Acid Plasma Levels Research Articles

Causal association of plasma n-3 PUFA with peptic ulcer disease: a two-sample Mendelian randomisation study.

Dietary n-3 PUFA may have potential benefits in preventing peptic ulcer disease (PUD). However, data from observational epidemiological studies are limited. Thus, we conducted a Mendelian randomisation analysis to reveal the causal impact of n-3 PUFA on PUD. Genetic variants strongly associated with plasma levels of total or individual n-3 PUFA including plant-derived α-linolenic acid and marine-derived EPA, DPA and DHA were enrolled as instrumental variables. Effect size estimates of the n-3 PUFA-associated genetic variants with PUD were evaluated using data from the UK biobank. Per one sd increase in the level of total n-3 PUFA in plasma was significantly associated with a lower risk of PUD (OR = 0·91; 95 % CI 0·85, 0·99; P = 0·020). The OR were 0·81 (95 % CI 0·67, 0·97) for EPA, 0·72 (95 % CI 0·58, 0·91) for DPA and 0·87 (95 % CI 0·80, 0·94) for DHA. Genetically predicted α-linolenic acid levels in plasma had no significant association with the risk of PUD (OR = 5·41; 95 % CI 0·70, 41·7). Genetically predicted plasma levels of n-3 PUFA were inversely associated with the risk of PUD, especially marine-based n-3 PUFA. Such findings may have offered an effective and feasible strategy for the primary prevention of PUD.

Development of an assay to quantify tranexamic acid levels in plasma

Dysregulations during blood clot breakdown (fibrinolysis) during vascular trauma can lead to excessive blood loss. Tranexamic acid (TXA) is an inhibitor of fibrinolysis that works by blocking the interaction between plasminogen and fibrin degradation products (FDPs) – a key step in fibrinolysis. Despite the widespread usage, there are no tests available in a clinical setting to monitor TXA levels. We developed a fluorescence resonance energy transfer (FRET)-based assay to quantify TXA concentrations in plasma by using 1) fluorescently labeled plasminogen, and 2) FDPs labelled with a fluorescence quencher. Once plasminogen binds the FDPs, the fluorescent signal is quenched. TXA causes plasminogen to dissociate from the FDPs, thus increasing fluorescence signal in a dose-dependent manner. The dose response was sensitive between 1 and 100 μM (0.16 and 15.7 mg/L). The intraassay and interassay variabilities were determined to be 5.7% and 3.0%, respectively. Limit of detection was estimated to be 0.28 μM (0.044 mg/L). When tested for measuring known levels of TXA added to plasma samples, the ratio between measured and expected TXA concentration was 1.0151. Our study demonstrates a novel assay that can rapidly quantify TXA concentrations in plasma samples, thus demonstrating its potential as an in-hospital tool.

Aerobic exercise alleviates statin-induced PCSK9 upregulation by increasing epoxyeicosatrienoic acid levels through the FoxO3a-Sirt6 axis

BackgroundStatins are the cornerstone of low-density lipoprotein cholesterol (LDL-C)-lowering therapy; however, the therapeutic efficacy of statins in countering atherosclerotic cardiovascular disease (ASCVD) is compromised by the concurrent elevation of proprotein convertase subtilisin/kexin type 9 (PCSK9), a pivotal molecule that increases LDL-C levels. Aerobic exercise lowers PCSK9 levels, but the underlying mechanism remains unclear. Therefore, we investigated how aerobic exercise can ameliorate statin-induced increases in PCSK9 levels. MethodsThree-week-old male American Institute of Cancer Research (ICR) mice were fed a high-fat-cholesterol diet (HFD) for 12 weeks and then administered atorvastatin alone or atorvastatin combined with aerobic exercise (Statin+Ex). Moreover, a total of 165 participants with stable coronary heart disease (CHD) enrolled at the inpatient and outpatient departments of the Second Xiangya Hospital of Central South University from January 2018 to July 2020 were randomized into the Statin group (male/female = 51/33) and Statin+Ex group (male/female = 52/29). Patients in the Statin+Ex group underwent treadmill exercise of 45–60 min/day for 7 days. ResultsAerobic exercise effectively alleviated statin-induced PCSK9 upregulation in human patients with CHD and hypercholesterolemic ICR mice (all p< 0.05). Mechanistically, our findings revealed that aerobic exercise induced elevated epoxyeicosatrienoic acids (EETs) plasma levels while concurrently reducing the activity of soluble epoxide hydrolase (sEH) (all p < 0.05), an enzyme responsible for EETs degradation. Further, EETs significantly suppressed PCSK9 expression, subsequently reducing the LDL-C levels (all p < 0.05); this effect was mediated via the activation of the Forkhead box O3a-Silent mating type information regulation 2 homolog 6 (FoxO3a-Sirt6) axis, with no impact on the Sterol Regulatory Element Binding Protein 2 and 3-hydroxy-3-methylglutaryl-CoA reductase(SREBP2-HMGCR) pathway. ConclusionOur study sheds light on the paradigm of "Exercise is Medicine", providing evidence to support the use of statins combined with exercise in reducing LDL-C levels, and unveils potential avenues for clinical applications of sEH inhibitors, presenting novel prospects for therapeutic interventions in ASCVD.

