Search Results (47)

The sodium-coupled citrate transporter NaCT (SLC13A5) imports extracellular citrate into cells. In the CNS, SLC13A5 is described to be expressed predominantly in neurons. Cytosolic citrate levels rely on citrate generated in mitochondria and imported from other CNS cells, regulating intermediary metabolism and supplying acetyl-CoA for lipid synthesis and histone acetylation. Despite evidence for NaCT’s role in neurometabolic homeostasis, its transcriptional behavior across Alzheimer’s disease (AD) progression and across astrocyte subtypes remains uncharacterized at single-cell resolution. We analyzed single-nucleus RNA sequencing data from 1,378,211 nuclei across 84 donors in the Seattle Alzheimer’s Disease Brain Cell Atlas (SEA-AD) Middle Temporal Gyrus dataset to profile SLC13A5 and seven citrate metabolism genes across a continuous AD pseudoprogression score. SLC13A5 expression was restricted to astrocytes (~20% prevalence) and concentrated in the Astro 2 supertype (24.0%), a homeostatic subtype characterized by low C3 (1.6%) and CD44 (5.5%), which expanded with pseudoprogression (Spearman rho = +0.345, FDR < 0.001). The A1-reactive Astro 3 supertype, where SLC13A5 prevalence was 0.87%, declined concordantly (rho = −0.393). Opposing compositional and transcriptional forces produced apparent stability in overall SLC13A5 prevalence. SLC13A3 and ACO1 showed progressive donor-level declines correlating with Braak stage and Thal phase (rho range: −0.307 to −0.349, FDR < 0.01). APOE4 carriers exhibited lower SLC13A5 prevalence specifically within Astro 2 nuclei (median 17.6% vs. 25.9%; Wilcoxon p = 0.025), though this association did not survive multivariate regression. No difference in Astro 2 SLC13A5 expression was detected between cognitively resilient and expected-AD donors with equivalent high Braak burden (p = 0.888). Contrary to the prevailing description of NaCT as a neuronal transporter, SLC13A5 transcript in the SEA-AD MTG dataset was detected almost exclusively in astrocyte nuclei, concentrated in the homeostatic Astro 2 subtype, and maintained as this subtype expanded with advancing AD pathology. Because these are nuclear transcript measurements, they delimit where SLC13A5 mRNA is detectable rather than establishing the cellular site of NaCT protein or activity, which requires in situ validation. Full article

Inborn errors of metabolism (IEMs) are a group of inherited genetic conditions that, in general, result from a specific enzyme defect. Clinical consequences caused by abnormal enzyme levels often disrupt affected metabolic pathways and their intermediary metabolites. Because diagnostic outcomes depend on early intervention, a timely and accurate diagnosis is essential. Quantitative targeted metabolomics (QTM) is an analytical approach that quantifies predefined metabolites and generates interpretable biochemical phenotypes. Instead of focusing solely on screening, expanded QTM methods enable higher coverage with multi-analyte profiling that can provide more comprehensive characterization of disease-associated metabolic perturbations, particularly in IEMs with overlapping biochemical profiles. This review summarizes diagnostic techniques for IEMs, outlines the principles and advantages of QTM, and evaluates its established role and emerging opportunities and limitations in advancing method development and deep metabolic phenotyping to support precision medicine. Full article

