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PubMed2026

Human brown fat metabolism associates with systemic branched-chain amino acids homeostasis.

Circulating branched-chain amino acids (BCAAs) are linked with insulin resistance, but the human tissues contributing to systemic BCAA homeostasis remain incompletely defined. Brown adipose tissue (BAT) is a metabolically active adipose depot associated with favourable insulin sensitivity, yet its role in BCAA metabolism in humans remains unclear. We tested whether human BAT metabolism is associated with circulating BCAA levels, BAT-resident BCAA-catabolic signatures, and longitudinal changes in systemic BCAA homeostasis. We studied 83 adults who underwent metabolic phenotyping, PET-CT assessment of cold-stimulated BAT metabolism, and serum metabolomic profiling at room temperature and during acute mild cold exposure. Supraclavicular BAT biopsies from 25 participants were analysed by transcriptomics and metabolomics, and 40 participants were re-examined for circulating BCAA profiles after approximately five years. Participants with high BAT metabolism had lower circulating BCAA levels than those with low BAT metabolism. Within BAT, metabolically active individuals exhibited lower relative BCAA abundance together with higher expression of genes involved in BCAA catabolism. These BAT BCAA-catabolic signatures aligned with thermogenic capacity and indices of systemic insulin sensitivity. In contrast, individuals with low BAT metabolism showed increases in circulating BCAAs over five years. Integrative analyses further linked circulating lipopolysaccharide, a marker of metabolic endotoxemia, with higher BAT BCAA and aminomalonate abundance, together with transcriptional patterns involving inflammatory and mitochondrial pathways. Together, these findings identify human BAT metabolism as a tissue phenotype linked to systemic BCAA homeostasis and extend the role of human BAT beyond thermogenesis, suggesting that BAT-associated BCAA handling may contribute to systemic metabolic health.

Humans↗

PubMed2024

Association between Branched-Chain amino acids and Epilepsy: A Mendelian randomized study.

BACKGROUND: Branched-chain amino acids (BCAAs) have been affected epilepsy, yet conclusions remain inconclusive, lacking causal evidence regarding whether BCAAs affect epilepsy. Systematic exploration of the causal relationship between BCAAs and epilepsy could hand out new ideas for the treatment of epilepsy. METHODS: Utilizing bidirectional Mendelian randomization (MR) study, we investigated the causal relationship between BCAA levels and epilepsy. BCAA levels from genome-wide association studies (GWAS), including total BCAAs, leucine levels, isoleucine levels, and valine levels, were employed. Causal relationships were explored applying the method of inverse variance-weighted (IVW) and MR-Egger, followed by sensitivity analyses of the results to evaluate heterogeneity and pleiotropy. RESULTS: Through strict genetic variant selection, we find some related SNPs, total BCAA levels (9), leucine levels (11), isoleucine levels (7), and valine levels (6) as instrumental variables for our MR analysis. Following IVW and sensitivity analysis, total BCAAs levels (OR = 1.14, 95 % CI = 1.019 ∼ 1.285, P = 0.022) and leucine levels (OR = 1.15, 95 % CI = 1.018 ∼ 1.304, P = 0.025) had significant correlation with epilepsy. CONCLUSIONS: There exists a causal relationship between the levels of total BCAAs and leucine with epilepsy, offering the new ideas into epilepsy potential mechanisms, holding significant implications for its prevention and treatment.

Humans↗

PubMed2026

Biological Mechanisms Underlying the Cardiovascular Effects of Branched-Chain Amino Acids: A Proteome-Wide Mendelian Randomization Study.

