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63 papers

Physical Activity and Metabolic Alterations in Children and Adolescents Across Different Weight Groups: A Systematic Review.

Leppänen MH et al. · Jul 1, 2026

Inadequate physical activity (PA) and increased sedentary time are key drivers of cardiometabolic disorders related to being overweight, and metabolomics offers a promising novel approach to study their associations. The aim of this systematic review was to assess the evidence on metabolites associated with PA and/or sedentary time among children and adolescents in different weight groups, integrating both intervention and observational studies to provide a comprehensive and broad synthesis of existing evidence. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, three databases (PubMed, Web of Science, and Scopus) were systematically searched for studies published from inception to December 2023 conducted in children and adolescents aged ≤ 18 years including metabolomics analyses focusing on PA, sedentary time, or cardiorespiratory fitness. Fifteen studies were included, and half of the studies were conducted in overweight individuals. Notable PA-induced or PA-associated alterations were seen in lipid, branched-chain amino acid and ammonia metabolism, and the citric acid and glucose-alanine cycles. The directions of the alterations seemed consistent across children and adolescents with normal body weight and overweight, but not in trained peers. Several metabolites and metabolite groups were identified as markers of higher PA and better cardiorespiratory fitness, reflecting favorable metabolic states in children and adolescents. However, there is still a great need for more in-depth metabolomics studies using state-of-the-art techniques in the fields of pediatric exercise science and public health. Training status, exercise modalities, and pubertal development are important covariates to consider in future studies.

Biochemistry, Genetics and Molecular Biology

Magel2 deficiency promotes cardiac remodeling and increases arrhythmogenic susceptibility in a mouse model relevant to Prader-Willi and Schaaf-Yang syndromes.

Dötsch L et al. · Jul 1, 2026

Prader-Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS) share overlapping phenotypic features, but potential cardiac involvement in both conditions remains poorly understood. Here, we investigated cardiac function in Magel2 knockout (KO) mice, a model relevant to PWS and SYS, to assess the impact of Magel2 deficiency on the heart. Echocardiographic analysis of 20-week-old Magel2-KO mice revealed concentric remodeling of the left ventricle together with reduced left ventricular end-diastolic volume and stroke volume, as well as a modest but significant reduction in ejection fraction. Electrophysiological studies identified sex-dependent alterations, particularly in males, characterized by shortened action potential duration and increased atrial potassium currents. Surface electrocardiography recordings showed no overt arrhythmias and visual inspection confirmed sinus rhythm during the monitoring period; however, the observed cellular alterations indicate increased arrhythmogenic susceptibility. In addition, aged Magel2-KO mice developed adult-onset obesity and exhibited elevated HbA1c levels consistent with impaired glycemic control. Given the minimal expression of Magel2 in cardiac tissue, these findings suggest that systemic and metabolic alterations may contribute to the observed cardiac phenotype. Together, these results demonstrate structural cardiac remodeling and electrophysiological changes consistent with increased arrhythmogenic susceptibility in Magel2-deficient mice, suggesting clinically relevant cardiac involvement in SYS and PWS. Our findings support consideration of structured cardiovascular monitoring to mitigate potential secondary cardiac complications in affected individuals.

Biochemistry, Genetics and Molecular Biology

Diacylglycerol enantiomer selectivity of diacylglycerol acyltransferases highlights metabolic specialization in triacylglycerol synthesis across the tree of life.