Supplementation and Mitigating Cognitive Decline in Older Adults With or Without Mild Cognitive Impairment or Dementia: A Systematic Review.

This systematic literature review aims to answer the question of how micronutrients might influence the development and progression of dementia. In the present work, we focused on an overview of an updated review of relevant literature published in the last two decades. This review aims to delineate the relationship between micronutrient supplementation and cognitive decline in older subjects. In carrying out this review, we followed PRISMA, and our literature search was performed on PubMed. This systematic review includes only primary studies that have investigated the efficacy of nutritional interventions for the prevention of dementia and improvement of cognitive function in subjects aged 65 years or older with normal cognition, mild cognitive impairment (MCI), or Alzheimer's disease (AD). A gross heterogeneity of studies forbids the possibility of a direct comparison of the results. A review of the inclusion criteria and restrictions has been conducted to check the validity and reliability of the results. In this review, thirty-three primary studies were included. Results have shown that supplementation with vitamin D, probiotics, and PUFAs would most likely reduce cognitive decline, dementia, or AD compared with vitamins A, B, C, and E, which were seen to be relatively ineffective. Of note, when considering vitamin B supplementation, positive effects were only observed in non-aspirin users having high ω-3 fatty acid (ω-3 FA) plasma levels. In some cases, however, there were genotypic differences in subjects in response to vitamin B supplementation.

Effects of Propolis Supplementation on Gut Microbiota and Uremic Toxin Profiles of Patients Undergoing Hemodialysis.

Propolis possesses many bioactive compounds that could modulate the gut microbiota and reduce the production of uremic toxins in patients with chronic kidney disease (CKD) undergoing hemodialysis (HD). This clinical trial aimed to evaluate the effects of propolis on the gut microbiota profile and uremic toxin plasma levels in HD patients. These are secondary analyses from a previous double-blind, randomized clinical study, with 42 patients divided into two groups: the placebo and propolis group received 400 mg of green propolis extract/day for eight weeks. Indole-3 acetic acid (IAA), indoxyl sulfate (IS), and p-cresyl sulfate (p-CS) plasma levels were evaluated by reversed-phase liquid chromatography, and cytokines were investigated using the multiplex assay (Bio-Plex Magpix®). The fecal microbiota composition was analyzed in a subgroup of patients (n = 6) using a commercial kit for fecal DNA extraction. The V4 region of the 16S rRNA gene was then amplified by the polymerase chain reaction (PCR) using short-read sequencing on the Illumina NovaSeq PE250 platform in a subgroup. Forty-one patients completed the study, 20 in the placebo group and 21 in the propolis group. There was a positive correlation between IAA and TNF-α (r = 0.53, p = 0.01), IL-2 (r = 0.66, p = 0.002), and between pCS and IL-7 (r = 0.46, p = 0.04) at the baseline. No significant changes were observed in the values of uremic toxins after the intervention. Despite not being significant, microbial evenness and observed richness increased following the propolis intervention. Counts of the Fusobacteria species showed a positive correlation with IS, while counts of Firmicutes, Lentisphaerae, and Proteobacteria phyla were negatively correlated with IS. Two months of propolis supplementation did not reduce the plasma levels of uremic toxins (IAA, IS, and p-CS) or change the fecal microbiota.

