Carnitine Levels Research Articles

Plasma linoelaidyl carnitine levels positively correlated with symptom improvement in olanzapine-treated first-episode drug-naïve schizophrenia.

Olanzapine (OLA) is one of the most commonly used second-generation antipsychotics for the treatment of schizophrenia. However, the heterogeneity of therapeutic response to OLA among schizophrenia patients deserves further exploration. The role of carnitine in the clinical response to OLA monotherapy remains unclear. The current study was designed to investigate whether carnitine and its derivatives are linked to the response to OLA treatment. Drug-naïve first-episode patients with schizophrenia were recruited and treated with OLA for 4weeks. Psychiatric symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) in pre and post treatment. After treatment, we found a significant decrease in 2-Octenoylcarnitine levels and a significant increase in linoelaidyl carnitine, 11Z-Octadecenylcarnitine and 9-Decenoylcarnitine levels. Furthermore, baseline linoelaidyl carnitine levels were correlated with the reduction of PANSS positive symptom subscore. Linear regression and logistic regression analyses found that the baseline linoelaidyl carnitine level was a predictive marker for the therapeutic response to OLA monotherapy for 4weeks. Our pilot study suggests that linoelaidyl carnitine levels at baseline may have a predictive role for the improvement of positive symptoms after OLA monotherapy in the patients with schizophrenia.

1H NMR-Based Metabolomics Reveals the Intrinsic Interaction of Age, Plasma Signature Metabolites, and Nutrient Intake in the Longevity Population in Guangxi, China.

Health and longevity populations have distinct metabolic and nutrient intake profiles. However, the relationship between biomarkers of longevity-related metabolites and dietary nutrient intake profiles, as well as metabolic markers associated with longevity features, have not been fully elucidated. Therefore, 1H nuclear magnetic resonance (1H NMR)-based plasma metabolomics profiling was conducted in the present study to identify potential metabolites which can be used as specific markers for the evaluation of healthy aging. Plasma samples were obtained from centenarians and nonagenarians from the longevous region, and elderly participants aged 60–89 from the longevous region, as well as a low centenarian ratio region. The results showed that participants from longevous regions exhibited higher plasma levels of citrate, tyrosine, choline, carnitine, and valine, as well as lower contents of VLDL, lactate, alanine, N-acetyl glycoprotein (NAG), trimethylamine oxide (TMAO), α-glucose, β-glucose, and unsaturated lipids. The differential plasma metabolites were associated with an alteration in glycolysis/gluconeogenesis; aminoacyl-tRNA biosynthesis; alanine, aspartate, and glutamate metabolism; and phenylalanine, tyrosine, and tryptophan biosynthesis in participants from longevous regions. The signature metabolites were associated with higher dietary fiber intake, as well as lower energy and fat intake. The results of the present study demonstrate key longevity signature metabolites in plasma, and the dietary patterns identified provide a basis for further health and longevity research.

Immunometabolic Reprogramming in Response to HIV Infection Is Not Fully Normalized by Suppressive Antiretroviral Therapy.

Background: HIV infection results in immunometabolic reprogramming. While we are beginning to understand how this metabolic reprogramming regulates the immune response to HIV infection, we do not currently understand the impact of ART on immunometabolism in people with HIV (PWH). Methods: Serum obtained from HIV-infected (n = 278) and geographically matched HIV seronegative control subjects (n = 300) from Rakai Uganda were used in this study. Serum was obtained before and ~2 years following the initiation of ART from HIV-infected individuals. We conducted metabolomics profiling of the serum and focused our analysis on metabolic substrates and pathways assocaited with immunometabolism. Results: HIV infection was associated with metabolic adaptations that implicated hyperactive glycolysis, enhanced formation of lactate, increased activity of the pentose phosphate pathway (PPP), decreased β-oxidation of long-chain fatty acids, increased utilization of medium-chain fatty acids, and enhanced amino acid catabolism. Following ART, serum levels of ketone bodies, carnitine, and amino acid metabolism were normalized, however glycolysis, PPP, lactate production, and β-oxidation of long-chain fatty acids remained abnormal. Conclusion: Our findings suggest that HIV infection is associated with an increased immunometabolic demand that is satisfied through the utilization of alternative energetic substrates, including fatty acids and amino acids. ART alone was insufficient to completely restore this metabolic reprogramming to HIV infection, suggesting that a sustained impairment of immunometabolism may contribute to chronic immune activation and comorbid conditions in virally suppressed PWH.

The Effect of Polyphenol Extract from Rosa Roxburghii Fruit on Plasma Metabolome and Gut Microbiota in Type 2 Diabetic Mice.

