Gut microbiota has been gaining increasing attention and its important role in the maintenance of a general good health condition is already established. The potential of gut microbiota modulation through diet is an important research focus to be considered. Lipids, as omega-3 fatty acids, are well known for their beneficial role on organs and corresponding diseases. However, their impact on gut microbiota is still poorly defined, and studies on the role of other polyunsaturated fatty acids, such as conjugated linoleic and linolenic acids, are even scarcer.

By using an in vitro human fermentation model, we assessed the effect of omega-3, CLA isomers, and punicic acid on microbiota modulation.

Fish oil, Omega-3, and CLA samples positively impact Akkermansia spp. and Bifidobacterium spp. growth. Moreover, all the samples supported Roseburia spp. growth after 24 h of fermentation and, importantly, they were able to maintain the Firmicutes: Bacteroidetes ratio near 1. All the bioactive fatty acid samples, except Pomegranate oil, were able to significantly increase butyrate levels compared to those found in the positive control (FOS) sample. Moreover, Fish oil and Omega-3 samples were able to increase the concentration of GABA, alanine, tyrosine, phenylalanine, isoleucine, and leucine between 12 and 24 h of fermentation.

The impact of the assessed polyunsaturated fatty acids in gut microbiota has been observed in its impact on key bacteria (Akkermansia, Bifidobacterium, and Roseburia) as well as their metabolic byproducts, including butyrate and amino acids, which could potentially play a role in modulating the gut-brain axis.

Diet can contribute to the development of metabolic disease including type 2 diabetes (T2D) by inducing metabolic inflammation. While the gut microbiota mediates the effects of diet, the diet can also exert its effects independent of gut microbes. The microbe-dependent and -independent effects of diet on inflammation remain to be elucidated. This review examines recent advances and dissects the specifics of both gut microbe-dependent and independent mechanisms through which diet impacts inflammation and glucose metabolism. We delineate how diet interacts with the gut microbiome and induces metabolic inflammation. We also describe the direct effects of dietary components and their related metabolites on the immune system, and explore how diet-induced sterile inflammation may contribute to metabolic disorders. It is important to consider both microbe-dependent and independent pathways when developing therapeutic approaches aimed at preventing T2D.

To explore the effects of branched-chain amino acids (BCAAs) on periodontal tissues and regulation of gelatinase secretion by human periodontal ligament stem cells (hPDLSCs).

The salivary BCAA levels (leucine, isoleucine, and valine) in the clinical participants were measured using mass spectrometry. A local injection model in the periodontium of Sprague Dawley rats was established to investigate the periodontal destruction induced by BCAAs. A BCAA-treatment model of hPDLSCs was established to detect the expression and activity of gelatinase and further explore the potential mechanism by which BCAAs enhance gelatinase secretion.

Compared to the healthy controls, the salivary levels of leucine (p = 0.0190), isoleucine (p = 0.0351), and valine (p = 0.0072) were significantly elevated in individuals with periodontitis. In vivo experiments revealed that BCAAs aggravated periodontal extracellular matrix degradation and alveolar bone resorption in rats. Three-dimensional reconstruction of the rat maxilla demonstrated an increase in the distance from the cementoenamel junction to the alveolar bone crest (p < 0.0001), and a decrease in the bone volume fraction (p < 0.0001). In vitro experiments demonstrated that BCAAs activate the phosphorylation of nuclear factor kappa-B (NF-κB) signaling pathway in the hPDLSCs and consequently induce the secretion of gelatinases. The absence of any of the components in the BCAAs attenuated this effect.

BCAAs increase gelatinase secretion through the NF-κB (p-p65) signaling pathway, consequently exacerbating periodontal tissue destruction. This provides a novel insight on the role of BCAAs in the host immune-inflammatory response and increases our understanding of the possible involvement of BCAAs in the periodontitis development.

Endothelial cells are multifunctional cells that form the inner layer of blood vessels and have a crucial role in vasoreactivity, angiogenesis, immunomodulation, nutrient uptake and coagulation. Endothelial cells have unique metabolism and are metabolically heterogeneous. The microenvironment and metabolism of endothelial cells contribute to endothelial cell heterogeneity and metabolic specialization. Endothelial cell dysfunction is an early event in the development of several cardiovascular diseases and has been shown, at least to some extent, to be driven by metabolic changes preceding the manifestation of clinical symptoms. Diabetes mellitus, hypertension, obesity and chronic kidney disease are all risk factors for cardiovascular disease. Changes in endothelial cell metabolism induced by these cardiometabolic stressors accelerate the accumulation of dysfunctional endothelial cells in tissues and the development of cardiovascular disease. In this Review, we discuss the diversity of metabolic programmes that control endothelial cell function in the cardiovascular system and how these metabolic programmes are perturbed in different cardiovascular diseases in a disease-specific manner. Finally, we discuss the potential and challenges of targeting endothelial cell metabolism for the treatment of cardiovascular diseases.

Cardiovascular diseases (CVDs), including heart failure (HF), hypertension, myocardial infarction (MI), and atherosclerosis, are increasingly linked to gut microbiota dysbiosis and its metabolic byproducts. HF, affecting over 64 million individuals globally, is associated with systemic inflammation and gut barrier dysfunction, exacerbating disease progression. Similarly, hypertension and MI correlate with reduced microbial diversity and an abundance of pro-inflammatory bacteria, contributing to vascular inflammation and increased cardiovascular risk. Atherosclerosis is also influenced by gut dysbiosis, with key microbial metabolites such as trimethylamine-N-oxide (TMAO) and short-chain fatty acids (SCFAs) playing crucial roles in disease pathogenesis. Emerging evidence highlights the therapeutic potential of natural compounds, including flavonoids, omega-3 fatty acids, resveratrol, curcumin, and marine-derived bioactives, which modulate the gut microbiota and confer cardioprotective effects. These insights underscore the gut microbiota as a critical regulator of cardiovascular health, suggesting that targeting dysbiosis may offer novel preventive and therapeutic strategies. Further research is needed to elucidate underlying mechanisms and optimize microbiome-based interventions for improved cardiovascular outcomes.