Background/Objectives: Chronic low-grade inflammation, underpinned by persistent activation of the NLRP3 inflammasome, is a central pathological mechanism in non-communicable diseases including cardiovascular disease, type 2 diabetes, inflammatory bowel disease, and neurodegeneration. Dietary polyphenols have been consistently associated with reduced inflammatory burden; however, the mechanisms underlying these effects remain incompletely understood. This review aims to characterize the gut microbiota–polyphenol–NLRP3 inflammasome axis as a central regulatory network through which diet modulates innate immune signaling and chronic inflammatory tone. Methods: A comprehensive narrative review of the available literature was conducted, integrating evidence from mechanistic studies in cell culture and animal models, microbiome research, metabolomics, and human epidemiological and interventional data. Results: The gut microbiota emerges as a critical biochemical intermediary that transforms dietary polyphenols into bioactive metabolites, including urolithins, phenyl-γ-valerolactones, protocatechuic acid, and short-chain fatty acids, with enhanced bioavailability and potent inflammasome-modulating properties. These compounds suppress NLRP3 activation through multiple converging mechanisms, including inhibition of NF-κB-dependent priming, mitochondrial quality control via mitophagy, Nrf2-mediated antioxidant responses, and HDAC inhibition. Evidence across cardiovascular, metabolic, neurological, and respiratory disease models supports the translational relevance of this axis. Conclusions: The microbiota–polyphenol–NLRP3 axis functions as an integrated, self-regulated network in which each component simultaneously shapes and is shaped by the others: dysbiosis primes NLRP3 and depletes protective metabolites, while inflammasome hyperactivation further destabilises microbial ecology; polyphenol biotransformation by specific taxa interrupts this feed-forward loop at multiple nodes, restoring homeostasis. Full article

Objective: Emphysema is an important chronic obstructive pulmonary disease (COPD) phenotype characterized by the destruction of air spaces distal to the terminal bronchiole. Aiming to detect potential emphysema biomarkers and to assess the systemic effects of emphysema in blood plasma, we conducted a small cross-sectional shotgun proteomics study. Methods: This study included N = 40 participants divided into four subgroups (N = 10 per group): patients with emphysema and COPD (CE), patients with COPD but without emphysema (CN), healthy smokers (HS) and healthy never-smokers (HN). The participants were sampled non-probabilistically to be similar in terms of age, sex and comorbidities. Participants’ blood plasma was analyzed using liquid chromatography–mass spectrometry. Bioinformatic analysis included detection of differentially expressed proteins (DEPs) and overrepresentation analysis (ORA). Results: Across all groups, a total of 994 proteins were identified, with NADP-dependent malic enzyme (NADP-ME; encoded by ME1) being the only DEP in the CE vs. CN contrast. Proteins such as BMP1, ADAMTSL-2, -4 and IGFBP4, -5, 6 were identified to be upregulated in CE vs. HN. Fibulin-1, -3 and several immunoglobulin components were identified to be downregulated in the CE vs. HN contrast. ORA revealed several enriched processes, including serine-type endopeptidase activity, insulin-like growth factor I and II binding, and signaling receptor binding. Conclusion: We propose NADP-ME, an important enzyme of intermediary metabolism and redox homeostasis, as a potential biomarker candidate of emphysema. Notably, NADP-ME is also implicated in anoikis resistance. Additionally, changes in the expression levels of BMP1, ADAMTSL-2 and -4, and fibulin suggest potential major systemic effects of extracellular matrix perturbation. As all data was derived from LC-MS analysis, these findings need to be further evaluated with complementary methods. Full article

Short-chain fatty acids (SCFAs) produced by gut microbial fermentation influence host metabolism and neuroinflammatory processes implicated in Alzheimer’s disease (AD). However, the relationship between fecal SCFAs, microbial taxa, and cerebral amyloid-β (Aβ) burden in cognitively unimpaired individuals remains unclear. Fecal SCFAs were quantified using GC-MS, and microbial species were profiled by shotgun metagenomics in 87 participants. Associations between SCFAs, demographics, APOE ε4 status, and Aβ burden were tested using nonparametric statistics and multivariable regression. Microbial–SCFA links were evaluated using Spearman correlations and multivariate ordinations, with mediation analysis exploring potential indirect pathways. Acetate was the predominant SCFA and demonstrated the most robust microbial associations. Higher acetate concentrations were positively associated with Bacteroides ovatus and Faecalibacterium prausnitzii, whereas lower acetate levels were linked to species such as Bifidobacterium animalis and Lachnoclostridium scindens. Stratified analyses indicated that individuals with elevated Aβ burden exhibited more pronounced species–SCFA relationships, including a notable association between Bacteroides thetaiotaomicron and butyrate. Multivariate ordination further identified a significant overall coupling between SCFA profiles and microbial community structure. Mediation analysis suggested that an Oscillospiraceae species may represent a potential intermediary linking valerate concentrations with Aβ status. SCFA concentrations were not strongly influenced by demographic or genetic factors, but specific species demonstrated robust associations with acetate levels. Distinct SCFA–microbial interaction patterns in Aβ High individuals suggest subtle early gut microbial alterations linked to amyloid burden. These findings highlight the potential role of SCFA-related microbial pathways in preclinical AD. Full article