Rosa roxburghii fruit is an underutilized functional food abundant in polyphenols. Polyphenols have been proved to have antidiabetic effects. This study investigates the effects of Rosa roxburghii fruit polyphenols extract (RPE) on plasma metabolites and gut microbiota composition in streptozotocin (STZ)- and high-fat diet- induced type 2 diabetes using metabolomics and 16S rRNA gene sequencing. The induced diabetic mice were fed with 400 mg/kg body weight RPE for 8 weeks. RPE demonstrated hypoglycemic, hypolipidemic, and anti-inflammatory effects. Colonic oxidative stress biomarkers were also lowered by RPE. Besides, RPE decreased plasma ceramides and tyrosine levels and increased carnitine and phosphatidylinositols levels, indicating improved insulin resistance, lipid metabolism, and immune response. Furthermore, RPE decreased abundances of Lachnospiraceae and Rikenellaceae and increased abundances of Erysipelotrichaceae and Faecalibaculum. Metabolic function prediction of the gut microbiota by PICRUSt demonstrated that RPE downregulated the phosphotransferase system. Taken together, these findings demonstrated that RPE has the potential to prevent type 2 diabetes by regulating the plasma metabolites and gut microbes.

Associations of Circulating Levels of Trimethylamine N-oxide, Choline, Carnitine, and Betaine with Inflammatory Markers Among Breast Cancer Survivors

ObjectivesWe examined the associations of circulating levels of trimethylamine N-oxide (TMAO) and its precursors (choline, carnitine, and betaine) with inflammatory markers in breast cancer survivors in Korea.MethodsA total of 431 women (285 premenopausal breast cancer) aged 30–78 years were included. Least-squares mean (LS-mean)s and 95% confidence interval (CI)s were estimated for plasma levels of high-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, IL-8, tumor necrosis factor-α (TNF-α), and adiponectin according to plasma levels of TMAO, choline, carnitine, and betaine, using the generalized linear models.ResultsAmong premenopausal breast cancer survivors, increasing circulating levels of choline were associated with increasing levels of IL-6, IL-8, and TNF-α; LS-means (95% CIs) of the lowest and the highest quartiles were 0.75 (0.56–0.96) and 1.01 (0.80–1.24) pg/mL (p for trend = 0.019) for IL-6, 11.49 (8.19–15.97) and 17.73 (12.96–24.13) pg/mL (p for trend = 0.005) for IL-8, and 9.45 (7.47–11.88) and 11.99 (9.63–14.88) pg/mL (p for trend = 0.021) for TNF-α, respectively. Increasing plasma betaine levels were associated with increasing levels of adiponectin but decreasing levels of hs-CRP and IL-6; LS-means (95% CIs) of the lowest and the highest quartiles were 7.25 (5.65–9.23) and 9.05 (7.10–11.47) μg/mL (p for trend = 0.044) for adiponectin, 0.68 (0.45–0.96) and 0.35 (0.16–0.57) mg/L (p for trend 0.017) for hs-CRP, and 0.98 (0.77–1.21) and 0.75 (0.57–0.97) pg/mL (p for trend = 0.013) for IL-6, respectively. However, plasma levels of TMAO and its precursors were not significantly associated with inflammatory markers in postmenopausal breast cancer survivors.ConclusionsIn this cross-sectional study of breast cancer survivors, increasing plasma levels of choline were associated with increasing levels of inflammatory markers, but plasma levels of betaine were inversely associated with these markers among premenopausal breast cancer survivors.Funding SourcesThis work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea Government (Ministry of Science and ICT) (No. 2014R1A2A2A01007794, 2019R1F1A1061017, and 2021R1F1A1062476).

High-fat diet-induced nonalcoholic steatohepatitis is accelerated by low carnitine and impaired glucose tolerance in novel murine models

AbstractCarnitine deficiency and impaired glucose tolerance (IGT) exacerbate liver steatosis. Given the current lack of ideal murine nonalcoholic steatohepatitis (NASH) models, we investigated new NASH models using jvs/+ mice with low carnitine and wild-type mice with low-dose alloxan-induced IGT. The jvs/+ and wild-type mice were divided into jvs/+ mice fed a high-fat diet (HFD) from 3 weeks of age (HF hetero group), wild-type mice with low-dose alloxan treatment fed HFD (AL + HF wild group), wild-type mice fed HFD (HF wild group), and two types of mice fed a normal diet—jvs/+ and wild-type (intact group). All mice were sacrificed at 20 or 40 weeks of age. All male HFD-fed mice showed obesity, IGT, high blood insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR), high liver enzyme levels, and high cholesterol levels. The degree of IGT was the worst in the AL + HF wild group, and blood insulin levels and HOMA-IR score were remarkably increased from 20 to 40 weeks of age. Almost all HFD-fed mice showed steatosis, fibrosis, and lobular inflammation in the centrilobular zone. These changes were accompanied by hepatocyte ballooning and were enhanced at 40 weeks of age. Furthermore, the incidence rate of nodular hyperplasia and adenoma in both the HF hetero and AL + HF wild groups was nearly 30%. We successfully established two novel murine models of NASH using male jvs/+ mice with low carnitine and male wild-type mice with IGT that eventually developed obesity, fatty liver, insulin resistance, liver fibrosis, and tumorigenesis. These results suggest that low carnitine levels and early-stage induction of IGT are important factors in the progression of NASH to tumorigenesis, similar to human NASH.