Profiling of Oxylipins as Markers of Oxidative Stress in Biological Samples.

Oxylipins are oxidized metabolites of polyunsaturated fatty acids (PUFAs). They represent a class of risk markers and/or therapeutic targets for diseases associated with inflammation, including cardiovascular disease and brain disorders. Because the biological activities of free PUFAs and oxylipins depend on their chemical structures and concentrations, monitoring PUFAs and oxylipin levels in biological systems is critical for understanding their roles in health and disease. Traditionally, accurate quantification of free PUFAs and oxylipins in biological samples was performed separately, as PUFAs are often 1000-fold more abundant than the derived oxidized fatty acids (oxylipins). This article describes a liquid chromatography multiple reaction monitoring tandem mass spectrometry method for the quantitative analysis of five free PUFAs and 88 oxylipins in various biological fluids, including plasma, platelet supernatants, and tissues. The same approach can also be used in conjunction with an alkaline hydrolysis step to quantify total oxylipins in fish oils. We observed that in some samples, linoleic acid levels in plasma and eicosapentaenoic acid and arachidonic acid levels in brain tissue were above the upper limit of quantification. To address this issue, we developed a data analysis method to obtain PUFA and oxylipin concentrations in these samples without additional sample preparation, thus significantly saving time and labor. © 2024 Wiley Periodicals LLC. Basic Protocol: Quantification of polyunsaturated fatty acids (PUFAs) and oxylipins using liquid chromatography multiple reaction monitoring tandem mass spectrometry Support Protocol 1: Preparation of internal standard mixed working solution Support Protocol 2: Preparation of standard mixed stock solution Support Protocol 3: Preparation of standard mixed working solution Alternate Protocol 1: Extraction and quantitation of free PUFAs and oxylipins from mouse brain tissue Alternate Protocol 2: Extraction and quantitation of total PUFAs and oxylipins from fish oil.

High linoleic acid levels in red blood cells predict a poor response to neoadjuvant chemotherapy in human epidermal growth factor receptor type 2-positive breast cancer patients

ObjectivePolyunsaturated fatty acids are categorized as ω-3 or ⍵-6. Previous studies demonstrate that breast cancers display a high expression of fatty acid synthase and high fatty acid levels. Our study sought to determine if changes in plasma or red blood cell membrane fatty acid levels were associated with the response to preoperative (neoadjuvant) chemotherapy in non-metastatic breast cancer patients. MethodsOur prospective study assessed fatty acid levels in plasma and red blood cell membrane. Response to neoadjuvant chemotherapy was evaluated by the presence or absence of pathologic complete response and/or residual cancer burden. ResultsA total of 28 patients were included. First, patients who achieved pathologic complete response had significantly higher neutrophil-to-lymphocyte ratio versus no pathologic complete response (P = 0.003). Second, total red blood cell membrane polyunsaturated fatty acids were higher in the absence of pathologic complete response (P = 0.0028). Third, total red blood cell membrane ⍵-6 polyunsaturated fatty acids were also higher in no pathologic complete response (P < 0.01). Among ⍵-6 polyunsaturated fatty acids, red blood cell membrane linoleic acid was higher in the absence of pathologic complete response (P < 0.01). Notably, plasma polyunsaturated fatty acid, ⍵-6, and linoleic acid levels did not have significant differences. A multivariate analysis confirmed red blood cell membrane linoleic acid was associated with no pathologic complete response; this was further confirmed by receiver operating characteristic analysis (specificity = 92.3%, sensitivity = 76.9%, and area under the curve = 0.855). ConclusionsPending further validation, red blood cell membrane linoleic acid might serve as a predictor biomarker of poorer response to neoadjuvant chemotherapy in non-metastatic human epidermal growth factor receptor type 2–positive breast cancer. Measuring fatty acids in red blood cell membrane could offer a convenient, minimally invasive strategy to identifying patients more likely to respond or those with chemoresistance.

