Disorders Of Amino Acid Metabolism Research Articles

Systematic impacts of fluoride exposure on the metabolomics of rats

Fluoride is widely present in the environment. Excessive fluoride exposure leads to fluorosis, which has become a global public health problem and will cause damage to various organs and tissues. Only a few studies focus on serum metabolomics, and there is still a lack of systematic metabolomics associated with fluorosis within the main organs. Therefore, in the current study, a non-targeted metabolomics method using gas chromatography-mass spectrometry (GC-MS) was used to research the effects of fluoride exposure on metabolites in different organs, to uncover potential biomarkers and study whether the affected metabolic pathways are related to the mechanism of fluorosis. Male Sprague-Dawley rats were randomly divided into two groups: a control group and a fluoride exposure group. GC-MS technology was used to identify metabolites. Multivariate statistical analysis identified 16, 24, 20, 20, 24, 13, 7, and 13 differential metabolites in the serum, liver, kidney, heart, hippocampus, cortex, kidney fat, and brown fat, respectively, in the two groups of rats. Fifteen metabolic pathways were affected, involving toxic mechanisms such as oxidative stress, mitochondrial damage, inflammation, and fatty acid, amino acid and energy metabolism disorders. This study provides a new perspective on the understanding of the mechanism of toxicity associated with sodium fluoride, contributing to the prevention and treatment of fluorosis.

Metabolomics analysis of the potential toxicological mechanisms of diquat dibromide herbicide in adult zebrafish (Danio rerio) liver.

Although diquat is a widely used water-soluble herbicide in the world, its sublethal adverse effects to fish have not been well characterised. In this study, histopathological examination and biochemical assays were applied to assess hepatotoxicity and combined with gas chromatography-mass spectrometry (GC-MS)-based metabolomics analysis to reveal overall metabolic mechanisms in the liver of zebrafish (Danio rerio) after diquat exposure at concentrations of 0.34 and 1.69mg·L-1 for 21days. Results indicated that 1.69mg·L-1 diquat exposure caused cellular vacuolisation and degeneration with nuclear abnormality and led to the disturbance of antioxidative system and dysfunction in the liver. No evident pathological injury was detected, and changes in liver biochemistry were not obvious in the fish exposed to 0.34mg·L-1 diquat. Multivariate statistical analysis revealed differences between profiles obtained by GC-MS spectrometry from control and two treatment groups. A total of 17 and 22 metabolites belonging to different classes were identified following exposure to 0.34 and 1.69mg·L-1 diquat, respectively. The metabolic changes in the liver of zebrafish are mainly manifested as inhibition of energy metabolism, disorders of amino acid metabolism and reduction of antioxidant capacity caused by 1.69mg·L-1 diquat exposure. The energy metabolism of zebrafish exposed to 0.34mg·L-1 diquat was more inclined to rely on anaerobic glycolysis than that of normal zebrafish, and interference effects on lipid metabolism were observed. The metabolomics approach provided an innovative perspective to explore possible hepatic damages on fish induced by diquat as a basis for further research.

The Metabolomic Characterization of Different Types of Coronary Atherosclerotic Heart Disease in Male.

Background In clinical practice, many patients with coronary atherosclerotic heart disease (CAD) have atypical clinical symptoms. It is difficult to accurately identify stable CAD or unstable CAD early through clinical symptoms and coronary angiography. This study aimed to screen the potential metabolite biomarkers in male patients with stable CAD and unstable CAD. Methods In this work, the metabolomic characterization of the male patients with healthy control (n = 42), stable coronary artery disease (n = 60), non-ST-elevation acute coronary syndrome (n = 45), including prepercutaneous corona intervention (n = 14), and postpercutaneous coronary intervention (n = 31) were performed by using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). The serum samples of patients were analyzed by multivariate statistics. Results Results showed that 17 altered metabolites were identified to have a clear distinction between the stable CAD group and the healthy subjects. Compared with the stable coronary artery disease group, 15 specific metabolite markers were found in the acute coronary syndrome group. The percutaneous coronary intervention also affected the metabolic behavior of patients with CAD. Conclusions In summary, CAD is closely related to energy metabolism, lipid metabolism, and amino acid metabolism disorders. The different metabolic pattern characteristics of healthy, stable coronary artery disease and acute coronary syndrome are constructed, which brings a novel theoretical basis for the early diagnosis of patients with stable and unstable CAD.