Addition of Prebiotics to the Ketogenic Diet Improves Metabolic Profile but Does Not Affect Seizures in a Rodent Model of Infantile Spasms Syndrome.

The ketogenic diet (KD) is an effective treatment for infantile spasms syndrome (IS). However, the KD has implications for somatic growth, development, and the gut microbiota. The impact of incorporating a prebiotic fiber (PRE, oligofructose-enriched inulin, 0.8 g/dL) into a KD diet on spasms, developmental milestones, fecal gut microbiota, metabolites, and hippocampal mitochondrial metabolism were examined. Following IS induction, animals were randomized to KD or KD + PRE diets. A third group without IS and suckled by dams was included as a normally developing reference group (R). PRE inclusion decreased ketones and increased circulating glucose levels but had no impact on spasms. In the liver, PRE increased triglyceride concentrations, decreased carnitine levels, and downregulated genes encoding enzymes responsible for ketogenesis. In the hippocampus, PRE increased glutathione levels but did not affect the maximal respiratory capacity of mitochondria. Analysis of the gut microbiota showed that KD + PRE increased microbial richness and the relative abundance of Bifidobacterium pseudolongum and Lactobacillus johnsonii. No differences in developmental milestones (i.e., surface righting, negative geotaxis, and open field behavior) were observed between KD and KD + PRE, except for ultrasonic vocalizations that were more frequent in KD + PRE. In summary, PRE did not impact spasms or developmental outcomes, but was effective in improving both metabolic parameters and gut microbiota diversity.

Association of Trimethylamine N-Oxide and Metabolites With Mortality in Older Adults

Little is known about the association of trimethylamine N-oxide (TMAO), a novel plasma metabolite derived from L-carnitine and phosphatidylcholine, and related metabolites (ie, choline, betaine, carnitine, and butyrobetaine) with risk of death among older adults in the general population. To investigate the associations of serial measures of plasma TMAO and related metabolites with risk of total and cause-specific death (ie, deaths from cardiovascular diseases [CVDs] and non-CVDs) among older adults in the US. This prospective cohort study involved 5333 participants from the Cardiovascular Health Study-a community-based longitudinal cohort of adults aged 65 years or older-who were followed up from June 1, 1989, to December 31, 2015. Participants were from 4 communities in the US (Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Allegheny County, Pennsylvania). Data were analyzed from March 17 to June 23, 2021. Plasma TMAO, choline, betaine, carnitine, and butyrobetaine levels were measured using stored samples from baseline (June 1, 1989, to May 31, 1990, or November 1, 1992, to June 31, 1993) and follow-up examination (June 1, 1996, to May 31, 1997). Measurements were performed through stable-isotope dilution liquid chromatography with tandem mass spectrometry using high-performance liquid chromatography with online electrospray ionization tandem mass spectrometry. Deaths (total and cause specific) were adjudicated by a centralized Cardiovascular Health Study events committee based on information from medical records, laboratory and diagnostic reports, death certificates, and/or interviews with next of kin. The associations of each metabolite with mortality were assessed using Cox proportional hazards regression models. Among 5333 participants in the analytic sample, the mean (SD) age was 73 (6) years; 2149 participants (40.3%) were male, 3184 (59.7%) were female, 848 (15.9%) were African American, 4450 (83.4%) were White, and 35 (0.01%) were of other races (12 were American Indian or Alaska Native, 4 were Asian or Pacific Islander, and 19 were of other races or ethnicities). During a median follow-up of 13.2 years (range, 0-26.9 years), 4791 deaths occurred. After adjustment for potential confounders, the hazard ratios for death from any cause (ie, total mortality) comparing extreme quintiles (fifth vs first) of plasma concentrations were 1.30 (95% CI, 1.17-1.44) for TMAO, 1.19 (95% CI, 1.08-1.32) for choline, 1.26 (95% CI, 1.15-1.40) for carnitine, and 1.26 (95% CI, 1.13-1.40) for butyrobetaine. Plasma betaine was not associated with risk of death. The extent of risk estimates was similar for CVD and non-CVD mortality. In this cohort study, plasma concentrations of TMAO and related metabolites were positively associated with risk of death. These findings suggest that circulating TMAO is an important novel risk factor associated with death among older adults.

