Metabolic Level Research Articles

Horizontal and longitudinal targeted metabolomics in healthy pregnancy and gestational diabetes mellitus.

The objective is to investigate the differences in urinary organic acid (OA) profiles and metabolism between healthy control (HC) pregnant women and those with gestational diabetes mellitus (GDM) during the second trimester and third trimester of pregnancy. A total of 66 HC pregnant women and 32 pregnant women with GDM were assessed for 107 hydrophilic metabolites in urine samples collected during the second and third trimester of pregnancy using tandem mass spectrometry. The urine OA profiles for each group were obtained, and metabolomic analysis and discussion were conducted. This study identified a total of 50 metabolic biomarkers. In the third trimester of pregnancy, short-chain dicarboxylic acids (DCAs) and tryptophan (Trp)-related metabolites were significantly upregulated in the urine of both the HC group and the GDM group. Comparatively, the glycine (Gly) levels and related synthetic precursor metabolites were lower in the GDM2 group. The overall dietary polyphenol metabolic intermediates level in the GDM group was lower than in the HC group. Among the pathways enriched for differentially expressed metabolites, the predominant metabolic pathway in the GDM group was the citric acid cycle. In contrast, in the HC group, it was the metabolism of alanine, aspartate, and glutamate. The study reveals the differences in metabolomics between pregnant women with HC and those with GDM, identifying several metabolites associated with the occurrence and development of GDM. Demonstrating the presence of abnormal mitochondrial and peroxisomal functions at the metabolite level in GDM will contribute to future exploration of the condition.

Impact of Berberine Hydrochloride-assisted Metformin on the Metabolism of Glycolipids and Serum Levels of TIMP-1 and TGF-β1 in Individuals with Type 2 Diabetes

Background Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance and impaired glucose metabolism, leading to hyperglycemia and increased risk of complications like renal fibrosis. Purpose This study’s purpose is to examine how berberine hydrochloride (BBR) and metformin (Met) work together to treat T2DM, as well as how these medications affect tissue type metalloproteinase-1 (TIMP-1), glucose, and lipid metabolism levels in the blood and transforming growth factor β1. Methods Using a random number table approach, overall, 100 individuals with T2DM between October 2020 and October 2022 were chosen and classified into two groups: An experimental group and an untreated group, each with 50 patients. The untreated group received Met therapy, whereas the experimental group received BBR based on the untreated group. The two groups were compared regarding efficacy, cholesterol and glucose metabolism, renal function and renal fibrosis indices, and the frequency of adverse responses. Results The experimental group’s effective rate was 96.00% higher than that of the untreated group (82.00%). Following treatment, the experimental group had lower levels of glycosylated hemoglobin (HbAlc), insulin resistance index (HOMA-IR), fasting blood glucose (FBG), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and cholesterol (TC) than the untreated group, while the untreated group had greater levels of high-density lipoprotein cholesterol (HDL-C). Following the course of therapy, the observation group’s levels of cystatin (Cys-C), urinary β2 microglobulin (β2-MG), urine albumin excretion rate (UAER), and urinary microalbumin (ALB) were all lesser compared to the untreated group. Following treatment, the experimental group’s transforming growth factor-β (TGF-β) levels, matrix metalloproteinase-9 (MMP-9), and TIMP-1 were lesser than those of the untreated group. Conclusion When Met and BBR are taken together, patients with type 2 diabetes can effectively control their glucose and lipid metabolism, as well as their levels of TGF-β1, MMP-9, and TIMP-1. They can also postpone renal interstitial fibrosis and eventually improve their kidney function, all with a high degree of safety and significant effects.

Towards measurements of absolute membrane potential in Bacillus subtilis using fluorescence lifetime.