Babesiosis is a significant vector-borne zoonotic disease with major global economic and health implications, affecting various vertebrate hosts. Babesia parasites are auxotrophic for essential nutrients, relying on their hosts for metabolic support. This study investigated salivary metabolomic changes in dogs naturally infected with Babesia canis (N = 14) compared to healthy controls (N = 14) using untargeted and targeted mass spectrometry-based approaches. Saliva, a biofluid rich in metabolites, undergoes alterations in response to systemic diseases, making it a promising medium for studying host-pathogen interactions. Metabolomic profiling was performed using a Dionex UltiMate 3000 UHPLC system coupled with a Thermo Orbitrap Q Exactive mass spectrometer. An untargeted analysis detected 2257 salivary features, of which, 868 were significantly altered, with seven metabolites identified by reference to standards. A targeted analysis revealed significant changes in seven metabolites. Functional bioinformatics indicated disruptions in amino acid, nucleotide, and lipid metabolism, alongside alterations in energy production pathways, and purine metabolism. These findings provide critical insights into the metabolic shifts underlying canine babesiosis, supporting the development of advanced diagnostic and therapeutic strategies in the future. This study highlights the intricate interplay between host and pathogen, particularly in nutrient acquisition and metabolic regulation.

Branched-chain amino acids (BCAA) have been implicated in the risk of cardiovascular disease. However, it is unclear whether dietary BCAA intake, specifically isoleucine, leucine, and valine are associated with coronary artery calcium (CAC) progression.

We included the participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study cohort for the analysis. Dietary intake of BCAA was assessed at year 7 of the study. CAC was measured using standardized computed tomography scans at years 15, 20, and 25. CAC progression was defined as follows: for participants with a baseline CAC of 0, progression was defined as CAC > 0 at follow-up; for those with 0 < baseline CAC < 100, progression was defined as an annualized change of ≥ 10; and for those with baseline CAC ≥ 100, progression was defined as an annualized percent change of ≥ 10%. Multivariate adjusted Cox regression models were utilized to examine the associations between BCAA intake and CAC progression.

Among 2381 included participants (average age 40.4 ± 3.5 years, 44.9% men), 629 participants (26.4%) exhibited CAC progression during a follow-up period of 8.90 ± 2.03 years. In the fully adjusted model, high intake of total BCAA, and its individual components, isoleucine, leucine, and valine were associated with an increased risk of CAC progression by 35.6% (HR, 1.356 [95% CI, 1.040-1.769]), 30.5% (HR, 1.305 [95% CI, 1.001-1.701]), 30.9% (HR, 1.309 [95% CI, 1.003-1.706]), and 33.9% (HR, 1.339 [95% CI, 1.026-1.747]), respectively, compared to their corresponding low intake groups. The associations were consistent across various subgroups, including age, sex, race, and body mass index, but were stronger in participants without baseline CAC (interaction P < 0.001). These results remained robust in a series of sensitivity analyses.

High dietary intake of BCAA, including isoleucine, leucine, and valine, were independently associated with an increased risk of CAC progression. The findings may implication for dietary modifications in primary prevention of subclinical atherosclerosis.

URL: https://www.

gov ; Unique identifier: NCT00005130.

This study aims to understand the metabolic mechanisms of unintentional weight loss in older adults. We investigated plasma metabolite associations of subsequent weight change over 2 years in 1536 previously weight stable participants (mean age 74.6 years, 50% women, 35% Black) from the Health, Aging and Body Composition (Health ABC) Study. Multinomial logistic regressions were used to examine associations of the 442 metabolites with weight loss with/without an intention and weight gain >3% annually relative to weight stability. The metabolite associations of unintentional weight loss differed from those of intentional weight loss and weight gain. Lower levels of aromatic amino acids, phospholipids, long-chain poly-unsaturated triglycerides, and higher levels of amino acid derivatives, poly-unsaturated fatty acids, and carbohydrates were associated with higher odds of unintentional weight loss after adjusting for age, sex, race, and BMI categories. Prevalent diseases attenuated four and lower mid-thigh muscle mass and poorer appetite each attenuated 2 of 77 identified metabolite associations by >20%, respectively. Other factors (e.g., energy expenditure, diet, and medication) attenuated all associations by <20%. While 16 metabolite associations were attenuated by 20%-48% when adjusting for all these risk factors, 47 metabolite associations remained significant. Altered amino acid metabolism, impaired mitochondrial fatty acid oxidation, and inflammaging implicated by identified metabolites appear to precede unintentional weight loss in Health ABC older adults. Furthermore, these pathways seem to be associated with prevalent diseases especially diabetes, lower muscle mass, and poorer appetite.

To investigate the relationship between circulating branched-chain amino acids (BCAAs) and the risk of major adverse cardiovascular events (MACE) in a national population-based cohort study.

UK Biobank, a prospective study involving 22 recruitment centers across the United Kingdom. For this analysis, we included 266,840 participants from the UK Biobank who had available BCAA data and no history of MACE at baseline. Cox regression analysis was conducted to evaluate these associations, adjusting for potential confounders.

During a 13.80 ± 0.83-year follow-up, 52,598 participants experienced MACE, with the incidence of MACE increasing progressively across quintiles of circulating BCAAs, isoleucine, leucine, and valine. Overall, the fifth quintile exhibited a 7-12% higher MACE risk compared to the second quintile. In males, BCAAs were not associated with MACE risk. However, increased risks were observed for isoleucine (8-12% in higher quintiles), leucine (9% in the first quintile and 6% in the fifth quintile), and valine (8% in the first quintile). In females, higher quintiles of BCAAs, isoleucine, leucine, and valine were associated with increased MACE risk, ranging from 9% to 12%. Among participants under 65y, higher quintiles of BCAAs, isoleucine, and leucine were associated with increased MACE risk, while valine showed no significant association. No association was found in participants aged 65 and older. These analyses were adjusted for multiple potential confounders.

Generally, higher levels of BCAAs, isoleucine, leucine, and valine were associated with an increased risk of MACE, except in participants older than 65. Additionally, in males, the lowest quintiles of leucine and valine were also associated with an increased risk of MACE.