Anaesthetic Management of a Patient with Multiple Acetyl CoA Dehydrogenase Deficiency: A Case Report

Multiple acetyl CoA dehydrogenase deficiency is a rare autosomal recessive disorder of amino acid, fatty acid, and choline metabolism. It is a mitochondrial disorder with defective electron transfer flavoproteins or electron transfer flavoprotein dehydrogenases. They are vital for β-oxidation of fatty acids, an essential fuel for skeletal and cardiac muscles. It is also an important source of energy during starvation for the brain. Acute deterioration of these patients can occur during stressful periods like starvation, surgery, infection, and exercise. The anaesthetic management is a challenge with special emphasis on minimizing starvation, ensuring hydration and glucose supplementation, and considering the various effects of anaesthetic agents on the mitochondrial function. The anaesthetic management of a patient with multiple acetyl CoA dehydrogenase scheduled for modified radical mastectomy is described. General anaesthesia can be administered safely in these patients with special emphasis on hydration, glucose supplementation, avoidance of stressors, and monitoring of metabolic status.

Inborn Errors of Metabolism: Becoming Ready for Rare.

Inborn errors of metabolism (IEMs) are a large group of disorders that can present in any age group and must be considered in the differential diagnosis for a variety of signs and symptoms appearing in infants and children. The rarity and complexity of these conditions often make them difficult to recognize, as they may mimic more common conditions. This review article discusses some of the more commonly presenting IEMs that are important for the general pediatrician to understand when evaluating a sick patient. Many of these diseases are also on the newborn screen, which pediatricians often encounter as first-line providers. Disorders that are discussed in detail herein include disorders of amino acid metabolism, including amino acidopathies and organic acidurias; urea cycle disorders; defects in fatty acid β-oxidation; disorders of carbohydrate metabolism, including the glycogen storage diseases and galactosemia; and lysosomal storage diseases.

Genetic Diagnosis in a Cohort of Adult Patients with Inherited Metabolic Diseases: A Single-Center Experience

Inherited metabolic diseases (IMDs) are genetic conditions that result in metabolism alterations. Although research-based Next Generation Sequencing (NGS) testing for IMD has been recently implemented, its application in a clinical diagnostic setting remains challenging. Thus, we aimed at investigating the genetic diagnostic approach in a cohort of adult patients with IMDs referred to our adult metabolic unit. A retrospective analysis was performed collecting demographic, clinical, and genetic data of patients referred to the Adult Metabolic Unit in Padua from November 2017 to March 2022. In total, 108 adult patients (mean age: 33 years ± 17, 55% women) were enrolled in the study, and 83 (77%) of the patients transitioned from the pediatric metabolic clinics. The most prevalent groups of IMDs were disorders of complex molecule degradation (32 patients) and disorders of amino acid metabolism (31) followed by disorders of carbohydrates (26). Molecular genetic diagnosis was reported by 69 (64%) patients, with the higher rate reported by patients referred from specialty other than pediatric (88% vs. 55%). Almost all the subjects (92%) with disorders of complex molecule degradation had a genetic diagnosis. Patients with disorders of amino acid metabolism and disorders of carbohydrates had almost the same rate of genetic test (39% and 38%, respectively). Among the patients without a genetic diagnosis that we tested, two novel mutations in disease-associated genes were detected. In our single-center cohort, a consistent proportion (36%) of subjects with IMDs reaches the adulthood without a genetic demonstration of the disease. This lack, even if in some cases could be related to disease-specific diagnostic approach or to different disease onset, could be detrimental to patient management and impact to some of the specific needs of adult subjects.