BACKGROUND: Ischemic heart disease (IHD) is the leading cause of morbidity and mortality. Branched-chain amino acids (BCAAs) are associated with higher IHD risk, but the underlying biological pathways remain unclear. OBJECTIVES: This study aims to explore these pathways using 2-step proteome-wide Mendelian randomization. METHODS: We examined the associations between genetic proxies for BCAAs and 2922 proteins in the United Kingdom Biobank Pharma Proteomics Project, supplemented by a meta-analysis with data from deCODE to identify proteins associated with BCAAs. Next, we tested their effects on IHD risk using Coronary Artery Disease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease Genetics Consortium (122,733 cases and 424,528 controls) and replicated in FinnGen (31,640 cases and 187,152 controls). We conducted sensitivity analyses using genetic instruments from deCODE. Proteins associated with IHD risk and, in a consistent direction, with genetically predicted BCAAs were considered potential mediators. RESULTS: Genetic proxies for BCAAs were associated with 40 proteins. Among these, 6 proteins showed consistent evidence of mediation, including complement C1s subcomponent, coagulation factor II, granulin, proprotein convertase subtilisin/kexin type 9, sex hormone-binding globulin, and V-set and transmembrane domain-containing protein 2-like. These proteins are involved in inflammation, coagulation, lipid metabolism, and cellular stress response. All associations were robust across different analytical methods and replicated in independent datasets. Mediation analysis showed that these proteins accounted for 6.5% to 32.1% of the association between BCAAs and IHD risk. CONCLUSIONS: This study identified 6 proteins that potentially link BCAAs to IHD, implicating pathways related to inflammation, coagulation, lipid metabolism, and cellular stress responses. To our knowledge, these findings provide novel mechanistic insights into the BCAA-IHD relationship and highlight potential protein targets for future prevention and intervention strategies.

Amino Acids, Branched-Chain↗

PubMed2025

Integrative metabolomic and proteomic analysis of diabetic kidney disease progression with younger-onset type 2 diabetes.

AIM: Younger-onset type 2 diabetes (YT2D) confers a disproportionately high risk of diabetic kidney disease (DKD), yet early biomarkers and underlying mechanisms remain poorly defined. We aimed to identify metabolites associated with DKD progression and integrate metabolomic and proteomic data to elucidate pathways involved in a multi-ethnic Asian cohort. MATERIALS AND METHODS: In this prospective study, 787 YT2D patients (diagnosed at ≤ age 40) were followed for a median of 5.7 years. DKD progression was defined as an annual decline in estimated glomerular filtration rate (eGFR) of ≥3 mL/min/1.73 m2 or ≥ 40% reduction in eGFR from baseline. Plasma metabolites were measured by nuclear magnetic resonance spectroscopy. Multivariable regression analysis was performed in a discovery (N = 550) and internal validation cohort (N = 237). Integrative metabolomic-proteomic analysis (N = 428) was performed using sparse partial least squares discriminant analysis (sPLS-DA). RESULTS: Ninety-eight metabolites were differentially expressed between DKD progressors and non-progressors, of which total branched-chain amino acids (BCAAs) (OR = 0.60, 95% CI 0.46-0.79), valine (OR = 0.62, 95% CI 0.48-0.81), and leucine (OR = 0.56, 95% CI 0.43-0.74) associated with DKD progression, independent of metabolic risk factors. Integrative analysis identified three components comprising 23 proteins and 30 metabolites, involved in the citrate cycle and apoptosis, which improved prediction of DKD progression beyond clinical risk factors (AUC 0.69-0.83). CONCLUSION: Lower plasma BCAA levels are independently associated with DKD progression in YT2D. Integrative multi-omics analysis highlights disruptions in metabolic and apoptotic pathways, providing insights into DKD pathophysiology and potential biomarkers for early risk stratification.

Humans↗

PubMed2026

Amino acid reprogramming and biofilm-specific tricarboxylate transporters in PET-degrading Piscinibacter sakaiensis.

