Search Results (792)

Background/Objectives: Prenatal exposure to famine can lead to lasting health effects through changes in DNA methylation. This study aims to evaluate the impact of prenatal exposure to the Chinses Great Famine (1959–1961) on human epigenome and the subsequent influence on blood lipids. Methods: We conducted an epigenome-wide association study (EWAS) of peripheral blood-based DNA methylation and prenatal exposure to the Chinese Great Famine as well as blood lipids among eight participants exposed to famine and eight sex-matched participants (born ≤ 3 years after the famine). Genome-wide DNA methylation sites were profiled using the Illumina EPIC BeadChip, which covers 850K methylation positions. Results: After EWAS analyses, seven probes in genes C8orf31, ELAVL1, U6, GBA2, SHOX2, SLC1A4, and NPHP4 reached p < 1 × 10⁻⁵. Of these, famine exposure was associated with decreased methylation levels of a GBA2 exonic probe cg08258661 (p = 4.9 × 10⁻⁶). After false discovery rate (FDR) correction, pathway enrichment analyses for genes harboring nominally significant (p < 0.05) probes identified 44 significant pathways (q < 0.05), and 5 pathways were related to lipid metabolism. After FDR correction in each pathway, probes cg02622866 (5’UTR of ATF2, p = 1.09 × 10⁻³), cg07316730 (body of GRB2, p = 1.32 × 10⁻³), and cg01105385 (body of PIK3R1, p = 1.94 × 10⁻³) in the PI2K-Akt signaling pathway were associated with blood LDL-C (q ≤ 0.04); probes cg09180702 (3’UTR of PIGQ, p = 9.21 × 10⁻⁵, and q = 0.04) and cg01421548 (body of HS3ST4, p = 5.23 × 10⁻⁵, and q = 0.01) in the metabolism pathway were associated with blood LDL-C and HDL-C, respectively; In addition, probe cg08460387 (5’UTR of MAN1C1, p = 1.09 × 10⁻⁴, and q = 0.02) in the vesicle-mediated transport pathway was associated with log-transformed blood triglycerides. Conclusions: Through an epigenetic study of the Chinese Great Famine, we identified six novel genes involved in lipid metabolism. Full article

Background/Objectives: Orofacial clefts (OFCs) are among the most common birth defects globally, sometimes exacerbated by adverse drug reactions (ADRs) from corticosteroids and antiepileptics. Comprehending the pharmacogenomic and pharmacogenetic elements that lead to ADRs is essential for enhancing precision medicine and clinical outcomes. This study examines rare genetic variants in drug-metabolizing and drug-transporting genes among Ghanaian and Nigerian families with a history of OFCs, intending to assess their pathogenicity and functional implications. Methods: We recruited 104 Ghanaian families and 26 Nigerian families, generating whole-genome sequencing (WGS) data from 390 individuals (130 case-parent trios). DNA isolated from saliva and buccal swab samples underwent WGS, and subsequent WGS data were analyzed through extensive bioinformatics analyses. Variants were called and annotated using the GATK workflow. The HOPE in silico modeling tool evaluated the structural impact of genetic variants on encoded proteins, while molecular docking using PyRx examined alterations in ligand binding affinity. Results: Our study revealed pathogenic variants in vital genes associated with drug metabolism and transport, specifically CYP1A2, CYP2C18, CYP27A1, CYP2B6, SLC6A2, and ABCC3. Structural modeling research demonstrated substantial size, charge, conformation, and hydrophobicity variations between wildtype and mutant proteins. Variants positioned near conserved regions or within functional domains were anticipated to be deleterious, potentially compromising protein function and ligand interactions. Molecular docking studies verified changes in binding affinities between wildtype and mutant proteins for common ligands. The identified variations were linked to the metabolism of frequently used pharmaceuticals in Africa, such as caffeine, ketoconazole, efavirenz, carbamazepine, and artemether. Conclusions: These findings highlight the need for pharmacogenetic screening to inform personalized medicine, diminish ADRs, and enhance the clinical care of OFCs in Sub-Saharan Africa. Full article