Parchuri P et al. · Jul 1, 2026

Triacylglycerols are the major energy storage lipids in plants, animals, and microorganisms, and are predominantly produced by acyl-CoA:diacylglycerol (DAG) acyltransferases (DGATs). Two enantiomers of the DAG substrate, sn-1,2 and sn-2,3, can be produced by different biological mechanisms; however, little is known about which species produce each enantiomer, the selectivity of DGAT isoforms for either enantiomer, or whether DGAT enantiomer selectivity varies across organisms. Here, DAG enantiomer selectivity of DGAT1 and DGAT2 was measured from eight seed plants, two mammals, one oleaginous yeast, and one photosynthetic microalga using enantiomer-specific in vitro DGAT assays. Across most plants, DGAT1 favored sn-1,2-DAG, whereas DGAT2 preferentially utilized sn-2,3-DAG. However, there were several exceptions. Mammalian DGAT1, DGAT2, and microbial DGAT1s efficiently used both DAG enantiomers, while microbial DGAT2s had unique selectivity. The selectivity of several DGATs for combined acyl-CoA and DAG enantiomer molecular species were also evaluated for biotechnical applications. Therefore, DGAT DAG enantiomer selectivity is common yet strongly dependent on lineage and isoform and likely shaped in part by species-specific metabolic context of triacylglycerol synthesis, turnover, and remodeling. This work expands our understanding of DGAT function and establishes a foundation for leveraging enantiomer-selective acyltransferases in metabolic engineering of tailored lipid products.

Biochemistry, Genetics and Molecular Biology

Fusion protein condensate formation via coiled-coil domains.

Narayan OP et al. · Jul 1, 2026

While recent research shows that biomolecular condensates play important roles in normal cellular processes and diseases, the driving forces in condensate formation are not well understood, especially regarding the role of structured self-associative protein domains. In this work, we study the contribution of a model structured domain, coiled-coil domain, in promoting condensate formation of fusion proteins (FPs). Starting from a large set of ~50,000 FPs, we systematically narrowed down to investigate 14 FPs and their corresponding 18 coiled-coil domains. We showed that all 14 FPs are capable of assembling condensates with high potency. When isolated from the rest of the protein contexts, 11 of the 18 coiled-coil domains can induce condensation on their own, despite their short length compared to their full-length counterparts. To understand the differences between coiled-coils that can drive condensate formation and those that cannot, we developed a "triad-extension" model and found the condensate-sufficient coiled-coil domains have a higher propensity to extend beyond perfectly end-to-end matched dimer/oligomer to promote condensate formation.

Biochemistry, Genetics and Molecular Biology

Cellular Heterogeneity During Arterial Aging.

Xu H et al. · Jul 1, 2026

Arterial aging is a major risk factor for cardiovascular disease and is associated with progressive changes in vascular structure and function, including arterial stiffening, reduced elasticity, extracellular matrix remodeling, chronic low-grade inflammation, and accumulation of senescence-associated cell states. Recent advances in single-cell RNA sequencing (scRNA-seq) have provided new opportunities to resolve the cellular heterogeneity underlying these age-related alterations in the arterial wall. In this review, we summarize current single-cell studies of arterial aging by focusing first on key phenotypic programs, including cellular senescence, extracellular matrix remodeling, inflammaging, and altered intercellular communication, and then discuss how these programs are reflected in endothelial cells, smooth muscle cells, fibroblasts, and immune cells. Across studies, aging is recurrently associated with endothelial dysfunction, smooth muscle cell phenotypic modulation, fibroblast-related matrix remodeling, and immune activation, although the degree of conservation varies depending on species, vascular bed, sex, and disease context. We further discuss emerging evidence that vascular aging involves not only cell-intrinsic transcriptional changes but also alterations in communication networks across the arterial wall. Although current single-cell studies have substantially improved our understanding of arterial aging, important limitations remain, including inconsistent cell-state annotation across studies, incomplete functional validation, and limited spatial and epigenetic resolution. Future integration of cross-species analyses with spatial transcriptomics, single-cell epigenomic approaches, and functional studies will help refine the cellular framework of arterial aging and improve its translational relevance.

Biochemistry, Genetics and Molecular Biology

Detection of a Target Nucleic Acid by Ligation-Assisted Fluorescence Enhancement of a Peptide Nucleic Acid (PNA) Twin Probe via Disulfide Binding.