Childhood Apraxia of Speech: Exploring Gluten Sensitivity and Changes in Glutamate and Gamma-Aminobutyric Acid Plasma Levels

BackgroundIndividuals with childhood apraxia of speech (CAS) were reported to have genetic variations related to gluten sensitivity and some neuroanatomic changes, which could be associated with alterations in neurotransmitters levels such as glutamate and gamma-aminobutyric acid (GABA). The aim was to measure the levels of antigliadin immunoglobulin A (IgA) antibody, glutamate, and GABA in the plasma of children with CAS compared with children with delayed language development (DLD) and neurotypical (NT) children. MethodsThe participants (N = 120) were in three groups: Group I for CAS (N = 30), Group II for DLD (N = 60), and Group III for NT (N = 30). The abilities of children in Groups I and II were evaluated. The plasma levels of antigliadin IgA, glutamate, and GABA were determined by enzyme-linked immunosorbent assay. ResultsThe intelligence quotient and expressive language age in Group I were low compared with Group II (P = 0.001; 0.004). The levels of antigliadin IgA and glutamate in Group I were higher compared with the other two groups, whereas the level of GABA was lower (P < 0.0001). An imbalance between glutamate and GABA was found in Group I. In Group II, no measures differed from NTs except lower GABA levels (P = 0.0007). ConclusionsThe elevated levels of antigliadin IgA antibody and glutamate demonstrated high sensitivity and specificity, differentiating children with CAS from children with DLD and NT children. The low levels of GABA contributed to the imbalance between the excitatory and inhibitory neurotransmitters’ levels detected in children with CAS.

Supplementation of dietary semen vaccariae extracts to lactating sow diets: effects on the production performance, milk components, and gene expression related to mammogenesis.

This study aimed to investigate the effects of dietary semen vaccariae extracts (SVE) on the production performance, colostrum components, and relative gene expression related to mammogenesis of lactating sows. 48 pregnant sows were selected and randomly allocated into four groups, with six replicates and two sows per replicate. The first group was the control (CON), while the other groups received the same diet further supplemented with 1.5, 3.0 and 4.5 g SVE per kg (SV1, SV2 and SV3, respectively). Compared with the control group, (1) the average daily gain was increased (p < 0.05) in SV1, SV2, and SV3 during the 11-21 days and 1-21 days of lactation; (2) the serum insulin-like growth factor-1, insulin, prolactin, and estrogen contents in SV1, SV2, and SV3 were increased (p < 0.05) on the 1st and 21st day of lactation; (3) The plasma Lysine, Threonine, and Tryptophan concentrations were also higher (p < 0.05) in SV1, SV2, and SV3 on the 1st and 21st day of lactation; (4) The milk Lysine, Methionine, Threonine, and Tryptophan concentrations were higher (p < 0.05) in SV1, SV2, and SV3 on the 1st and 21st day of lactation; (5) The milk lactose ratio and milk protein content were increased (p < 0.05) in the groups treated with semen vaccariae on the 1st day of lactation, while the milkfat ratio and milk protein content were increased (p < 0.05) in SV2 and SV3 on the 21st day of lactation; (6) the immunoglobulin M, A, and G contents were increased (p < 0.05) in the groups treated with the semen vaccariae on the first day of lactation; and (7) the relative PRLR, STAT5a, FcRn, CSN2, and LALBA expressions were higher (p < 0.05) in the groups treated with the semen vaccariae on the 1st and 21st day of lactation. In this study, the optimum dosage was 3.0 g/kg semen vaccariae, which increased the average daily gain of piglets, total lactation yield, and serum hormone levels, improved the amino acid levels in plasma, and facilitated the milk quality, up-regulated the relative gene expressions in the mammogenesis.

The impact of pancreatic fibrosis at fibronectin and hyaluronic acid plasma levels: preliminary study results

The impact of pancreatic fibrosis at fibronectin and hyaluronic acid plasma levels: preliminary study results

Effects of Thymoquinone on Urotensin-II and TGF-β1 Levels in Model of Osteonecrosis in Rats.