Membrane potential (MP) changes can provide a simple readout of bacterial functional and metabolic state or stress levels. While several optical methods exist for measuring fast changes in MP in excitable cells, there is a dearth of such methods for absolute and precise measurements of steady-state membrane potentials (MPs) in bacterial cells. Conventional electrode-based methods for the measurement of MP are not suitable for calibrating optical methods in small bacterial cells. While optical measurement based on Nernstian indicators have been successfully used, they do not provide absolute or precise quantification of MP or its changes. We present a novel, calibrated MP recording approach to address this gap. In this study, we used a fluorescence lifetime-based approach to obtain a single-cell resolved distribution of the membrane potential and its changes upon extracellular chemical perturbation in a population of bacterial cells for the first time. Our method is based on (i) a unique VoltageFluor (VF) optical transducer, whose fluorescence lifetime varies as a function of MP via photoinduced electron transfer (PeT) and (ii) a quantitative phasor-FLIM analysis for high-throughput readout. This method allows MP changes to be easily visualized, recorded and quantified. By artificially modulating potassium concentration gradients across the membrane using an ionophore, we have obtained a Bacillus subtilis-specific MP versus VF lifetime calibration and estimated the MP for unperturbed B. subtilis cells to be -65 mV (in MSgg), -127 mV (in M9) and that for chemically depolarized cells as -14 mV (in MSgg). We observed a population level MP heterogeneity of ∼6-10 mV indicating a considerable degree of diversity of physiological and metabolic states among individual cells. Our work paves the way for deeper insights into bacterial electrophysiology and bioelectricity research.

Highly Efficient Dual-Probe Strategy toward Single-Cell Metabolite Analysis.

As cancer progresses, detached cancer cells metastasize through the circulatory system, followed by intricate metabolic rewiring for adaptation and propagation. The dynamic process of metastasis, despite being responsible for the majority of cancer-related deaths, still remains inadequately comprehended. Here, we proposed a microfluidic platform combining the dual-probe strategy for the detection of metastasize-related metabolic levels at single-cell resolution. Unique design facilitates intracellular and extracellular detection within the same cell captured at individual chambers, promoting the understanding of single-cell correlation metabolites analyses. Metabolite profiling of the model cells verified the positive correlation between upregulated intracellular NAD(P)H and the increased secretion of matrix metalloproteinases (MMPs). Furthermore, Zn2+-mediated metabolite analysis demonstrated the correlation in single cells, which could be utilized as a reference for the development of zinc-based antitumor therapies. The strategy provides valuable evidence of a relatively higher risk of metastasis for malignancies through unraveling the intricate metabolic heterogeneities arising from both intrinsic and extrinsic factors within individual cells.

In vivo itaconate tracing reveals degradation pathway and turnover kinetics.

Itaconate is an immunomodulatory metabolite that alters mitochondrial metabolism and immune cell function. This organic acid is endogenously synthesized via tricarboxylic acid (TCA) metabolism downstream of TLR signaling. Itaconate-based treatment strategies are being explored to mitigate numerous inflammatory conditions. However, little is known about the turnover rate of itaconate in circulation, the kinetics of its degradation, and the broader consequences on metabolism. By combining mass spectrometry and in vivo 13 C itaconate tracing, we demonstrate that itaconate is rapidly eliminated from plasma, excreted via urine, and fuels TCA cycle metabolism specifically in the liver and kidneys. These studies further revealed that itaconate is converted into acetyl-CoA, mesaconate, and citramalate in mitochondria. Itaconate administration also influenced branched-chain amino acid metabolism and succinate levels, indicating a functional impact on succinate dehydrogenase (SDH) and methylmalonyl-CoA mutase (MUT) activity. Our findings uncovered a previously unknown aspect of the itaconate metabolism, highlighting its rapid catabolism in vivo that contrasts findings in cultured cells.

A Multi-dimensional Validation Strategy of Pharmacological Effects of Radix Isatidis Mixtures Against the Co-infection of Mycoplasma gallisepticum and Escherichia coli in Poultry