Background: Colorectal cancer (CRC) is significantly associated with multiple metabolic diseases, with plasma metabolites potentially mediating this relationship. This large-scale metabolomics study aims to (1) quantify the genetic correlations and causal effects between 10 metabolic disease-related phenotypes and CRC risk; (2) identify the plasma metabolites mediating these effects; and (3) explore downstream regulatory genes and druggable targets. Methods: Using linkage disequilibrium score regression and two-sample Mendelian randomization, we assessed the causal relationships between each metabolic trait and CRC. A total of 1091 plasma metabolites and 309 metabolite ratios were identified and analyzed for mediating effects by a two-step MR approach. Colocalization analyses evaluated shared genetic loci. The findings were validated in the UK Biobank for metabolite-trait associations. The expression of candidate genes was explored using data from TCGA, GTEx, and GEO. A FADS1-centered protein–protein interaction (PPI) network was constructed via STRING. Results: BMI, waist circumference, basal metabolic rate, insulin resistance and metabolic syndrome exhibited both genetic correlation and causal effects on CRC. Five plasma metabolites—mannonate, the glucose/mannose ratio, plasma free asparagine, 1-linolenoyl-2-linolenoyl-GPC (18:2/18:3), and the mannose/trans-4-hydroxyproline ratio—were identified as shared central mediators. A colocalization analysis showed rs174546 linked CRC and 1-linolenoyl-2-linoleoyl-GPC. Validation in the UK Biobank confirmed the associations between phosphatidylcholine (the lipid class of this metabolite), adiposity measures, and CRC risk. An integrative analysis of TCGA, GTEx, and GEO revealed consistent upregulation of FADS1/2/3 and FEN1 in CRC, with high FADS1 expression predicting a poorer prognosis and showing the distinct cell-type expression in adipose and colon tissue. The PPI network mapping uncovered nine FADS1 interacting proteins targeted by supplements such as α-linolenic acid and eicosapentaenoic acid. Conclusions: This study systematically reveals, for the first time, the shared intermediary plasma metabolites and their regulatory genes in the causal pathway from metabolic diseases to CRC. These findings provide candidate targets for subsequent functional validation and biomarker development. Full article

Aging is characterized by a progressive decline in physiological function that impairs performance and increases vulnerability to disease and mortality. Delaying this deterioration is key to promoting healthy aging. Age-associated functional decline is closely linked to alterations in intermediary metabolism, including disrupted lipid metabolism and impaired mitochondrial function. Counteracting these metabolic changes, particularly those affecting basal metabolic rate and energy utilization, may be a feasible strategy to extend healthspan. The Renin-Angiotensin System (RAS), which controls blood pressure through Angiotensin II, an octapeptide hormone generated from Angiotensin I by Angiotensin-Converting Enzyme (ACE), has been identified as a potential target for aging therapies. ACE inhibitors, such as the commonly prescribed vasodilator lisinopril, have been shown to exert beneficial effects on healthspan. Disentangling their systemic effects from direct cellular actions on intermediary metabolism is challenging in humans but can be pursued in model organisms. Drosophila melanogaster expresses two ortholog of mammalian ACE, Ance and Acer, which have diverged to acquire different functions. Since fundamental cellular processes are evolutionarily conserved and flies have an open circulatory system, Drosophila provides a versatile model for translational studies on ACE inhibition and aging. Recent studies in Drosophila reveal sex-, age-, and genetic background-specific effects of lisinopril on metabolic rates and aging-related organismal phenotypes. Integrating preclinical findings from Drosophila with clinical studies will be essential to define the therapeutic potential of RAS inhibition in extending lifespan and delaying aging. Full article