Serum Microelements, Amino Acids and Acyl Carnitines Levels in Pregnancies Complicated with Preeclampsia: A Prospective Study

Background: To evaluate the feasibility of serum microelements, amino acids and acyl carnitine levels to predict maternal complications and adverse infant outcomes in pregnancies complicated by preeclampsia. Methods: We launched a prospective study including 81 pregnant patients. Serum microelements, amino acids and acyl carnitine levels were tested using external calibration technique or high-performance liquid chromatography tandem mass spectrometry. Concentrations of metabolites were compared between the preeclampsia and control groups. Logistic regression models were used to assess the relevance between the metabolites and pregnancy outcomes in preeclampsia patients without severe features. Results: Concentrations of some microelements, amino acids and acyl carnitines were significantly higher or lower in preeclampsia patients. Women with severe preeclampsia had significantly lower (hexadecanoyl carnitine + octadecenoyl carnitine)/acetyl carnitine [(C16 + C18:1)/C2] compared to mothers without severe features. Lower (C16 + C18:1)/C2 was found in women who developed maternal complications (p = 0.07) or experienced adverse infant outcomes (p < 0.01) compared with those who did not in patients without severe features. Levels of (C16 + C18:1)/C2 at enrollment resulted in moderate prediction rates for maternal outcomes [areas under the curves (AUC) 0.746, 95% Confidence Interval (CI) 0.543, 0.948] and perinatal outcomes (AUC 0.871, 95% CI 0.729, 1.000). Conclusions: Maternal levels of microelements, amino acids and acyl carnitines were associated with preeclampsia. Levels of (C16 + C18:1)/C2 seemed to be a potential biomarker in the prediction of maternal complications and adverse infant outcomes in preeclampsia patients without severe features. Further studies are needed to validate its predictive application.

Methylene Blue – A Potential Therapeutic Treatment for Sodium Fluoroacetate Poisoning

Sodium fluoroacetate (1080) is a toxic metabolic poison with no known antidote. Its use is strictly regulated within the United States, but it is commonly used as a pesticide in Australia, Israel, Japan, Mexico, New Zealand, and South Korea. 1080 has been identified as a possible terrorist weapon, and exposure is extremely difficult to diagnose given its overlapping symptoms with other common diseases. An abandoned U.S. patent indicated that methylene blue (MB) could be used as a potential countermeasure to 1080 poisoning when combined with monosodium glutamate (MSG). In this study, MB was used as a stand‐alone treatment to determine if it is capable of rescuing cellular metabolism or decreasing 1080 lethality.Male Sprague‐Dawley rats were exposed to increasing concentrations of 1080 (0.5, 1.1, 2.1, 4.2, and 8.4 mg/kg) based on a LD50 logarithmic scale. A low dose of MB (11 mg/kg) was administered via intraperitoneal injection (i.p.) at 0.5 hr and 2 hr post‐exposure. Euthanasia occurred 24 hours post‐exposure and blood was collected from the descending aorta. Serum was separated after collection and stored at ‐80 °C. Bronchoalveolar lavage fluid (BALF) was also collected from the right lung using phosphate buffered saline (PBS) and then stored at ‐80 °C. Gas chromatography‐mass spectrometry (GCMS) was performed on serum samples to identify potential metabolic compounds of interest. From the GCMS data, L‐carnitine and methylmalonic acid (MMA) were proposed as potential markers of 1080 exposure. To quantitate circulating levels, an L‐carnitine colorimetric/fluorometric assay and a methylmalonic acid enzyme‐linked immunosorbent assay (ELISA) were performed. Based on previous data indicating cardiopulmonary effects of 1080, a high sensitivity rat cardiac troponin‐I ELISA was used to determine cardiac damage, and BALF was tested for the presence of protein and hemoglobin.The coenzyme‐A linked form of MMA is converted into succinyl‐CoA for use in the TCA cycle. MMA levels were relatively low and unchanged across all groups, except for rats receiving a 1.1 mg/kg dose of 1080. L‐carnitine is a compound involved in metabolism via the carnitine shuttle system, and is activated when ATP concentration decreases, allowing transport of fatty acid chains into the mitochondria to help replenish the ATP supply. Carnitine levels varied across the exposure concentrations in the groups treated with MB, but at the 2.1 mg/kg exposure dose, treatment with MB appeared to decrease the amount of circulation carnitine. Hemorrhagic pulmonary edema is a symptom of 1080 poisoning, and MB was able to significantly reduce the presence of hemoglobin in BALF for 0.5, 1.1, and 2.1 mg/kg groups. Treatment with MB was able to shift the LD50 curve of 1080 to 3.29 mg/kg from 2.18 mg/kg, giving a protective ratio of 1.53. MB was also able to increase the probability of survival of animals at the 8.4 mg/kg exposure dose. Overall, while MB has shown some promise as treatment for 1080, further testing is needed to determine how viable it is and identify any likely biomarkers for screening to lead to an accurate diagnose.

Metabolomics Applied to Cord Serum in Preeclampsia Newborns: Implications for Neonatal Outcomes.

