolution and Chronification.

Chronic pain remains a significant health challenge with limited effective treatments. This study investigates the metabolic changes underlying pain progression and resolution, uncovering a novel compensatory mechanism in sensory neurons. Using the hyperalgesic priming model in male mice, we demonstrate that nerve growth factor (NGF) initially disrupted mitochondrial pyruvate oxidation, leading to acute allodynia. Surprisingly, this metabolic disruption persisted even after the apparent resolution of allodynia. We discovered that during the resolution phase, sensory neurons exhibit increased glutamine oxidation and upregulation of the major glutamine transporter ASCT2 in dorsal root ganglia (DRGs). This compensatory response plays a crucial role in pain resolution, as demonstrated by our experiments. Knockdown of ASCT2 prevents the resolution of NGF-induced allodynia and precipitates the transition to a chronic state. Furthermore, we show that the glutamine catabolite α-ketoglutarate attenuated glycolytic flux and alleviated allodynia in both acute and chronic phases of the hyperalgesic priming model. The importance of ASCT2 is further confirmed in a translational model, where its knockdown prevented the resolution of allodynia following plantar incision. These findings highlight the pivotal role of metabolic changes in pain resolution and identify ASCT2-mediated glutamine metabolism as a potential therapeutic target for chronic pain. Understanding these endogenous mechanisms that promote pain resolution can guide the development of novel interventions to prevent the transition pain from acute to chronic.Significance Statement Chronic pain is a widespread health issue with limited effective treatments. This study unveils a critical metabolic mechanism in sensory neurons that determines whether acute pain resolves or becomes chronic. We discovered that pain resolution depends on a compensatory increase in glutamine metabolism, mediated by the transporter ASCT2, rather than normalization of initial metabolic disruptions. This finding significantly advances our understanding of pain chronification and identifies a novel therapeutic target. By elucidating how the body naturally resolves pain, we open new avenues for developing treatments that could prevent acute pain from transitioning to chronic pain or treat existing chronic pain. This research has the potential to transform pain management strategies and improve quality of life for millions of pain sufferers.

5-oxoETE promote thrombosis in antiphospholipid syndrome by triggering NETs formation through PLC/PKC/ERK pathway.

One mechanism by which antiphospholipid syndrome (APS) IgG contribute to thrombotic events in patients with APS is through the potentiation of neutrophil extracellular traps (NETs) release. However, the exact mechanism by which APS IgG induces NETs formation and thrombosis has not been fully elucidated. We conducted untargeted metabolomics on serum samples from thrombotic APS patients to identify metabolic changes. The effect of 5-oxoETE on NETs formation and oxidative stress was evaluated in vitro by treating neutrophils with various concentrations of 5-oxoETE. The involvement of the PLC/PKC/ERK signaling pathway in 5-oxoETE-induced NETs formation was examined using pharmacological inhibitors. In vivo, we assessed the effects of inhibiting 5-oxoETE synthesis or blocking its receptor (OXE-R) on NETs formation and thrombosis in APS mouse models. Serum metabolomics revealed significantly elevated levels of 5-oxoETE in APS patients. In vitro experiments demonstrated that 5-oxoETE, via OXE-R activation of the PLC/PKC/ERK signaling pathway, increased NETs formation and oxidative stress in a dose-dependent manner. In vivo, inhibiting 5-oxoETE synthesis or OXE-R reduced NETs formation and attenuated venous thrombosis in APS mice models. This study identifies 5-oxoETE as a critical mediator of NET formation and thrombosis in APS. Targeting 5-oxoETE or OXE-R may offer a promising therapeutic approach for thrombotic APS and other NET-associated autoimmune diseases.

Influence of a structured, 1-year-long dietary intervention regarding body composition and cardiovascular risk (ARCTIC) in coeliac disease: a protocol of a multicentre randomised controlled trial

IntroductionCoeliac disease (CD) affects 1% of the population worldwide. The only available evidence-based treatment is a strict gluten-free diet (GFD), which can readily lead to weight gain and unfavourable metabolic...