Exploring the Barriers and Motivators to Dietary Adherence among Caregivers of Children with Disorders of Amino Acid Metabolism (AAMDs): A Qualitative Study.

Dietary intervention is generally accepted as the mainstay of treatment for patients with disorders of amino acid metabolism (AAMDs). However, dietary adherence to a low-protein diet is always reported as a common challenge among these patients. This study explored the perception of barriers and motivators to dietary adherence among caregivers of AAMD patients in Malaysia. Twenty caregivers of children with AAMDs receiving ongoing treatment at the genetic clinic participated in an online focus group discussion from November to December 2021. Findings showed a total of five interrelated main themes identified from focus group discussion (FGD) exploring parents’ experiences related to the management of their child’s daily diet. The barriers to dietary adherence were burden of dietary treatment, diet and dietary behavior, parenting challenges, limited knowledge related to dietary treatment, and challenges in healthcare system delivery. Key factors facilitating good dietary adherence include good knowledge of dietary treatment, parental coping strategies, social coping, and dietary behavior. In conclusion, despite the existence of several barriers to the implementation of dietary treatment, caregivers managed to use a wide range of coping strategies to overcome some, if not all, of the challenges. The important next step is to develop, in conjunction with multidisciplinary healthcare professionals, feasible implementation strategies that could address these barriers and at the same time improve the quality of life of caregivers.

Retrospective Evaluation of Inborn Errors of Metabolisms in the Level III Neonatal Intensive Care Unit

Objective: Inborn errors of metabolisms (IEMs) are a heterogeneous group of disorders that can occur as a result of inherited or spontaneous mutations, are rare when considered alone, but have many diseases as a group. Although they are generally thought of as diseases of the neonatal period, 50% of these also occur outside the neonatal period, and some are not diagnosed until adulthood. The aim of this study is to examine the frequency, clinical and laboratory features of inborn errors of metabolism in the neonatal period.
 Methods: The results of 60 patients who were diagnosed with IEMs as a result of the study, out of 1400 patients who were followed up and treated in the Children's Hospital Neonatal Intensive Care Unit between January 2018 and December 2020, were evaluated.
 Results: In this study, it consisted of 60 cases, 30 (%50) of which were girls and 30 (%50) were boys (50%). The median age of the patients included in the study was 3 (1-25) days at admission, median weight was 3100 (1000-4000) g, and gestational week was found to be median 39 (27-40) weeks at admission. The most common complaints were feeding difficulty 43(72%), tachypnea 27 (45%) and vomiting 5 (8.3%). The most common laboratory findings were metabolic acidosis 39 (65%) and 36 (60%) hypoglycemia. There was a history of consanguinity in 46 (76.6%) cases, and a history of sibling death in 30 (50%). The mother had a history of abortion in 5 (8.3%) patients who did not have a history of sibling death. The most common diagnoses were Urea cycle disorder 13 (21.7%), organic acidemia 12 (20%), galactosemia 10 (16.7%) and amino acid metabolism disorders 9 (15%).
 Conclusion: Inborn errors of metabolisms, which are a group of diseases that can occur in different spectrums with clinical, biochemical and genetic heterogeneity, should be kept in mind especially in regions where consanguineous marriages are high. In cases such as metabolic acidosis, which presents with nonspecific symptoms such as malnutrition, tachypnea and jaundice in the neonatal period and cannot be explained in laboratory examinations, care should be taken and they should be referred to centers for further investigation.

Toxic Metabolites and Inborn Errors of Amino Acid Metabolism: What One Informs about the Other.