Plastic-degrading bacteria predominantly colonize polymer surfaces as biofilms, yet it remains unclear whether the biofilm phenotype contributes to metabolism beyond retaining extracellular enzymes. Here, we combine population-level RNA-sequencing across three conditions-biofilm cells on polyethylene terephthalate (PET), planktonic cells incubated with PET, and planktonic cells on maltose-with single-cell Raman spectroscopy to characterize the PET response of Piscinibacter sakaiensis (formerly Ideonella sakaiensis). This integrated approach reveals two metabolically distinct response layers. A carbon-source-driven response shared by all PET-exposed cells is dominated by a broad amino acid reprogramming, led by upregulation of branched-chain amino acid transport genes, enhanced serine biosynthesis, and reduced chemotaxis. A biofilm-specific layer selectively induces tripartite tricarboxylate transporter genes from three distinct genomic loci. This transcriptional feature is accompanied by a single-cell phenotype consistent with a protein-rich and saturated membrane. These results suggest that biofilm formation is not limited to enzyme retention but is associated with selective activation of transport systems, consistent with a putative role in capturing PET-derived intermediates at the polymer interface. This two-layer model separates general metabolic adaptation to PET from biofilm-specific functions and provides a framework for understanding how surface-associated bacterial physiology contributes to plastic degradation.IMPORTANCEPolyethylene terephthalate (PET) degradation in natural and engineered environments is largely mediated by surface-attached microbial communities, yet the physiological role of biofilm state during plastic degradation remains poorly understood. Using the model PET degrader Piscinibacter sakaiensis, we show that biofilm-associated cells are not simply retained near the polymer surface but exhibit a distinct metabolic program characterized by selective induction of tripartite tricarboxylate transporters. In contrast, extensive amino acid reprogramming occurs in both biofilm and planktonic PET-exposed cells, indicating that it is driven by carbon source rather than surface attachment. These findings reveal that PET degradation involves two separable physiological layers: a general metabolic response to PET-derived carbon shared across cell phenotypes, and a biofilm-specific transport response potentially linked to substrate capture at the plastic interface. This work advances our understanding of how microbial physiology is organized during plastic biodegradation and identifies transport processes as previously unrecognized components of PET-degrading biofilms.

PET biodegradation↗

PubMed2025

Breeding of yeast strains with intracellular amino acid accumulation for value-added alcoholic beverages.

The yeast Saccharomyces cerevisiae converts amino acids into volatile compounds with fruity and floral aromas during fermentation. These amino acid-derived aroma compounds play a critical role in defining the taste and flavor of alcoholic beverages such as sake, beer, and wine. The productivity of amino acid-derived aroma compounds depends on the intracellular availability of their precursor amino acids. Therefore, breeding yeast strains that accumulate amino acids provides a practical approach to developing alcoholic beverages with more unique and attractive sensory characteristics. In this minireview, we describe the isolation of yeast strains that overproduce branched-chain amino acids and phenylalanine, obtained through conventional mutagenesis of industrial brewing yeasts. We also discuss the mechanisms responsible for the increased production of these amino acids in the mutant strains, including altered feedback regulation and transcriptional control of key enzymes involved in their biosynthesis. In addition, we briefly introduce a plasmid-free genome editing system that enables precise modification of metabolic pathways without the integration of foreign DNA, allowing the construction of strains that are not classified as genetically modified organisms. This method represents a promising tool that allows flexible and fine-tuned engineering of yeast metabolic pathways, including the development of strains with tailored aroma profiles.

Saccharomyces cerevisiae↗

PubMed2026

Influenza A Virus Coinfection Alters Streptococcus pneumoniae Gene Expression during Upper Respiratory Tract Colonization.

Streptococcus pneumoniae (Spn) asymptomatically colonizes the upper respiratory tract (URT), a niche from which it can transmit to another host or cause invasive disease in the same host. The in vivo transcriptional adaptations that Spn undergoes during nasopharyngeal colonization, particularly during influenza A virus (IAV) coinfection, are poorly understood. Here, we leveraged an established infant mouse model of colonization, shedding, and transmission to perform genome-wide transcriptomic profiling of Spn during mono- and during IAV co-infection. Compared with broth-grown controls, pneumococci isolated from the URT exhibited distinct transcriptional programs, with over 200 genes differentially expressed across time points. Genes involved in carbohydrate uptake and metabolism, glycan degradation, amino sugar and nucleotide sugar metabolism, and amino acid biosynthesis were consistently enriched during colonization, highlighting metabolic adaptation to the nasopharyngeal niche. In contrast, IAV coinfection induced a markedly distinct transcriptional signature, including upregulation of branched-chain amino acid biosynthesis, bacteriocin production, and phosphate acquisition systems. Notably, the pilus islet-1 locus was upregulated during Spn-IAV coinfection. Functional studies demonstrated that while the pilus was dispensable for colonization under mono- and coinfection conditions, it promoted high-shedding events and enhanced inflammatory responses during IAV coinfection. However, reduced inflammation and reduced high shedding events from pups inoculated with a pilus-deficient mutant did not alter transmission frequency in the infant mouse model. Collectively, our findings define the in vivo transcriptional landscape of Spn during URT colonization and reveal distinct bacterial adaptations during viral coinfection, providing insight into mechanisms that influence pneumococcal persistence, inflammation, and transmission.