Salivary microbiota composition before and after use of proton pump inhibitors in patients with laryngopharyngeal reflux: a self-control study

BackgroundIssues associated with proton pump inhibitor (PPI) usage have been documented. PPIs affect the gastrointestinal microbiome, as well as the saliva microbiota of healthy individuals. However, the alterations in the saliva microbiota of laryngopharyngeal reflux (LPR) patients remain unclear. This study aims to examine the composition of saliva microbiota in LPR patients before and after PPI usage through a self-controlled study.MethodsThirty-two adult LPR patients participated in the study. Saliva samples were collected before and after an 8-week regimen of twice-daily administration of 20-mg esomeprazole. The impact of PPI administration on bacterial communities was assessed using 16 S rRNA gene sequencing. The functional and metabolic changes in saliva microbial communities after PPI usage were analyzed using PICRUSt2 based on our 16 S rRNA gene sequencing results.ResultsThe alpha diversity within the salivary microbiota, as measured by the PD-whole-tree index, exhibited a significant difference between samples collected before and after PPI application (P = 0.038). Additionally, PCoA analysis of unweighted UniFrac distances (beta diversity) revealed distinct separation of saliva sample microbiota structures before and after PPI application in LPR patients, with statistical significance (Adonis test, R2 = 0.063, P< 0.010). Taxon-based analysis indicated that PPI administration increased the abundance of Epsilonproteobacteria, Campylobacterales, Campylobacteraceae, Campylobacter, and Campylobacter_gracilis, while reducing the abundance of Lactobacillaceae and Lactobacillus in salivary samples ( P< 0.050). Using LEfSe to compare bacterial abundances, Bacillaceae and Anoxybacillus were found to be enriched before PPI usage in LPR patients. Furthermore, the proportion of genes responsible for indole alkaloid biosynthesis in the salivary microbiota of LPR patients significantly increased after PPI therapy (P< 0.050).ConclusionsThese findings indicate that PPIs induce alterations in the salivary microbiota of LPR patients.Chinese clinical trial registryNo. ChiCTR2300067507. Registered on January 10,2023 retrospectively.Level of evidence4.

The brain-body energy conservation model of aging.

Aging involves seemingly paradoxical changes in energy metabolism. Molecular damage accumulation increases cellular energy expenditure, yet whole-body energy expenditure remains stable or decreases with age. We resolve this apparent contradiction by positioning the brain as the mediator and broker in the organismal energy economy. As somatic tissues accumulate damage over time, costly intracellular stress responses are activated, causing aging or senescent cells to secrete cytokines that convey increased cellular energy demand (hypermetabolism) to the brain. To conserve energy in the face of a shrinking energy budget, the brain deploys energy conservation responses, which suppress low-priority processes, producing fatigue, physical inactivity, blunted sensory capacities, immune alterations and endocrine 'deficits'. We term this cascade the brain-body energy conservation (BEC) model of aging. The BEC outlines (1) the energetic cost of cellular aging, (2) how brain perception of senescence-associated hypermetabolism may drive the phenotypic manifestations of aging and (3) energetic principles underlying the modifiability of aging trajectories by stressors and geroscience interventions.

COSMIC Database and Structural Modeling Analysis of CYP2D6 Mutations in Human Cancers.

Single nucleotide polymorphisms (SNPs) in cytochrome P450 (CYP450) enzymes alter the metabolism of a variety of drugs. Numerous medications, including chemotherapies, are metabolized by CYP450 enzymes, making the expression of this suite of enzymes in tumor cells relevant to prescription regimens for cancer patients. We analyzed the characteristics of mutations of the CYP2D6 enzymes in cancer patients obtained from the Catalogue of Somatic Mutations in Cancer (COSMIC), including mutation type, age of the patient, tissue type, and histology. Mutations were analyzed through the Cancer-Related Analysis of Variants Toolkit (CRAVAT) software along with CHASM and VEST4 algorithms to determine the likelihood of being a driver and/or pathogenic mutation. For mutations with significant CHASM and VEST4 scores, structural analysis of each corresponding mutant protein was performed. The effect of each mutation was evaluated for its impact on the overall protein stability and ligand binding using Foldit Standalone and SwissDock, respectively. Structural analysis revealed that several missense mutations in CYP2D6 resulted in altered stability after energy minimization. Three missense mutations of CYP2D6 significantly altered docking stability and those located on alpha-helices near the docking site had a more significant impact than those not found in secondary protein structures. In conclusion, we have identified a series of mutations to CYP2D6 enzymes with possible relevance to cancer pathologies. Significance Statement CYP2D6 is responsible for the metabolism of many anti-cancer drugs. This study identified and characterized a series of mutations in the CYP2D6 enzyme that occurred in tumors. We found it likely that many of these mutations would alter enzyme function, leading to changes in drug metabolism in the tumor. We provide a basis for predicting the likelihood of a patient carrying these mutations to identify patients who may benefit from a precision medicine approach to drug selection and dosing.

