Arachidonic Research Articles

Multidimensional Plasma Lipids Affect Preeclampsia/Eclampsia: A Mendelian Randomization Study.

Circulating lipids play a crucial role during pregnancy and may impact various pregnancy-related diseases. This study employed a two-sample Mendelian randomization (MR) framework to investigate the causal relationship between alterations in multidimensional plasma lipid levels and the risk of preeclampsia or eclampsia, offering deeper insight into this association. The inverse variance weighted (IVW) method was utilized as the main analysis. Summary statistics from plasma lipidomics of 7174 Finnish individuals and summary data on preeclampsia/eclampsia from the FinnGen consortium involving 219 817 European participants were employed. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy. The study identified 17 lipid species from a total of 179 lipid species associated with susceptibility to preeclampsia/eclampsia. Notably, ten species, including six triacylglycerols (TAGs) (50:1, 48:1, 56:4, 49:2, 48:2, 54:3), a diacylglycerol (DAG) (16:1_18:1), and three sphingomyelins (SMs) (d36:1, d34:1, d38:1), were found to increase the risk of preeclampsia/eclampsia. Conversely, seven species, including five phosphatidylcholines (PCs) (16:1_20:4, O-18:1_20:4, 18:1_20:4, 16:0_20:4, 17:0_20:4) and two phosphatidylethanolamines (PEAs) (18:0_20:4, 16:0_20:4), all containing arachidonic acid (ARA) in the sn-2 position, were associated with a reduced risk of preeclampsia/eclampsia (all p < 0.05). The results of thestratified analysis were consistent with these findings. Furthermore, reverse MR analysis indicated that preeclampsia/eclampsia does not causally affect plasma levels of these lipids. Our findings established a causal relationship between specific plasma lipid species and modulation of preeclampsia/eclampsia risk, providing improved resolution for risk assessment and potential therapeutic targets in the disease.

Lipophilic index of serum phospholipids in patients with type 2 diabetes and atherosclerotic cardiovascular disease: links with metabolic control, vascular inflammation and platelet activation.

Little is known about the mechanisms underlying the association of the serum phospholipid lipophilic index (LI) with atherosclerotic cardiovascular disease (ASCVD) in patients with type 2 diabetes (T2D). Therefore, we investigated whether the LI is associated with glucometabolic control, meta-inflammation, thrombin generation, fibrin clot properties, endothelial function and platelet activation in T2D patients with angiographically documented ASCVD. We studied 74 T2D patients with ASCVD, aged 65.6 ± 6.8 years, with a median diabetes duration of 10 years and median HbA1c of 7.0%. Serum phospholipid fatty acids (FAs) were measured by gas chromatography. The serum phospholipid LI was calculated as the sum of the products of the proportion (% of total FAs) with the melting points (°C) of each individual FA, divided by the sum of the proportions of all FAs. Levels of HbA1c, insulin, leptin, adiponectin, lipid profiles, inflammatory markers (hsCRP, interleukin-6, TNF-α), Lp-PLA2 (a biomarker of vascular inflammation), endothelial function (sICAM-1, sVCAM-1, FMD, NMD), thrombin generation, fibrin clot properties and platelet activation, measured by light transmission aggregometry with arachidonic acid [AA] and adenosine diphosphate [ADP], were assessed. Patients with LI > 16.9°C (median) had higher HbA1c concentrations by 5.9% compared to the remaining subjects (p = 0.035). In this group, HbA1c levels ≥ 7.0% were found more often than in individuals with LI ≤ 16.9°C (62.2 vs. 35.1%; p = 0.020). Subjects with LI > 16.9°C had higher levels of TCh by 17.1% (p = 0.012), LDL-Ch by 29.4% (p = 0.003), interleukin-6 by 22.2% (p = 0.031) and Lp-PLA2 by 32.4% (p = 0.040), compared to the remaining patients. Moreover, they had increased maximal platelet aggregation induced by AA (p = 0.045), but not by ADP. Serum phospholipid LI correlated with HbA1c (r = 0.24; p = 0.037), TCh (r = 0.36; p = 0.002), LDL-Ch (r = 0.38; p < 0.001), interleukin-6 (r = 0.27; p = 0.020) and Lp-PLA2 (r = 0.26; p = 0.026). There were no intergroup differences in endothelial function, thrombin generation and fibrin clot properties. Regression analysis showed that HbA1c ≥ 7.0% and serum levels of LDL-Ch, interleukin-6 and Lp-PLA2 were predictors of LI > 16.9°C in adjusted models. In well-controlled T2D patients with ASCVD, the higher serum phospholipid LI is associated with worse glucometabolic control, enhanced vascular inflammation and higher platelet reactivity during aspirin treatment at cyclooxygenase-1-selective doses.