Preeclampsia (PE) is one of the leading causes of maternal and perinatal morbidity and mortality. However, it is still uncertain how PE affects neonate metabolism. We conducted an untargeted metabolomics analysis of cord blood to explore the metabolic changes in PE neonates. Umbilical cord serum samples from neonates with preeclampsia (n = 29) and non-preeclampsia (non-PE) (n = 32) pregnancies were analyzed using the UHPLC-QE-MS metabolomic platform. Different metabolites were screened, and pathway analysis was conducted. A subgroup analysis was performed among PE neonates to compare the metabolome between appropriate-for-gestational-age infants (n = 21) and small-for-gestational-age (SGA) infants (n = 8). A total of 159 different metabolites were detected in PE and non-PE neonates. Creatinine, N4-acetylcytidine, sphingomyelin (D18:1/16:0), pseudouridine, uric acid, and indolelactic acid were the most significant differential metabolites in the cord serum of PE neonates. Differential metabolite levels were elevated in PE neonates and were involved in the following metabolic pathways: glycine, serine, and threonine metabolism; sphingolipid, glyoxylate, and dicarboxylate metabolism; and arginine biosynthesis. In PE neonates, SGA neonates showed increased levels of hexacosanoyl carnitine and decreased abundance of 3-hydroxybutyric acid and 3-sulfinoalanine. Taurine-related metabolism and ketone body-related pathways were mainly affected. Based on the UHPLC-QE-MS metabolomics analysis, we identified the metabolic profiles of PE and SGA neonates. The abundance of metabolites related to certain amino acid, sphingolipid, and energy metabolism increased in the umbilical cord serum of PE neonates.

Dynamics of the infant gut microbiota in the first 18 months of life: the impact of maternal HIV infection and breastfeeding

BackgroundAccess to antiretroviral therapy (ART) during pregnancy and breastfeeding for mothers with HIV has resulted in fewer children acquiring HIV peri- and postnatally, resulting in an increase in the number of children who are exposed to the virus but are not infected (HEU). HEU infants have an increased likelihood of childhood infections and adverse growth outcomes, as well as increased mortality compared to their HIV-unexposed (HUU) peers. We explored potential differences in the gut microbiota in a cohort of 272 Nigerian infants born to HIV-positive and negative mothers in this study during the first 18 months of life.ResultsThe taxonomic composition of the maternal vaginal and gut microbiota showed no significant differences based on HIV status, and the composition of the infant gut microbiota at birth was similar between HUU and HEU. Longitudinal taxonomic composition of the infant gut microbiota and weight-for-age z-scores (WAZ) differed depending on access to breast milk. HEU infants displayed overall lower WAZ than HUU infants at all time points. We observed a significantly lower relative abundance of Bifidobacterium in HEU infants at 6 months postpartum. Breast milk composition also differed by time point and HIV infection status. The antiretroviral therapy drugs, lamivudine and nevirapine, as well as kynurenine, were significantly more abundant in the breast milk of mothers with HIV. Levels of tiglyl carnitine (C5) were significantly lower in the breast milk of mothers without HIV. ART drugs in the breast milk of mothers with HIV were associated with a lower relative abundance of Bifidobacterium longum.ConclusionsMaternal HIV infection was associated with adverse growth outcomes of HEU infants in this study, and these differences persist from birth through at least 18 months, which is a critical window for the development of the immune and central nervous systems. We observed that the relative abundance of Bifidobacterium spp. was significantly lower in the gut microbiota of all HEU infants over the first 6 months postpartum, even if HEU infants were receiving breast milk. Breastfeeding was of benefit in our HEU infant cohort in the first weeks postpartum; however, ART drug metabolites in breast milk were associated with a lower abundance of Bifidobacterium.7evEDGTh3wF9QF2c-7o-e3Video abstract

NMR metabolic composition profiling of high pressure pasteurized milk preserved by hyperbaric storage at room temperature

1 H NMR spectroscopy was used to study the effect of hyperbaric storage (HS) on the chemical composition of high pressure pasteurized milk (HPP milk). A subsequent multivariate analysis (MVA) was applied to distinguish samples stored under different conditions. Three different pressure levels (50/75/100 MPa), at naturally variable uncontrolled room temperature (≈ 20 °C), and up to 40 days of storage were compared with controls at atmospheric pressure and room temperature (AP/RT) or under refrigeration (RF). Only AP/RT samples presented spoilage compounds as lactate, methylamine and trimethylamine derived from microbial deterioration of milk. However, RF spectral profiles were closer to initial milk samples than the HS profiles, mainly in the aliphatic region which corresponds to an increase in soluble proteins for the HS samples. Additionally, MVA revealed higher levels of citrate, carnitine, lactose, and orotate in initial and RF samples, while HS samples had higher levels of acetate, N-acetylglucosamine, choline and galactose. In conclusion, although HS and RF samples were separated by MVA, there was no presence of microbial spoilage compounds in the spectra, being HS at RT an eco-friendlier alternative to preserve foods than traditional RF. • High-pressure pasteurized milk (HPP milk) presented a typical 1D 1 H NMR spectrum. • Refrigerated (RF) samples were closer to the initial samples of HPP milk. • Hyperbaric storage (HS) showed higher levels of acetate, choline and galactose. • RF presented higher levels of citrate, carnitine, lactose and orotate. • HS raised soluble protein, potentially with higher digestibility/nutritional value.