In inborn errors of metabolism, such as amino acid breakdown disorders, loss of function mutations in metabolic enzymes within the catabolism pathway lead to an accumulation of the catabolic intermediate that is the substrate of the mutated enzyme. In patients of such disorders, dietarily restricting the amino acid(s) to prevent the formation of these catabolic intermediates has a therapeutic or even entirely preventative effect. This demonstrates that the pathology is due to a toxic accumulation of enzyme substrates rather than the loss of downstream products. Here, we provide an overview of amino acid metabolic disorders from the perspective of the ‘toxic metabolites’ themselves, including their mechanism of toxicity and whether they are involved in the pathology of other disease contexts as well. In the research literature, there is often evidence that such metabolites play a contributing role in multiple other nonhereditary (and more common) disease conditions, and these studies can provide important mechanistic insights into understanding the metabolite-induced pathology of the inborn disorder. Furthermore, therapeutic strategies developed for the inborn disorder may be applicable to these nonhereditary disease conditions, as they involve the same toxic metabolite. We provide an in-depth illustration of this cross-informing concept in two metabolic disorders, methylmalonic acidemia and hyperammonemia, where the pathological metabolites methylmalonic acid and ammonia are implicated in other disease contexts, such as aging, neurodegeneration, and cancer, and thus there are opportunities to apply mechanistic or therapeutic insights from one disease context towards the other. Additionally, we expand our scope to other metabolic disorders, such as homocystinuria and nonketotic hyperglycinemia, to propose how these concepts can be applied broadly across different inborn errors of metabolism and various nonhereditary disease conditions.

Shenkang Injection for Treating Renal Fibrosis-Metabonomics and Regulation of E3 Ubiquitin Ligase Smurfs on TGF-β/Smads Signal Transduction.

At present, TGF-β is the most critical fibrogenic factor known. Smad ubiquitin ligase Smurfs play an important role in the regulation of the TGF-/Smads signaling pathway, which is linked to metabolite changes in renal fibrosis. Previous studies have shown that Shenkang injection can prevent and treat chronic kidney disease through multiple channels of action. However, the precise relationship between Shenkang injection and the regulation of the TGF-/Smads signaling pathway in the treatment of chronic kidney disease is unknown. Here, we evaluated the pharmacological effects of Shenkang injection on ubiquitination and metabolic changes of the TGF-β/Smads signaling pathway in UUO mice using pathology-related indicators, immunoprecipitation, subcellular co-location, and metabonomics analysis. Our findings indicate that Shenkang injection can promote nuclear translocation of Smurf1 and Smurf2 to TGF- membrane receptors TR-I and Smad2 and ubiquitinated degradation of these proteins. Furthermore, the formation of TβR-I/TβR-II, TβR-I/Smad2, and TβR-I/Smad3 complexes was inhibited to negatively regulate the TGF-β/Smad signaling pathway induced renal tubular epithelial transdifferentiation (EMT). The EMT process is not very relevant in vivo, although it is clear that TGF-β induces EMT in cultured cells, which has been demonstrated by numerous teams around the world. However, this is not the case with the in vivo models of kidney fibrosis, especially UUO. In addition, Shenkang injection can improve amino acid metabolism, purine metabolism, and fatty acid metabolism disorders.

Unmet Needs of Children with Inherited Metabolic Disorders in the COVID-19 Pandemic.

ObjectiveCrucial information is lacking on unmet needs of children with rare inherited metabolic disorders during the coronavirus disease 2019 pandemic from low- and middle-income countries. We aimed to identify the unmet needs of children with rare inherited metabolic disorders from Turkey.Materials and MethodsIn a cross-sectional observational design, all children with rare inherited metabolic disorders aged 0-18 years followed at Ankara University School of Medicine Department of Pediatrics Pediatric Metabolism Division were recruited and interviewed via phone calls. The Expanded Guide for Monitoring Child Development enabled assessment of unmet needs and environmental context during coronavirus disease 2019 pandemic. Step-wise logistic regression analysis was used to determine independent factors associated with unmet needs.ResultsThe sample comprised 229 children (54.1% boys) with rare inherited metabolic disorders (36.7% diet-dependent disorders). Most common diagnoses were amino acid metabolism disorders (40.2%). Of all, 29.3% of the mothers reported depression, 25.3% loss of job of family members during the pandemic. All children had unmet needs: at least 73.0% in health care, 96.8% in education, 78.3% in special services/rehabilitation. Having significant developmental delay and/or disability (odds ratio = 2.31, 95% CI: 1.14-4.67) emerged as the only independent factor associated with unmet needs in health care.ConclusionChildren with rare inherited metabolic disorders and their families in Turkey experience unmet needs in many domains during coronavirus disease 2019 pandemic. Urgent action is needed to address the unmet needs of children with rare inherited metabolic disorders, especially those who has significant developmental delays and/or disabilities for this pandemic and possible future crisis.