Journal Article↗

PubMed2026

Influenza A virus co-infection alters Streptococcus pneumoniae gene expression during upper respiratory tract colonization.

Streptococcus pneumoniae (Spn) asymptomatically colonizes the upper respiratory tract (URT), a niche from which it can transmit to another host or cause invasive disease in the same host. The in vivo transcriptional adaptations that Spn undergoes during nasopharyngeal colonization, particularly during influenza A virus (IAV) co-infection, are poorly understood. Here, we leveraged an established infant mouse model of colonization, shedding, and transmission to perform genome-wide transcriptomic profiling of Spn during mono- and during IAV co-infection. Compared with broth-grown controls, pneumococci isolated from the URT exhibited distinct transcriptional programs, with over 200 genes differentially expressed across time points. Genes involved in carbohydrate uptake and metabolism, glycan degradation, amino sugar and nucleotide sugar metabolism, and amino acid biosynthesis were consistently enriched during colonization, highlighting metabolic adaptation to the nasopharyngeal niche. In contrast, IAV co-infection induced a markedly distinct transcriptional signature, including upregulation of branched-chain amino acid biosynthesis, bacteriocin production, and phosphate acquisition systems. Notably, the pilus islet-1 locus was upregulated during Spn-IAV co-infection. Functional studies demonstrated that while the pilus was dispensable for colonization under mono- and co-infection conditions, it promoted high-shedding events and enhanced inflammatory responses during IAV co-infection. However, reduced inflammation and reduced high-shedding events from pups inoculated with a pilus-deficient mutant did not alter transmission frequency in the infant mouse model. Collectively, our findings define the in vivo transcriptional landscape of Spn during URT colonization and reveal distinct bacterial adaptations during viral co-infection, providing insight into mechanisms that influence pneumococcal persistence, inflammation, and transmission.

RNA-seq↗

PubMed2026

Circular RNAs orchestrate integrated post-transcriptional responses to combined heat and drought stress in rice.

Circular RNAs (circRNAs) are emerging post-transcriptional regulators, yet their landscape and functional roles in rice under combined abiotic stress remain largely unexplored. Here, we systematically reanalyzed strand-specific RNA-seq data to characterize circRNAs responsive to simultaneous heat and drought stress. Following quality control, read mapping, and dual-algorithm prediction using CIRI2 and CIRCexplorer2, we identified 208 high-confidence circRNAs distributed across all 12 chromosomes. Comparative profiling revealed 83 circRNAs uniquely expressed in control samples, 51 in stressed samples, and 74 shared between conditions, indicating stress-dependent circularization. Junction-read analysis highlighted a spectrum of circularization strength, ranging from highly abundant circRNAs with dominant junction reads to low-confidence candidates masked by linear transcript background. Genomic annotation showed that circRNAs primarily originated from exonic and intergenic regions, with a pronounced negative-strand bias; several genes generated multiple circRNA isoforms via alternative back-splicing. Functional enrichment of host genes suggested involvement in protein folding, nutrient reservoir activity, RNA degradation, and branched-chain amino acid catabolism, implicating roles in stress adaptation and metabolic regulation. Differential expression analysis identified seven circRNAs specifically induced under combined stress conditions. Network topology analysis pinpointed key miRNAs-including osa-miR414, osa-miR1439, and osa-miR2919-as candidate topological hubs within the predicted network. Their predicted target genes, such as those encoding stress-responsive transcription factors and signaling proteins, suggest potential roles in coordinating post-transcriptional responses to combined stress. Network topology analysis pinpointed key miRNAs-including osa-miR414, osa-miR1439, and osa-miR2919-as candidate topological hubs within the predicted network. Their predicted target genes, such as those encoding stress-responsive transcription factors and signaling proteins, suggest potential roles in coordinating post-transcriptional responses to combined stress. Overall, this study provides a comprehensive map of circRNAs in rice under combined heat and drought stress, suggests their potential as ceRNAs based on predictive analysis, and lays a foundation for future experimental validation of circRNA-mediated regulation.