Ouchi Y et al. · Jul 1, 2026

The development of methods for detecting specific nucleic acids is important for early diagnosis and treatment of diseases at the genetic level. We have developed a pair of pyrene (Pyr)-modified peptide nucleic acids (PNAs), PNA twin probe, as a tool for such detection. In this study, we prepared Pyr-PNAs containing chloroacetyl (-COCH 2 Cl) or thiol (-SH) groups at the termini by solid-phase peptide synthesis. By analyzing various candidates, we clarified that a pair of Pyr-PNAs, each containing an SH group, formed a disulfide bond through the hybrid formation of two PNAs with complementary DNA, resulting in excimer emission at 455 nm. Furthermore, we demonstrated that these Pyr-PNAs provide fluorescent detection of intracellular target RNAs through enhanced excimer emission via the ligation. This work should aid future studies aimed at the specific fluorescent detection of RNA in living cells.

Biochemistry, Genetics and Molecular Biology

Human umbilical cord mesenchymal stromal cell-derived exosomes from MSCs pretreated with inflammatory factors attenuate renal injury of diabetic mice by regulating macrophage polarization.

Li C et al. · Jul 1, 2026

Diabetic nephropathy (DN), a major complication of diabetes mellitus (DM), is characterized by severe clinical manifestations, impaired quality of life, and a high risk of progression to end-stage renal disease, underscoring the urgent need for effective therapeutic interventions. Mesenchymal stromal cell-derived exosomes (MSC-Exo) have emerged as promising candidates for mitigating inflammatory injury in DN due to their immunomodulatory properties, and exosomes derived from MSCs pretreated with inflammatory factors such as TNF-α and IFN-γ may possess enhanced therapeutic potential. In this study, exosomes isolated from human umbilical cord MSCs were characterized by transmission electron microscopy, nanoparticle tracking analysis, and western blotting. Their therapeutic effects were evaluated in diabetic mice, focusing on renal inflammation and macrophage polarization. Both normal MSC-Exo (Norm-Exo) and TNF-α&IFN-γ-pretreated MSC-Exo (TNF-α&IFN-γ-Exo) effectively ameliorated kidney injury and promoted M2 macrophage polarization, with TNF-α&IFN-γ-Exo showing superior efficacy. High-glucose-stimulated RAW264.7 cells were used to explore the underlying mechanisms, and high-throughput RNA sequencing identified inhibitor of DNA binding 3 (ID3) as a molecule involved in MSC-Exo-regulated macrophage polarization. Loss-of-function experiments confirmed that ID3 knockdown alone recapitulated the effects of exosomes, promoting M2 polarization and suppressing M1 markers. Conversely, ID3 overexpression attenuated exosome efficacy. Mechanistically, ID3 partially mediated exosome-induced inhibition of the NF-κB pathway. The translational relevance of these findings was further validated in PMA-differentiated THP-1 human macrophages. Collectively, these findings demonstrate that MSC-Exo-particularly TNF-α&IFN-γ-Exo-attenuate diabetic renal injury by modulating macrophage polarization through ID3 regulation, highlighting a novel cell-free immunomodulatory approach for DN therapy.

Biochemistry, Genetics and Molecular Biology

UPLC-QTOF-MS/MS and Antifungal Activity of a Fraction Enriched in Saponins From Sarcomphalus joazeiro Against Candida spp.

da Silva ARP et al. · Jul 1, 2026

The development of antifungal resistance is a complex process that involves the interaction between hosts, drugs, and microbial factors, all of which contribute to therapeutic ineffectiveness. For this reason, studies on natural products as possible therapeutic alternatives are increasingly necessary in order to gain a better understanding of plant compounds that may be more effective in treating infections caused by fungal pathogens. In this context, this study aimed to investigate the antifungal potential of the saponin-enriched fraction of the Sarcomphalus joazeiro species against the Candida albicans, Candida tropicalis, and Candida krusei strains. The selection of this species for study is due to its rich phytochemical composition and the vast traditional knowledge of its medicinal properties. The fraction obtained from the stem bark of S. joazeiro was analyzed by UPLC-QTOF-MS/MS, in which compounds such as triterpenoids, flavonoids, acids, and saponins were identified. Therefore, the results obtained in this study contribute to understanding the antifungal potential of the S. joazeiro species fraction against fungal infections, especially those caused by Candida spp.

