Search Results (683)

Carboxypeptidase A4 (CPA4) is an exopeptidase that cleaves peptide bonds at the C-terminal domain within peptides and proteins. It preferentially cleaves peptides with terminal aromatic or branched chain amino acid residues such as phenylalanine, tryptophan, or leucine. CPA4 was first discovered in prostate cancer cells, but it is now known to be expressed in various tissues throughout the body. Its physiologic expression is governed by latexin, a noncompetitive endogenous inhibitor of CPA4. Nevertheless, the overexpression of CPA4 has been associated with the progression and aggressiveness of many malignancies, including prostate, pancreatic, breast and lung cancer, to name a few. CPA4’s role in cancer has been attributed to its disruption of many cellular signaling pathways, e.g., PI3K-AKT-mTOR, STAT3-ERK, AKT-cMyc, GPCR, and estrogen signaling. The dysregulation of these pathways by CPA4 could be responsible for inducing epithelial--mesenchymal transition (EMT), tumor invasion and drug resistance. Although CPA4 has been found to regulate cancer aggressiveness and poor prognosis, no comprehensive review summarizing the role of CPA4 in cancer is available so far. In this review, we provide a brief description of peptidases, their classification, history of CPA4, mechanism of action of CPA4 as a peptidase, its expression in various tissues, including cancers, its role in various tumor types, the associated molecular pathways and cellular processes. We further discuss the limitations of current literature linking CPA4 to cancers and challenges that prevent using CPA4 as a biomarker for cancer aggressiveness and predicting drug response and highlight a number of future strategies that can help to overcome the limitations. Full article

Understanding the metabolic characteristics of pineapple varieties is crucial for market expansion and diversity. This study performed comparative metabolomic analysis on the “Comte de Paris” (BL) and three Taiwan-introduced varieties: “Tainong No. 11” (XS), “Tainong No. 23” (MG), and “Tainong No. 13” (DM). A total of 551 metabolites were identified across the four varieties, with 231 metabolites exhibiting no significant differences between all varieties. This included major sugars such as sucrose, glucose, and fructose, as well as key acids like citric, malic, and quinic acids, indicating that the in-season maturing fruits of different pineapple varieties can all achieve good sugar–acid accumulation under suitable conditions. The differentially accumulated metabolites (DAMs) that were identified among the four varieties all primarily belonged to several major subclasses, including phenolic acids, flavonoids, amino acids and derivatives, and alkaloids, but the preferentially accumulated metabolites in each variety varied greatly. Specifically, branched-chain amino acids (L-leucine, L-isoleucine, and L-valine) and many DAMs in the flavonoid, phenolic acid, lignan, and coumarin categories were most abundant in MG, which might contribute to its distinct and enriched flavor and nutritional value. XS, meanwhile, exhibited a notable accumulation of aromatic amino acids (L-phenylalanine, L-tryptophan), various phenolic acids, and many lignans and coumarins, which may be related to its unique flavor profile. In DM, the dominant accumulation of jasmonic acid might contribute to its greater adaptability to low temperatures during autumn and winter, allowing off-season fruits to maintain good quality. The main cultivar BL exhibited the highest accumulation of L-ascorbic acid and many relatively abundant flavonoids, making it a good choice for antioxidant benefits. These findings offer valuable insights for promoting different varieties and advancing metabolome-based pineapple improvement programs. Full article

Type 10 17β-hydroxysteroid dehydrogenase (17β-HSD10) is the HSD17B10 gene product. It plays an appreciable part in the carcinogenesis and pathogenesis of neurodegeneration, such as Alzheimer’s disease and infantile neurodegeneration. This mitochondrial, homo-tetrameric protein is a central hub in various metabolic pathways, e.g., branched-chain amino acid degradation and neurosteroid metabolism. It can bind to other proteins carrying out diverse physiological functions, e.g., tRNA maturation. It has also previously been proposed to be an Aβ-binding alcohol dehydrogenase (ABAD) or endoplasmic reticulum-associated Aβ-binding protein (ERAB), although those reports are controversial due to data analyses. For example, the reported k_m value of some substrate of ABAD/ERAB was five times higher than its natural solubility in the assay employed to measure k_m. Regarding any reported “one-site competitive inhibition” of ABAD/ERAB by Aβ, the k_i value estimations were likely impacted by non-physiological concentrations of 2-octanol at high concentrations of vehicle DMSO and, therefore, are likely artefactual. Certain data associated with ABAD/ERAB were found not reproducible, and multiple experimental approaches were undertaken under non-physiological conditions. In contrast, 17β-HSD10 studies prompted a conclusion that Aβ inhibited 17β-HSD10 activity, thus harming brain cells, replacing a prior supposition that “ABAD” mediates Aβ neurotoxicity. Furthermore, it is critical to find answers to the question as to why elevated levels of 17β-HSD10, in addition to Aβ and phosphorylated Tau, are present in the brains of AD patients and mouse AD models. Addressing this question will likely prompt better approaches to develop treatments for Alzheimer’s disease. Full article