Background/Objectives: Metal transporter gene SLC39A8 and single nucleotide polymorphism (SNP) rs13107325 are associated with risk factors for atherosclerosis and cardiovascular disease (CVD). However, it is unclear how dietary manganese intake impacts CVD risk factors. The aim of this study was to use the UK Biobank population cohort (276,436 participants, Caucasian genetic ancestry, no genetic kinship) to investigate whether rs13107325 and dietary manganese are associated with CVD risk. Methods: A cross-sectional design and quantile (median) regression was used to determine associations of rs13107325 and dietary manganese intake with indicators of CVD risk. Results: SNP rs13107325 was associated with CVD risk factors, including greater body mass index (BMI) (beta ± SE per rs13107325 allele = 0.283 ± 0.0392, false discovery rate (FDR) < 10⁻¹⁰) and triglycerides (beta ± SE = 0.0308 ± 0.00761, FDR < 0.001) and reduced high density lipoprotein (HDL) (beta ± SE = −0.0298 ± 0.00343, FDR < 10⁻¹⁵). SNP rs13107325 was also associated with lower systolic (beta ± SE = −0.601 ± 0.172, FDR < 10⁻³) and diastolic blood pressure (beta ± SE = −0.531 ± 0.100, FDR < 10⁻⁵). Dietary manganese intake was positively correlated with measures of favorable cardiovascular health, such as lower BMI (beta ± SE per mg dietary manganese = −0.531 ± 0.0118, FDR < 10⁻³⁰⁰), reduced triglycerides (beta ± SE = −0.0451 ± 0.00229, FDR < 10⁻⁵⁰), increased HDL (beta ± SE = 0.00958 ± 0.00103, FDR < 10⁻¹⁵), and lower blood pressure (systolic beta ± SE = −0.529 ± 0.0520, FDR < 10⁻²⁰; diastolic beta ± SE = −0.562 ± 0.0302, FDR < 10⁻⁵⁰). Conclusions: The favorable associations of dietary manganese opposed many deleterious trends associated with rs13107325. Increased dietary manganese may promote cardiovascular health and offset many risks to cardiovascular health linked to SNP rs13107325. Full article

Background: Despite advances in gene-targeted and immunotherapies, many aggressive cancers—including glioblastoma and triple-negative breast cancer—remain refractory to treatment. Mounting evidence implicates metabolic reprogramming, especially dysregulation of glucose and glutamine metabolism, as a core hallmark of tumor progression. Natural compounds with metabolic-modulatory effects have emerged as promising adjuncts in oncology. Research Question and Objectives: This review investigates the following question: How can metabolic-targeted therapies—particularly those modulating the Warburg effect and glutamine metabolism—improve cancer treatment outcomes, and what role do natural compounds play in this strategy? The objectives were to (1) evaluate the therapeutic potential of metabolic interventions targeting glucose and glutamine metabolism, (2) assess natural compounds with metabolic regulatory activity, (3) examine integration of metabolic-targeted therapies with conventional treatments, and (4) identify metabolic vulnerabilities in resistant malignancies. Methods: A qualitative systematic review (QualSR) was conducted following PRISMA guidelines. A total of 87 peer-reviewed studies published between 2000 and 2024 were included. Inclusion criteria required clearly defined mechanistic or clinical endpoints and, for clinical trials, sample sizes ≥ 30. Data extraction focused on tumor response, survival, metabolic modulation, and safety profiles. Results: Curcumin significantly reduced serum TNF-α and IL-6 (both p = 0.001) and improved antioxidant capacity (p = 0.001). EGCG downregulated ERα (p = 0.002) and upregulated tumor suppressors p53 and p21 (p = 0.001, p = 0.02). High-dose intravenous vitamin C combined with chemoradiotherapy yielded a 44.4% pathologic complete response rate in rectal cancer. Berberine suppressed Akt/mTOR signaling and glutamine transporter SLC1A5 across tumor types (q < 10⁻¹⁰). However, poor bioavailability (e.g., EGCG t½ = 3.4 ± 0.3 h) and systemic toxicity limit their standalone clinical application. Conclusions: Metabolic-targeted therapies—particularly natural compounds acting on glucose and glutamine pathways—offer a viable adjunct to standard cancer therapies. Clinical translation will require biomarker-driven patient stratification, improved delivery systems, and combination trials to optimize the therapeutic impact in treatment-resistant cancers. Full article