Biochemistry, Genetics and Molecular Biology

Integrating Functional Consequence Annotation With PAH Allelic Phenotype Values Refines Prediction of Tetrahydrobiopterin Responsiveness.

Himmelreich N et al. · Jul 1, 2026

Tetrahydrobiopterin (BH4; sapropterin) responsiveness in phenylalanine hydroxylase (PAH) deficiency is genotype dependent, yet many patients remain untested. Allelic phenotype values (APV) summarize allele severity, but responsiveness can be heterogeneous within APV strata. We assessed whether integrating functional consequence annotation from Ensembl variant effect predictor (VEP) improves genotype-based prediction of BH4 response. We analyzed 23 640 individuals with biallelic PAH genotypes and BH4 status (RESP, S-RESP, N-RESP, or not tested). Tested individuals were used for model development (responders defined as RESP+S-RESP; nonresponders as N-RESP). APV values were assigned from published APV resources and merged at the variant level. Functional consequence predictors were derived from VEP output and included strict predicted loss-of-function (pLoF) flags, splice-impact scores (SpliceAI maximum delta score), and missense pathogenicity predictions (SIFT and PolyPhen). Genotype predictors were constructed using a milder-versus-severer allele framework, with the milder allele defined as the allele with the higher APV. Models were evaluated using genotype-held-out cross-validation (GroupKFold by genotype). Among 4640 tested individuals, 2044 (44.1%) were BH4 responders. Responder rates were enriched in milder phenotypes and increased monotonically across milder-allele APV bins. In genotype-held-out evaluation, integrating functional consequence predictors with APV improved discrimination modestly overall and more clearly in intermediate APV genotypes. Genotype predicts BH4 responsiveness with high performance under stringent genotype-held-out validation, and VEP-derived functional consequence annotation provides modest complementary value beyond APV, particularly for intermediate-severity genotypes.

Biochemistry, Genetics and Molecular Biology

Synthesis, Characterization, Antioxidant Evaluation, Cytotoxicity Studies, and Molecular Docking of Novel Sulfonamide Derivatives.

Bouraoui O et al. · Jul 1, 2026

A series of novel sulfonamide derivatives (4a-i) was synthesized via a three-step sequence involving Schiff base formation, sodium borohydride reduction to the corresponding secondary amines (2a-i), and subsequent treatment with p-toluenesulfonyl chloride in the presence of sodium carbonate. The structures of all intermediates and final products were unambiguously confirmed by FT-IR, 1 H NMR, 13 C NMR, and HRMS analyses. The antioxidant activity of the target compounds was assessed using the DPPH radical scavenging assay with BHT as a reference standard. Among the synthesized derivatives, compound 4d exhibited the most pronounced antioxidant activity, surpassing BHT at concentrations of 37.5 and 62.5 µg/mL. The cytotoxicity of the compounds was evaluated against human ovarian carcinoma (A2780) and prostate cancer (LNCaP) cell lines using the MTT assay, with docetaxel as a positive control. Compounds 4g, 4h, and 4i demonstrated the highest cytotoxic potency against both cell lines, with compound 4h displaying a log IC 50 value of 1.343 µg/mL against LNCaP cells. Structure-activity relationship analysis suggests that the methoxy substituent enhances cytotoxic activity, likely through increased lipophilicity and electron-donating effects facilitating interactions with biological targets. Molecular docking studies were performed to further rationalize the observed biological activities.

Biochemistry, Genetics and Molecular Biology