Objectives: We aimed to investigate the therapeutic effects of thymoquinone (TMQ) treatment in osteonecrotic rats by evaluating protein levels, osteonecrosis (ON) levels, fatty acid degeneration, oxidative status, and plasma levels of Urotensin-II (U-II) and transforming growth factor-beta (TGF-β1). Materials and Methods: 40 weight-matched adult male Wistar rats were grouped as control (n = 10), methylprednisolone acetate (MPA) (n = 10), thymoquinone (TMQ) (n = 10), and MPA + TMQ (n = 10). To induce ON, 15-week-old animals were subcutaneously injected with MPA at a dose of 15 mg/kg twice weekly for 2 weeks. TMQ was injected into 15-week-old rats via gastric gavage at a dose of 80 mg/kg per day for 4 weeks. The rats in the MPA + TMQ group were administered TMQ 2 weeks before the MPA injection. At the end of the treatments, cardiac blood samples and femur samples were collected for biochemical and histological evaluations. Results: In the control and TMQ groups, no ON pattern was observed. However, in tissues exposed to MPA, TMQ treatment resulted in significantly decreased ON levels compared to the MPA group. The number of cells that were positive for 8-OHdG and 4-HNE was significantly lower in the MPA + TMQ group than in the MPA group (p < 0.05). In terms of TGF-β1 and U-II levels, we observed that both TGF-β1 (367.40 ± 23.01 pg/mL vs. 248.9 ± 20.12 pg/mL) and U-II protein levels (259.5 ± 6.0 ng/mL vs. 168.20 ± 7.90 ng/mL) increased significantly in the MPA group compared to the control group (p < 0.001). Furthermore, TGF-β1 (293.50 ± 14.18 pg/mL) and U-II (174.80 ± 4.2 ng/mL) protein levels were significantly decreased in the MPA + TMQ group compared to the MPA group (p < 0.05 and p < 0.01, respectively). There was a statistically positive correlation (p < 0.05) between the TGF-β1 and U-II protein levels in all groups (p = 0.002, rcontrol = 0.890; p = 0.02, rTMQ = 0.861; p = 0.024, rMPA+TMQ = 0.868) except for the MPA group (p < 0.03, rMedrol = -0.870). Conclusions: As far as we know, this is the first study to demonstrate the curative functions of TMQ on ON by causing a correlated decrease in the expression of U-II and TGF-β1 in the femoral heads of rats.

Microvesicle-associated and circulating microRNAs in diabetic dyslipidemia: miR-218, miR-132, miR-143, and miR-21, miR-122, miR-155 have biomarker potential

BackgroundCirculating MicroRNAs (miRNAs) carried by microvesicles (MVs) have various physiological and pathological functions by post-transcriptional regulation of gene expression being considered markers for many diseases including diabetes and dyslipidemia. We aimed to identify new common miRNAs both in MVs and plasma that could be predictive biomarkers for diabetic dyslipidemia evolution.MethodsFor this purpose, plasma from 63 participants in the study (17 type 2 diabetic patients, 17 patients with type 2 diabetes and dyslipidemia, 14 patients with dyslipidemia alone and 15 clinically healthy persons without diabetes or dyslipidemia) was used for the analysis of circulating cytokines, MVs, miRNAs and MV-associated miRNAs.ResultsThe results uncovered three miRNAs, miR-218, miR-132 and miR-143, whose expression was found to be significantly up-regulated in both circulating MVs and plasma from diabetic patients with dyslipidemia. These miRNAs showed significant correlations with important plasma markers, representative of this pathology. Thus, MV/plasma miR-218 was negatively correlated with the levels of erythrocyte MVs, plasma miR-132 was positively connected with MV miR-132 and negatively with uric acid and erythrocyte plasma levels, and plasma miR-143 was negatively related with creatinine levels and diastolic blood pressure. Also, three miRNAs common to MV and plasma, namely miR-21, miR-122, and miR-155, were identified to be down-regulated and up-regulated, respectively, in diabetic dyslipidemia. In addition, MV miR-21 was positively linked with cholesterol plasma levels and plasma miR-21 with TNFα plasma levels, MV miR-122 was negatively correlated with LDL-c levels and plasma miR-122 with creatinine and diastolic blood pressure and positively with MV miR-126 levels, MV miR-155 was positively associated with cholesterol and total MV levels and negatively with HDL-c levels, whereas plasma miR-155 was positively correlated with Il-1β plasma levels and total MV levels and negatively with MV miR-223 levels.ConclusionsIn conclusion, miR-218, miR-132, miR-143, and miR-21, miR-122, miR-155 show potential as biomarkers for diabetic dyslipidemia, but there is a need for more in-depth studies. These findings bring new information regarding the molecular biomarkers specific to diabetic dyslipidemia and could have important implications for the treatment of patients affected by this pathology.