Profound metabolomic alterations occur during COVID-19. Early identification of the subset of hospitalised COVID-19 patients at risk of developing severe disease is critical for optimal resource utilization and prompt treatment. This work explores the metabolomic profile of hospitalised adult COVID-19 patients with severe disease, and establishes a predictive signature for disease progression. Within 48 hours of admission, serum samples were collected from 148 hospitalised patients for nuclear magnetic resonance (NMR) spectroscopy. Lipoprotein profiling was performed using the 1H-NMR-based Liposcale test, while low molecular weight metabolites were analysed using one-dimensional Carr-Purcell-Meiboom-Gill pulse spectroscopy and an adaptation of the Dolphin method for lipophilic extracts. Severe COVID-19, per WHO's Clinical Progression Scale, was characterized by altered lipoprotein distribution, elevated signals of glyc-A and glyc-B, a shift towards a catabolic state with elevated levels of branched-chain amino acids, and accumulation of ketone bodies. Furthermore, COVID-19 patients initially presenting with moderate disease but progressing to severe stages exhibited a distinct metabolic signature. Our multivariate model demonstrated a cross-validated AUC of 0.82 and 72% predictive accuracy for severity progression. NMR spectroscopy-based metabolomic profiling enables the identification of moderate COVID-19 patients at risk of disease progression, aiding in resource allocation and early intervention.

Erectile dysfunction (ED) is a prevalent male sexual dysfunction that remarkably impacts patients' quality of life and is also recognized as a precursor to cardiovascular disease (CVD) events. Branched-chain amino acids (BCAAs) are derived from dietary intake and mainly involved in energy metabolism. Previous studies have underscored the association between BCAAs and CVD, but the causal link between BCAAs and ED remains uncertain.

The bidirectional Mendelian randomization (MR) study used the genetic data from genome-wide association studies (GWAS) to identify single nucleotide polymorphisms (SNPs) associated with total BCAAs, leucine, isoleucine, and valine. The genetic data for ED were acquired from the FinnGen study (n = 95,178). The primary method used to assess causal associations was the inverse variance-weighted (IVW) method, supplemented by MR-Egger, weighted median, and simple median analyses. Cochrane's Q test was utilized to evaluate heterogeneity within the results, while the MR-Egger intercept test was utilized to evaluate the Level pleiotropy. A sensitivity analysis was performed employing leave-one-out analysis.

The MR analysis results indicate a positive correlation between levels of total BCAA (OR = 1.984, 95 % CI = 1.018-3.868, P = 0.044), leucine (OR = 2.277, 95 % CI = 1.121-4.626, P = 0.023), isoleucine (OR = 2.584, 95 % CI = 1.167-5.722, P = 0.019), valine (OR = 1.894, 95 % CI = 1.119-3.206, P = 0.017), and the risk of ED. Sensitivity tests confirmed the accuracy and robustness of the study findings. Moreover, the reverse MR analysis found no association between ED and the BCAAs.

The results of this analysis indicate a positive association between the circulating BCAA concentrations and the risk of ED, but their underlying mechanisms require further investigation.

Exposure to environmental contaminants is globally universal. However, communities vary in the specific combination of contaminants to which they are exposed, potentially contributing to variation in human health and creating "locally situated biologies." We investigated how environmental exposures differ across environments by comparing exposure profiles between two contexts that differ markedly across political, economic, and sociocultural factors-Namqom, Formosa, Argentina, and New Haven, Connecticut, United States.

We collected infant urine, maternal urine, and human milk samples from mother-infant dyads in Formosa (n = 13) and New Haven (n = 21). We used untargeted liquid chromatography with high-resolution mass spectrometry (LC-HRMS) to annotate environmental contaminants and endogenous metabolites in these samples, and we analyzed the data using exposome-wide association studies (EWAS) followed by pathway enrichment.

We found statistically significant differences between the chemical exposure profiles of the Argentinian and US mothers, mostly involving pesticides; however, we observed similarities in the infant urine and human milk environmental contaminant profiles, suggesting that the maternal body may buffer infant exposure through human milk. We also found that infants and mothers were exposed to contaminants that were associated with alterations in amino acid and carbohydrate metabolism. Infants additionally showed alterations in vitamin metabolism, including vitamins B1, B3, and B6.

Differences in chemical exposure profiles may be related to structural factors. Despite variation in the composition of exposure profiles between the two study sites, environmental contaminant exposure was associated with similar patterns in human physiology when we considered contaminants comprehensively rather than individually, with implications for metabolic and cardiovascular disease risk as well as infant cognitive development.

Cardiovascular disease is the most common cause of mortality globally, accounting for approximately one out of three deaths. The main underlying pathology is atherosclerosis, a dyslipidemia-driven, chronic inflammatory disease. The interplay between immune cells and non-immune cells is of great importance in the complex process of atherogenesis. During atheroprogression, intracellular metabolic pathways, such as amino acid metabolism, are master switches of immune cell function. Autophagy, an important stress survival mechanism involved in maintaining (immune) cell homeostasis, is crucial during the development of atherosclerosis and is strongly regulated by the availability of amino acids. In this review, we focus on the interplay between amino acids, especially L-leucine, L-arginine, and L-glutamine, and autophagy during atherosclerosis development and progression, highlighting potential therapeutic perspectives.

Aging-induced aortic stiffness has been associated with altered fatty acid metabolism. We studied aortic stiffness using cardiac magnetic resonance (CMR)-assessed ventriculo-arterial coupling (VAC) and novel aortic (AO) global longitudinal strain (GLS) combined with targeted metabolomic profiling. Among community older adults without cardiovascular disease, VAC was calculated as aortic pulse wave velocity (PWV), a marker of arterial stiffness, divided by left ventricular (LV) GLS. AOGLS was the maximum absolute strain measured by tracking the phasic distance between brachiocephalic artery origin and aortic annulus. In 194 subjects (71 ± 8.6 years; 88 women), AOGLS (mean 5.6 ± 2.1%) was associated with PWV (R = -0.3644, p < 0.0001), LVGLS (R = 0.2756, p = 0.0001) and VAC (R = -0.3742, p <0.0001). Stiff aorta denoted by low AOGLS <4.26% (25th percentile) was associated with age (OR 1.13, 95% CI 1.04-1.24, p = 0.007), body mass index (OR 1.12, 95% CI 1.01-1.25, p = 0.03), heart rate (OR 1.04, 95% CI 1.01-1.06, p = 0.011) and metabolites of medium-chain fatty acid oxidation: C8 (OR 1.005, p = 0.026), C10 (OR 1.003, p = 0.036), C12 (OR 1.013, p = 0.028), C12:2-OH/C10:2-DC (OR 1.084, p = 0.032) and C16-OH (OR 0.82, p = 0.006). VAC was associated with changes in long-chain hydroxyl and dicarboxyl carnitines. Multivariable models that included acyl-carnitine metabolites, but not amino acids, significantly increased the discrimination over clinical risk factors for prediction of AOGLS (AUC [area-under-curve] 0.73 to 0.81, p = 0.037) and VAC (AUC 0.78 to 0.87, p = 0.0044). Low AO GLS and high VAC were associated with altered medium-chain and long-chain fatty acid oxidation, respectively, which may identify early metabolic perturbations in aging-associated aortic stiffening. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02791139.