This study investigates the effects of saline, alkaline, and combined saline–alkaline water environments on the growth, muscle quality, gene expression, and metabolic profiles of largemouth bass (Micropterus salmoides). Juvenile fish were exposed to five water conditions for 60 days: freshwater (FW), saline water (SW, 10 ppt), alkaline water (AW, 15 mmol/L), and two saline–alkaline combinations (SAW-1: 4 ppt + 10 mmol/L; SAW-2: 6 ppt + 15 mmol/L). While growth rate was similar across groups, SAW-2 caused a significant decrease in survival rate and induced notable alterations in muscle texture and fiber structure. Transcriptomic analyses revealed group-specific enrichment of stress-responsive pathways. The FoxO signaling pathway acts as a central regulator of muscle maintenance and energy reallocation. The solute carrier gene slc38a4 and glula (glutamine synthetase), both closely associated with ammonia detoxification via glutamine synthesis and transport, were upregulated under saline–alkaline stress, indicating enhanced capacity for nitrogen metabolism. In addition, two key regulators of muscle remodeling, loc119898415 and tbx18, were significantly upregulated, suggesting a potential chromatin–transcription program underlying compensatory myogenesis and muscle fiber adaptation in response to environmental challenges. Metabolomic profiling showed an accumulation of osmoprotectants (betaine, taurine) in SW and SAW-2 groups, suggesting enhanced stress resistance. Multiomics integration further indicated coordinated regulation between lipid metabolism and insulin signaling, potentially mediated by the FoxO pathway. These results offer practical guidance for improving largemouth bass aquaculture under inland saline–alkaline conditions. Full article

Objectives: Sen Ling Cao (SLC) is an excellent health food that has health-promoting functions, such as alleviating physical fatigue and boosting immune function. Currently, SLC is predominantly marketed and administered as an oral liquid, which suffers from the disadvantages of inconvenient transport and limited versatility. In this study, we investigated the preparation of direct compression (DC) tablets of SLC. Methods: Hydroxypropyl methylcellulose E3 (HPMC E3), polyvinylpyrrolidone K30 (PVP K30), hydroxypropyl cellulose EF (HPC EF), and maltodextrin (MD) were selected as modifying agents; and ammonium bicarbonate (NH₄HCO₃) and sodium bicarbonate (NaHCO₃) were employed as pore-forming agents. Co-spray drying was utilized to prepare 13 kinds of composite particles with different structures. Subsequently, their physical properties and compacting parameters were characterized comprehensively. Finally, the various composite particles were directly compacted into tablets to study the respective effects on the properties of DC tablets. Results: The results demonstrated that (i) the SLC composite particles have been successfully produced by co-spray drying, and processing involves physical changes; (ii) the tensile strength (TS) values of PCP-SLC-HPMC-NH₄HCO₃, PCP-SLC-PVP-NaHCO₃, PCP-SLC-HPC-NaHCO₃, and PCP-SLC-HPMC-NaHCO₃ were 9.8, 7.2, 8.3, and 7.7 times higher than that of SLC; (iii) all the modifiers studied could improve the DC properties of problematic SLC to some degree, and the combination of HPMC and NH₄HCO₃ showed to be the best to markedly improve both the compactibility and flowability of SLC. Conclusions: Overall, the design of porous composite particles, composite particles, and porous composite particles in this study successfully produced qualified tablets with high SLC loadings via DC. These findings are favorable for promoting the development and application of natural botanical tablets through DC. Full article