Natural drugs possess exceptional pharmacological properties, yet their development is often hindered by a lack of clarity regarding the mechanisms of their pharmacological actions. Building on our previous research, we employed a co-infection model with Mycoplasma gallisepticum (MG) and Escherichia coli (E. coli) to investigate the pharmacological action of Radix Isatidis Mixtures (RIM). To further demonstrate the various mechanisms underlying the pharmacological effects of RIM, we conducted a validation study focusing on gene expression, protein interactions, metabolic pathways, and molecular docking. Through a multi-omics joint analysis network, we identified key targets and metabolites associated with co-infection and conducted targeted verification experiments with RIM aqueous extracts. The experimental results indicated that, compared to the co-infection group, the RIM treatment group significantly modulated the expression of select genes and proteins, particularly MMP2 and TLR4, with a high level of statistical significance (p < 0.01). At the metabolic level, the treatment group exhibited significantly reduced expression levels of Dopamine and γ-Aminobutyric acid. Notably, the molecular docking results highlighted compounds with the most favorable binding affinities: Salvianolic acid A (-10.1 kcal/mol), Licorice (-9.3 kcal/mol), and Isoglycyrrhiza (-8.7 kcal/mol). In conclusion, our multi-level experiments demonstrated that RIM possesses the characteristics of multi-pathway and multi-target treatment for co-infection.

Diurnal rhythm of carotenoid metabolism in the intertidal red algal seaweed Neoporphyra haitanensis

Biological rhythms governing metabolic and developmental processes are widespread in organisms, ranging from prokaryotic cyanobacteria to mammals and flower plants. Species of the genus Porphyra sensu lato (e.g., Porphyra, Pyropia, Neoporphyra, etc.) are major red algal seaweeds important to the marine fisheries industry in northeast Asia. Over a long evolutionary history, these seaweeds have adapted to the intertidal zone environment, which is characterized by periodic extreme stresses such as high light, high temperature, high salinity, and drought. However, very little is known about the rhythmic regulation of these seaweeds in response to the shifting environment. In this study, we entrained N. haitanensis thalli with a 12 h/12 h light/dark regime under constant temperature and light intensity, and analyzed the contents of carotenoid constituents and the transcript abundances of genes involved in carotenoid metabolism. Our results clearly demonstrated a 1.52 (zeaxanthin)–2.13 (β-carotene)-fold change between the highest and lowest amounts of carotenoids, and a 7.66 (NhCHYB)–224.00 (NhZISO)-fold change in the expression levels of genes, over the course of a day. These variations indicate that the fluctuations at both metabolic and transcriptional levels of carotenoid metabolism during the light/dark shifting are significant and cannot be neglected, highlighting the need to use a series of parallel non-treated controls instead of a pre-treatment control to avoid the potential confounding effects of the treatment and the diurnal rhythm.

Cassia mimosoides L. decoction improves non-alcoholic fatty liver disease by modulating the pregnane X receptor

Cassia mimosoides L. (CML) is a traditional Chinese medicine (TCM), which is frequently used in the clinical practice of TCM in the Lingnan region of China for the treatment of obesity. However, it is not clear whether decoction of cassia seeds has beneficial effects on non-alcoholic fatty liver disease (NAFLD). This study investigates the effect of CML on NAFLD and its underlying mechanisms. The high-fat diet (HFD) was used to induce NAFLD mice, and 40 male C57BL/6J mice were divided into Control, HFD, and CML groups (CML-low 1.5g/kg, CML-medium 2.25g/kg, CML-high 4.5g/kg). The mouse primary hepatocytes (MPHs) of wild type (WT) and PXR-/- mice were induced using OAPA and divided into Control, OAPA, and CML groups (10mg/L, 100mg/L). Glycolipid metabolism, inflammation, and oxidative stress levels were detected in vivo and in vitro. Compared to the HFD group, the CML groups demonstrated reduced body weight, triglycerides, total cholesterol, blood glucose, and mRNA levels of the lipid metabolism genes Srebp-1c and ACC1 in mice (p<0.05 or 0.01). The ELISA results indicated that CML inhibited the production of IL-1β, IL-6, and TNF-α (p<0.05). Furthermore, CML increased the SOD level (p<0.01) to improve oxidative stress. RNA-seq expression showed that CML suppressed the transcriptional level of pregnane X receptor (PXR)(p<0.05). In vitro experiments, the protective effect of CML against OAPA-induced lipid accumulation and inflammation observed in WT MPHs disappeared in PXR-/- MPHs (IC50: 1.04mg/mL). CML decoction ameliorates NAFLD mainly by inhibiting the PXR signaling pathway, which provides a theoretical basis for the broad application of CML in clinical practice.