Prior efforts have revealed changes in gut microbiome, circulating metabolome, and multimodal neuroimaging features in cerebral small vessel disease (CSVD). However, there is a paucity of research integrating the multi-omic information to characterize the role of the microbiota-gut-brain axis in CSVD.

We collected gut microbiome, fecal and blood metabolome, multimodal magnetic resonance imaging data from 37 CSVD patients with white matter hyperintensities and 46 healthy controls. Between-group comparison was performed to identify the differential gut microbial taxa, followed by performance of multi-stage microbiome-metabolome-neuroimaging-neuropsychology correlation analyses in CSVD patients.

Our data showed both depleted and enriched gut microbes in CSVD patients. Among the differential microbes, Haemophilus and Akkermansia were associated with a range of metabolites enriched for Aminoacyl-tRNA biosynthesis pathway. Furthermore, the affected metabolites were associated with neuroimaging measures involving gray matter morphology, spontaneous intrinsic brain activity, white matter integrity, and global structural network topology, which were in turn related to cognition and emotion in CSVD patients.

Our findings provide an integrative framework to understand the pathophysiological mechanisms underlying the interplay between gut microbiota dysbiosis and CSVD, highlighting the potential of targeting the microbiota-gut-brain axis as a therapeutic strategy in CSVD patients.

Polycystic Ovary Syndrome (PCOS) is a metabolic disorder characterized by hyperandrogenism and related symptoms in women of reproductive age. Emerging evidence suggests that chronic low-grade inflammation plays a significant role in the development of PCOS. The gut microbiota, a complex bacterial ecosystem, has been extensively studied for various diseases, including PCOS, while the underlying mechanisms are not fully understood. This review comprehensively summarizes the changes in gut microbiota and metabolites observed in PCOS and their potential association with the condition. Additionally, we discuss the role of abnormal nuclear factor κB signaling in the pathogenesis of PCOS. These findings offer valuable insights into the mechanisms of PCOS and may pave the way for the development of control and therapeutic strategies for this condition in clinical practice. By bridging the gap between mouse models and clinical patients, this review contributes to a better understanding of the interplay between gut microbiota and inflammation in PCOS, thus paving new ways for future investigations and interventions.

Understanding the complex link between inflammation, gut health, and dietary amino acids is becoming increasingly important in the pathophysiology of inflammatory bowel disease (IBD). This study tested the hypothesis that a leucine-rich diet could attenuate inflammation and improve gut health in a mouse model of IBD. Specifically, we investigated the effects of a leucine-rich diet on dextran sulfate sodium (DSS)-induced colitis in germ-free (GF) SAMP1/YitFC (SAMP) mice colonized with human gut microbiota (hGF-SAMP). hGF-SAMP mice were fed one of four different diets: standard mouse diet (CHOW), American diet (AD), leucine-rich AD (AD + AA), or leucine-rich CHOW diet (CH + AA). Body weight, myeloperoxidase (MPO) activity, gut permeability, colonoscopy scores, and histological analysis were measured. Mice on a leucine-rich CHOW diet showed a decrease in fecal MPO prior to DSS treatment as compared to those on a regular diet (p > 0.05); however, after week five, prior to DSS, this effect had diminished. Following DSS treatment, there was no significant difference in gut permeability, fecal MPO activity, or body weight changes between the leucine-supplemented and control groups. These findings suggest that while a leucine-rich diet may transiently affect fecal MPO levels in hGF-SAMP mice, it does not confer protection against DSS-induced colitis symptoms or mitigate inflammation in the long term.

Coronary artery disease (CAD) remains a leading cause of death worldwide and imposes a substantial socioeconomic burden on healthcare. Improving risk stratification in clinical practice could help to combat this burden. As amino acids are biologically active metabolites whose involvement in CAD remains largely unknown, this study investigated associations between circulating amino acid levels and CAD phenotypes. A high-coverage quantitative liquid chromatography-mass spectrometry approach was applied to acquire the serum amino acids profile of age- and sex-coarsened-matched patients with CAD (n = 46, 66.9 years, 74.7% male) and healthy individuals (n = 120, 67.4 years, 74.7% male) from the COmPLETE study. Multiple linear regressions were performed to investigate associations between amino acid levels and (a) the health status (CAD vs. healthy), (b) the number of affected coronary arteries, or (c) the left ventricular ejection fraction. Regressions were adjusted for age, sex, daily physical activity, sampling, and fasting time. Urea cycle amino acids (ornithine, citrulline, homocitrulline, aspartate, and arginine) were significantly and negatively associated with CAD, the number of affected coronary arteries, and the left ventricular ejection fraction. Lysine, histidine, and the glutamine/glutamate ratio were also significantly and negatively associated with the CAD phenotypes. Overall, patients with CAD displayed lower levels of urea cycle amino acids, highlighting a potential role for urea cycle amino acid profiling in cardiovascular risk stratification.Trial registrationThe study was registered on https://www.clinicaltrials.gov (NCT03986892) on June 5, 2019.

Metabolic regulation of various amino acids have been proven to be effective in preventing cardiovascular disease (CVD). The impact of tryptophan, an essential amino acid, on the risk of developing CVD has not been fully elucidated.

The aim of this meta-analysis was to systematically review evidence of the effects of tryptophan on CVD risk.

The PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Infrastructure (CNKI) databases were searched to collect relevant trials from inception to August 2024. The means and hazard ratios (HRs) were extracted and pooled. Subgroup analysis was performed to identify pooled effect estimates, and sensitivity analysis was conducted to assess the robustness of the pooled estimates.