This study investigated the complexity of neurotransmitter-related gene regulation in peripheral blood mononuclear cells (PBMCs) of patients with obsessive–compulsive disorder (OCD), aiming to identify clinically relevant molecular markers. We analyzed three key genes: SLC6A4 (serotonin transporter), MAOB (monoamine oxidase B, a dopamine-degrading enzyme), and COMT (catechol-O-methyltransferase, a dopamine/norepinephrine metabolizing enzyme). OCD patients exhibited significant downregulation of SLC6A4 and MAOB, accompanied by upregulation of MB-COMT. The contrasting expression of MAOB and MB-COMT suggests a dysregulated compensatory mechanism in dopamine homeostasis, which contributes to clinical heterogeneity and variability in treatment for OCD. Epigenetic analysis revealed that downregulation of SLC6A4 was associated with hypermethylation of the gene promoter, demonstrating the critical role of epigenetic mechanisms in neurotransmitter system dysregulation. Moreover, gene–gene correlations identified distinctive molecular expression patterns that reliably discriminated OCD patients from healthy individuals, proposing their potential as peripheral biomarkers. In conclusion, serotonergic and dopaminergic abnormalities characterize OCD, where epigenetic regulation contributes to gene dysregulation. The identified molecular signatures may explain the inefficiency of treatments and support biomarker-guided clinical approaches. Given that peripheral gene regulation and core neurotransmitter systems are similar, this study contributes to the biological picture of OCD, indicating the accuracy of diagnoses and treatments. Full article

Thyroid hormones (THs) are essential for brain development, and their dysregulation is associated with cognitive deficits and neurodevelopmental disorders. Down syndrome (DS), caused by trisomy 21, is frequently associated with thyroid dysfunction and impaired neurogenesis. Here, we investigated THs signaling dynamics during neural differentiation using human induced pluripotent stem cells (hiPSCs) derived from individuals with DS and controls. We analyzed the gene expression of key THs regulators—deiodinases, transporters, and receptors—and downstream target genes in hiPSCs, hiPSC-derived neural progenitor cells (NPCs), hiPSC-derived astrocytes, and hiPSC-derived neurons. DS-derived hiPSCs, hiPSC-derived NPCs, and hiPSC-derived neurons exhibited 2- to 7-fold increases in the gene expression of DIO2 and 3- to 8-fold reductions in DIO3, alongside 1- to 3-fold downregulation of THRA and THRB isoforms. hiPSC-derived astrocytes showed a 4-fold decrease in the gene expression of DIO2, a 4-fold increase in DIO3, upregulation of SLC16A10 (2-fold), and downregulation of SLC7A5 (0.5-fold) and THs receptors (0.5- to 12-fold). hiPSC-derived neurons exhibited marked downregulation of the gene expression of HOMER1 (0.5-fold), GRIN3A (14-fold), and GRIN3B (4-fold), accompanied by impaired spontaneous activity in multi-electrode array recordings. These findings reveal a robust, cell-type-specific imbalance between THs availability and signaling competence in DS hiPSC-derived neural cells, providing mechanistic insight into THs-related contributions to the function of DS hiPSC-derived neural cells and identifying potential therapeutic targets. Full article

The impact of maternal dietary restriction and hydroxytyrosol (HT) supplementation during the last third of gestation on plasma malondialdehyde (MDA) concentration, total antioxidant capacity (ABTS assay), and peripheral blood gene expression related to antioxidant defence, immune response, and energy metabolism was evaluated in beef cows and calves. Two feeding treatments in late gestation (T100% vs. T60% of nutrient requirements) and two HT levels (Control vs. HT at 180 mg/kg of diet) were evaluated during gestation (n = 46 cows) and lactation (n = 37 cows and calves). In pregnant cows, undernutrition led to inhibition of glucose oxidation (PDK4), decreased lipid synthesis (HMGCS1 and SCD) and TLR signalling; T60% cows showed higher plasma MDA (p < 0.05) with no positive effect of HT on antioxidant capacity. Contrarily, during lactation, earlier HT supplementation upregulated antioxidant capacity and modulated antioxidant gene expression (p < 0.05). In calves, there was an increase in SOD1, CAT, and GPX1, especially in the T60%-HT group (p < 0.05). Interestingly, HT supplementation increased glucose transport (SLC2A1/GLUT1) during pregnancy and lactation (p < 0.05). However, it caused different effects on immunometabolic regulation in both dams and calves, depending on maternal diet. Overall, maternal HT supplementation under restricted nutritional conditions promoted postpartum antioxidant capacity and modulated immune and metabolic gene expression in cows and calves. Full article