Oryza↗

PubMed2023

Metabolomic profiling of glucose homeostasis in African Americans: the Insulin Resistance Atherosclerosis Family Study (IRAS-FS).

INTRODUCTION: African Americans are at increased risk for type 2 diabetes. OBJECTIVES: This work aimed to examine metabolomic signature of glucose homeostasis in African Americans. METHODS: We used an untargeted liquid chromatography-mass spectrometry metabolomic approach to comprehensively profile 727 plasma metabolites among 571 African Americans from the Insulin Resistance Atherosclerosis Family Study (IRAS-FS) and investigate the associations between these metabolites and both the dynamic (SI, insulin sensitivity; AIR, acute insulin response; DI, disposition index; and SG, glucose effectiveness) and basal (HOMA-IR and HOMA-B) measures of glucose homeostasis using univariate and regularized regression models. We also compared the results with our previous findings in the IRAS-FS Mexican Americans. RESULTS: We confirmed increased plasma metabolite levels of branched-chain amino acids and their metabolic derivatives, 2-aminoadipate, 2-hydroxybutyrate, glutamate, arginine and its metabolic derivatives, carbohydrate metabolites, and medium- and long-chain fatty acids were associated with insulin resistance, while increased plasma metabolite levels in the glycine, serine and threonine metabolic pathway were associated with insulin sensitivity. We also observed a differential ancestral effect of glutamate on glucose homeostasis with significantly stronger effects observed in African Americans than those previously observed in Mexican Americans. CONCLUSION: We extended the observations that metabolites are useful biomarkers in the identification of prediabetes in individuals at risk of type 2 diabetes in African Americans. We revealed, for the first time, differential ancestral effect of certain metabolites (i.e., glutamate) on glucose homeostasis traits. Our study highlights the need for additional comprehensive metabolomic studies in well-characterized multiethnic cohorts.

Humans↗

PubMed2026

Exploratory proteomic and metabolomic profiling of pleural effusions identifies histone H4 and alanine as promising complementary markers for pleural tuberculosis.

The diagnosis of pleural tuberculosis (Pl-TB) remains challenging. Histopathological analysis and pathogen detection in pleural biopsies are informative but limited. We investigated differentially expressed proteins and metabolites in pleural effusions from patients with Pl-TB, malignancies, and other pathologies. A proteomic analysis of pooled pleural effusions identified 45 proteins exclusively detected or upregulated in Pl-TB samples, many linked to infectious processes. Conversely, 18 proteins were uniquely found or upregulated in malignant pleural effusions, mainly associated with detoxification and hemostasis. To validate these findings, we employed targeted proteomics in individual samples. Eight proteins were validated: S100-A9, histone H4, insulin-like growth factor-binding protein 2, fibrinogen beta chain, ficolin-3, immunoglobulin heavy constant alpha 1, sulfhydryl oxidase 1, and histidine-rich glycoprotein. Additionally, NMR-based metabolomics identified 13 metabolites with differential abundance between Pl-TB and non-TB samples. Notably, N-acetyl-glycoprotein and the branched-chain amino acids, alanine and lysine differed between groups. Proteomic and metabolomic analyses revealed distinct molecular profiles between Pl-TB and non-TB patients, despite intra-group variability. To address this, we applied classification models. Histone H4 and alanine consistently emerged as discriminative features. Overall, this study provides novel insights into the molecular landscape of Pl-TB. The combined quantification of proteins and metabolites may improve differential diagnosis, although should be further validated in larger, independent cohorts before clinical application.

Humans↗

PubMed2026

The gut microbiota-obesity axis in the pathogenesis and prognosis of breast cancer.