The relationship between cognitive impairment and fatty acids and carnitine in hemodialysis patients

Background/AimThe prevalence of cognitive impairment (CI) is high in hemodialysis patients. In this study, the relationship between CI and serum carnitine, plasma omega-3, omega-6 and omega-3/omega-6 fatty acid ratio was evaluated in hemodialysis patients. Materials and methodsSixty two patients [male: 40 (64.5%), mean age 51±13 years] were included in this cross-sectional study. Serum total and free-carnitine levels were determined by ELISA. Plasma omega-3 [eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA)] and omega-6 [arachidonic acid (AA), dihomo gamma linoleic acid (DGLA)] levels were measured using LC-ESI-MS/MS. According to the Montreal Cognitive Assessment (MoCA) scores, ≤24 points were considered as CI. MoCA score ≤24 and >24 were determined as Group 1 and Group 2, respectively. ResultsGroup 1 had significantly higher AA+DGLA/EPA+DHA ratios and lower free-carnitine, DHA and EPA+DHA levels compared to Group 2 (P=0.008, P=0.040, P=0.032, P=0.032, respectively). Group 1 had a statistically lower education level (P<0.05). Negative correlation was found between MoCA scores and AA+DGLA/EPA+DHA ratios (rs=−0.284, P=0.026). Free-carnitine levels were positively correlated with EPA and EPA+DHA levels (rs=0.278, P=0.030 and rs=0.271, P=0.034, respectively), and negative correlated with AA+DGLA/EPA+DHA ratios (rs=−0.414, P=0.001). In multivariate logistic regression analysis, MoCA scores was associated with AA+DGLA/EPA+DHA ratio (P=0.009) and education level (P<0.001). ConclusionIt was determined that high AA+DGLA/EPA+DHA ratio and low education level could be independent risk factors of the CI. It has been shown that free-carnitine level can have positive effects on plasma EPA+DHA and AA+DGLA distributions. Low omega-3 fatty acid levels may be associated with CI in hemodialysis patients, and low carnitine level may contribute partially to this process. In addition, cognitive education programs may have an effect on preventing CI in hemodialysis patients with low education levels.

Relevance of Biotin Deficiency in Patients with Inflammatory Bowel Disease and Utility of Serum 3 Hydroxyisovaleryl Carnitine as a Practical Everyday Marker.

Background: Biotin, a water-soluble B vitamin, has demonstrable anti-inflammatory properties. A biotin-deficient diet induced a colitis-like phenotype in mice, alleviable by biotin substitution. Mice with dextran sulfate sodium (DSS)-induced colitis showed biotin deficiency and diminished levels of sodium-dependent multivitamin transporter, a protein involved in biotin absorption. Biotin substitution induced remission by reducing activation of NF-κB, a transcription factor involved in intestinal permeability and inflammatory bowel disease (IBD). We investigated for the first time a possible clinical role of biotin status in IBD. Methods: In a comparative, retrospective, cross-sectional study, serum samples of 138 patients with IBD (67 female; 72 Crohn’s disease (CD), 66 ulcerative colitis (UC)) aged 18–65 years and with a mean age (±SD) of 42.5 ± 14.3 years as well as 80 healthy blood donors (40 female; 40.0 ± 10.0 years; range 20–60 years) were analyzed. Inflammation was defined as hsCRP ≥5 mg/L, and to determine biotin status, serum 3-hydroxyisovaleryl carnitine (3HIVc) levels were measured by LC-MS/MS. Results: A total of 138 patients with IBD (67f; 72CD/66 UC; 42.5 ± 14.3 years) were enrolled: 83/138 had inflammation. Mean serum 3HIVc levels were significantly higher in IBD patients but unaffected by inflammation. Biotin deficiency (95th percentile of controls: >30 nmol/L 3HIVc) was significantly more common in IBD patients versus controls. Conclusion: High serum 3HIVc levels and biotin deficiency were associated with IBD but not inflammatory activity or disease type. Our findings suggest biotin may play a role as cause or effect in IBD pathogenesis. Routine assessment and supplementation of biotin may ameliorate IBD and support intestinal integrity.

Anesthetic management of patients with carnitine deficiency or a defect of the fatty acid β-oxidation pathway: A narrative review.