Effect of fucoidan supplementation on glycolipid metabolism, systemic inflammation and gut microbiota in prediabetes: A randomized controlled trial

Prediabetes is characterized as a transitional phase between normal blood glucose and diabetes, and the potential role of fucoidan in the progression of diabetes is still debated. The randomized, double-blind, placebo-controlled trial was designed to assess the effect of fucoidan supplementation on glycolipid metabolism, systemic inflammation and gut microbiota in individuals with prediabetes. A total of 70 Chinese participants with prediabetes were randomized to either fucoidan or placebo group, receiving daily doses of 1000 mg fucoidan or placebo capsules for 12 weeks. Glycolipid metabolism and systemic inflammation levels were assessed using standard laboratory techniques, while gut microbiota was analyzed by 16S rRNA sequencing. Following the 12-week intervention period, subjects consuming fucoidan exhibited a lower increase in GSP and a notable reduction in TNF-α, IL-6 and LPS compared to those receiving placebo (P < 0.05). Furthermore, fucoidan supplementation led to an increased abundance of Megamonas and Blautia while decreasing Klebsiella (P < 0.05). These findings suggested that the daily administration of 1000 mg fucoidan may partially modulate glucose metabolism and improve systemic inflammation, potentially linked to its modulation of gut microbiota in Chinese individuals with prediabetes. Thus, fucoidan could be considered as a potential dietary supplement for diabetes prevention.

A new perspective on bone development in vitamin D deficiency-associated obese children

Vitamin D is crucial for maintaining bone health and development, and bone mineral accumulation during childhood and adolescence affects long-term bone health. Vitamin D deficiency has been widely recognized as one of the main causes of osteoporosis and fractures, especially during the growth and development stage of children. Recent studies have shown that vitamin D deficiency may affect the deviation of bone development in children by mediating lipid metabolism disorders, but its specific mechanism of action has not been fully elucidated. In this study, through clinical correlation analysis, it was found that vitamin D deficiency was negatively correlated with lipid metabolism levels. Subsequently, lipidomic analysis of vitamin D-deficient mice and children showed that triglycerides were the main lipid metabolites. It was found that the triglyceride synthesis pathway plays a key role in bone development in vitamin D-deficient obese children. Our study found that vitamin D deficiency mediates bone dysplasia by affecting triglyceride synthesis. These findings provide new insights into the mechanisms by which vitamin D deficiency affects bone development in children, which may guide more precise clinical interventions and support the development of new clinical treatments.

CD38 Coordinates with NF-κB to Promote Cochlear Inflammation in Noise-Induced Hearing Loss: the Protective Effect of Apigenin.

Noise exposure is one of the most common causes of sensorineural hearing loss. Although many studies considered inflammation to be a major contributor to noise-induced hearing loss, the process of cochlear inflammation is still unclear. Studies have found that activation of the NF-κB signaling pathway results in the accumulation of macrophages in the inner ear plays an important role in hair cell damage. In this study, tandem mass tag (TMT) technique was used to analyze the changes in basilar membrane proteome expression before and after acoustic injury. After noise exposure, the nicotinamide adenine dinucleotide (NAD) metabolism level was decreased, and the NF-κB signaling pathway was activated. The expression of CD38, the main NAD hydrolase in mammals, may directly lead to inflammation onset. Then, anakinra, an IL-1 receptor blocker, and apigenin, a CD38 inhibitor, were administered to animals to protect against noise-induced hearing loss. Our results showed that anakinra had little influence on the hearing threshold shift, while apigenin significantly reduce the threshold shift of hearing by inhibiting the expression of NF-κB and CD38 can be a promising target for protecting against noise-induced hearing loss.

Morphological features of white adipose tissue in rats with different levels of energy metabolism in visceral obesity