11C]PS13 Demonstrates Pharmacologically Selective and Substantial Binding to Cyclooxygenase-1 in the Human Brain.

Our laboratory recently developed [11C]PS13 as a PET radioligand to selectively measure cyclooxygenase-1 (COX-1). The cyclooxygenase enzyme family converts arachidonic acid into prostaglandins and thromboxanes, which mediate inflammation. The total brain uptake of [11C]PS13, which is composed of both specific binding and background uptake, can be accurately quantified with gold standard methods of compartmental modeling. This study sought to quantify the specific binding of [11C]PS13 to COX-1 in healthy human brain using scans performed with arterial input function at baseline and after blockade by the COX-1-selective inhibitor ketoprofen. Methods: Eight healthy volunteers underwent two 90-min [11C]PS13 PET scans with radiometabolite-corrected arterial input function, at baseline and about 2 h after oral administration of ketoprofen (75 mg). Results: Two-tissue compartment modeling effectively identified the total uptake of radioactivity in the brain (as distribution volume), showing the highest densities in the hippocampus, the occipital cortex, and the banks of the central sulcus. All brain regions exhibited displaceable and specific binding, and thus none could be used as a reference region. Ketoprofen blocked approximately 84% of the binding sites on COX-1 in the whole brain. After full occupancy was extrapolated, the average whole-brain values of [11C]PS13 were 1.6 ± 0.8 mL·cm-3 for specific uptake, 1.7 ± 0.6 mL·cm-3 for background uptake, and 1.1 ± 0.5 for the specific-to-background ratio. The hippocampus had the highest specific-to-background ratio value of 2.7 ± 0.9. Conclusion: [11C]PS13 exhibited high specific binding to COX-1 in the human brain, but its quantification requires arterial blood sampling.

Discovery and Molecular Characterization of a Novel 9S-Lipoxygenase from Enhygromyxa salina for Fatty Acid Biotransformations.

Iron-dependent lipoxygenases (LOXs) are involved in the synthesis of oxylipins from polyunsaturated fatty acids. However, they are usually difficult to overexpress in functional form in microbial cell factories. Moreover, 9-LOXs, generating 9-hydroperoxy fatty acids from C18 polyunsaturated fatty acids, have rarely been found from microbial sources. Here, we discovered a novel 9S-LOX in the marine myxobacterium Enhygromyxa salina (Es-9S-LOX). The recombinant enzyme produced in Escherichia coli exhibited remarkable activity in the dioxygenation of linoleic acid (LA, 1), α-linolenic acid, γ-linolenic acid, and arachidonic acid specifically at the C9 position to yield the product with (S)-configuration at catalytic efficiency of 3.94, 1.42, 1.38, and 0.69 μM-1·s-1, respectively. The elucidated X-ray crystal structure of Es-9S-LOX reveals a long and narrow hydrophobic pocket that allows the substrate to be near the metal ion and the oxygen tunnel. The enzyme was successfully used in a chemoenzymatic reaction to generate a hydroxy fatty acid from LA. Our study thus contributes to the valorization of renewable polyunsaturated fatty acids into a variety of fatty acid derivatives, including hydroxy fatty acids.

Melatonin alleviates heat stress-induced spermatogenesis dysfunction in male dairy goats by regulating arachidonic acid metabolism mediated by remodeling the gut microbiota.