Plasma Fatty Acid Composition, Oxidative and Inflammatory Status, and Adherence to the Mediterranean Diet of Patients with Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is a complex and increasingly prevalent cardiometabolic disorder worldwide. As of today, NAFLD is a pathology without specific pharmacological treatment, with the Mediterranean diet (MedDiet) being the most widely used approach for its management. The objective of this study is to assess the effects of adherence to the Mediterranean diet on fatty acid plasma levels, as well as on the oxidative and inflammatory status of NAFLD patients. A total of 100 adult patients (40-60 years old) diagnosed with NAFLD and from the Balearic Islands, Spain, were classified into three groups according to their adherence to the MedDiet. Consumption was assessed using a validated 143-item semiquantitative Food Frequency Questionnaire. Food items (g/day) were categorised according to their processing using the NOVA system. Anthropometrics, blood pressure, aminotransferases, Dietary Inflammatory Index (DII), inflammatory biomarkers, and fatty acid levels were measured in the plasma of NAFLD patients. High adherence to the MedDiet is associated to a highly plant-based diet, low ultra-processed food (UPF) consumption, low intake of dietary lipids, low intake of animal fats, high intake of monounsaturated fatty acid (MUFA; mainly palmitoleic acid), low intake of saturated fatty acids (SFAs; practically all dietary SFAs), low intake of trans-fatty acids, high intake of omega-3 fatty acids (mainly eicosapentaenoic acid), a higher n-6:n-3 in ratio, low intake of omega-6 fatty acids, and a low level of interleukin-6 (IL-6). High adherence to the MedDiet is related to a better fatty acid profile in the plasma, fewer SFAs and more MUFA and polyunsaturated fatty acids (PUFAs), a plasma biochemical profile, better proinflammatory status, and decreased ultra-processed food consumption of NAFLD patients.

Uric acid plasma levels are associated with C-reactive protein concentrations and the extent of coronary artery lesions in patients with acute coronary syndromes.

Many studies have pointed out that inflammation plays a pivotal role in pathophysiology of acute coronary syndromes (ACS) because several inflammatory molecules impair the endothelial functions in the coronary circulation and promote atherothrombotic events. Recently, many clinical/experimental evidences indicate that elevated plasma levels of uric acid (UA) might be considered a risk factor for developing ACS. It has been reported that elevated UA doses impair physiologic functions of endothelial cells, shifting them toward a pro atherothrombotic phenotype. In the present manuscript, we investigated the relationship between UA plasma levels, inflammatory burden, and extension of coronary atherosclerotic disease in patients with ACS. Patients with a clinical presentation of ACS (ST-elevated and non-ST-elevated myocardial infarction) admitted to the Vanvitelli Catheterization Laboratory at Monaldi Hospital in 2019, before the COVID-19 pandemia, were retrospectively analyzed. Biochemical profile, type of ACS presentation, as well as extension of coronary atherosclerosis were assessed. A total of 132 ACS patients were included in the analysis, and grouped into 3 tertiles according to the UA values (UA < 4.72mg/dl, UA between 4.72 and 6.15mg/dl, and UA > 6.15mg/dl). Patients with UA plasma levels ≥ 6.15mg/dL showed higher levels of C-reactive protein (mean of 5.1mg/dL) as compared to patients with lower UA plasma levels. Moreover, the former group of patients showed higher levels of cardiac troponin and CPK, and presented more often with multivessel disease and complex coronary stenosis (type C of Ellis classification). Even though monocentric and with limited sample size, the present study shows that plasma levels of UA and hs-CRP are elevated in ACS patients and are associated with a more severe coronary disease, suggesting a potential role of UA in the pathophysiology of acute coronary events.

Studying sex differences in responses to fibroblast growth factor 21 administration in obese mice consuming a sweet-fat diet.