This pilot, randomized, double-blind, placebo-controlled trial investigated the effects of branched-chain amino acids (BCAAs)—provided in a 2:1:1 ratio of leucine:isoleucine:valine—combined with exercise on fatigue, physical performance, and quality of life in older adults. Twenty participants (63% female; BMI: 35 ± 2 kg/m²; age: 70.5 ± 1.2 years) were randomized to 8 weeks of either exercise + BCAAs (100 mg/kg body weight/d) or exercise + placebo. The program included moderate aerobic and resistance training three times weekly. Physical function was assessed using handgrip strength, chair stands, gait speed, VO₂ max, and a 400 m walk. Psychological health was evaluated using the CES-D, Fatigue Assessment Scale (FAS), Insomnia Severity Index (ISI), and global pain, fatigue, and quality of life using a visual analog scale (VAS). Significant group x time interactions were found for handgrip strength (p = 0.03), chair stands (p < 0.01), and 400 m walk time (p < 0.01). Compared to exercise + placebo, exercise + BCAAs showed greater improvements in strength, mobility, and endurance, along with reductions in fatigue (−45% vs. +92%) and depressive symptoms (−29% vs. +5%). Time effects were also observed for ISI (−30%), FAS (−21%), and VAS quality of life (16%) following exercise + BCAA supplementation. These preliminary results suggest that BCAAs combined with exercise may be an effective way to improve physical performance and reduce fatigue and depressive symptoms in older adults. Full article

Childhood obesity is a major global health problem, and its management involves a multidisciplinary approach that includes lifestyle changes, dietary interventions, and the use of dietary supplements. In this review, we summarize current findings on the role of amino acids in pediatric obesity, with a particular focus on their involvement in metabolic pathways and weight regulation. The involvement of branched-chain and aromatic amino acids in the pathophysiology and potential management of pediatric obesity is highlighted in recent studies. Both experimental and clinical studies have shown that obese children often exhibit altered plasma amino acid profiles, including increased levels of leucine, isoleucine, valine, phenylalanine, and tyrosine, as well as decreased levels of glycine and serine. These imbalances are correlated with insulin resistance, inflammation, and early metabolic dysfunction. One of the mechanisms through which branched-chain amino acids can promote insulin resistance is the activation of the mammalian target of rapamycin (mTOR) signaling pathway. Metabolomic profiling has demonstrated the potential of specific amino acid patterns to predict obesity-related complications before they become clinically evident. Early identification of these biomarkers could be of great help for individualized interventions. Although clinical studies indicate that changes in dietary amino acids could lead to modest weight loss, improved metabolic profiles, and increased satiety, further studies are needed to establish standardized recommendations. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra, resulting in motor symptoms such as bradykinesia, tremor, rigidity, and postural instability, as well as a wide variety of non-motor manifestations. Branched-chain amino acids (BCAAs)—leucine, isoleucine, and valine—are essential nutrients involved in neurotransmitter synthesis, energy metabolism, and cellular signaling. Emerging evidence suggests that BCAA metabolism is intricately linked to the pathophysiology of PD. Dysregulation of BCAA levels has been associated with energy metabolism, mitochondrial dysfunction, oxidative stress, neuroinflammation, and altered neurotransmission. Furthermore, the branched-chain ketoacid dehydrogenase kinase (BCKDK), a key regulator of BCAA catabolism, has been implicated in PD through its role in modulating neuronal energetics and redox homeostasis. In this review, we synthesize current molecular, genetic, microbiome, and clinical evidence on BCAA dysregulation in PD to provide an integrative perspective on the BCAA–PD axis and highlight directions for future translational research. We explored the dualistic role of BCAAs as both potential neuroprotective agents and metabolic stressors, and critically examined the therapeutic prospects and limitations of BCAA supplementation and BCKDK targeting. Full article

Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, treats type 2 diabetes by blocking renal glucose reabsorption and promoting urinary glucose excretion. This mechanism lowers blood glucose concentrations independently of insulin. The resulting caloric loss also contributes to weight reduction. Although these effects are well documented in patients with diabetes, their magnitude and underlying mechanisms in healthy individuals remain poorly understood. Background/Objectives: We investigated metabolic alterations after a single 10 mg dose of dapagliflozin in healthy adults with normal body-mass indices (BMIs) using untargeted metabolomics. Methods: Thirteen healthy volunteers completed this study. Plasma was collected before and 24 h after dosing. Untargeted metabolic profiling was performed with ultra-high-performance liquid chromatography–quadrupole time-of-flight/mass spectrometry. Results: Twenty-five endogenous metabolites were annotated; ten were putatively identified. Eight metabolites increased significantly, whereas two decreased. Up-regulated metabolites included phosphatidylcholine (PC) species (PC O-36:5, PC 36:3), phosphatidylserine (PS) species (PS 40:2, PS 40:3, PS 36:1, PS 40:4), lysophosphatidylserine 22:1, and uridine. Dehydroepiandrosterone sulfate and bilirubin were down-regulated. According to the Human Metabolome Database, these metabolites participate in glycerophospholipid, branched-chain amino acid, pyrimidine, and steroid-hormone metabolism. Conclusions: Dapagliflozin may affect pathways related to energy metabolism and homeostasis beyond glucose regulation. These data provide a reference for future investigations into energy balance and metabolic flexibility in metabolic disorders. Full article

This study addresses the challenge of chitosan (CS) being difficult to dissolve in water due to its highly ordered crystalline structure. Chitosan is modified with chloroacetic acid to reduce its crystallinity and enhance its water solubility. Through single-factor experiments, the optimal conditions for preparing carboxymethyl chitosan film (CMCS) were determined: under conditions of 50 °C, a cellulose substrate (CS) concentration of 18.75 g/L, a NaOH concentration of 112.5 g/L, and a chloroacetic acid concentration of 18.75 g/L, the reaction proceeded for 5 h. Under these conditions, the resulting carboxymethyl chitosan film exhibited the best flocculation effect, forming chitosan films in water that had flocculation activity toward mung bean starch protein wastewater. The successful introduction of carboxyl groups at the N and O positions of the chitosan molecular chain, which reduced the crystallinity of chitosan and enhanced its water solubility, was confirmed through analysis using scanning electron microscopy (SEM), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). The prepared carboxymethyl chitosan film (CMCS) was applied in the flocculation recovery of protein. Through single-factor and response surface experiments, the optimal process conditions for flocculating and recovering protein with CMCS were determined: a CMCS dosage of 1.1 g/L, a reaction time of 39.6 min, a reaction temperature of 42.7 °C, and a pH of 5.2. Under these conditions, the protein recovery rate reached 56.97%. The composition and amino acid profile of the flocculated product were analyzed, revealing that the mung bean protein flocculated product contained 62.33% crude protein. The total essential amino acids (EAAs) accounted for 52.91%, non-essential amino acids (NEAAs) for 47.09%, hydrophobic amino acids for 39.56%, and hydrophilic amino acids for 12.67%. The ratio of aromatic to branched-chain amino acids was 0.31, and the ratio of basic to acidic amino acids was 1.68. These findings indicate that the recovered product has high surface activity and good protein stability, foaming ability, and emulsifying properties. Full article

Background: Exfoliation glaucoma (XFG) represents a form of deleterious ocular aging of unclear etiology. We evaluated prediagnostic nuclear magnetic resonance (NMR)-based metabolites in relation to XFG risk, expanding on our prior findings of XFG-related metabotypes using liquid chromatography-mass spectrometry (LC-MS). Methods: We identified 217 XFG cases and 217 matched controls nested within three prospective health professional cohorts with plasma collected a mean 11.8 years before case identification. Plasma metabolites were analyzed using the targeted NMR Nightingale platform. Conditional logistic models and Metabolite Set Enrichment Analysis were performed. Multiple comparison issues were addressed using the number of effective tests (NEF) and false discovery rate (FDR). Results: Among 235 profiled metabolites, higher glucose was significantly associated with a lower risk of XFG (odds ratio (95%CI) = 0.42 (0.26, 0.7); NEF = 0.03). Among metabolite classes, lipoprotein subclasses and branched-chain amino acids were inversely associated, while relative lipoprotein lipid concentrations were adversely associated (FDR < 0.05). Conclusion: NMR profiling revealed that glucose, branched-chain amino acids, lipoprotein subclasses, and relative lipoprotein lipid concentrations may play important roles in XFG etiology. Full article