BACKGROUND: Breast cancer (BC) remains a major global health concern, accounting for 11.7% of all cancer cases and ranking as the second leading cause of female cancer-related deaths worldwide. Increasing evidence highlights the interplay between gut microbiota (GM) dysbiosis and obesity-associated metabolic dysfunction in BC progression. This review aims to elucidate the role of GM in obese patients with BC. METHODS: A systematic literature search was conducted in PubMed and Web of Science databases for publications from July 2015 to January 2025. Search terms combined BC, GM, obesity, dysbiosis, immunity, and microbiome. Article selection prioritized studies investigating microbial alterations in BC patients, mechanistic links between obesity and cancer progression, and GM-targeted interventions. Both original studies and authoritative reviews were included, supplemented by manual reference screening. DISCUSSION: Obesity may trigger systemic inflammation, altered adipokine secretion, and disrupted steroid hormone metabolism via gut-derived β-glucuronidase activity, thereby exacerbating BC occurrence and recurrence. GM dysbiosis-driven metabolites such as branched-chain amino acids (BCAAs) and short-chain fatty acids (SCFAs) can activate oncogenic signaling pathways and immunosuppressive myeloid-derived suppressor cells (MDSCs), fostering tumor immune evasion. Conversely, dietary interventions, probiotics, and fecal microbiota transplantation (FMT) can alleviate dysbiosis, strengthen gut barriers, and restore anti-tumor immunity, improving chemotherapy response and reducing recurrence. However, challenges persist in deciphering BC subtype-related microbial signatures and optimizing microbiota-targeted therapies. CONCLUSION: Future longitudinal studies are needed to clarify causal relationships, validate microbial biomarkers, and translate preclinical findings into clinical applications. Addressing the gut-breast axis may offer transformative potential for precision oncology in obesity-driven BC.

Humans↗

PubMed2026

Genome-scale insights into metabolic streamlining and photosynthetic energy balance in the extremophile green alga Picocystis salinarum (Picocystophyceae, Chlorophyta).

Picocystis salinarum is an early-diverging chlorophyte and the sole described member of the Picocystophyceae, frequently dominating hypersaline and alkaline lakes despite extreme physicochemical constraints. To elucidate the genomic foundations of its ecological success, we generated a fully annotated, chromosome-scale nuclear genome assembly of the type strain originally isolated from a saline pond in San Francisco Bay. The 18.5-Mb genome comprises 30 chromosomal assemblies, exhibits clear diploidy, and contains multiple copies of intact Ty3/Gypsy and Ty1/Copia long terminal repeat retrotransposons encoding polyproteins with atypical accessory domains. Phylogenomic analyses reveal strong affinity with the Nephroselmidophyceae. Comparative analyses reveal extensive metabolic streamlining, including the absence of a queuosine salvage pathway, the 2-methylcitrate cycle, β-oxidation of propionate, and branched-chain amino acid catabolism, traits retained in several marine prasinophyte lineages. In contrast, the genome preserves multiple ancestral bacterial derived systems. Notably, P. salinarum features a complete chloroplast NADH dehydrogenase-like complex, including all membrane, electron binding, and assembly components, a configuration not previously reported in sequenced chlorophyte algae. This retention implies substantial capacity for cyclic electron flow and chlororespiration, processes expected to be critical in chronically low-light and chemically extreme environments. The genome further reveals a distinctive biochemical CO2-concentrating mechanism centered on plastid-targeted phosphoenolpyruvate carboxykinase, complete plastid peptidoglycan biosynthetic and remodeling pathways, and partial retention of lipid-A-related machinery. Conversely, P. salinarum lacks canonical non-photochemical quenching proteins while retaining xanthophyll-cycle enzymes that support slower photoprotective responses. Together, these features define a coordinated genomic architecture that underpins the specialization of P. salinarum to hypersaline, alkaline, and persistently low-light ecosystems.

3‐deoxy‐D‐manno‐octulo↗

PubMed2025

Stacked mutations in multi-copy AHAS genes enhance sulfonylurea herbicide resistance in soybean.

Weeds are a major factor that negatively impact crop yields. Developing herbicide-resistant germlines is crucial for efficient weed control. Sulfonylurea- and pyrimidinyl benzoate-based herbicides inhibit the function of acetohydroxyacid synthase (AHAS), a key enzyme in the biosynthesis of branched-chain amino acids in plants. To create soybean plants resistant to these classes of herbicides, we performed base editing of AHAS genes in Glycine max. A guide RNA was designed to target the codon for proline-182 in GmAHAS2, with the prediction that off-target base editing might also occur in the GmAHAS3 and GmAHAS4 genes. We selected six genome-edited soybean lines, each carrying distinct mutations in GmAHAS2, GmAHAS3, or GmAHAS4. These lines were treated with three different AHAS-targeting herbicides to evaluate resistance. The results show that the number of mutated GmAHAS genes and the mutation patterns significantly influence herbicide resistance.