Diabetes type 2 (DT2) entails significant health, economic, and productivity repercussions around the world. Poor glycaemic control, defined as an HbA1c >7.0%, has been associated with a number of complications. In spite of the large share of healthcare resources allocated to DT2 treatment, the proportion of controlled Mexican patients is among the lowest in the world (34.4%). Certain protein-encoding genetic polymorphisms involved in metformin transport may affect glycaemic control. We focused on determining the frequency of rs2289669, rs2252281, rs12943590, and rs34834489 polymorphisms in Mexican-Mestizo patients from the Tertiary Care Regional Hospital of Ixtapaluca, State of Mexico, Mexico, as well as assessing their possible association with therapeutic efficacy, as estimated through glycated haemoglobin. The individual polymorphism analysis did not reveal an association with glycaemic control; however, when combined with rs72552763 and rs622342, we found a significant positive correlation between HbA1c levels and metformin dose, which prevailed among patients carrying allelic variants of rs2289669 or rs12943590 who were also simultaneously carrying allelic variants of rs72552763 or rs622342. Patients carrying the reference allele of rs34834489 reported a significant positive correlation between HbA1c levels and metformin dose as well, regardless of their rs72552763 or rs622342 genotype. Thus, we identified alleles and allelic combinations of SLC47A1, SLC47A2, and SLC22A1 polymorphisms posing a potential glycaemic control risk in Mexican-Mestizo patients. Full article

Percocypris pingi was listed in the China Vertebrate Red List in 2015, and albino P. pingi exhibits remarkable ocular phenotypes due to melanin synthesis defects, including the deficiency of melanin granules in the iris and retinal pigment epithelium (RPE). However, the regulatory mechanism of pigment loss in the eyes of albino P. pingi has not yet been clarified. This study systematically revealed the potential mechanisms underlying the obstruction of ocular melanin synthesis in albino P. pingi through histopathological analysis, transcriptomics, and proteomics techniques. The results showed that the synergistic effects of abnormal H⁺ transport mediated by SLC45A2, excessive activation of retinol metabolism, and cytoskeletal transport disorders led to the inhibition of tyrosinase activity and retention of pigment granules, ultimately causing melanin deficiency in the eyes. This study first elucidates the molecular network of ocular albinism in fish from a multi-omics perspective, providing a new perspective for the mechanistic research of pigmentation disorders in vertebrates. Full article

Renal phosphate transporters NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3) play a crucial role in phosphate reabsorption in the proximal tubule. Biallelic loss-of-function variants in SLC34A1 and SLC34A3 cause two rare phosphate-wasting tubulopathies: idiopathic infantile hypercalcemia (IIH) and hereditary hypophosphatemic rickets with hypercalciuria, respectively. The phenotypes associated with these diseases are highly variable and sometimes overlap. Here, we report a rare case of a six-month-old girl of consanguineous parents with symptoms related to these diseases, including failure to thrive, nephrocalcinosis, hypercalcemia, hypophosphatemia with low TRP, elevated levels of 1,25-(OH)₂D₃, and suppressed PTH. An exome sequencing analysis was carried out to determine the genetic variants associated with her disease. Bioinformatics tools were used to assess variant pathogenicity. We identify a novel homozygous mutation in the SLC34A1 gene, c.1361C>T; p.(T454M), and a previously described heterozygous SLC34A3 101 bp deletion. Mutation p.(T454M) affects transmembrane domain 5 of the NaPi-IIa protein, which is involved in substrate binding, probably impairing phosphate transport. Our results suggest the diagnosis of IIH type 2 in our patient and highlight the importance of exome analysis in diagnosing these tubulopathies. We suggest that the coexistent heterozygous SLC34A3 deletion could increase the risk of renal calcifications and the severity of other symptoms. Full article