In animals, obesity caused by consumption of a sweet-fat diet (SFD) is the most adequate mouse model of human diet-induced obesity. Fibroblast growth factor 21 (FGF21) reduces body weight, beneficially affects taste preferences, and corrects glucose metabolism in obese mice. Sex is known to influence FGF21 effects in different models of diet-induced and hereditary obesity. In mice with SFD-induced obesity, the effects of FGF21 have been studied only in males. The aim of this study was to compare the effects of FGF21 on body weight, food preferences and glucose and lipid metabolism in C57Bl/6J male and female mice with SFD-induced obesity. Mice were fed with a diet consisting of standard chow, lard and cookies for 10 weeks, then they were injected with FGF21 (1 mg per 1 kg) or vehicle for 7 days. Body weight, weights of different types of food, blood parameters, glucose tolerance, gene and protein expression in the liver, gene expression in the white, brown adipose tissues, and the hypothalamus were assessed. FGF21 administration reduced body weight, did not alter total energy consumption, and activated orexigenic pathways of hypothalamus in mice of both sexes. However, sex dimorphism was found in the realization of the orexigenic FGF21 action at the transcriptional level in the hypothalamus. Metabolic effects of FGF21 were also sex-specific. Only in males, FGF21 exerted beneficial antidiabetic action: it reduced fatty acid and leptin plasma levels, improved glucose-tolerance, and upregulated hepatic expression of Ppargc1, Fasn, Accα, involved in lipid turnover, gene Insr and protein glucokinase, involved in insulin action. Only in obese females, FGF21 induced preference of standard diet to sweet food. Thus, in mouse model of obesity induced by consumption of a sweet-fat diet, the catabolic effect of FGF21 was not sex-specific and hormonal, transcriptional and behavioral effects of FGF21 were sex-specific. These data suggest elaboration of different approaches to use FGF21 analogs for correction of metabolic consequences of obesity in different sexes.

Hyperuricaemia Does Not Interfere with Aortopathy in a Murine Model of Marfan Syndrome.

Redox stress is involved in the aortic aneurysm pathogenesis in Marfan syndrome (MFS). We recently reported that allopurinol, a xanthine oxidoreductase inhibitor, blocked aortopathy in a MFS mouse model acting as an antioxidant without altering uric acid (UA) plasma levels. Hyperuricaemia is ambiguously associated with cardiovascular injuries as UA, having antioxidant or pro-oxidant properties depending on the concentration and accumulation site. We aimed to evaluate whether hyperuricaemia causes harm or relief in MFS aortopathy pathogenesis. Two-month-old male wild-type (WT) and MFS mice (Fbn1C1041G/+) were injected intraperitoneally for several weeks with potassium oxonate (PO), an inhibitor of uricase (an enzyme that catabolises UA to allantoin). Plasma UA and allantoin levels were measured via several techniques, aortic root diameter and cardiac parameters by ultrasonography, aortic wall structure by histopathology, and pNRF2 and 3-NT levels by immunofluorescence. PO induced a significant increase in UA in blood plasma both in WT and MFS mice, reaching a peak at three and four months of age but decaying at six months. Hyperuricaemic MFS mice showed no change in the characteristic aortic aneurysm progression or aortic wall disarray evidenced by large elastic laminae ruptures. There were no changes in cardiac parameters or the redox stress-induced nuclear translocation of pNRF2 in the aortic tunica media. Altogether, the results suggest that hyperuricaemia interferes neither with aortopathy nor cardiopathy in MFS mice.