Effect of fecal microbiota transplantation on type 1 diabetes mellitus in non-obese diabetic mice and its underlying mechanism

Objective: To investigate the effects of fecal microbiota transplantation (FMT) on non-obese diabetic (NOD) mice of type 1 diabetes mellitus (T1DM) and its underlying mechanisms. Methods: A total of 8-9 week-female NOD mice were randomly divided into control (n=36) and FMT groups (n=36) according to the random number table. Fecal microbiota from C57BL/6 mice were transplanted into FMT group, and control group were transplanted with microbiota from themselves, once every two days for 5 times. The insulitis score and incidence of T1DM were compared between two groups;16S rRNA gene sequencing was used to evaluate the structure of fecal bacteria in NOD mice. The expressions of intestinal barrier related genes were detected by real-time quantitative PCR. The proportions of regulatory T cells (Tregs), helper T cell (Th)-1 and Th17 in the enteric-pancreatic immune axis were detected by flow cytometry. Amino acid in serum was measured by amino acid metabolomics. Results: Incidence of T1DM in NOD mice from FMT group was 40.9% (9/22), lower than 72.7% (13/22) from control group at 26 weeks of age (P=0.034). FMT promoted colonization of probiotics such as Lactobacillus, Clostridium_sp_ND2, Candidatus_Arthromitus and Clostridiaceae_1; mRNA of intestinal barrier related genes were up-regulated in FMT group [ mucins(Muc)-1: 0.93±0.29 vs 2.97±0.79, P=0.036; Muc2: 0.72±0.39 vs 10.70±3.54, P=0.019;Muc3: 1.79±0.69 vs 10.97±2.78, P=0.009;Muc4: 1.01±0.23 vs 2.42±0.49, P=0.029;Occludin(Ocln): 0.96±0.08 vs 1.81±0.36, P=0.045; Claudin(Cldn)-1:0.94±0.17 vs 2.20±0.43, P=0.022] compared to control. The proportions of Treg in mesenteric lymphoid node, pancreatic lymph node and peyer's patches of FMT group [(6.10±0.49)% vs (7.54±0.27)%, P=0.020;(5.28±0.39)% vs (6.42±0.34)%, P=0.048;(6.78±0.42)% vs (7.88±0.13)%, P=0.029] were increased compared to control,while proportions of Th1 [(1.02±0.06)% vs (0.83±0.06)%, P=0.040;(0.82±0.10)% vs (0.56±0.05)%, P=0.038;(1.28±0.12) vs (0.85±0.07), P=0.012] and proportions of Th17 [(0.40±0.01)% vs (0.30±0.02)%, P=0.004;(0.40±0.02)% vs (0.31±0.02)%, P=0.008;(0.51±0.06) vs (0.36±0.02), P=0.027] were decreased. The contents of leucine [(92.86±7.32) vs (91.87±12.62) μmol/L, P=0.027], valine [(162.74±15.97) vs (155.89±25.70) μmol/L, P=0.046] and isoleucine [(75.65±5.59) vs (73.61±9.67) μmol/L, P=0.048] in serum were decreased in FMT group. Conclusions: FMT can alleviate insulitis and T1DM occurrence in NOD mice, of which mechanism may be related to remodeling gut microbiota and improving intestinal barrier function, affecting immune response of enteric-pancreatic immune axis, correcting amino acid metabolism disorder and reducing the accumulation of branch chain amino acids in NOD mice.