Histomorphological changes of visceral white adipose tissue in obesity as a function of the level of energy metabolism in the body have not been sufficiently studied. The aim of this study was to investigate and compare the structural changes of visceral white adipose tissue in rats with different metabolic levels and severe visceral obesity. The study was carried out on male Wistar rats aged 3 months at the start of the experiment. Control animals received standard diet. Experimental rats were fed a high calorie diet for 12 weeks. At the end of the experiment, rats from both the control and experimental groups were divided into low and high level of energy metabolism depending on the intensity of total oxygen consumption. Histological preparations of visceral white adipose tissue were prepared according to the standard method. Histomorphometry was performed on digital images using the “Image J 1.34p” computer program. Biochemical methods were used to determine the concentration of triglycerides, lipids and cholesterol in blood serum. The method of multifrequency bioimpedance was used to assess the biophysical properties of visceral white adipose tissue. The data obtained were processed by methods of variational statistics using one-way analysis of variance. It was shown that long-term use of a high-calorie diet led to the development of visceral obesity, which was manifested by a significant increase in the weight of visceral fat and an increase in the concentration of indicators of lipid metabolism in blood serum. It was found that a high-calorie diet altered the morphological structure of the rat’s visceral white adipose tissue, leading to adipocyte hypertrophy, reduced blood volume and increased the amount of connective tissue in it. The bioelectrical properties of the visceral white adipose tissue changed, as evidenced by an increase in its electrical impedance and a decrease in its frequency dispersion coefficient. The intensity of structural, biochemical and biophysical changes in the visceral white adipose tissue was more pronounced in rats with low level of energy metabolism and depended on the degree of obesity. The results obtained are important for practical medicine in the development of new effective methods for the prevention and treatment of obesity in patients according to level of energy metabolism.

Nocturnal sentry duty and cardiometabolic characteristics in armed forces personnel.

Sleep deprivation can lead to increased body weight and blood pressure (BP), but the latent effects of partial sleep deprivation related to required night sentry duties within a short-term period on cardiometabolic characteristic changes in military personnel are unclear. To investigate the association between night sentry duty frequency in the past 3 months and cardiometabolic characteristics in armed forces personnel. A total of 867 armed forces personnel who were aged 18-39 years and did not take any antihypertensive medications in Taiwan in 2020 were included. The frequency of night sentry duty was self-reported via a questionnaire (average number of night sentry shifts per month for the past 3 months). Hemodynamic status was assessed via the resting BP and pulse rate (PR). Cardiometabolic risk factors were defined according to the International Diabetes Federation criteria. Multivariable linear regression analyses of the associations between night sentry duties and PR, BP, and other metabolic syndrome (MetS) marker levels were performed, with adjustments for age, sex, substance use, body mass index and aerobic fitness. Multiple logistic regression analysis was carried out to determine the associations between night sentry duties and the prevalence of each MetS feature. There was an association between night sentry duties and PR [standardized β (standard error) = 0.505 (0.223), P =0.02], whereas there was no association with systolic and diastolic BP. In addition, there was an inverse association between night sentry duties and high-density lipoprotein cholesterol (HDL-C) levels [standardized β = -0.490 (0.213), P = 0.02], whereas there was no association with the other metabolic marker levels. Compared with personnel without night sentry duties, those with ≥ 1 night sentry shift/month had a greater risk of impaired fasting glucose (≥ 100 mg/dL) [odds ratio: 1.415 (confidence interval: 1.016-1.969)], whereas no associations with other MetS features were found. Among military personnel, the burden of night sentry duty was positively associated with the resting PR but inversely associated with HDL-C levels. In addition, personnel with partial sleep deprivation may have a greater risk of impaired fasting glucose than those without partial sleep deprivation.

Transcriptomic Analysis of Neocaridina denticulata sinensis Gills Following FPPS Knockdown Reveals Its Regulatory Role in Immune Response.

Farnesyl pyrophosphate synthase (FPPS) is a key enzyme in the terpenoid biosynthesis pathway, responsible for converting isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) into farnesyl pyrophosphate (FPP). In crustaceans, FPPS plays an important role in various physiological processes, particularly in synthesizing the crustacean-specific hormone methyl farnesoate (MF). This study analyzed the evolutionary differences in the physicochemical properties, subcellular localization, gene structure, and motif composition of FPPS in Neocaridina denticulata sinensis (named NdFPPS) compared to other species. The significant evolutionary divergence of FPPS was observed in crustaceans, likely linked to its role in MF synthesis. After the RNA interference (RNAi)-mediated knockdown of NdFPPS, transcriptomic analysis of gills revealed the significant enrichment of differentially expressed genes (DEGs) in pathways related to metabolism and immunity. Gene set enrichment analysis (GSEA) showed that most of these immune-related pathways were significantly suppressed, suggesting that NdFPPS may indirectly regulate the immune response by modulating metabolic levels. During the early stages of Vibrio parahaemolyticus infection, the expression of NdFPPS in the gills was significantly downregulated and subsequently returned to its original levels. Overall, our results provide new perspectives on the role of FPPS in immune regulation and enrich the functional information of FPPS.