Data were collected from 34,370 people under follow-up for CVD events in 13 studies, including cohort studies and case-control studies. They were categorized into three groups on the basis of sample type and indicators: the plasma tryptophan level group, the plasma tryptophan CVD hazard group, and the urinary tryptophan CVD hazard group. The CVD included in this study were coronary artery disease, heart failure, and peripheral artery disease. Twelve studies on plasma tryptophan were meta-analyzed. The plasma tryptophan levels in CVD patients were generally lower than those in individuals without CVD (SMD = -8.57, 95%CI (-15.77, -1.37), P = 0.02). Decreased circulating tryptophan levels are associated with cardiovascular disease risk (HR = 0.85, 95%CI (0.78, 0.92), P < 0.00001).

Decreased circulating tryptophan levels are associated with an increased risk of CVD events. Intervention in circulating tryptophan levels may be indicated to help prevent CVD.

Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder originating from defects in the branched-chain α-ketoacid dehydrogenase (BCKDH) complex encoded by BCKDHA, BCKDHB and DBT. This condition presents a spectrum of symptoms and potentially fatal outcomes. Although numerous mutations in the BCKDH complex genes associated with MSUD have been identified, the relationship between specific genotypes remains to be fully elucidated.

Our objective was to predict the pathogenicity of these genetic mutations and establish potential links between genotypic alterations and the clinical phenotypes of MSUD.

Retrospective population-based cohort.

We analyzed 20 MSUD patients from the Children's Hospital at Zhejiang University School of Medicine (Hangzhou, China), recorded from January 2010 to December 2023. Patients' blood samples were collected by heel-stick through neonatal screening, and amino acid profiles were measured by tandem mass spectrometry. In silico methods were employed to assess the pathogenicity, stability and biophysical properties. Various computation tools were utilized for assessment, namely PredictSNP, MAGPIE, iStable, Align GVGD, ConSurf and SNP effect.

We detected 25 distinct mutations, including 12 novel mutations. The BCKDHB gene was the most commonly affected (53.3%) compared to the BCKDHA gene (20.0%) and DBT gene (26.7%). In silico webservers predicted all novel mutations were disease-causing.

This study highlights the genetic complexity of MSUD and underscores the importance of early detection and intervention. Integrating neonatal screening with advanced sequencing methodologies is pivotal in ensuring precise diagnosis and effective management of MSUD, thereby significantly improving the prognosis for individuals afflicted with this condition.

Vascular endothelial cells (ECs), the inner layer of blood vessels, were previously considered to be a passive lining that facilitates cellular and molecular exchange. However, recent studies have revealed that ECs can respond to various stimuli and actively regulate vascular function and skin inflammation. Specific subtypes of ECs are known to have significant roles in a diverse range of physiological and pathological processes in the skin. This review suggests that EC dysfunction is both causal and consequential in the pathogenesis of psoriasis. Further investigations into dysregulated pathways in EC dysfunction may provide new insights for the treatment of psoriasis.

Ferroptosis, an iron-dependent non-apoptotic regulated cell death process, is associated with the pathogenesis of various diseases. Amino acids, which are indispensable substrates of vital activities, significantly regulate ferroptosis. Amino acid metabolism is involved in maintaining iron and lipid homeostasis and redox balance. The regulatory effects of amino acids on ferroptosis are complex. An amino acid may exert contrasting effects on ferroptosis depending on the context. This review systematically and comprehensively summarized the distinct roles of amino acids in regulating ferroptosis and highlighted the emerging opportunities to develop clinical therapeutic strategies targeting amino acid-mediated ferroptosis.

Chromium (Cr) exposure is associated with various respiratory system diseases, but there are limited studies investigating its impact on lung function in young adults. The Cr exposure-related metabolomic changes are not well elucidated. This study recruited 608 students from a university in Shandong Province, China in 2019. We used cohort design fitted with linear mixed-effects models to assess the association between blood Cr concentration and lung function. In addition, we performed metabolomic and lipidomic analyses of baseline serum samples (N = 582) using liquid chromatography-mass spectrometry. Two-step statistical analysis (analysis of variance and mixed-linear effect model) was used to evaluate the effect of blood Cr exposure on metabolites. We found that blood Cr was associated with decreased lung function in young adults. Each 2-fold increase in blood Cr concentrations was significantly associated with decreased FEV1 and FVC by 35.26 mL (95 % CI: -60.75, -9.78) and 38.56 mL (95 % CI: -66.60, -10.51), respectively. In the metabolomics analysis, blood Cr exposure was significantly associated with 14 key metabolites. The changed metabolites were mainly enriched in six pathways including lipid metabolism, amino acid metabolism, and cofactor vitamin metabolism. Blood Cr may affect lung function through oxidative stress and inflammation related pathways.

3-Bromofluoranthene (3-BrFlu) is the secondary metabolite of fluoranthene, which is classified as a polycyclic aromatic hydrocarbon, through bromination and exists in the fine particulate matter of air pollutants. Endothelial dysfunction plays a critical role in the pathogenesis of cardiovascular and vascular diseases. Little is known about the molecular mechanism of 3-BrFlu on endothelial dysfunction in vivo and in vitro assay. In the present study, 3-BrFlu included concentration-dependent changes in ectopic angiogenesis of the sub-intestinal vein and dilation of the dorsal aorta in zebrafish. Disruption of vascular endothelial integrity and up-regulation of vascular endothelial permeability were also induced by 3-BrFlu in a concentration-dependent manner through pro-inflammatory responses in vascular endothelial cells, namely, SVEC4-10 cells. Generation of pro-inflammatory mediator PGE2 was induced by 3-BrFlu through COX2 expression. Expression of COX2 and generation of pro-inflammatory cytokines, including TNFα and IL-6, were induced by 3-BrFlu through phosphorylation of NF-κB p65, which was mediated by phosphorylation of MAPK, including p38 MAPK, ERK and JNK. Furthermore, generation of intracellular ROS was induced by 3-BrFlu, which is associated with the down-regulated activities of the antioxidant enzyme (AOE), including SOD and catalase. We also found that 3-BrFlu up-regulated expression of the AOE and HO-1 induced by 3-BrFlu through Nrf-2 expression. However, the 3-BrFlu-induced upregulation of AOE and HO-1 expression could not be revised the responses of vascular endothelial dysfunction. In conclusion, 3-BrFlu is a hazardous substance that results in vascular endothelial dysfunction through the MAPK-mediated-NFκB pro-inflammatory pathway and intracellular ROS generation.