Carnitine is essential for the transport of long-chain fatty acids from the cytoplasm to the mitochondrial matrix. The carnitine shuttle transports long-chain fatty acylcarnitine to the mitochondrial matrix. Subsequently, long-chain fatty acyl CoA, which is split from long-chain fatty acylcarnitine by carnitine palmitoyltransferase II, undergoes fatty acid β-oxidation. Acetyl CoA is produced from long-chain fatty acyl CoA via fatty acid β-oxidation and aids in the synthesis of adenosine triphosphate via the tricarboxylic acid cycle and electron transport chain. In addition, in the fasting state, it leads to ketone body production in the liver and glucose production via gluconeogenesis. However, patients with compromised fatty acid β-oxidation, owing to carnitine deficiency as well as defects in carnitine transport and the fatty acid β-oxidation pathway, develop hypoglycemia, cardiomyopathy, arrhythmia, and hypotonia. These conditions are attributed to the accumulation of released fatty acids and acylcarnitine. This review aimed to shed light on the anesthetic management of patients with compromised fatty acid β-oxidation undergoing various surgeries by assessing relevant case reports associated with fatty acid β-oxidation disorder in PubMed. Pre-anesthetic and intraoperative evaluation should include monitoring of glucose and carnitine levels and specific cardiac tests, such as echocardiography. Considering that propofol is dissolved in 10% long-chain fatty acids, propofol infusion should be avoided because of increased long-chain fatty acid loading in patients with compromised fatty acid β-oxidation. Thus, anesthesia using opioids (remifentanil and fentanyl), midazolam, dexmedetomidine, etomidate, and non-depolarizing neuromuscular blocking agents would be appropriate in such patients.

Metabolomic profiling in small vessel disease identifies multiple associations with disease severity.

Cerebral small vessel disease is a major cause of vascular cognitive impairment and dementia. There are few treatments, largely reflecting limited understanding of the underlying pathophysiology. Metabolomics can be used to identify novel risk factors to better understand pathogenesis and to predict disease progression and severity.We analysed data from 624 patients with symptomatic cerebral small vessel disease from two prospective cohort studies. Serum samples were collected at baseline and patients underwent MRI scans and cognitive testing at regular intervals with up to 14 years of follow-up. Using ultra-performance liquid chromatography–mass spectrometry and nuclear magnetic resonance spectroscopy, we obtained metabolic and lipidomic profiles from 369 annotated metabolites and 54 764 unannotated features and examined their association with respect to disease severity, assessed using MRI small vessel disease markers, cognition and future risk of all-cause dementia.Our analysis identified 28 metabolites that were significantly associated with small vessel disease imaging markers and cognition. Decreased levels of multiple glycerophospholipids and sphingolipids were associated with increased small vessel disease load as evidenced by higher white matter hyperintensity volume, lower mean diffusivity normalized peak height, greater brain atrophy and impaired cognition. Higher levels of creatine, FA(18:2(OH)) and SM(d18:2/24:1) were associated with increased lacune count, higher white matter hyperintensity volume and impaired cognition. Lower baseline levels of carnitines and creatinine were associated with higher annualized change in peak width of skeletonized mean diffusivity, and 25 metabolites, including lipoprotein subclasses, amino acids and xenobiotics, were associated with future dementia incidence.Our results show multiple distinct metabolic signatures that are associated with imaging markers of small vessel disease, cognition and conversion to dementia. Further research should assess causality and the use of metabolomic screening to improve the ability to predict future disease severity and dementia risk in small vessel disease. The metabolomic profiles may also provide novel insights into disease pathogenesis and help identify novel treatment approaches.

Evaluation of the relationship between serum carnitine levels and intradialytic complications in children with kidney failure.

Carnitine plays a crucial role in the metabolism of fatty acids as well as energy production. Previous research has suggested a significant decrease in carnitine levels in patients with kidney failure and those undergoing hemodialysis. Therefore, we designed this study to assess the prevalence and characteristics of carnitine deficiency and its association with hemodialysis complications in the pediatric population. This research was a pilot study of 29 children undergoing hemodialysis. Before hemodialysis, a 5-mL blood sample was drawn from each patient through a peripheral vein to measure serum-free carnitine levels, complete blood count with differential, blood urea nitrogen (BUN), creatinine, and electrolytes. Each patient was observed for intradialytic complications, including muscle cramps and hypotension, during 12 sessions of hemodialysis. We included 26 participants with a mean age of 14.23years undergoing hemodialysis. Carnitine deficiency was revealed in 54.8% of our participants. Also, there was no significant correlation between carnitine deficiency and age, gender, and BUN levels (P = 0.698, P = 0.43, and P > 0.05, respectively). Intradialytic complications, including episodes of hypotension and muscle cramps, were more frequent in patients with carnitine deficiency (P = 0.02, P = 0.01, respectively). Other reasons for muscle cramps, such as fluid overload, nutritional status, dialysis regimen, and other important lab results (phosphorus, magnesium, etc.), were ruled out. In conclusion, we found a higher prevalence of carnitine deficiency in pediatric hemodialysis patients. Carnitine deficiency was significantly associated with increased intradialytic symptoms, including muscle spasms and hypotension. Our results could support a potential role of carnitine supplementation in pediatric patients with kidney failure for controlling intradialytic complications, but this requires further investigation. A higher resolution version of the Graphical abstract is available as Supplementary information.