Pharmacotherapy in the geriatric population is one of the greatest challenges in modern medicine. Elderly patients, characterized by multimorbidity and the resulting polypharmacy, are significantly more exposed to adverse drug reactions (ADRs), which often lead to hospitalization and a decline in quality of life. Understanding the reasons for this difference requires an analysis of the physiological changes that occur during the aging process at the molecular level. This article presents a perspective on the molecular aspects of geriatric pharmacotherapy, focusing on the fundamental mechanisms that are modified with age. The analysis covers changes in pharmacokinetics, including the role and regulation of cytochrome P450 (CYP) enzymes, whose activity, especially in phase I reactions, is significantly reduced. The age-dependent dysfunction of drug transporters from the ABC (ATP-binding cassette) and SLC (solute carrier) families in key organs such as the intestines, liver and kidneys is discussed, which affects the absorption, distribution and elimination of xenobiotic compounds, including drugs. The article also provides a comprehensive analysis of the blood–brain barrier (BBB), describing changes in neurovascular integrity, including the dysfunction of tight junctions and a decrease in the activity of P-glycoprotein, sometimes referred to as multidrug resistance protein (MDR). This increases the susceptibility of the central nervous system to the penetration and action of drugs. In the realm of pharmacodynamics, changes in the density and sensitivity of key receptors (serotonergic, dopaminergic, adrenergic) are described based on neuroimaging data, explaining the molecular basis for increased sensitivity to certain drug classes, such as anticholinergics. The paper also explores new research perspectives, such as the role of the gut microbiome in modulating pharmacokinetics by influencing gene expression and the importance of pharmacoepigenetics, which dynamically regulates drug response throughout life via changes in DNA methylation and histone modifications. The clinical implications of these molecular changes are also discussed, emphasizing the potential of personalized medicine, including pharmacogenomics, in optimizing therapy and minimizing the risk of adverse reactions. Such an integrated approach, incorporating data from multiple fields (genomics, epigenomics, microbiomics) combined with a comprehensive geriatric assessment, appears to be the future of safe and effective pharmacotherapy in the aging population. Full article

SLC35A2-CDG is a congenital disorder of glycosylation caused by mutations in the SLC35A2 gene encoding a Golgi-localized UDP-galactose transporter. This transporter plays an essential role in glycan synthesis by transporting UDP-galactose from the cytoplasm into the Golgi lumen. Its dysfunction leads to impaired galactose-containing glycans and various neurological symptoms, although the underlying mechanisms remain largely unknown. We identified a novel SLC35A2-CDG patient carrying a pathogenic variant (c.617_620del, p.(Gln206ArgfsTer45)) who exhibited neurological abnormalities including bilateral ventriculomegaly. To investigate the disease mechanism, we established the first Drosophila model of SLC35A2-CDG. Knockout of Ugalt, the fly ortholog of SLC35A2, resulted in embryonic lethality, indicating its essential role. Knockdown of Ugalt reduced mucin-type O-glycans on muscles and neuromuscular junctions (NMJs), without affecting N-glycans. Ugalt knockdown larvae exhibited mislocalized NMJ boutons accompanied by a deficiency in basement membrane components on muscles. This phenotype resembles that of mutants of dC1GalT1 and dGlcAT-P, both involved in mucin-type O-glycosylation. Genetic interaction between Ugalt and dC1GalT1 was confirmed through double knockdown and double heterozygous analyses. Given that Drosophila NMJs are widely used as a model for mammalian central synapses, our findings suggest that Ugalt regulates NMJ architecture via mucin-type O-glycosylation and provide insights into the molecular basis of neurological abnormalities in SLC35A2-CDG. Full article

Solute carrier family 12 (SLC12) encodes electroneutral cation-coupled chloride cotransporters responsible for transmembrane ion transport (Na⁺, K⁺, and Cl⁻), which play a critical role in aquatic osmoregulation. However, the SLC12 gene of Exopalaemon carinicauda (EcSLC12) has not been systematically identified or functionally characterized. In this study, six EcSLC12 genes were identified across the genome and classified into N(K)CC, KCC, CCC9, and CIP subfamilies. Three NKCC1 homologous genes (EcSLC12A2.1, EcSLC12A2.2, and EcSLC12A2.3) were reported for the first time in crustaceans. The EcSLC12 family exhibited distinct expression patterns in response to low-salinity, high-alkalinity, and saline–alkaline stress. EcSLC12A2.2 was highly expressed in the gill, and its expression was closely correlated with saline–alkaline acclimation. Additionally, EcSLC12A2.2 knockdown decreased E. carinicauda survival under saline–alkaline stress. Thus, EcSLC12A2.2 plays critical roles in osmotic regulation and saline–alkaline acclimation. This study provides crucial insights into E. carinicauda’s saline–alkaline tolerance mechanisms, and the discovery of multiple NKCC1 homologs fills a gap in the crustacean SLC12 gene family research. Full article