Heat stress (HS) commonly occurring in summer has gradually become a factor threatening the reproductive performance of male dairy goats by reducing their fecundity. Despite the melatonin is applied to relieve HS, it is still unclear whether melatonin protects against reproductive damage induced by HS in dairy goats and how it works. The purpose of the present study is to evaluate the role of melatonin in alleviating HS-induced spermatogenesis dysfunction in male dairy goats and further explore its mechanism. HS impaired spermatogenesis, sperm formation in the testes, and sperm maturation in the epididymis of dairy goats, resulting in decreased sperm quality. Melatonin rescued the decrease of sperm quality induced by HS via decreasing inflammatory and oxidative stress levels in testicular tissue and enhancing intercellular barrier function within the testes. Amplicon-based microbiota analysis revealed that despite gut microbiota differences between melatonin-treated dairy goats and NC dairy goats to some extent, melatonin administration tends to return the gut microbiota of male dairy goats under HS to the levels of natural control dairy goats. To explore whether the protective role of melatonin in sperm quality is mediated by regulating gut microbiota, fecal microbiota of HS dairy goats with or without melatonin treatment were transferred to HS mice, respectively. We found HS mice that had received fecal bacteria of HS dairy goats experienced serious testicular injury and dyszoospermia, while this phenomenon was ameliorated in HS mice that had received fecal bacteria of dairy goats treated with melatonin, indicating melatonin alleviates HS-induced spermatogenic damage in a microbiota dependent manner. We further found that the testicular tissue of both HS dairy goats and mice transplanted with HS dairy goat feces produced large amounts of arachidonic acid (AA)-related metabolites, which were closely associated with semen quality. Consistently, supplementation with AA has been shown to elevate the levels of inflammation and oxidative stress in the testicular tissue of mice, disrupting intercellular connections and ultimately leading to spermatogenic disorders. This study has revealed that melatonin can effectively alleviate spermatogenic disorders in dairy goats caused by HS. This beneficial effect was primarily achieved through the modulation of gut microbiota, which subsequently inhibited the excessive synthesis of AA in testicular tissue. These discoveries are of great significance for preventing or improving the decline in male livestock reproductive performance caused by HS, enhancing the reproductive efficiency of elite male breeds, and ultimately improving the production efficiency of animal husbandry. Video Abstract.

Abstract 4134926: Association of Eicosanoid Metabolites with Body Mass Index

Introduction: The specific molecular pathways from obesity to inflammation to cardiovascular disease remain unclear. Eicosanoids are a unique class of bioactive lipids that govern the upstream initiation of pro- and anti-inflammatory activity. Objective: We leveraged a novel lipidomic platform to quantify &gt; 800 eicosanoid metabolites and examined their association with body mass index (BMI). Methods: We studied Multi-Ethnic Study of Atherosclerosis (MESA) participants with available samples for eicosanoid analysis. Eicosanoids and related metabolites were assessed using a directed, non-targeted mass spectrometry-based platform. We examined the cross-sectional association of eicosanoid metabolites with BMI using multivariable linear regression models. Analyses were considered significant at FDR q-value &lt;0.01. Results: A total of 5101 individuals (age 63 ± 10 years; 53% women, 60% non-Whites) were included. The mean BMI was 28.3 ± 5.1 kg/m2. Of 811 eicosanoids analyzed, 255 showed a significant association with BMI (see Figure for putative metabolite identities; FDR q-value &lt;0.01 for all). Derivatives of docosahexaenoic acid (DHA; 19,20 DiHDPA, β = - 0.206, standard error [SE] = 0.013) and eicosatetraenoic acid (11(S) HEPE, β = - 0.180, SE = 0.014) were associated with lower BMI. Linoleic acid derivatives (12,13 diHOME, an exercise-induced lipokine) had a similar association. Conversely, derivatives of linoleic acid (13-oxoODE, β = 0.241, SE = 0.01) and arachidonic acid (11-HETE, β = 0.236, SE = 0.017) were associated with higher BMI. Other derivatives of linoleic acid (15 (S) HETrE) and prostaglandin (11b PGF2α) were also associated with higher BMI. Conclusions: We found that specific eicosanoid metabolites, including DHA and linoleic acid derivatives with known anti-inflammatory, atheroprotective, and beneficial metabolic effects (e.g., 19,20 DiHDPA; 12,13 diHOME), were associated with lower BMI. By contrast, specific arachidonic acid and prostaglandin derivatives with known pro-inflammatory and adverse CV effects (e.g. oxylipin 11-HETE; PGF2α; 13-oxoODE) were associated with higher BMI. These findings further the understanding of specific inflammatory pathways underlying the development of obesity-related CVD.

