Search Results (3,708)

Background: Cerebrotendinous Xanthomatosis (CTX) is a rare, inherited metabolic disease caused by pathogenic variants in CYP27A1. The clinical presentation of this progressive disease includes cognitive deficits, ataxia, peripheral neuropathy, and pyramidal signs, as well as bilateral cataracts and tendon xanthomas. In some cases, CTX also includes parkinsonism. The goals of this study are to develop a data source that provides improved characterization and awareness of parkinsonism in CTX. Methods: We conducted a systematic review of the literature according to PRISMA guidelines to identify all published individuals diagnosed with CTX and parkinsonism. Clinical signs, imaging findings and treatment response to both chenodeoxycholic acid and dopaminergic medications were examined for 72 subjects. Results: The average age of onset of parkinsonism in these CTX patients was 42 years, illustrating the early onset nature of parkinsonism in CTX. Functional dopaminergic imaging revealed the loss of presynaptic dopaminergic neurons in the substantia nigra which points to neurodegeneration of the dopaminergic system as the underlying pathophysiology for parkinsonism in CTX. Brain MRI showed abnormalities in the basal ganglia in 38% of subjects. MRI also showed abnormalities in the cerebellum in 88% of subjects which is typical for CTX and can be utilized to distinguish subjects with CTX and parkinsonism from individuals with other forms of atypical parkinsonism. Dopaminergic medication mitigated parkinsonism signs in most individuals with CTX. Conclusion: CTX is a neurometabolic disease that can result in levodopa-responsive parkinsonism that should be included in the differential for atypical parkinsonism. Full article

The functional components in cereals (rice and barley), such as gamma-aminobutyric acid (GABA), resistant starch (RS), and alkaloids, play crucial roles in human health, offering benefits such as improved cardiovascular function, enhanced gut microbiota, and potential anticancer properties. Rice (Oryza sativa) and barley (Hordeum vulgare) are key dietary staples with distinct genetic architectures influencing the biosynthesis and accumulation of these bioactive compounds. In this study, we explore the interaction and divergence of gene loci associated with GABA, RS, and alkaloid pathways in rice and barley, leveraging comparative genomics to identify conserved and species-specific regulatory mechanisms. We highlight key quantitative trait loci (QTLs) and candidate genes, such as GAD (glutamate decarboxylase) for GABA synthesis, SSIIa and GBSS for RS formation, and alkaloid biosynthesis genes including CYP80G2. Additionally, we discuss the health implications of these functional components, including their roles in reducing hypertension, managing diabetes, and exhibiting neuroprotective effects. Understanding the genetic differences between rice and barley in accumulating these compounds can guide biofortification strategies to enhance nutritional quality in cereal crops, ultimately benefiting human health and dietary outcomes. Full article

Microplastics (MPs) are a major contaminant in aquatic environments. Due to their size, they are likely to cause deleterious effects. In this study, we assessed the effects of MPs obtained from two commercially available plastics (PP and PET) in the polychaeta Hediste diversicolor after different periods (4 and 28 days). Toxic effects were assessed by measuring burrowing and spontaneous activities, phase I (CYP1A1, 1A2, and 3A4) activities), conjugation metabolism (GSTs), and antioxidant defense (CAT). Behavioral traits and phase I activities were nonresponsive to the presence of both plastics and for the two durations of exposure, indicating that these organisms are not affected by exposure to MPs and do not metabolize them. Conjugation metabolism was inhibited, which may be explained by the MPs’ capability of inhibiting certain enzymes. CAT activity was increased in animals acutely exposed to PP and decreased in animals chronically exposed to PET. This study shows that PP- and PET-MPs do not cause adverse effects on H. diversicolor. Full article