Serum metabonomics reveal the effectiveness of human placental mesenchymal stem cell therapy for primary sclerosing cholangitis.

The metabolic patterns of human placental-derived mesenchymal stem cell (hP-MSC) treatment for primary sclerosing cholangitis (PSC) remain unclear, and therapeutic effects significantly vary due to individual differences. Therefore, it is crucial to investigate the serological response to hP-MSC transplantation through small molecular metabolites and identify easily detectable markers for efficacy evaluation. Using Mdr2-/- mice as a PSC model and Mdr2+/+ mice as controls, the efficacy of hP-MSC treatment was assessed based on liver pathology, liver enzymes, and inflammatory factors. Serum samples were collected for 12C-/13C-dansylation and DmPA labeling LC-MS analysis to investigate changes in metabolic pathways after hP-MSC treatment. Key metabolites and regulatory enzymes were validated by qRT-PCR and Western blotting. Potential biomarkers of hP-MSC efficacy were identified through correlation analysis and machine learning. Collectively, the results of the liver histology, serum liver enzyme levels, and inflammatory factors supported the therapeutic efficacy of hP-MSC treatment. Based on significant differences, 41 differentially expressed metabolites were initially identified; these were enriched in bile acid, lipid, and hydroxyproline metabolism. After treatment, bile acid transport was accelerated, whereas bile acid production was reduced; unsaturated fatty acid synthesis was upregulated overall, with increased FADS2 and elongase expression and enhanced fatty acid β-oxidation; hepatic proline 4-hydroxylase expression was decreased, leading to reduced hydroxyproline production. Correlation analysis of liver enzymes and metabolites, combined with time trends, identified eight potential biomarkers: 2-aminomuconate semialdehyde, L-1-pyrroline-3-hydroxy-5-carboxylic acid, L-isoglutamine, and maleamic acid were more abundant in model mice but decreased after hP-MSC treatment. Conversely, 15-methylpalmitic, eicosenoic, nonadecanoic, and octadecanoic acids were less abundant in model mice but increased after hP-MSC treatment. This study revealed metabolic regulatory changes in PSC model mice after hP-MSC treatment and identified eight promising biomarkers, providing preclinical evidence to support therapeutic applications of hP-MSC.

Maternal infection with SARS-CoV-2 during early pregnancy induces hypoxia at the maternal-fetal interface.

The coronavirus disease 2019 (COVID-19) pandemic increases the risk of adverse fetal outcomes during pregnancy. Maternal infection during pregnancy, particularly with cytomegalovirus (CMV), hepatitis B and C virus, and human immunodeficiency virus can have detrimental effects on both mother and fetus, potentially leading to adverse outcomes such as spontaneous abortion or neonatal infection. However, the impact of severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection on the maternal-fetal interface remains poorly understood. In this study, we initially utilised immunofluorescence and immunohistochemical to investigate placental samples from pregnant women who were infected with SARS-CoV-2 during the first trimester. Our data indicate that infection in the first trimester induces an upregulation of hypoxia inducible factor (HIF) levels at the maternal-fetal interface. Subsequently, single-cell RNA sequencing and metabolomics sequencing analyses reveal alterations in maternal-fetal interface. Remarkably, immune cells exhibited low expression levels of HIF possibly associated with immune activation. Furthermore, our findings demonstrate a gradual reduction in transcriptome and metabolic changes as gestation progressed beyond 12-16 weeks compared to samples obtained at 6-8 weeks gestation. Overall, our study suggests that early-stage SARS-CoV-2 infection during the first trimester leads to severe hypoxia and aberrant cell metabolism at the maternal-fetal interface which gradually resolves as pregnancy progresses. Nevertheless, these abnormal changes may have long-term implications for maternal-fetal interface development.