The Altered Lipid Composition and Key Lipid Metabolic Enzymes in Thiacloprid-Resistant Myzus persicae, with Special Attention Paid to the Function of MpTHEM6a

Neonicotinoid resistance is increasingly prevalent in the agricultural pest Myzus persicae. Lipids play a critical role in insect defense systems, but their contribution to insect neonicotinoid resistance is disregarded. We conducted metabolomics and transcriptomics studies on M. persicae thiacloprid-resistant (THG-R) and -susceptible (FFJ-S) populations. A total of 149 lipid metabolites were identified, with 90 upregulated and 59 downregulated in THG-R compared to in FFJ-S. Metabolites in the arachidonic acid (AA) pathway substantially varied between THG-R and FFJ-S. For example, arachidonic acid, (±)11-HETE, and prostaglandin B1 were significantly upregulated, while prostaglandin A1, tetranor-PGDM, 8,15-diHETE, and (±)11(12)-EET were significantly decreased in THG-R. Transcriptomics profiles and qPCR indicated that lipid metabolic enzymes, including fatty acid synthase (FAS), the elongase of very-long-chain fatty acids (ELO), fatty acid desaturase (FAD), and phospholipase (PL) genes, were not overexpressed in THG-R. Among the twelve thioesterase genes, only MpTHEM6a was significantly upregulated in THG-R. Knocking down the expression of MpTHEM6a in THG-R significantly increased the toxicity of the three neonicotinoids, reduced the lifespan of adults, and decreased the number of nonviable nymphs produced by female adults. The metabolites AA, (±)11-HETE, and prostaglandin B1 are potential biomarkers in neonicotinoid-resistant M. persicae. MpTHEM6a may become a potential target for combating neonicotinoid-resistant M. persicae.

Effects of the rs174575 single nucleotide polymorphism in FADS2 on levels of long-chain PUFA: a meta-analysis.

The influence of the SNP rs174575 (C/G) within the fatty acid desaturase 2 gene on the levels of long-chain PUFA was determined through statistical meta-analysis. Six databases were searched to retrieve the relevant literature. Original data were analysed using Stata 17·0, encompassing summary statistics, tests for heterogeneity, assessment of publication bias, subgroup analysis and sensitivity analysis. A total of ten studies were identified and grouped into twelve trials. Our results showed that individuals who carried the minor G allele of rs174575 had significantly higher dihomo-γ-linolenic acid levels (P = 0·005) and lower arachidonic acid levels (P = 0·033) than individuals who were homozygous for the major allele. The subgroup analysis revealed that the G-allele carriers of rs174575 were significantly positively correlated with linoleic acid (P = 0·002) and dihomo-γ-linolenic acid (P < 0·001) and negatively correlated with arachidonic acid (P = 0·004) in the European populations group. This particular SNP showed a potential association with higher concentrations of dihomo-γ-linolenic acid (P = 0·050) and lower concentrations of arachidonic acid (P = 0·030) within the breast milk group. This meta-analysis has been registered in the PROSPERO database (ID: CRD42023470562).

Associations of the serum n-6 PUFA concentrations with exercise-induced myocardial ischaemia in middle-aged and older men.

n-6 PUFA, especially linoleic acid (LA) but also arachidonic acid (AA), have been inversely associated with CHD. However, mechanisms underlying these associations are not fully known. We investigated the associations of the serum concentrations of total n-6 PUFA, LA, AA, γ-linolenic acid (GLA) and dihomo-γ-linolenic acid (DGLA), with the odds of myocardial ischaemia during exercise, a predictor of future cardiac events. A total of 1871 men without a history of CHD from the Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) aged 42-60 years were included. All participants performed a maximal symptom-limited exercise stress test, using an electrically braked bicycle ergometer. Multivariable-adjusted logistic regression was used to assess the OR for exercise-induced myocardial ischaemia in quartiles of the serum n-6 PUFA concentrations. After multivariable adjustment, men in the highest v. the lowest serum AA concentration had 50 % lower odds for exercise-induced myocardial ischaemia (OR 0·50, 95 % CI 0·34, 0·76; P-trend across quartiles < 0·001). For the other PUFA, the OR (95 % CI) were 1·00 (0·69, 1·46; P-trend = 0·89) for LA, 1·07 (0·75, 1·53; P-trend = 0·40) for GLA and 0·74 (0·51, 1·07; P-trend = 0·16) for DGLA. Among the n-6 PUFA, higher serum concentration of AA was associated with lower odds for myocardial ischaemia during an exercise test in middle-aged and older men. This may provide one mechanism for the previously observed possible cardioprotective properties of AA. Our findings also suggest that n-6 PUFA should not be considered as one homogenous group.