Perfluorooctanoic acid (PFOA) and its replacement, GenX, are per- and polyfluoroalkyl substances (PFASs) widely used in industrial and consumer applications. Pregnant women are a vulnerable population to environmental pollutants. The maternal effects of GenX and PFOA exposure during pregnancy have not been fully elucidated. In this study, pregnant mice received daily oral doses of GenX (2 mg/kg/day), PFOA (1 mg/kg/day), or Milli-Q water (control) throughout gestation. Histopathological analyses revealed significant liver abnormalities in both exposure groups, including hepatocyte swelling, cellular disarray, eosinophilic degeneration, karyopyknosis, lipid vacuolation, and increased inflammatory responses. Through transcriptomics analyses, it was found that multiple metabolic and inflammatory pathways were enriched in both exposure groups. In the GenX group, overexpression of CYP4A, c-Myc, and Oatp2 proteins and decreased expression of EGFR and β-catenin in the liver suggested disruption of lipid and bile acid metabolism. In the PFOA group, significantly upregulated protein levels of NLRP3, GSDMD, caspase-1, IL-18, and IL-1β indicated hepatic pyroptosis. Despite these distinct pathways, both compounds triggered inflammatory cytokine release in the liver, consistent with the results of the transcriptomics analysis, suggesting shared mechanisms of inflammatory liver injury. Taken together, our findings provided novel insights into the hepatotoxicity mechanisms of GenX and PFOA exposure during pregnancy, underscoring the potential health risks associated with PFAS exposure. Full article

The mineralocorticoid receptor (MR), traditionally associated with renal function, has also been identified in various extrarenal tissues, including the heart, brain, and dorsal root ganglion (DRG) neurons in rodents. Previous studies suggest a role for the MR in modulating peripheral nociception, with MR activation in rat DRG neurons by its endogenous ligand, aldosterone. This study aimed to determine whether MR, its protective enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), its endogenous ligand aldosterone, and the aldosterone-synthesizing enzyme CYP11B2 are expressed in human DRG neurons and whether they colocalize with key pain-associated signaling molecules as potential targets for genomic regulation. To this end, we performed mRNA transcript profiling and immunofluorescence confocal microscopy on human and rat DRG tissues. We detected mRNA transcripts for MR, 11β-HSD2, and CYP11B2 in human DRG, alongside transcripts for key thermosensitive and nociceptive markers such as TRPV1, the TTX-resistant sodium channel Nav1.8, and the neuropeptides CGRP and substance P (Tac1). Immunofluorescence analysis revealed substantial colocalization of MR with 11β-HSD2 and CGRP, a marker of unmyelinated C-fibers and thinly myelinated Aδ-fibers, in human DRG. MR immunoreactivity was primarily restricted to small- and medium-diameter neurons, with lower expression in large neurons (>70 µm). Similarly, aldosterone colocalized with CYP11B2 and MR with nociceptive markers including TRPV1, Nav1.8, and TrkA in human DRG. Importantly, functional studies demonstrated that prolonged intrathecal inhibition of aldosterone synthesis within rat DRG neurons, using an aldosterone synthase inhibitor significantly downregulated pain-associated molecules and led to sustained attenuation of inflammation-induced hyperalgesia. Together, these findings identify a conserved peripheral MR signaling axis in humans and highlight its potential as a novel target for pain modulation therapies. Full article

Estrogens are considered the most important risk factor for the development of breast cancer. Therefore, attempts are being made to reduce their level through diminished synthesis on one hand and to protect against the formation of DNA-damaging estrogen metabolites on the other. Cytochromes P450 (CYPs) play key roles in estrogen synthesis and catabolism, leading to potentially carcinogenic metabolites. CYP19 (aromatase) catalyzes the conversion of androgens to estrogens. The estrogen receptor-dependent pathway induces cell growth. CYP1 family enzymes, particularly CYP1B1, are involved in the redox cycling of estrogen metabolites and the subsequent estrogen–DNA adducts formation. Naturally occurring phytochemicals of different classes were shown to modulate the CYP expression and activity in cell-free systems or breast cancer cells. One of the most promising CYP19 inhibitors is chrysin (flavone), while stilbenes seem to be the most effective CYP1B1 inhibitors. In most cases, their effect is not specific. Therefore, different approaches are made to find the best candidate for the drug prototype of a new therapeutic or chemopreventive agent and to improve its pharmacokinetic parameters. This review presents and discusses the possible effects on major CYPs involved in estrogen metabolism by phytochemicals from the most investigated classes, namely flavonoids, stilbenes, and glucosinolates breakdown products. Full article