POS-331 L-carnitine ameliorates diabetic kidney disease by alleviating mitochondrial abnormality and fatty acid accumulation in SDT-fatty rats

Abnormal fatty acid metabolism is associated with the progression of diabetic kidney disease (DKD). Carnitine plays a central role in fatty acid β-oxidation and energy production by transporting long-chain fatty acids from the cytoplasm to the mitochondria. Recently, we found that significant ectopic fat was accumulated in the kidney tissue in DKD patients compared with those in minimal change kidney disease patients independent of proteinuria levels, suggesting the abnormal carnitine dynamics in DKD. Juvenile visceral steatosis (jvs) mice, described as an animal model for systemic carnitine deficiency caused by a mutation in slc22a5 gene, introduce a marked ectopic fat accumulation in the kidney. These findings suggest that abnormal carnitine dynamics in DKD cause ectopic fat accumulation due to abnormality of the fatty acid metabolism. However, the association between abnormalities of carnitine metabolism and the progression of DKD is unknown. Therefore, we investigated the kinetics of carnitine and the effect of L-carnitine therapy in type 2 DKD model rats. Spontaneously Diabetic Torii (SDT) fatty rat, an obese type 2 diabetic model was used. Unilateral nephrectomy was performed and 0.3% salt water was administered at 6 weeks of age, and created a renal dysfunction model in SDT fatty rat (DKD model). Age-matched male Sprague-Dawley (SD) rat was used as a control. Experiment 1: We compared 3 groups; ①SD rats (n=8) ②SDT fatty rats (n=8) ③DKD rats (n=8). Experiment 2: We compared 3 groups; ①SD rats with sham operation (n=8) ②DKD rats (n=7) ③DKD rats treated with L-carnitine administration (0.75% L-carnitine diet) for 10 weeks (n=6). All rats were sacrificed at 17 weeks old. Carnitine was measured by the enzyme cycling method. Acylcarnitine was analyzed by the tandem-mass spectrometry. Plasma and renal free carnitine levels were significantly decreased and long-chain acylcarnitine levels were significantly increased in DKD rats compared with those in SD and SDT fatty rats. The renal expression levels of organic cation / carnitine transporter 2 (OCTN2), carnitine palmitoyl transferase 1a (CPT1a), CPT2 and carnitine acetyltransferase (CrAT) were significantly decreased in DKD rats compared with those in SD and SDT fatty rats. Similarly, acetyl-CoA carboxylase (ACC) activity was significantly increased and peroxisome proliferator-activated receptor γ co-activator 1α (PGC1α) and peroxisome proliferator-activated receptor α (PPARα) activity were decreased in DKD rats. Further, marked ectopic fat accumulation in the renal tubules and glomeruli in DKD model rats was observed. L-carnitine administration significantly improved renal function, urinary albumin excretion, interstitial fibrosis and renal ectopic fat accumulation in DKD model rats. L-carnitine administration ameliorated the decrease of renal OCTN2, CPT1a, CPT2 and CrAT protein expression, and significantly improved ACC, PGC1α, and PPARα activity in DKD model rats. Furthermore, L-carnitine administration mitigated lipid peroxidation and mitochondrial dysfunction in DKD rats Abnormal carnitine kinetics and dynamics might play an important role in the progression of DKD. L-carnitine administration might be a promising therapeutic strategy for improving renal function by alleviating mitochondrial dysfunction in DKD rat model.

Evaluation of plasma carnitine status in patients diagnosed with juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood and manifests mainly as autoinflammation of the joints and other tissues. Several treatment options such as nonsteroidal antiinflammatory drugs, methotrexate, and intra-articular steroids are widely used to relieve and improve this inflammation. Secondary carnitine deficiency can be detected in chronic diseases by either renal loss or increased demand. While carnitine status can be associated with several conditions, in the present study our aim is to determine the levels of free carnitine and acyl-carnitine in Turkish JIA patients. One hundred and fourteen patients diagnosed with juvenile idiopathic arthritis and 50 healthy individuals who served as the control group were included in the study. A fasting blood sample was collected from the children in both groups to determine free carnitine and acylcarnitine ester by quadripole electrospray tandem mass spectrometry (ESI-MS/ MS). Screening of acyl-carnitine profile revealed free carnitine, C14, C14:2, C16, C16-OH, and C18 carnitine levels were higher (p < 0.0001, p < 0.0001, p < 0.001, p < 0.001, and p = 0.011, respectively), while C2, C3, C4, C6, C8, C10, C10:1, C10:2, C3DC, C4DC, C5DC, C4-OH, and C18:1-OH carnitine levels were lower (p < 0.0001) in JIA patients in comparison to the control group. Total acyl-carnitine levels (p < 0.001) and acyl-carnitine to free carnitine ratio (p < 0.001) were also lower in JIA patients than the control group. Free carnitine levels were significantly higher (48.05 ± 13.36 μmol/L) in patients under antiinflammatory drug therapy than those who did not receive any treatment (43.18 ± 7.96 μmol/L) (p = 0.004). In the present study we were not able to define secondary carnitine deficiency in JIA patients, although free carnitine and acyl-carnitine variations were detected in JIA patients. In conclusion, routine carnitine supplementation is not recommended in all patients with JIA.