Structural and Functional Biology of Mammalian ALOX Isoforms with Particular Emphasis on Enzyme Dimerization and Their Allosteric Properties

The human genome involves six functional arachidonic acid (AA) lipoxygenase (ALOX) genes, and the corresponding enzymes (ALOX15, ALOX15B, ALOX12, ALOX12B, ALOXE3, ALOX5) have been implicated in cell differentiations and in the pathogenesis of inflammatory, hyperproliferative, metabolic, and neurological disorders. Humans express two different AA 15-lipoxygenating ALOX isoforms, and these enzymes are called ALOX15 (15-LOX1) and ALOX15B (15-LOX2). Chromosomal localization, sequence alignments, and comparison of the enzyme properties suggest that pig and mouse ALOX15 orthologs (leukocyte-type 12-LOX) on the one hand and rabbit and human ALOX15 orthologs on the other (reticulocyte-type 15-LOX1) belong to the same enzyme family despite their different reaction specificities with AA as a substrate. In contrast, human ALOX12 (platelet-type 12-LOX), as well as pig and mouse ALOX15 (leukocyte-type 12-LOX), belong to different enzyme families, although they exhibit a similar reaction specificity with AA as a substrate. The complex multiplicity of mammalian ALOX isoforms and the controversial enzyme nomenclatures are highly confusing and prompted us to summarize the current knowledge on the biological functions, enzymatic properties, and allosteric regulation mechanisms of mammalian ALOX15, ALOX15B, and ALOX12 orthologs that belong to three different enzyme sub-families.

The potential clinical value of platelet aggregation in colorectal tumor progression

ObjectiveThe present study is to examine whether platelet aggregation function, platelet count and mean platelet volume are indicators that related to clinicopathological characteristics of colorectal cancer.MethodsA total of 546 patients with colorectal tumors and 118 healthy controls were enrolled, and patients with colorectal tumors were grouped according to malignancy, prognosis, recurrence and metastasis. The parameters of platelet aggregation function included max aggregation ratio, average aggregation ratio and max aggregation time were detected. 546 patients were induced by arachidonic acid, meanwhile, 415 of which were additionally induced by adenosine diphosphate. Of 118 healthy controls, 60 cases were induced by arachidonic acid and 58 cases were induced by adenosine diphosphate. We evaluated the intergroup significance of these indexes by receiver operating characteristic analysis.ResultsThe levels of max aggregation ratio, average aggregation ratio and platelet count were related to progression including cancerization, radical operation and recurrence and metastasis (P < 0.05). Notably, max aggregation ratio-arachidonic acid is the best indicator for predicting these three progressions with the areas under receiver operating characteristic curve of 0.685, 0.652, and 0.649, respectively.ConclusionCorrelations between max aggregation ratio, average aggregation ratio and colorectal tumor progression were observed with a certain clinical value.

Lipopolysaccharide-mediated effects of the microbiota on sleep and body temperature

Recent research suggests that microbial molecules translocated from the intestinal lumen into the host’s internal environment may play a role in various physiological functions, including sleep. Previously, we identified that butyrate, a short-chain fatty acid produced by intestinal bacteria, and lipoteichoic acid, a cell wall component of gram-positive bacteria, induce sleep when their naturally occurring translocation is mimicked by direct delivery into the portal vein. Building upon these findings, we aimed to explore the sleep signaling potential of intraportally administered lipopolysaccharide (LPS), a primary component of gram-negative bacterial cell walls, in rats. Low dose of LPS (1 μg/kg) increased sleep duration and prolonged fever, without affecting systemic LPS levels. Interestingly, administering LPS systemically outside the portal region at a dose 20 times higher did not affect sleep, indicating a localized sensitivity within the hepatoportal region for the sleep and febrile effects of LPS. Furthermore, both the sleep- and fever-inducing effects of LPS were inhibited by indomethacin, a prostaglandin synthesis inhibitor, and replicated by intraportal administration of prostaglandin E2 or arachidonic acid, suggesting the involvement of the prostaglandin system in mediating these actions.

Antiedematogenic and anti-inflammatory effects of the essential oil from the fruits of Piper tuberculatum Jacq. (Piperaceae) in animal models.