Malaria persists as a paradigmatic model of co-evolutionary complexity, emerging from the dynamic interplay among a human host, Anopheles vectors, and Plasmodium falciparum parasites. In human populations, centuries of selective pressures have sculpted an intricate and heterogeneous immunogenetic landscape. Classical adaptations, such as hemoglobinopathies, are complemented by a diverse array of genetic polymorphisms that modulate innate and adaptive immune responses. These genetic traits, along with the acquisition of functional immunity following repeated exposures, mitigate disease severity but are continually challenged by the parasite’s highly evolved mechanisms of antigenic variation and immunomodulation. Such host adaptations underscore an evolutionary arms race that perpetually shapes the clinical and epidemiological outcomes. Intermediaries in malaria transmission have evolved robust responses to both natural and anthropogenic pressures. Their vector competence is governed by complex polygenic traits that affect physiological barriers and immune responses during parasite development. Recent studies reveal that these mosquitoes exhibit rapid behavioral and biochemical adaptations, including shifts in host-seeking behavior and the evolution of insecticide resistance. Mechanisms such as enhanced metabolic detoxification and target site insensitivity have emerged in response to the widespread use of insecticides, thereby eroding the efficacy of conventional interventions like insecticide-treated bed nets and indoor residual spraying. These adaptations not only sustain transmission dynamics in intervention saturated landscapes but also challenge current vector control paradigms, necessitating the development of innovative, integrated management strategies. At the molecular level, P. falciparum exemplifies evolutionary ingenuity through extensive genomic streamlining and metabolic reconfiguration. Its compact genome, a result of strategic gene loss and pruning, is optimized for an obligate parasitic lifestyle. The repurposing of the apicoplast for critical anabolic functions including fatty acid, isoprenoid, and haem biosynthesis highlights the parasite’s ability to exploit host derived nutrients efficiently. Moreover, the rapid accumulation of mutations, coupled with an elaborate repertoire for antigenic switching and epigenetic regulation, not only facilitates immune escape but also accelerates the emergence of antimalarial drug resistance. Advanced high throughput sequencing and functional genomics have begun to elucidate the metabolic epigenetic nexus that governs virulence gene expression and antigenic diversity in P. falciparum. By integrating insights from molecular biology, genomics, and evolutionary ecology, this study delineates the multifaceted co-adaptive dynamics that render malaria a recalcitrant global health threat. Our findings provide critical insights into the molecular arms race at the heart of host–pathogen vector interactions and underscore promising avenues for the development of next generation therapeutic and vector management strategies aimed at sustainable malaria elimination. Full article

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), previously referred to as Non-Alcoholic Fatty Liver Disease (NAFLD), is a prevalent chronic liver condition strongly linked to Type 2 Diabetes Mellitus (T2DM) and obesity. Globally, MASLD is the most common cause of chronic liver disease. The bidirectional relationship between MASLD and T2DM underscores the pivotal role of insulin resistance in disease progression, which contributes to hepatic steatosis, oxidative stress, and inflammation, forming a vicious cycle. MASLD is also associated with heightened risks of cardiovascular and chronic kidney diseases, necessitating comprehensive treatment approaches. While lifestyle interventions and weight loss remain the cornerstone of management, their sustainability is challenging. This review highlights the evolving pharmacological landscape targeting MASLD and its advanced form, Metabolic Dysfunction-Associated Steatohepatitis (MASH). Currently, Resmetirom is the only FDA-approved drug for MASH. Current and investigational therapies, including insulin-sensitizing agents like peroxisome proliferator-activated receptor (PPAR) agonists, glucose-lowering drugs such as sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA), drugs that target intermediary metabolism such as Vitamin E, de novo lipogenesis inhibitors, and emerging agents targeting the gut-liver axis and oxidative stress, are explored. These therapies demonstrate promising effects on hepatic steatosis, inflammation, and fibrosis, providing new avenues to address the multifaceted pathophysiology of MASLD. Full article