Carvedilol Confers Ferroptosis Resistance in HL-1 Cells by Upregulating GPX4, FTH1, and FTL1 and Inducing Metabolic Remodeling Under Hypoxia/Reoxygenation

Hypoxia/reoxygenation (HR) often occurs under cardiac pathological conditions, and HR-induced oxidative stress usually leads to cardiomyocyte damage. Carvedilol, a non-selective β-blocker, is used clinically to treat cardiac ischemia diseases. Moreover, Carvedilol has also been reported to have an antioxidant ability by reducing lipid peroxidation. However, the mechanism of Carvedilol to inhibit lipid peroxidation is still elusive. To explore the protective mechanism of Carvedilol to resist lipid peroxidation on cardiomyocytes, HL-1 cells were cultured under normoxia, hypoxia, and HR and treated with Carvedilol to investigate the alteration on metabolism, protein expression, and mRNA level to explain its oxidative mechanism. The study found that Carvedilol upregulated glutathione peroxidase 4 (GPX4) protein expression to resist HR-induced lipid peroxidation by metabolic remodeling under HR. Also, Carvedilol promoted ferroptosis-related genes, ferritin heavy chain 1 (FTH1) and ferritin light chain 1 (FTL1) mRNA levels, to reduce lipid peroxidation under both hypoxia and HR. In conclusion, our study explores a mechanism by which Carvedilol inhibits ferroptosis by upregulating GPX4, FTH1, and FTL1 levels to downregulate lipid peroxidation under HR. The study provides a potential strategy for using Carvedilol in clinical applications, inspiring further research and development in the area of heart diseases.

Baseline Tumor Burden Assessed With AI‐Guided PET/CT Total Metabolic Tumor Volume (TMTV) and LDH Levels Predict Efficacy of CAR‐T in Aggressive B‐Cell Lymphoma

ABSTRACTDisease burden is a critical determinant of outcomes in CAR‐T therapy for B‐cell lymphomas, and one of the most widely used techniques for its assessment is Total Metabolic Tumor Volume (TMTV) measured via [18F]FDG PET/CT. Biological parameters may further refine the risk profile. We analyzed baseline [18F]FDG PET/CT scans from 40 patients treated with CAR‐T, using an AI‐based automated segmentation algorithm to determine TMTV. Our analysis identified that a baseline TMTV greater than 48.4 cm³ and elevated LDH independently predicted progression‐free survival (PFS) after CAR‐T therapy (HR 4.28, p = 0.007, and HR 8.20, p &lt; 0.001, respectively). We then proposed a 0‐to‐2 risk score, assigning one point each for elevated TMTV and elevated LDH. All patients with a score of two experienced a PFS of less than 90 days following CAR‐T infusion. Among the remaining patients, those with 0 points versus 1 point demonstrated a 3‐month PFS of 100% versus 85%, a 6‐month PFS of 92% versus 53%, and a 12‐month PFS of 83% versus 53%, respectively. Importantly, patients with high baseline TMTV who achieved a TMTV reduction to less than 1.99 cm³ by day 30 had a PFS of 66%, significantly better compared to those who did not achieve this reduction. AI‐guided TMTV assessment, combined with LDH levels, provides a rapid and sensitive method for risk stratification at the bedside, which could help optimize patient management prior to CAR‐T therapy.