Knockout of Nur77 Leads to Amino Acid, Lipid, and Glucose Metabolism Disorders in Zebrafish.

Orphan nuclear receptor Nur77 has been reported to be implicated in a diverse range of metabolic processes, including carbohydrate metabolism and lipid metabolism. However, the detailed mechanism of Nur77 in the regulation of metabolic pathway still needs to be further investigated. In this study, we created a global nur77 knockout zebrafish model by CRISPR/Cas9 technique, and then performed whole-organism RNA sequencing analysis in wildtype and nur77-deficient zebrafish to dissect the genetic changes in metabolic-related pathways. We found that many genes involved in amino acid, lipid, and carbohydrate metabolism changed by more than twofold. Furthermore, we revealed that nur77−/− mutant displayed increased total cholesterol (TC) and triglyceride (TG), alteration in total amino acids, as well as elevated glucose. We also demonstrated that the elevated glucose was not due to the change of glucose uptake but was likely caused by the disorder of glycolysis/gluconeogenesis and the impaired β-cell function, including downregulated insb expression, reduced β-cell mass, and suppressed insulin secretion. Importantly, we also verified that targeted expression of Nur77 in the β cells is sufficient to rescue the β-cell defects in global nur77−/− larvae zebrafish. These results provide new information about the global metabolic network that Nur77 signaling regulates, as well as the role of Nur77 in β-cell function.

Amino Acid and Fatty Acid Metabolism Disorders Trigger Oxidative Stress and Inflammatory Response in Excessive Dietary Valine-Induced NAFLD of Laying Hens.

Non-alcoholic fatty liver disease (NAFLD) is a chronic and metabolic liver disease and commonly occurs in humans with obesity and type 2 diabetes mellitus (T2DM); such a condition also exists in animals such as rodents and laying hens. Since the pathogenesis of fatty liver hemorrhagic syndrome (FLHS) of laying hens is similar to human NAFLD, hen's FLHS is commonly selected as a study model of NAFLD. Altered circulating amino acids, particularly elevated branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs), are consistently reported in patients with NAFLD and T2DM. How long-term dietary individual BCAA, such as valine, impacts amino acid and fatty acid metabolism remains unknown. In this study, we demonstrated that when laying hens are fed with dietary valine at different levels (59, 0.64, 0.69, 0.74, and 0.79%) in a feeding trial that lasted for 8 weeks, long-term exposure to excessive valine diets at 0.74 and 0.79% levels could induce amino acid imbalance, impair amino acid metabolism, increase fatty acid synthesis, and inhibit fatty acid utilization. Long-term intake of excessive dietary valine could result in impaired amino acid metabolism via inhibiting C/EBP-β/asparagine synthetase (Asns). This process is mediated by downregulating the general control nonderepressible-eukaryotic initiation factor 2α- activating transcription factor (GCN2-eIF2α-ATF4) pathway and elevating corresponding circulating BCAAs and AAAs levels, which could ultimately result in amino acid imbalance. High levels of dietary valine stimulated lipid deposition by suppressing the GCN2-eIF2α-ATF4-fibroblast growth factor-19 (FGF19)-target of rapamycin complex 1 (TORC1) signaling pathway to promote fatty acid synthesis, repress fatty acid utilization, and eventually accelerate the development of NAFLD. The Spearman correlation analysis revealed that circulating amino acid imbalance is significantly associated with fatty acid metabolism disorder and enhanced oxidative stress. The inhibition of the GCN2-TORC1 pathway induced autophagy suppression to trigger liver oxidative stress and inflammatory response. In conclusion, our results revealed the adverse metabolic response to excessive dietary valine mediated by amino acid and fatty acid metabolism disorders. This study also suggested reducing dietary valine as a novel approach to preventing and treating NAFLD in humans and FLHS in laying hens.