Piper tuberculatum, traditionally known as 'pimenta-d'arda,' 'pimenta-longa,' or 'pimenta de macaco,' has been used in Brazilian folk medicine to treat inflammatory symptoms, It is used for its sedative effects in pain relief.Considering this species' significant essential oil content, the present study aimed to evaluate the anti-edematogenic and anti-inflammatory effects of the essential oil Piper tuberculatum (EOPT) in vivo. To this end, Swiss mice (Mus musculus) of both sexes were treated orally with the EOPT at 50, 100, and 250 mg/Kg. The rotarod and open field evaluated the potential activity in the central nervous system. At the same time, formalin and abdominal writhing tests were carried out to perform the pharmacological screening of the essential oil. Next, the anti-edematogenic effect was assessed using paw edema models induced by carrageenan, dextran, histamine, and arachidonic acid. The anti-inflammatory activity was then characterized in peritonitis (acute) and granuloma (chronic) models. All the EOPT doses (50, 100, and 250 mg/kg) had analgesic effects associated with anti-inflammatory mechanisms in screening models. Accordingly, the treatment (EOPT 100 mg/Kg) inhibited the inflammatory process in acute and chronic models. In conclusion, EOPT has analgesic, antiedematogenic, and anti-inflammatory effects, highlighting its potential use in developing anti-inflammatory drugs.

Targeting tRNA-Derived Non-Coding RNA Alleviates Diabetes-Induced Visual Impairment through Protecting Retinal Neurovascular Unit.

Diabetes is a major risk factor for compromised visual health, leading to retinal vasculopathy and neuropathy, both of which are hallmarks of neurovascular unit dysfunction. Despite the critical impact of diabetic retinopathy, the precise mechanism underlying neurovascular coupling and effective strategies to suppress neurovascular dysfunction remain unclear. In this study, the up-regulation of a tRNA-derived stress-induced RNA, 5'tiRNA-His-GTG, in response to diabetic stress is revealed. 5'tiRNA-His-GTG directly regulates Müller glia action and indirectly alters endothelial angiogenic effects and retinal ganglion cell (RGC) survival in vitro. Downregulation of 5'tiRNA-His-GTG alleviates diabetes-induced retinal neurovascular dysfunction, characterized by reduced retinal vascular dysfunction, decreased retinal neurodegeneration, and improved visually-guided behaviors in vivo. Mechanistically, 5'tiRNA-His-GTG acts as a key regulator of retinal neurovascular dysfunction, primarily by modulating arachidonic acid (AA) metabolism via the CYPs pathway. The 5'tiRNA-His-GTG-CYP2E1-19(S)-HETE signaling axis is identified as a key driver of retinal neurovascular dysfunction. Thus, targeting 5'tiRNA-His-GTG presents a promising therapeutic strategy for treating vasculopathy and neuropathy associated with diabetes mellitus. Modulating this novel signaling pathway can open up new avenues for intervention in diabetic retinopathy and its related complications.

Based on Serum Pharmacochemistry and Metabolomics Studied the Pharmacodynamic Material Basis and Mechanism of Rubi Fructus (Fupenzi) in Improving the Symptom of Kidney-Yang Deficiency.

Rubi fructus (Fupenzi) is the immature fruit of East China Rubi fructus, which is widely used in medicine, food, health food and other fields. Since ancient times, Fupenzi has been considered to be an important medicine for tonifying the kidney in terms of nourishing the liver and kidney, fixing essence and reducing urine, but its effective components and mechanism are not clear. In this paper, the effective components of Rubi fructus were analyzed by detecting the components of Fupenzi in vivo and in vitro. Adenine was used to replicate the model of kidney yang deficiency, and organ index, biochemical index and histopathology were used to evaluate the effect of different doses of Fupenzi on tonifying kidney yang. Metabonomics technique was used to analyze the metabolic regulation mechanism of Fupenzi in improving kidney yang deficiency syndrome. The results showed that 61 chemical constituents of Fupenzi were identified in vitro, including 18 flavonoids, 19 organic acids, 5 coumarins, 8 terpenoids, 7 amino acids and 4 other components. A total of 51 chemical components were identified, including 30 prototype components and 21 metabolic components, which may be the effective components of Fupenzi. The results of pharmacodynamics showed that compared with the model group, the renal index, testicular index and epididymal index of rats in each Fupenzi group were significantly improved (p<0.01), cAMP significantly increased (p<0.05), cGMP decreased (p<0.05) and cAMP/cGMP ratio increased significantly (p<0.05). The content of ACTH in low dose group increased significantly (p<0.05), while the content of ACTH in middle and high dose groups increased, but there was no significant difference. The results of HE staining showed that compared with the model group, the kidney, testis and epididymis of rats in each treatment group were significantly improved. In general, these changes may be mainly through primary bile acid biosynthesis, linoleic acid metabolism, steroid hormone biosynthesis, β-alanine metabolism, glutathione metabolism, porphyrin and chlorophyll metabolism, unsaturated fatty acid biosynthesis, arachidonic acid metabolism, arginine and proline metabolism and other metabolic pathways to improve adenine-induced metabolic disorders in rats with kidney-yang deficiency syndrome.