Baicalin alleviates intestinal inflammation and microbial disturbances by regulating Th17/Treg balance and enhancing Lactobacillus colonization in piglets

BackgroundIntestinal inflammation is a common and serious health problem in piglet production, especially enteritis caused by pathogenic Escherichia coli (E. coli). This condition often leads to high mortality, slow weight gain, and significant economic losses.ResultsIn this study, we isolated an E. coli strain, SKLAN202302, from the colon of diarrheal piglets to create an intestinal inflammation model for evaluating the protective effects of baicalin. Piglets infected with E. coli exhibited significant reductions in body weight, feed intake, small intestine length, and ileal goblet cell count (P < 0.05), along with deteriorated ileal morphology. However, baicalin supplementation resulted in body weights, feed intake, and intestinal morphology similar to those of the control group. Notably, there was a significant increase in the colonization of Lactobacillus species, particularly Lactobacillus_reuteri, Lactobacillus_amylovorus, and Lactobacillus_johnii, compared to the E. coli group (P < 0.05). At the metabolic and transcriptional levels, E. coli infection increased inflammatory mediators, including eicosanoids (leukotriene F4, prostaglandin F1a, leukotriene E4, thromboxane B2, prostaglandin G2, and PGH2), monosaccharides, and TCA cycle intermediates (oxoglutaric acid, glutaric acid, adipic acid, citric acid, and isocitric acid) in the ileum. It also promoted the expression of genes related to autoimmune diseases and the Th17 differentiation signaling pathway (CTLA4, IFN-ALPHA-8, IL12RB2, TRAV3, TRAV16, FOS, and VEGFA), as well as inflammatory factors. Conversely, baicalin supplementation not only counteracted these effects but also enhanced the presence of metabolites such as phospholipids [including lysoPC (P-18:1(9Z)/0:0), PC (17:0/0:0), lysoPC (16:1(9Z)/0:0), PC (18:0/0:0), lysoPC (18:0/0:0), PA (10:0/i-16:0), and PA (10:0/8:0)] and amino acids. It also regulated genes within the IL-17 signaling pathway (IL4, CCL17, CXCL10, IFNG, and CXCL2), suggesting a mechanism by which baicalin mitigates E. coli-induced intestinal and microbial disturbances. Subsequent flow cytometry analysis showed that E. coli infection increased the numbers of CD3+ and Foxp3+ cells, decreased IL-17A+ cells, and reduced Th17/Treg ratios. Baicalin supplementation restored these parameters to control levels.ConclusionsBaicalin supplementation effectively alleviates E. coli-induced intestinal inflammation and microbial disturbances in piglets by enhancing beneficial Lactobacillus colonization, counteracting inflammatory mediators, and regulating immune-related gene expression and the Th17/Treg balance. These findings highlight baicalin’s potential in alleviating intestinal inflammation.Graphical abstract

Uric Acid Correlates with Serum Levels of Mineral Bone Metabolism and Inflammation Biomarkers in Patients with Stage 3a-5 Chronic Kidney Disease.

Background and Objectives: Uric acid (UA) and the markers of mineral bone metabolism and inflammation are commonly altered in patients with chronic kidney disease (CKD) and are associated with the risk of cardiovascular complications and death. Studies point to a link between high serum UA and mineral bone homeostasis and inflammation, but controversy remains. The aim of this study was to evaluate the relationship between UA levels and mineral bone metabolism and inflammation biomarkers in a sample of Mexican patients with CKD 3a-5. Materials and Methods: This cross-sectional study included 146 Mexican patients with CKD 3a-5. In addition, 25 healthy subjects were included in the study with the aim of generating reference data for comparisons. Metabolic parameters including UA serum concentrations, mineral bone metabolism (parathormone (PTH), fibroblast growth factor 23 (FGF23), calcium, and phosphate), and inflammation (interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α)) biomarkers were measured in all of the samples and compared as a function of the estimated glomerular function rate (eGFR) or UA levels. Results: Intact PTH, FGF23, and cytokines were higher in advanced CKD stages. Patients with hyperuricemia had significantly higher values of FGF23 and TNF-α compared with those without hyperuricemia. The eGFR was found to be significantly and negatively correlated with all markers. Uric acid was significantly correlated with phosphate, iPTH, FGF23, and TNF-α, whereas iPTH was significantly correlated with FGF23, TNF-α, and FGF23. Finally, a multivariate analysis confirmed the relationship of eGFR with all the tested biomarkers, as well as other relationships of iPTH with UA and TNF-α and of FGF23 with UA and TNF-α. Conclusions: This study supports the relationship between uric acid and levels of mineral bone metabolism and inflammation biomarkers in patients with CKD at middle to advanced stages. In the follow-up of patients with CKD, monitoring and controlling UA levels through nutritional or pharmacological interventions could help in the prevention of alterations related to mineral bone metabolism.