Nonalcoholic fatty liver disease (NAFLD) is known to be associated with atherosclerosis. This study focused on upstream changes in the process by which NAFLD leads to atherosclerosis. The study aimed to confirm the association between NAFLD and the cardio-ankle vascular index (CAVI), an indicator of subclinical atherosclerosis, and explore metabolites involved in both by assessing 94 plasma polar metabolites.

A total of 928 Japanese community-dwellers (306 men and 622 women) were included in this study. The association between NAFLD and CAVI was examined using a multivariable regression model adjusted for confounders. Metabolites commonly associated with NAFLD and CAVI were investigated using linear mixed-effects models in which batch numbers of metabolite measurements were used as a random-effects variable, and false discovery rate-adjusted p-values were calculated. To determine the extent to which these metabolites mediated the association between NAFLD and CAVI, mediation analysis was conducted.

NAFLD was positively associated with CAVI (coefficients [95% Confidence intervals (CI)]=0.23 [0.09-0.37]; p=0.001). A total of 10 metabolites were involved in NAFLD and CAVI, namely, branched-chain amino acids (BCAAs; valine, leucine, and isoleucine), aromatic amino acids (AAAs; tyrosine and tryptophan), alanine, proline, glutamic acid, glycerophosphorylcholine, and 4-methyl-2-oxopentanoate. Mediation analysis showed that BCAAs mediated more than 20% of the total effect in the association between NAFLD and CAVI.

NAFLD was associated with a marker of atherosclerosis, and several metabolites related to insulin resistance, including BCAAs and AAAs, could be involved in the process by which NAFLD leads to atherosclerosis.

Rhamnus utilis Decne. (Family Rhamnaceae Juss.) leaf is commonly prepared as a anti-inflammatory herbal medicine and used for tea production. To investigate the mechanism of Rhamnus utilis Decne. aqueous extract (RDAE) against acute alcoholic liver disease (ALD) in mice. The ALD mouse (Male ICR) model was induced via intragastric administration of 52 % alcohol. Mice in each group were treated by gavage once daily with the RDAE (1.12, 2.25, 4.500 g/kg). The expression of proteins involved in the MAPKs/NF-κB/COX-2-iNOS pathway was measured by western blotting. Non-targeted metabolomics was used to determine metabolic profiles and critical pathways, while targeted metabolomics validated key amino acid metabolites. After administration of RDAE, the body mass of mice was significantly increased. The liver index was significantly decreased. Meanwhile, the serum levels of AST, ALT, TG, TC, MDA, TNF-α, IL-1β and IL-6 were significantly decreased (P < 0.05, P < 0.01), but GSH level was inversely increased (P < 0.05). Metabolomic analysis revealed nine major pathways involved in the therapeutic effect of RDAE, including fructose and mannose metabolism. The levels of 7 amino acids including leucine, proline and alanine/sarcosine were significantly upregulated. Additionally, protein levels of p-NF-κB (p65)/NF-κB (p65), p-ERK1/2/ERK1/2, p-JNK/JNK, p-p38/p38, COX-2 and iNOS were significantly decreased (P < 0.01, P < 0.05). RDAE is used to treat acute ALD by improving lipid metabolism, inhibiting the expression of pro-inflammatory cytokines and regulating MAPKs/NF-κB/COX-2-iNOS signalling pathway. These findings provide valuable insights for acute ALD therapy based on traditional Chinese medicine (TCM).

Branched-chain amino acids (BCAAs), comprising leucine (Leu), isoleucine (Ile), and valine (Val), are essential nutrients vital for protein synthesis and metabolic regulation via specialized signaling networks. Their association with cardiovascular diseases (CVDs) has become a focal point of scientific debate, with emerging evidence suggesting both beneficial and detrimental roles. This review aims to dissect the multifaceted relationship between BCAAs and cardiovascular health, exploring the molecular mechanisms and clinical implications. Elevated BCAA levels have also been linked to insulin resistance (IR), type 2 diabetes mellitus (T2DM), inflammation, and dyslipidemia, which are well-established risk factors for CVD. Central to these processes are key pathways such as mammalian target of rapamycin (mTOR) signaling, nuclear factor kappa-light-chain-enhancer of activate B cells (NF-κB)-mediated inflammation, and oxidative stress. Additionally, the interplay between BCAA metabolism and gut microbiota, particularly the production of metabolites like trimethylamine-N-oxide (TMAO), adds another layer of complexity. Contrarily, some studies propose that BCAAs may have cardioprotective effects under certain conditions, contributing to muscle maintenance and metabolic health. This review critically evaluates the evidence, addressing the biological basis and signal transduction mechanism, and also discusses the potential for BCAAs to act as biomarkers versus active mediators of cardiovascular pathology. By presenting a balanced analysis, this review seeks to clarify the contentious roles of BCAAs in CVD, providing a foundation for future research and therapeutic strategies required because of the rising prevalence, incidence, and total burden of CVDs.

The increasing studies indicated that cardiovascular diseases, such as coronary artery disease (CAD), usually induce and exacerbate psychological problems, including anxiety and depression. These psychological issues are admitted as independent risk factors of heart disease as well. The interaction between CAD and anxiety and depression deteriorates the development and prognosis of CAD, which severely threatens the quality of life of patients. Although the existing mechanisms revealed the pathological relationship between CAD and anxiety and depression, there are few studies investigating the correlation between CAD and anxiety and depression from the aspect of gut microbiota (GM) and its metabolites. Therefore, in this review, we summarized whether GM and its metabolites are the emergent bridge between CAD and anxiety and depression. The results showed that there are four kinds of jointly up-regulated bacteria (i.e., Staphylococcus, Escherichia coli, Helicobacter pylori, and Shigella) and five kinds of jointly down-regulated bacteria (i.e., Prevotella, Lactobacillus, Faecalibacterium prausnitzii, Collinsella, and Bifidobacterium) in CAD as well as anxiety and depression. In addition, in CAD and anxiety and depression, the dysbiosis of the former four kinds of bacterium frequently leads to the outburst of inflammatory response, and the dysbiosis of the latter five kinds of bacterium is usually related to the metabolic abnormality of short-chain fatty acids, bile acids, and branched-chain amino acids. Therefore, we believe that GM and its metabolites act as the emergent bridge between CAD and anxiety and depression. The findings of this review provide novel insights and approaches for the clinical treatment of patients with both CAD and anxiety and depression.