Equine asthma is a chronic respiratory disease characterised by neutrophilic inflammation, airway hyperresponsiveness, and impaired pulmonary function. Obesity, increasingly prevalent among domestic horses, has been identified as a potential risk factor for exacerbating inflammatory conditions. This study aimed to explore whether obesity modifies neutrophil metabolism and inflammatory responses in horses affected by asthma. Six asthmatic horses in clinical remission were categorised into two groups: obese and non-obese, based on body condition score. Serum levels of interleukin-1β (IL-1β) and peripheral blood neutrophil counts were significantly higher in obese horses, indicating a heightened systemic inflammatory state. Neutrophils from obese horses displayed a stronger oxidative burst following zymosan stimulation and elevated IL-1β gene expression in response to lipopolysaccharide, suggesting a hyperinflammatory phenotype. Metabolomic profiling of neutrophils identified 139 metabolites, with notable differences in fatty acids, branched-chain amino acids, and tricarboxylic acid (TCA) cycle intermediates. Pathway enrichment analysis revealed significant alterations in fatty acid biosynthesis, amino acid metabolism, and glutathione-related pathways. Elevated levels of itaconate, citraconic acid, and citrate in obese horses indicate profound metabolic reprogramming within neutrophils. These results suggest that obesity promotes a distinct neutrophil phenotype marked by increased metabolic activity and heightened responsiveness to inflammatory stimuli. This altered profile may contribute to the persistence or worsening of airway inflammation in asthmatic horses. The findings underscore the importance of addressing obesity in the clinical management of equine asthma and open avenues for further research into metabolic-targeted therapies in veterinary medicine. Full article

This review examines human digestive physiology and metabolic adaptations in the context of evolutionary dietary patterns, particularly those emphasizing carnivorous and scavenging behaviors. By integrating metabolomic data with archaeological, anatomical, and microbiological evidence, the study explores how early hominins adapted to intermittent but energy-dense animal-based diets. The analysis highlights the development of hepatic insulin resistance, enhanced fat and protein metabolism, and shifts in gut microbiota diversity as physiological signatures of meat consumption. Comparative evaluations of digestive enzyme profiles, intestinal morphology, and salivary composition underscore humans’ omnivorous flexibility and partial carnivorous specialization. Additionally, biomarkers such as ketone bodies, branched-chain amino acids, and trimethylamine-N-oxide are identified as metabolic indicators of habitual meat intake. These adaptations, though once evolutionarily advantageous, are discussed in relation to current metabolic disorders in modern nutritional contexts. Overall, this review presents a metabolomic framework for understanding the evolutionary trajectory of human digestion and its implications for health and dietary recommendations. Full article

Background: Pulmonary arterial hypertension (PAH) is a rare and severe condition characterized by increased pulmonary arterial pressure and vascular resistance. Women are more susceptible to PAH yet have higher survival rates than men, a phenomenon called the “estrogen paradox”. This study aims to investigate the sex-based differences in PAH using plasma untargeted metabolomics. Methods: Plasma samples were collected from 43 PAH patients and 37 healthy controls. The samples were analyzed using two complementary analytical techniques: gas chromatography–mass spectrometry (GC-QqQ/MS) and liquid chromatography–mass spectrometry (LC-Q-ToF/MS). The metabolic differences between male and female PAH patients and controls were identified using multivariate statistical analyses. Results: Our results show changes in the lipid, fatty acid, and amino acid metabolism in both sexes. Women presented additional changes in the carbohydrate, bile acid, and nucleotide metabolism. The metabolites affected by PAH in women included decreased threonine, tryptophan, and lipid intermediates and elevated bile acids. Men were found to have additional changes in the heme catabolism, cholesterol synthesis, and lipoxygenase pathways. The metabolites affected by PAH in men included decreased branched-chain amino acids and increased bilirubin, phospholipids, and oxidized fatty acids. Conclusions: The gender differences observed in the development of PAH are likely multifactorial. While estrogens and potentially other sex hormones have been implicated in modulating relevant biological pathways, their exact role in disease progression and pathogenesis remains to be fully elucidated. The specific metabolic changes in women and men point to distinct disease mechanisms, potentially explaining the differences in prevalence, prognosis, and treatment response of patients with PAH. The obtained results should be validated with the use of targeted quantitative analyses and larger numbers of patients. Full article