#4592 A HIGH PROTEIN DIET INDUCES DEPRESSION-LIKE BEHAVIOR IN CKD RODENT MODELS

Abstract Background and Aims The prevalence of depression among patients with Chronic Kidney Disease (CKD) is higher than the general population. Around 21-27% of CKD patients is estimated to be affected by depression. Several studies hypothesized that mood disorders may be due to reduced family support, older age, low educational status and low quality of life. However, adults with CKD are also known to exhibit altered tryptophan metabolism causing reduced plasma levels of tryptophan and elevated kynurenine and kynurenic acid. Moreover, CKD patients show increased levels of indoxyl sulfate and indole-3-acetic acid, two protein-bound uremic toxins deriving from the gut microbiome metabolism of tryptophan. We postulate that depression is not just due to reduced quality of life but also to a biological reason. In addition, we hypothesize that a high protein diet may influence tryptophan metabolism and therefore affect depression symptoms. Method Eighteen Sprague-Dawley male rats (Janvier, Le Genest- St Isle, France), 7-8 weeks old, were induced with CKD utilizing 5/6 nephrectomy and were randomly assigned to a low protein (n = 10) or a high protein (n = 8) diet. A sham-operated control group for each diet was used (n = 7 respectively). The splash test was adopted to assess depressive symptoms in rats. In short, the splash test is a behavioral test consisting in sprinkling a 10% sucrose solution on the dorsal coat of a rat. Latency (time before the initiation of grooming) and duration of grooming were recorded for 5 min and used as an indication of self-care behavior. Delayed and reduced grooming is considered as a depression-like behavior of rats. Blood and urine creatinine were determined with standard laboratory techniques. Total plasmatic concentrations of tryptophan, kynurenine, kynurenic acid and indoxyl sulfate were measured using LC-MS/MS. Results The latency before the starting of the grooming behavior was significantly higher (p = .0499) in CKD rats on a high protein diet compared to sham rats on the same diet while no difference was seen between the low protein groups. CKD rats reported significantly higher plasma levels of indoxyl sulfate and kynurenic acid and reduced tryptophan. Interestingly, kynurenic acid plasma levels were significantly reduced when administering a low protein diet to CKD rats (p = .0025). Among CKD rats, the latency to the grooming behavior was correlated with plasmatic levels of creatinine clearance (Spearman r = -.57, p value = .019), indoxyl sulfate (Spearman r = .64, p value = .007), and kynurenic acid (Spearman r = .63, p value = .009). The total grooming time was shorter in both CKD groups compared to the sham rats, but not significantly (p = .4881 and p = .4312, respectively). Conclusion These results suggest that biological factors contribute to depression onset and that the decline of kidney function and the accumulation of uremic toxins are potential risk factors for depression. Dietary interventions such as a low protein diet, are potential strategies to lower the plasmatic levels of uremic toxins which may alleviate depressive-like symptoms.

ANMCO statement: Uric acid and cardiovascular disease: evidence and therapeutic approach

Pathophysiologic processes promoted by uric acid, including inflammation and oxidative stress, play a key role in the pathogenesis of several cardiovascular diseases. Furthermore, a number of epidemiological studies have shown an association between uric acid plasma levels and multiple cardiovascular risk factors. This ANMCO statement provides an update on available evidence regarding the association between elevated plasma uric acid levels and cardiovascular disease risk and the safety and efficacy of uric acid lowering agents (allopurinol and febuxostat) used in patients with urate crystal deposits. In addition, it summarizes practical indications for the use of these drugs in at-risk patients or in patients with cardiovascular disease.

Chronic-binge ethanol feeding in mice associates with downregulation of hepatic xanthine oxidase, resulting in reduced uric acid levels in plasma and liver

Chronic-binge ethanol feeding in mice associates with downregulation of hepatic xanthine oxidase, resulting in reduced uric acid levels in plasma and liver

CYP4F2 is a human-specific determinant of circulating N-acyl amino acid levels

N-acyl amino acids are a large family of circulating lipid metabolites that modulate energy expenditure and fat mass in rodents. However, little is known about the regulation and potential cardiometabolic functions of N-acyl amino acids in humans. Here, we analyze the cardiometabolic phenotype associations and genomic associations of four plasma N-acyl amino acids (N-oleoyl-leucine, N-oleoyl-phenylalanine, N-oleoyl-serine, and N-oleoyl-glycine) in 2,351 individuals from the Jackson Heart Study. We find that plasma levels of specific N-acyl amino acids are associated with cardiometabolic disease endpoints independent of free amino acid plasma levels and in patterns according to the amino acid head group. By integrating whole genome sequencing data with N-acyl amino acid levels, we identify that the genetic determinants of N-acyl amino acid levels also cluster according to amino acid head group. Furthermore, we identify the CYP4F2 locus as a genetic determinant of plasma N-oleoyl-leucine and N-oleoyl-phenylalanine levels in human plasma. In experimental studies, we demonstrate that CYP4F2-mediated hydroxylation of N-oleoyl-leucine and N-oleoyl-phenylalanine results in metabolic diversification and production of many previously unknown lipid metabolites with varying characteristics of the fatty acid tail group, including several that structurally resemble fatty acid hydroxy fatty acids (FAHFAs). These studies provide a structural framework for understanding the regulation and disease-associations of N-acyl amino acids in humans and identify that the diversity of this lipid signaling family can be significantly expanded through CYP4F-mediated ω-hydroxylation.