Ipsilateral hip and knee joints ochronotic arthropathy treated by total joint replacement, a case report

BackgroundOchronotic arthropathy affecting the hip and knee joints is one of the musculoskeletal manifestations of alkaptonuria which results from a tyrosine amino acid metabolism disorder. The condition has no definitive management; however, end-stage joint arthritis is well treated by total joint replacement.Case presentationWe present a case of a healthy male patient who presented with left hip and bilateral knee (more on the left side) progressive pain and limitation of motion how was diagnosed as having advanced arthritis and was treated by total hip and total knee replacement for the left hip and knee joints respectively. Intraoperatively, the tissues had blackish discoloration characterizing ochronosis. This patient was diagnosed as having ochronotic arthropathy based on the intraoperative findings.ConclusionsAccurate diagnosis of ochronotic arthropathy could only be reached intraoperatively; furthermore, end-stage joint arthritis could be treated efficiently by total joint replacement surgery.

Integrative analysis of metabolomics and proteomics reveals amino acid metabolism disorder in sepsis

BackgroundSepsis is defined as a systemic inflammatory response to microbial infections with multiple organ dysfunction. This study analysed untargeted metabolomics combined with proteomics of serum from patients with sepsis to reveal the underlying pathological mechanisms involved in sepsis.MethodsA total of 63 patients with sepsis and 43 normal controls were enrolled from a prospective multicentre cohort. The biological functions of the metabolome were assessed by coexpression network analysis. A molecular network based on metabolomics and proteomics data was constructed to investigate the key molecules.ResultsUntargeted metabolomics analysis revealed widespread dysregulation of amino acid metabolism, which regulates inflammation and immunity, in patients with sepsis. Seventy-three differentially expressed metabolites (|log2 fold change| > 1.5, adjusted P value < 0.05 and variable importance in the projection (VIP) > 1.5) that could predict sepsis were identified. External validation of the hub metabolites was consistent with the derivation results (area under the receiver operating characteristic curve (AUROC): 0.81–0.96/0.62–1.00). The pentose phosphate pathway was found to be related to sepsis-associated encephalopathy. Phenylalanine metabolism was associated with sepsis-associated acute kidney injury. The key molecular alterations of the multiomics network in sepsis compared to normal controls implicate acute inflammatory response, platelet degranulation, myeloid cell activation involved in immune response and phenylalanine, tyrosine and tryptophan biosynthesis, and arginine biosynthesis.ConclusionsIntegrated analysis of untargeted metabolomics and proteomics revealed characteristic metabolite and protein alterations in sepsis, which were mainly involved in inflammation-related pathways and amino acid metabolism. This study depicted the pathological characteristics and pathways involved in sepsis and potential therapeutic targets.

Detection of the Disorders of Glycerophospholipids and Amino Acids Metabolism in Lung Tissue From Male COPD Patients.

Background: At present, few studies have reported the metabolic profiles of lung tissue in patients with COPD. Our study attempted to analyze the lung metabolome in male COPD patients and to screen the overlapping biomarkers of the lung and plasma metabolomes. Methods: We performed untargeted metabolomic analysis of normal lung tissue from two independent sets (the discovery set: 20 male COPD patients and 20 controls and the replication set: 47 male COPD patients and 27 controls) and of plasma samples from 80 male subjects containing 40 COPD patients and 40 controls. Results: We found glycerophospholipids (GPs) and Amino acids were the primary classes of differential metabolites between male COPD patients and controls. The disorders of GPs metabolism and the valine, leucine and isoleucine biosynthesis metabolism pathways were identified in lung discovery set and then also validated in the lung replication set. Combining lung tissue and plasma metabolome, Phytosphingosine and l-tryptophan were two overlapping metabolites biomarkers. Binary logistic regression suggested that phytosphingosine together with l-tryptophan was closely associated with male COPD and showed strong diagnostic power with an AUC of 0.911 (95% CI: 0.8460-0.9765). Conclusion: Our study revealed the metabolic perturbations of lung tissues from male COPD patients. The detected disorders of GPs and amino acids may provide an insight into the pathological mechanism of COPD. Phytosphingosine and l-tryptophan were two novel metabolic biomarkers for differentiating COPD patients and controls.