Background: Childhood and adolescent obesity often coexist with micronutrient deficiencies and metabolic alterations, particularly in marginalized communities. Objectives: This cross-sectional study evaluated the biochemical, anthropometric, and dietary characteristics of 55 children and adolescents (ages 4–13) from Tlaltizapán, Mexico, to identify the early metabolic risk factors associated with excess weight. Methods: Nutritional intake was assessed through six-day dietary recalls and analyzed for adequacy against the national reference values. Anthropometric and biochemical indicators—including the BMI-for-age Z-score, waist-to-height ratio (WHtR), lipid profile, and plasma amino acid levels—were stratified by age and weight status. Results: Overall, 36.4% of participants were overweight or obese. Alarmingly, 89.4% of children and 94.1% of adolescents had low HDL levels, regardless of their BMIs. Several participants with a normal BMI showed elevated WHtR, triceps skinfold, and plasma branched-chain amino acids, suggesting hidden metabolic risks. The dietary analysis revealed an excess intake of sugars, proteins, and fats, alongside insufficient fiber, vitamins, and minerals. The adolescents had poorer adherence to dietary recommendations than children. Conclusions: These findings underscore the limitations of BMI alone and support the use of WHtR, skinfolds, and biochemical markers to detect preclinical obesity. Urgent, targeted nutritional strategies are needed in semi-rural areas to address the double burden of obesity and undernutrition. Full article

Background/Objectives: Diabetic kidney disease (DKD) is a major complication of type 2 diabetes mellitus (T2DM), and recent research highlights that amino acid composition—rather than total protein intake alone—may influence DKD risk. This study aimed to evaluate the associations between dietary protein intake, specific amino acid profiles, and the risk of DKD among adults with T2DM. Methods: A total of 378 T2DM patients were enrolled in this cross-sectional study. Dietary intake was assessed via a 24 h recall and a validated semi-quantitative food frequency questionnaire. Nutrient analysis was based on the Taiwanese Food Composition Database. Participants were categorized into three protein intake groups: Group 1 (≤0.8 g/kg), Group 2 (0.9–1.2 g/kg), and Group 3 (≥1.3 g/kg). Cox proportional hazards models were used to evaluate the associations of crude protein, branched-chain amino acids to aromatic amino acids (BCAA/AAA) ratio, and ketogenic amino acid intake with DKD risk. Adjustments were made for age, sex, diabetes duration, and blood pressure. Results: While crude protein intake showed no significant association with DKD risk, higher intake of ketogenic amino acids (e.g., leucine and lysine) was consistently and significantly associated with reduced DKD risk (adjusted HR range = 0.698–0.716, p < 0.01). Our findings highlight the protective potential of ketogenic amino acids such as leucine and lysine, which were significantly associated with lower DKD risk. The BCAA/AAA ratio also showed a downward trend in DKD risk, though not statistically significant. Kaplan–Meier analysis revealed that moderate protein intake (0.9–1.2 g/kg) corresponded to the most favorable DKD-free survival. Conclusions: Our findings suggest that, beyond total protein quantity, the intake of ketogenic amino acids may play a protective role in DKD prevention. Moderate protein consumption combined with higher leucine and lysine intake appears beneficial. These results support incorporating amino acid profiling in dietary strategies for DKD risk reduction. Further longitudinal and interventional studies are recommended to validate these associations. Full article

6-PPD quinone (6-PPDQ) is a derivative from 6-PPD, an antioxidant added in tires. Leucine is an important amino acid that needs to be obtained from the diet. In Caenorhabditis elegans, we examined the effect of 6-PPDQ exposure at environmentally relevant concentrations (ERCs) on the content of leucine and underlying mechanisms. In nematodes, 0.1–10 μg/L of 6-PPDQ decreased leucine content. The expression of the aat-1-encoding amino acid transmembrane transporter was decreased by 0.1–10 μg/L of 6-PPDQ, and leucine content was reduced by aat-1 RNAi. Meanwhile, the expression of bcat-1-encoding branched-chain amino acid transferase was increased by 0.1–10 μg/L of 6-PPDQ, and leucine content was increased by bcat-1 RNAi. Additionally, the expressions of dbt-1 and ivd-1 encoding two enzyme genes governing NADH and FADH₂ generations were decreased by 0.1–10 μg/L of 6-PPDQ, and their expressions in 6-PPDQ exposed nematodes were increased by bcat-1 RNAi. After 6-PPDQ exposure, NADH content was reduced by dbt-1 RNAi, and FADH₂ content was reduced by ivd-1 RNAi. Moreover, 6-PPDQ-induced mitochondrial dysfunction and other aspects of toxicity (such as intestinal ROS generation and lipofuscin accumulation, inhibited locomotion, and reduced brood size) were suppressed by bcat-1 RNAi and strengthened by dbt-1 and ivd-1 RNAi. The 6-PPDQ-induced toxicity and the decrease in dbt-1 and ivd-1 expressions could be inhibited by following leucine (5 mM) treatment. Our results demonstrate the important association of leucine adsorption and catabolism with 6-PPDQ toxicity induction. Full article