Higher levels of plasma glycine are linked to a reduced risk, while increased levels of total branched-chain amino acids (tBCAAs) are associated with a higher risk of essential hypertension and coronary heart disease (CHD). As these metabolic components are interconnected, analyzing the tBCAAs/glycine ratio may help to understand their interplay in the pathogenesis of cardiovascular disease.

The Cox regression approach was combined with the development of novel genetic tools for assessments of associations between plasma metabolomic data (glycine, tBCAAs, and tBCAAs/glycine ratio) from the UK Biobank and the development of hypertension and CHD. Genome-wide association study was performed on 186 523 White UK Biobank participants to identify new independent genetic instruments for the 2-sample Mendelian randomization analyses. P-gain statistic >10 identified instruments associated with tBCAAs/glycine ratio significantly stronger compared with individual amino acids. Outcomes of genome-wide association study on hypertension and CHD were derived from the UK Biobank (nonoverlapping sample), FinnGen, and CARDIoGRAMplusC4D.

The tBCAAs/glycine ratio was prospectively associated with a higher risk of developing hypertension and CHD (hazard ratio quintile Q5 versus Q1, 1.196 [95% CI, 1.109-1.289] and 1.226 [95% CI, 1.160-1.296], respectively). Mendelian randomization analysis demonstrated that tBCAAs/glycine ratio (P-gain >10) was a risk factor for hypertension (meta-analyzed inverse-variance weighted causal estimate 0.45 log odds ratio/SD (95% CI, 0.26-0.64) and CHD (0.48 [95% CI, 0.29-0.67]) with an absolute effect significantly larger compared with the effect of glycine (-0.06 [95% CI, -0.1 to -0.03] and -0.08 [95% CI, -0.11 to -0.05], respectively) or tBCAAs (0.22 [95% CI, 0.09-0.34] and 0.12 [95% CI, 0.01-0.24], respectively).

The total BCAAs/glycine ratio is a key element of the metabolic signature contributing to hypertension and CHD, which may reflect biological pathways shared by glycine and tBCAAs.

Acute kidney injury (AKI) can cause distal cardiac dysfunction; however, the underlying mechanism is unknown. Oxidative stress is proved prominent in AKI-induced cardiac dysfunction, and a possible bridge role of oxidative-stress products in cardio-renal interaction has been reported. Therefore, this study aimed to investigate the critical role of circulating reactive oxygen species (ROS) in mediating cardiac dysfunction after bilateral renal ischemia-reperfusion injury (IRI). We observed the diastolic dysfunction in the mice following renal IRI, accompanied by reduced ATP levels, oxidative stress, and branched-chain amino acids (BCAA) accumulation in the heart. Notably, ROS levels showed a sequential increase in the kidneys, circulation, and heart. Treatment with tempol, an ROS scavenger, significantly restored cardiac diastolic function in the renal IRI mice, corroborating the bridge role of circulating ROS. Accumulating evidence has identified oxidative stress as upstream of Mst1/Hippo in cardiac injury, which could regulate the expression of downstream genes related to mitochondrial quality control, leading to lower ATP, higher ROS and metabolic disorder. To verify this, we examined the activation of the Mst1/Hippo pathway in the heart of renal IRI mice, which was alleviated by tempol treatment as well. In vitro, analysis revealed that Mst1-knockdown cardiomyocytes could be activated by hydrogen peroxide (H2O2). Analysis of Mst1-overexpression cardiomyocytes confirmed the critical role of the Mst1/Hippo pathway in oxidative stress and BCAA dysmetabolism. Therefore, our results indicated that circulating ROS following renal IRI activates the Mst1/Hippo pathway of myocardium, leading to cardiac oxidative stress and diastolic dysfunction. This finding provides new insights for the clinical exploration of improved treatment options for cardiorenal syndrome.

Exposure to environmental elements can alter gut microbiota, further affecting host health. Exploring the interrelationships among element exposure, gut microbiota and blood pressure (BP) during pregnancy, as well as the mediating roles of gut microbiota, is warranted, which holds implications for maternal and offspring health. In a prospective cohort study between 2017-2018, 733 pregnant women were included. The serum elements and gut microbiota during the second trimester were assessed, and BP was collected during the second and third trimester and before delivery. Fourteen associations were identified between serum elements and BP, including positive associations of zinc (Zn) and thallium (Tl) with systolic BP during the second trimester. Rubidium (Rb) showed a positive association with Pielou's evenness. Serum elements, such as Tl and Rb, were significantly associated with the relative abundance of bacteria and co-abundance groups (CAGs). Alpha diversity was negatively associated with BP levels and trajectories. Moreover, 15 associations between gut microbiota and BP were shown. Finally, mediation analysis confirmed that CAG2 and Pielou's evenness mediated the associations of Tl and Rb with BP, respectively. We concluded that serum elements can contribute to BP changes during pregnancy through gut microbiota, suggesting gut microbiota-targeted approach as a potential intervention.

Human immunodeficiency virus (HIV) infection and the ensuing acquired immunodeficiency syndrome (AIDS) disproportionally affect young women, yet understanding of the factors promoting heterosexual transmission in the female genital tract is limited. Colonization with highly diverse, Lactobacillus-deficient communities (HDCs) increases a woman's risk of acquiring HIV-1 compared with colonization with Lactobacillus-dominated low diversity communities (LDCs). The polymicrobial nature of these communities has made it challenging to elucidate the microbial mechanisms responsible for modulating HIV susceptibility. Here, we analyzed conserved changes in small-molecule metabolites present in the cervicovaginal lavage fluid collected from women colonized with HDCs and LDCs with the goal of identifying possible chemicals influencing HIV infection. As in previous studies, we found that the catabolite of the branched-chain amino acid valine, 2-hydroxyisovalerate (2-HV), was a consistent component of dysbiotic HDC microbiota. Effects of 2-HV on HIV infection were assessed. In experimental infections with HIV, treatment with 2-HV increased infections of resting CD4+ T cells. To understand bacterial production of 2-HV in more detail, we cultured purified HDC and LDC bacteria and used mass spectrometry to identify two HDC bacteria that synthesize high levels of 2-HV. In contrast, protective vaginal Lactobacilli did not produce high levels of 2-HV. A genomic analysis of genes encoding 2-HV synthetic pathways showed a correlation between high-level production of 2-HV and pathways for synthesis of the immediate precursor 2-ketoisovalerate. Thus, 2-HV is a candidate mediator linking vaginal microbiome structure and heterosexual HIV transmission in women.