Influence of Silicate Concentrations on Growth, Carotenoid, and Fatty Acid Profiles of the Marine Diatom Conticribra weissflogii

Enhancing microalgal growth and bioactive compound production is becoming a duty for improving photosynthetic microorganisms. In this study, the growth, carotenoid, and fatty acid profiles of Conticribra weissflogii were studied under four different silicate concentrations and silicate-deficient conditions in an f/2 medium with continuous aeration, light intensity (30 ± 2 µmol m−2 s−1), salinity (25 ± 2‰), pH (8), and temperature (25 ± 2 °C). At the end of the experiment, we observed that a silicate concentration of 120 mg L−1 produced the maximum biomass dry weight (0.86 g L−1), carotenoid content (1.63 µg mL−1), and fucoxanthin content (1.23 mg g−1) in C. weissflogii. The eicosapentaenoic acid (EPA) (11,354.37 µg g−1), docosahexaenoic acid (DHA) (2516.16 µg g−1), gamma-linolenic acid (C18:3n6) (533.51 µg g−1), and arachidonic acid (C20:4n6) (1261.83 µg g−1) contents were significantly higher at Si 120 mg L−1. The results further showed the maximum fatty acid content in C. weissflogii at Si 120 mg L−1. However, the silicate-deficient conditions (Si 0 mg L−1) resulted in higher levels of saturated fatty acids (38,038.62 µg g−1). This study presents a practical approach for the large-scale optimization of biomass, carotenoid, fucoxanthin, and fatty acid production in C. weissflogii for commercial purposes.

Integrated untargeted/targeted metabolomics identifies a putative oxylipin signature in patients with atrial fibrillation and coronary heart disease.

Atrial fibrillation (AF) and coronary heart disease (CHD) are closely related to metabolic dysregulation. However, the metabolic characteristics of AF patients with concomitant CHD remain unclear. The aims of this study were to elucidate the metabolic profiles of patients with AF and CHD to seek new therapeutic targets and related factors of AF combined with CHD. Untargeted metabolomics and targeted oxylipins profiling were performed to characterize the serum metabolome landscape of patients with AF, CHD, and AF comorbid CHD. The serum metabolic fingerprints of patients with AF comorbid CHD were significantly differentiated from normal controls (NC) and individuals with AF or CHD alone, and the differentiated metabolites dominated by a variety of lipid alterations in the phospholipid and fatty acid metabolism. Furthermore, the targeted profiles of oxylipins demonstrated that the levels of arachidonic acid derivatives including prostaglandins, leukotrienes, hydroxy-docosahexaenoic acids, hydroxy-eicostetraenoic acids and hydroxy-eicosatrienoic acids in patients with AF and CHD were significantly different from those in the NC, AF, and CHD groups. Several prostaglandins were positively associated with echocardiographic indicators of myocardial remodeling. This study updates metabolic insights of AF and CHD and provides potential therapeutic targets for preventing or treating AF comorbid CHD.

An integrative lipidomics and transcriptomics study revealing Bavachin and Icariin synergistically induce idiosyncratic liver injury

Objectives: Reports of traditional Chinese medicine (TCM)-related liver injury have increased over recent years; however, identifying susceptibility-related components and biomarkers remains challenging due to the heterogeneous nature of TCM and idiosyncratic drug-induced liver injury (IDILI). Psoraleae Fructus (PF) and Epimedii Folium (EF), commonly found in TCM prescriptions, have been implicated in IDILI, but their constituents and underlying mechanisms are poorly understood. Methods: In this study, we identified bavachin (Bav) and icariin (Ica) as susceptibility components for IDILI in PF and EF using a TNF-α-mediated mouse model. Lipidomics and transcriptomics were used to investigate their related mechanism. Results: Liver biochemistry and histopathology analyses revealed that co-exposure to Bav, Ica, and a non-toxic dose of TNF-α prestimulation induced significant liver injury, while Bav and Ica alone did not. Lipidomics identified seven differentially abundant metabolites in the Bav/Ica/TNF-α group compared to the Ica/TNF-α or Bav/TNF-α groups, mainly enriched in alpha-linolenic acid (ALA), arachidonic acid (AA), and linoleic acid (LA) metabolic pathways. Additionally, transcriptomics revealed 49 differentially expressed genes (DEGs) in the Bav/TNF-α vs Bav/Ica/TNF-α and Ica/TNF-α vs Bav/Ica/TNF-α groups, primarily associated with the PI3K/AKT/mTOR signaling pathway and sphingolipid metabolism. Integrative lipidomics and transcriptomics analyses identified significant positive correlations between five differential metabolites (DMs) – PC (O-16:0_14:1), PG (22:1_20:3), PI (16:0_14:1), PS (18:0_19:2), and TG (17:0_18:2_22:5) – and ten DEGs – Nr0b2, Btbd19, Btg2, Fam222a, Fam83f, Gtse1, Anln, Gja4, Srrm4, and Zfp13. Conslusions: Collectively, these results suggest that alterations in intracellular metabolism and gene expression levels may contribute to the synergistic induction of IDILI by the incompatible pair Bav and Ica in the presence of TNF-α.