Nearly 5% of the glucose-6-phosphate (Glc6P) in cells is diverted into the hexosamine biosynthetic pathway (HBP) to synthesize glucosamine-6-phosphate (GlcN6P) and uridine diphosphate N-acetyl-glucosamine-6-phosphate (UDP-GlcN6P). Fructose-6-phosphate (Fru6P) is a common intermediary between glycolysis and the HBP. Changes in HBP regulation cause abnormal protein N-glycosylation and O-linked-N-acetylglucosamine modification (O-GlcNAcylation), affecting protein function and modifying cellular responses to signals. The HBP enzymes glucosamine-6-phosphate deaminases 1 and 2 (GNPDA1 and 2) turn GlcN6P back into Fru6P and ammonium, and have been implicated in cancer and metabolic diseases. Despite the plentiful literature on this topic, the mechanisms involved are just beginning to be studied. In this review, we summarize, for the first time, the current knowledge regarding the possible roles of the isoenzymes of both GNPDAs in the pathogenesis and development of metabolic diseases and cancer from a molecular point of view, highlighting their importance not only in supplying carbon from glycolysis, but also in ammonia metabolism. Full article

Biochemical phenotyping has been the milestone for diagnosing and managing patients affected by inborn errors of intermediary metabolism (IEiM); however, identifying the genotype responsible for these monogenic disorders greatly contributes to achieving these goals. Herein, whole-exome sequencing (WES) was used to determine the genotypes of 95 unrelated Mexican pediatric patients suspected of having IEiM. They were classified into those bearing specific biochemical abnormalities (Group 1), and those presenting unspecific biochemical profiles (Group 2). The overall concordance between the initial biochemical diagnosis and final genotypic diagnoses was 72.6% (N = 69/95 patients), with the highest concordance achieved in Group 1 (91.3%, N = 63/69), whereas the concordance was limited in Group 2 (23.07%). This finding suggests that previous biochemical phenotyping correlated with the high WES diagnostic success. Concordance was high for urea cycle disorders (94.1%) and organic acid disorders (77.4%). The identified mutational spectrum comprised 83 IEiM-relevant variants (pathogenic, likely pathogenic, and variants of uncertain significance or VUS), including three novel ones, distributed among 29 different genes responsible for amino acid, organic acid, urea cycle, carbohydrate, and lipid disorders. Inconclusive WES results (7.3%, N = 7/95) relied on monoallelic pathogenic genotypes or those involving two VUS for autosomal-recessive IEiMs. A second monogenic disease was observed in 10.5% (N = 10/95) of the patients. According to the WES results, modifications in treatment had to be made in 33.6% (N = 32/95) of patients, mainly attributed to the presence of a second monogenic disease, or to an actionable trait. This study includes the largest cohort of Mexican patients to date with biochemically suspected IEiM who were genetically diagnosed through WES, underscoring its importance in medical management. Full article

Parkinson’s disease (PD) is a progressive age-related neurodegenerative disorder affecting millions of people worldwide. Essentially, it is characterised by selective degeneration of dopamine neurons of the nigro-striatal pathway and intraneuronal aggregation of misfolded α-synuclein with formation of Lewy bodies and Lewy neurites. Moreover, specific small molecules of intermediary metabolism may have a definite pathophysiological role in PD. These include dopamine, levodopa, reduced glutathione, glutathione disulfide/oxidised glutathione, and the micronutrients thiamine and ß-Hydroxybutyrate. Recent research indicates that these small molecules can interact with α-synuclein and regulate its folding and potential aggregation. In this review, we discuss the current knowledge on interactions between α-synuclein and both the small molecules of intermediary metabolism in the brain relevant to PD, and many other natural and synthetic small molecules that regulate α-synuclein aggregation. Additionally, we analyse some of the relevant molecular mechanisms potentially involved. A better understanding of these interactions may have relevance for the development of rational future therapies. In particular, our observations suggest that the micronutrients ß-Hydroxybutyrate and thiamine might have a synergistic therapeutic role in halting or reversing the progression of PD and other neuronal α-synuclein disorders. Full article