Herbicide Resistance↗

PubMed2025

BCKDHA-BCKDHB digenic gene therapy restores metabolic homeostasis in two mouse models and a calf with classic maple syrup urine disease.

Classic maple syrup urine disease (MSUD) results from biallelic mutations in genes that encode the branched-chain α-ketoacid dehydrogenase E1α (BCKDHA), E1β (BCKDHB), or dihydrolipoamide branched-chain transacylase (DBT) subunits, which interact to form the mitochondrial BCKDH complex that decarboxylates ketoacid derivatives of leucine, isoleucine, and valine. MSUD is an inborn error of metabolism characterized by recurrent life-threatening neurologic crises and progressive brain injury that can only be managed with an exacting prescription diet or allogeneic liver transplant. To develop a gene replacement therapy for MSUD, we designed a dual-function recombinant adeno-associated virus serotype 9 (rAAV9) vector to deliver codon-optimized BCKDHA and BCKDHB (rAAV9.hA-BiP-hB) to the liver, muscle, heart, and brain. rAAV9.hA-BiP-hB restored coexpression of BCKDHA and BCKDHB as well as BCKDH holoenzyme activity in BCKDHA-/- HEK293T cells and did not perturb physiologic branched-chain amino acid homeostasis in wild-type mice at a systemic dose of 2.7 × 1014 vector genomes per kilogram. In two models of severe MSUD (Bckdha-/- and Bckdhb-/- mice) and a newborn calf homozygous for BCKDHA c.248C>T, one postnatal injection prevented perinatal death, normalized growth, restored coordinated expression of BCKDHA and BCKDHB in the skeletal muscle, liver, heart, and brain, and stabilized MSUD biomarkers in the face of high protein ingestion. In summary, we developed a one-time BCKDHA-BCKDHB systemic dual-gene replacement strategy that holds promise as a therapeutic alternative to prescription diet and liver transplant for treatment of MSUD types 1A and 1B, the two most common forms of MSUD in humans.

Animals↗

PubMed2026

Loss of ovarian function and estrogen therapy remodel the brain's synaptic and metabolic proteome.

Menopause is linked to cognitive decline and reduced brain metabolism, whereas estrogen (E2) therapy has been shown to mitigate these effects. Understanding the molecular mechanisms by which ovarian hormones and E2 influence neuroprotection is essential for developing strategies to maintain brain health in women. In this study, we examined how the loss of ovarian hormones, with or without E2 treatment, affects the brain proteome and mitochondrial energy production in aged female C57BL/6J mice (36-40 wk). The mice underwent sham or ovariectomy (OVX) surgery and were fed a high-fat diet for 10 wk; 6 wk after surgery, OVX mice received either sesame oil or E2 treatment for 4 wk. Proteomic analysis of brain homogenates revealed 4,992 proteins regulated by E2, with pathway analysis showing increased signaling proteins related to synaptogenesis. OVX reduced proteins involved in synaptic function, branched-chain amino acid and ketone metabolism, the tricarboxylic acid cycle, and oxidative phosphorylation (Complexes I, IV, and V), whereas E2 restored protein expression within these pathways. Despite alterations in OxPhos proteins, basal and state 3 mitochondrial respiration remained unchanged, although notable impairments in Complex IV enzymatic activity were apparent in OVX, which were partially reversed by E2 treatment. Overall, these results indicate that E2 supports brain health by maintaining proteins crucial for synaptic integrity and metabolism, while partially offsetting the functional decline in mitochondrial bioenergetics associated with menopause.NEW & NOTEWORTHY The menopausal transition, marked by declining estrogen levels, alters cognition, neuroplasticity, and brain metabolism. Although hormone therapy benefits cognition, its molecular effects on the brain remain unclear. Using whole-brain proteomics in aged ovariectomized (OVX) mice with or without estrogen treatment, we found that OVX reduced proteins linked to synaptogenesis and mitochondrial metabolism. Estrogen reversed these declines, restoring pathways supporting neuronal signaling and energy balance, identifying estrogen-regulated proteins critical for maintaining brain health during menopause.

Animals↗

PubMed2026

Untargeted-targeted metabolomics: energy metabolism characteristics in heart failure staging and discovery of novel biomarkers.