Age-Associated Alterations in the Metabolome of Human Vitreous in Bacterial Endophthalmitis.

Endophthalmitis is a severe inflammatory condition due to intraocular infections that often leads to irreversible blindness. This study aimed to understand the age-dependent metabolic alterations in the vitreous of patients with bacterial endophthalmitis. The study included the vitreous metabolome of patients with bacterial endophthalmitis (group 1, n = 15) and uninfected controls (group 2, n = 14), which were further stratified into three groups according to their age: young (0-30years), middle (31-60years), and elderly (>60years). Vitreous samples were subjected to untargeted metabolomic analysis using high-resolution mass spectrometry (HRMS)m and acquired mass spectrometry data were analyzed using MetaboAnalyst 6.0. The altered metabolites with log2FC of ≥2/≤2, P < 0.05, and variable importance in projection > 1 were considered significant. In a total of 109 endogenous metabolites identified, young and elderly patients with endophthalmitis showed 52 (elevated, 25; reduced, 27; P < 0.05) and 27 (elevated, 19; reduced, 8; P < 0.05) significantly altered metabolites, respectively, compared to their age-matched controls. Additionally, 27 metabolites were differentially expressed in young patients with endophthalmitis compared to the older group. The crucial metabolic pathways dysregulated in the older infected population were de novo purine synthesis and salvage, carnitine, polyamine (spermidine), lipids (prostaglandins), and amino acid (taurine, methionine, histidine) which could possibly be attributed to the increased disease severity and inflammation observed in a clinical setting. Despite the erratic metabolic changes observed in the younger group infected with endophthalmitis when compared to age-matched controls, dysregulation in the specific pathways such as purine, carnitine, arachidonic acid, and polyamine metabolism could possibly alter the immunological exacerbation observed in the older group.

Environmental concentrations of 6PPD and 6PPD-quinone induce hepatic lipid metabolism disorders in male black-spotted frogs

Aquatic environments are generally contaminated with N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD) and its oxidation product 6PPD-quinone (6PPD-Q). Recently, 6PPD-Q was found lethally toxic to some specific species, especially salmonid silverfish. This study investigated male black-spotted frogs (Pelophylax nigromaculatus) exposed to 6PPD and 6PPD-Q with different environmental concentrations (0, 1, and 10 μg/L) for 21 days, after which biochemical, metabolomic, gene expression analyses, and molecular docking were conducted. 6PPD and 6PPD-Q were both found to bioaccumulate in frogs’ livers in a dose-dependent manner and produce a significant reduction of the hepatosomatic index. Metabolomics data showed that 6PPD and 6PPD-Q induced distinct alterations in metabolite expression, predominantly within pathways associated with the biosynthesis of unsaturated fatty acids as well as the metabolism of arachidonic and linoleic acids. Exposure to 10 μg/L 6PPD and 6PPD-Q increased the cholesterol level by 2.22 and 4.35 folds, and the triglyceride level by 1.90 and 2.25 folds, respectively. 6PPD-Q inhibited the enzyme activity and gene expression involved in lipolysis, and promoted the lipid synthesis. Moreover, 6PPD and 6PPD-Q bound to peroxisome proliferators-activated receptors of α and γ. In conclusion, 6PPD and 6PPD-Q with environmental concentrations induced frogs’ lipid metabolism disorders. These findings contribute to our understanding of 6PPD and 6PPD-Q health risks in amphibians.