The placenta operates during gestation as the primary communication organ between the mother and fetus. It is essential for gas, nutrient exchange, and fetal waste transfer. The placenta also produces a wide range of hormones and other factors that influence maternal physiology, including survival and activity of the corpus luteum of the ovary, but the means whereby the placenta shapes fetal development remain less clear, although the fetal brain is thought to be dependent upon the placenta for factors that play roles in its early differentiation and growth, giving rise to the term “placenta–brain axis”. Placental hormones transit via the maternal and fetal vasculature, but smaller placental molecules require protection from fetal and maternal metabolism. Such biomolecules include small RNA, mRNA, peptides, lipids, and catecholamines that include serotonin and dopamine. These compounds presumably shuttle to maternal and fetal systems via protective extracellular vesicles (EVs). Placental EVs (pEVs) and their components, in particular miRNA (miRs), are known to play important roles in regulating maternal systems, such as immune, cardiovascular, and reproductive functions. A scant amount is known about how pEVs affect fetal cells and tissues. The composition of pEVs can be influenced by gestational diseases. This review will provide critical insight into the roles of pEVs as the intermediary link between maternal and fetal systems, the impact of maternal pathologies on pEV cargo contents, and how an understanding of biomolecular changes within pEVs in health and disease might be utilized to design early diagnostic and mitigation strategies to prevent gestational diseases and later offspring disorders. Full article

Metabolic syndrome (MetS) implies different conditions where insulin resistance constitutes a major hallmark of the disease. The disease incurs a high risk for the development of cardiovascular complications, and takes its toll in regard to the gut–liver axis (pancreas, primary liver and colorectal)-associated immunity. The modulation of immunometabolic responses by immunonutritional factors (IFs) has emerged as a key determinant of the gut–liver axis’ metabolic and immune health. IFs from plant seeds have shown in vitro and pre-clinical effectiveness primarily in dealing with various immunometabolic and inflammatory diseases. Only recently have immunonutritional studies established the engagement of innate intestinal immunity to effectively control immune alterations in inflamed livers preceding the major features of the MetS. However, integrative analyses and the demonstration of causality between IFs and specific gut–liver axis-associated immunometabolic imbalances for the MetS remain ill-defined in the field. Herein, a better understanding of the IFs with a significant role in the MetS, as well as within the dynamic interplay in the functional differentiation of innate immune key effectors (i.e., monocytes/macrophages), worsening or improving the disease, could be of crucial relevance. The development of an adequate intermediary phenotype of these cells can significantly contribute to maintaining the function of T_regs and innate lymphoid cells for the prevention and treatment of MetS and associated comorbidities. Full article

Achilles tendinopathy (TP) is characterized as the third most common disease of the musculoskeletal system, and occurs in three phases. There is currently no evidence of effective treatment for this medical condition. In this study, the modulatory effects of the minimally invasive technique intratissue percutaneous electrolysis (EPI) and combinations of EPI with four nutritional factors included in the diet, hydroxytyrosol (HT), maslinic acid (MA), glycine, and aspartate (AA), on hepatic intermediary metabolism was examined in Wistar rats with induced tendinopathy at various stages of TP. Results obtained showed that induced tendinopathy produced alterations in the liver intermediary metabolisms of the rats. Regarding carbohydrate metabolism, a reduction in the activity of pro-inflammatory enzymes in the later stages of TP was observed following treatment with EPI alone. Among the combined treatments using nutritional factors with EPI, HT+EPI and AA+EPI had the greatest effect on reducing inflammation in the late stages of TP. In terms of lipid metabolism, the HT+EPI and AA+EPI groups showed a decrease in lipogenesis. In protein metabolism, the HT+EPI group more effectively reduced the inflammatory effects of induced TP. Treatment with EPI combined with nutritional factors might help regulate intermediary metabolism in TP disease and reduce the inflammation process. Full article