BACKGROUND: Heart Failure represents the severe stage of various heart diseases. Its global morbidity and mortality are on the rise, making it a serious public health issue that imposes a heavy burden on patients' families and society. Currently, there are relatively few systematic studies on the changes in specific metabolites and pathways in different stages of heart failure, such as Stage A, Stage B and Stage C. AIMS: Using untargeted-targeted metabolomics to explore the metabolic characteristics of Heart Failure, and screen out serum metabolic markers with potential diagnostic and prognostic value. METHODS: This study is a cross-sectional study. A total of 210 heart failure patients from Xiyuan Hospital of China Academy of Chinese Medical Sciences were enrolled between October 2023 and October 2024. Among them, 60 patients were selected for targeted metabolomics analysis via stratified sampling. Serum samples of the patients were collected and pretreated with methanol, then metabolites were detected using untargeted and targeted LC-MS respectively. After the raw data were processed with MSDIAL, pattern recognition was performed using principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA). Differential metabolites with variable importance in projection (VIP) > 1 and P < 0.05 were screened, and relevant pathways were analyzed via enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: Untargeted metabolomics revealed that, compared with patients in Stages A and B, those with heart failure in Stage C had decreased serum levels of alanine, creatine, and branched-chain amino acids, along with increased levels of citric acid, fumaric acid, and malic acid. The differential metabolites were primarily enriched in pathways including the citric acid cycle, central carbon metabolism, and amino acid metabolism, indicating that energy metabolism plays a crucial role in the occurrence and progression of HF. Targeted metabolomics validated the findings from untargeted metabolomics: compared with Stage A, the level of phosphoenolpyruvate in Stage B was reduced; and in comparison with patients in Stage A or B, patients in Stage C showed decreased serum levels of multiple energy metabolites (e.g., glucose-6-phosphate, fructose-6-phosphate, 3-phosphoglyceric acid, AMP, ADP and ATP) as well as increased levels of malic acid, which is consistent with the characteristics of the "hypermetabolism-energy starvation" paradox. CONCLUSION: Stage C of heart failure is characterized by energy metabolism collapse (decreased ATP and TCA compensation), and differential metabolites (such as malic acid) may serve as potential candidate biomarkers pending longitudinal validation.

Humans↗

PubMed2026

Integrated transcriptomic and metabolomic analyses provide new insights into the response of black rockfish (Sebastes schlegelii) larvae to temperature fluctuations.

Sebastes schlegelii usually encounter elevated and fluctuating water temperatures near its upper thermal limit in summer, yet the hepatic responses of larvae to repeated temperature fluctuation regimes remain unclear. To address this question, S. schlegelii larvae were exposed for 8 days to four thermal regimes: constant 18 °C (CT), constant 28 °C (HT), intermittent cooling from 18 to 8 °C followed by recovery to 18 °C (FL), and intermittent warming from 18 to 28 °C followed by recovery to 18 °C (FH). Survival rate was evaluated, and integrated liver transcriptomic and metabolomic analyses were performed. Final survival rates were 96.67% in the CT group, 97.78% in the FL group, and 77.78% in the FH group. Survival rate in the HT group (38.89%) was significantly lower than that in the other three groups (P < 0.05). HTvsCT, FLvsCT, FHvsCT, and FHvsHT comparisons identified 2598, 1207, 622, and 2404 differentially expressed genes and 627, 606, 690, and 610 differential metabolites, respectively. KEGG enrichment analyses of DEGs and SDMs in HTvsCT highlighted HSP-mediated proteostasis, endoplasmic-reticulum protein processing, branched-chain and sulfur amino acid metabolism, glutathione metabolism, and central carbon metabolism, with upregulated hsp90aa1, bckdha, gclc, and pfkp and reduced levels of branched-chain amino acids and methionine. Compared with HT, FH showed attenuated disturbances in proteostasis, amino acid and redox regulation, and central carbon metabolism, together with recovery-associated glycerophospholipid turnover. FL primarily induced polyunsaturated fatty acid (PUFA)-related membrane lipid remodeling. These findings indicate that hepatic responses differed between continuous high-temperature exposure and temperature fluctuations and between fluctuation regimes.

Animals↗