Hypertension, a major contributor to cardiovascular morbidity, is closely linked to amino acid metabolism. Amino acids, particularly branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs), may play pivotal roles in the pathogenesis and potential management of hypertension. This review investigated the relationships between amino acid profiles, specifically BCAAs and AAAs, and hypertension, and examined their potential as diagnostic and therapeutic targets. An in-depth analysis was conducted on studies highlighting the associations of specific amino acids such as arginine, glycine, proline, glutamine, and the BCAAs and AAAs with hypertension. BCAAs and AAAs, alongside other amino acids like arginine, glycine, and proline, showed significant correlations with hypertension. These amino acids influence multiple pathways including nitric oxide synthesis, vascular remodeling, and neurotransmitter production, among others. Distinct amino acid profiles were discerned between hypertensive and non-hypertensive individuals. Amino acid profiling, particularly the levels of BCAAs and AAAs, offers promising avenues in the diagnostic and therapeutic strategies for hypertension. Future studies are crucial to confirm these findings and to delineate amino acid-based interventions for hypertension treatment.

Branched-chain amino acids (BCAA) are essential for maintaining intestinal mucosal integrity. However, only a few studies have explored the role of BCAA in the modulation of intestinal inflammation. In this study, we investigated in vitro effects of BCAA on the inflammatory response induced by lipopolysaccharide (LPS) (1 µg/mL) in Caco-2 cells. Caco-2 cells were assigned to six groups: control without BCAA (CTL0), normal BCAA (CTL; 0.8 mM leucine, 0.8 mM isoleucine, and 0.8 mM valine); leucine (LEU; 2 mM leucine), isoleucine (ISO; 2 mM isoleucine), valine (VAL; 2 mM valine), and high BCAA (LIV; 2 mM leucine, 2 mM isoleucine, and 2 mM valine). BCAA was added to the culture medium 24 h before LPS stimulation. Our results indicated that BCAA supplementation did not impair cell viability. The amino acids leucine and isoleucine attenuated the synthesis of IL-8 and JNK and NF-kB phosphorylation induced by LPS. Furthermore, neither BCAA supplementation nor LPS treatment modulated the activity of glutathione peroxidase or the intracellular reduced glutathione/oxidized glutathione ratio. Therefore, leucine and isoleucine exert anti-inflammatory effects in Caco-2 cells exposed to LPS by modulating JNK and NF-kB phosphorylation and IL-8 production. Further in vivo studies are required to validate these findings and gather valuable information for potential therapeutic or dietary interventions.

Chronic subdural hematoma (CSDH) is one of the most common neurosurgical diseases with atypical manifestations. The aim of this study was to utilize urine metabolomics to explore potential biomarkers for the diagnosis and prognosis of CSDH.

Seventy-seven healthy controls and ninety-two patients with CSDH were enrolled in our study. In total, 261 urine samples divided into the discovery group and validation group were analyzed by LC-MS. The statistical analysis and functional annotation were applied to discover potential biomarker panels and altered metabolic pathways.

A total of 53 differential metabolites were identified in this study. And the urinary metabolic profiles showed apparent separation between patients and controls. Further functional annotation showed that the differential metabolites were associated with lipid metabolism, fatty acid metabolism, amino acid metabolism, biotin metabolism, steroid hormone biosynthesis, and pentose and glucuronate interconversions. Moreover, one panel of Capryloylglycine, cis-5-Octenoic acid, Ethisterone, and 5,6-DiHETE showed good predictive performance in the diagnosis of CSDH, with an AUC of 0.89 in discovery group and an AUC of 0.822 in validation group. Another five metabolites (Trilobinol, 3'-Hydroxyropivacaine, Ethisterone, Arginyl-Proline, 5-alpha-Dihydrotestosterone glucuronide) showed the levels of them returned to a healthy state after surgery, showing good possibility to monitor the recovery of CSDH patients.

The findings of the study revealed urine metabolomic differences between CSDH and controls. The potentially diagnostic and prognostic biomarker panels of urine metabolites were established, and functional analysis demonstrated deeper metabolic disorders of CSDH, which might conduce to improve early diagnose of CSDH clinically.

Metabolic reprogramming of vascular smooth muscle cell (VSMC) plays a critical role in the pathogenesis of thoracic aortic dissection (TAD). Previous researches have mainly focused on dysregulation of fatty acid or glucose metabolism, while the impact of amino acids catabolic disorder in VSMCs during the development of TAD remains elusive. Here, we identified branched-chain amino acid (BCAA) catabolic defect as a metabolic hallmark of TAD. The bioinformatics analysis and data from human aorta revealed impaired BCAA catabolism in TAD individuals. This was accompanied by upregulated branched-chain α-ketoacid dehydrogenase kinase (BCKDK) expression and BCKD E1 subunit alpha (BCKDHA) phosphorylation, enhanced vascular inflammation, and hyperactivation of mTOR signaling. Further in vivo experiments demonstrated that inhibition of BCKDK with BT2 (a BCKDK allosteric inhibitor) treatment dephosphorylated BCKDHA and re-activated BCAA catabolism, attenuated VSMCs phenotypic switching, alleviated aortic remodeling, mitochondrial reactive oxygen species (ROS) damage and vascular inflammation. Additionally, the beneficial actions of BT2 were validated in a TNF-α challenged murine VSMC cell line. Meanwhile, rapamycin conferred similar beneficial effects against VSMC phenotypic switching, cellular ROS damage as well as inflammatory response. However, co-treatment with MHY1485 (a classic mTOR activator) reversed the beneficial effects of BT2 by reactivating mTOR signaling. Taken together, the in vivo and in vitro evidence showed that impairment of BCAA catabolism resulted in aortic accumulation of BCAA and further caused VSMC phenotypic switching, mitochondrial ROS damage and inflammatory response via mTOR hyperactivation. BCKDK and mTOR signaling may serve as the potential drug targets for the prevention and treatment of TAD.