Dynamic changes in the transcriptome and metabolome of pig ovaries across developmental stages and gestation

BackgroundThe ovary is a central organ in the reproductive system that produces oocytes and synthesizes and secretes steroid hormones. Healthy development and regular cyclical change in the ovary is crucial for regulating reproductive processes. However, the key genes and metabolites that regulate ovarian development and pregnancy have not been fully elucidated. This study conducted high-throughput RNA sequencing and untargeted metabolite profiling of the ovarian tissues from Chenghua pigs at four stages, including postnatal day 3 (D3), puberty at the age of about 125 days (Pub), sexual maturity at the age of about 365 days (Y1), and 105 days after pregnancy at the age of about 360 days (Pre).ResultsA total of 9,264 and 1,593 differentially expressed genes (DEGs) were identified during ovarian development and pregnancy. Several key genes involved in ovarian development, including SQLE, HMGCS1, MSMO1, SCARB1, CYP11A1, HSD3B1, HSD17B1, and SERPINE1 were identified. Similarly, LUM, FN1, PLAUR, SELP, SDC1, and VCAN were considered to be associated with pregnancy maintenance. Overexpression of HSD17B1 in granulosa cells significantly upregulated estrogen synthesis-related genes (HSD3B1, CYP11A1, and STAR); meanwhile, overexpression of PLAUR promotes granulosa cell proliferation. Furthermore, 66, 24, 77, and 7 differentially expressed miRNAs (DEMis) were found, leading to the selection of key miRNAs such as ssc-miR-206, ssc-miR-107, ssc-miR-429, ssc-miR-210, and ssc-miR-133a-3p by differential miRNA-targeted mRNA interaction network; meanwhile, ssc-miR-133a-3p was validated to have a targeting relationship with KCNA1 by dual-luciferase reporter systems assay. At the metabolic levels, androstenedione, 17a-hydroxyprogesterone, dehydroepiandrosterone, and progesterone were identified, with their synthesis regulated by these DEGs in the ovarian steroidogenesis pathway. Furthermore, treatment of cells with androstenedione upregulated the expression of HSD3B1, CYP11A1, and STAR.ConclusionsThis study revealed the dynamic changes in the transcriptome and metabolome of pig ovaries across developmental stages and gestation, indicating that it may provide new theoretical insights for improving sow fertility.

Levels of Bile Acid Metabolism Are Associated With Alterations of Gut Microbes in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is viewed as a metabolism associated disease, and bile acid metabolism is reported to occupy a significant role in the progression of HCC. However, little is known about the association between gut microbes and bile acid metabolism in HCC. Our study was designed to clarify the role of bile acid metabolism and microbiome in the progression of HCC. We investigated the relationship between bile acid metabolism and prognosis and immune cells by mining GSE14520. We studied the microbial profiles and metabolic alterations between the low bile acid group and high bile acid group using 16S rRNA sequencing and metabolomics. HCC patients in the high bile acid metabolism group showed better survival outcome compared with those in the low bile acid metabolism. Immune analysis displayed the close correlation between low bile acid metabolism and infiltration of CD4 + T cells, and the close relationship between high bile acid metabolism and infiltration of CD8 + T cells, macrophage cells in HCC. 16S rRNA sequencing results demonstrated that Blautia, Ruminococcus_gnavus_group, Erysipelotrichaceae_UCG-003 were mostly enriched in the low bile acid group. Metabolomics of the 109 fecal samples showed that the most enriched metabolites in the low total bile acid group were dihydrocytochalasin B, cucurbic acid and 27-Norcholestanehexol. Finally, KEGG enrichment analysis identified secondary bile acid biosynthesis and endocrine resistance as the most significant metabolic pathways. High bile acid metabolism was associated with more infiltration of CD8 + T cells, macrophage cells, and better prognosis in HCC. Levels of bile acid were significantly associated with altered gut microbes and metabolites in HCC. Further research related to gut microbes and bile acid metabolism may provide a novel insight into the pathogenesis and therapeutic strategy of HCC.