OP006: Is it time to move beyond acylcarnitine profiles? Lessons from the clinical application of a high-definition LC-MS/MS acylcarnitine method.

Acylcarnitines are intermediate metabolites of the mitochondria that serve as biomarkers for inherited disorders of fatty acid oxidation and amino acid metabolism. The prevailing clinical method used to study acylcarnitines involves flow-injection tandem mass spectrometry (FI-MS/MS) with precursor ion scanning. This approach, often called “acylcarnitine profile analysis”, is associated with a number of limitations; foremost the inability to separate and therefore distinguish isobaric/isomeric acylcarnitine species.

The Utility of Genomic Testing for Hyperphenylalaninemia.

Hyperphenylalaninemia (HPA), the most common amino acid metabolism disorder, is caused by defects in enzymes involved in phenylalanine metabolism, with the consequent accumulation of phenylalanine and its secondary metabolites in body fluids and tissues. Clinical manifestations of HPA include mental retardation, and its early diagnosis with timely treatment can improve the prognosis of affected patients. Due to the genetic complexity and heterogeneity of HPA, high-throughput molecular technologies, such as next-generation sequencing (NGS), are becoming indispensable tools to fully characterize the etiology, helping clinicians to promptly identify the exact patients’ genotype and determine the appropriate treatment. In this review, after a brief overview of the key enzymes involved in phenylalanine metabolism, we represent the wide spectrum of genes and their variants associated with HPA and discuss the utility of genomic testing for improved diagnosis and clinical management of HPA.

Nontargeted and targeted metabolomics approaches reveal the key amino acid alterations involved in multiple myeloma.

PurposeMultiple myeloma (MM), a kind of malignant neoplasm of clonal plasma cells in the bone marrow, is a refractory disease. Understanding the metabolism disorders and identification of metabolomics pathways as well as key metabolites will provide new insights for exploring diagnosis and therapeutic targets of MM.MethodsWe conducted nontargeted metabolomics analysis of MM patients and normal controls (NC) using ultra-high-performance liquid chromatography (UHPLC) combined with quadrupole time-of-flight mass spectrometry (Q-TOF-MS) in 40 cases of cohort 1 subjects. The targeted metabolomics analysis of amino acids using multiple reaction monitoring-mass spectrometry (MRM-MS) was also performed in 30 cases of cohort 1 and 30 cases of cohort 2 participants, to comprehensively investigate the metabolomics disorders of MM.ResultsThe nontargeted metabolomics analysis in cohort 1 indicated that there was a significant metabolic signature change between MM patients and NC. The differential metabolites were mainly enriched in metabolic pathways related to amino acid metabolism, such as protein digestion and absorption, and biosynthesis of amino acids. Further, the targeted metabolomics analysis of amino acids in both cohort 1 and cohort 2 revealed differential metabolic profiling between MM patients and NC. We identified 12 and 14 amino acid metabolites with altered abundance in MM patients compared to NC subjects, in cohort 1 and cohort 2, respectively. Besides, key differential amino acid metabolites, such as choline, creatinine, leucine, tryptophan, and valine, may discriminate MM patients from NC. Moreover, the differential amino acid metabolites were associated with clinical indicators of MM patients.ConclusionsOur findings indicate that amino acid metabolism disorders are involved in MM. The differential profiles reveal the potential utility of key amino acid metabolites as diagnostic biomarkers of MM. The alterations in metabolome, especially the amino acid metabolome, may provide more evidences for elucidating the pathogenesis and development of MM.