Origanum majorana L. (O. majorana) (Lamiaceae) is an aromatic Mediterranean plant widely used in food, cosmetics, and traditional medicine due to its aroma and rich content of bioactive compounds. While its leaves and flowers are commonly utilized, lignified stems are often discarded. This study compared hydroalcoholic extracts from the leaves and flowers (valuable fraction, VF) and stems (by-product, BP). Phytochemical analysis revealed qualitatively similar profiles, identifying 20 phenolic compounds, with Rosmarinic acid and Salvianolic acid B as the most and second most abundant, respectively. Antioxidant activity was evaluated in vitro using DPPH (IC₅₀ [µg/mL]: VF 30.11 ± 3.46; BP 31.72 ± 1.46), H₂O₂ (IC₅₀ [µg/mL]: VF 103.09 ± 4.97; BP 119.55 ± 10.58), and O₂^•− (IC₅₀ [µg/mL]: VF 0.71 ± 0.062; BP 0.79 ± 0.070). Both extracts (20 µg/mL) fully restored oxidative balance in hemin-stressed AC16 cardiomyocytes, without altering the expression of catalase, heme-oxygenase 1, superoxide dismutase 2, or ferritin. Anti-inflammatory activity in LPS-stimulated RAW 264.7 macrophages showed that VF (IC₅₀ 400 µg/mL) reduced ^•NO release to control levels, while BP achieved a ~60% reduction. Cytotoxicity was assessed on cancer cell lines: CaCo-2 (IC₅₀ [µg/mL]: VF 154.1 ± 6.22; BP 305.2 ± 15.94), MCF-7 (IC₅₀ [µg/mL]: VF 624.6 ± 10.27; BP 917.9 ± 9.87), and A549 (IC₅₀ [µg/mL]: VF 720.8 ± 13.66; BP 920.2 ± 16.79), with no cytotoxicity on normal fibroblasts HFF-1 (IC₅₀ > 1000 µg/mL for both extracts). Finally, both extracts slightly inhibited only CYP1A2 (IC₅₀ [µg/mL]: VF 497.45 ± 9.64; BP 719.72 ± 11.37) and CYP2D6 (IC₅₀ [µg/mL]: VF 637.15 ± 14.78, BP 588.70 ± 11.01). These results support the potential reuse of O. majorana stems as a sustainable source of bioactive compounds for nutraceutical and health-related applications. Full article

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent condition worldwide and represents a major global health challenge. Pharmacological and pharmacodynamic results indicate that aspirin eugenol ester (AEE) performs various pharmacological activities. However, it is unclear whether AEE can ameliorate the NAFLD. This study investigated the ameliorative effects of AEE on glucose and lipid metabolism disorders by in vitro and in vivo experiments. In the cellular model, TC increased to 0.104 μmol/mg and TG increased to 0.152 μmol/mg in the model group, while TC decreased to 0.043 μmol/mg and TG decreased to 0.058 μmol/mg in the AEE group. In the model group, the area occupied by lipid droplets within the visual field was significantly elevated to 17.338%. However, the administration of AEE resulted in a substantial reduction in this area to 10.064%. AEE significantly reduced the lipid droplet area and TC and TG levels (p < 0.05), increased bile acids in the cells and in the medium supernatant (p < 0.05), and significantly up-regulated the expression of LRH-1, PPARα, CYP7A1, and BSEP mRNA levels (p < 0.05) compared to the model group. In the animal model, different doses of AEE administration significantly down-regulated the levels of TC, TG, LDL, GSP, and FBG (p < 0.05) compared to the high-fat-diet (HFD) group, and 216 mg/kg of AEE significantly improved hepatocellular steatosis, attenuated liver injury, and reduced the area of glycogen staining (p < 0.05). In the HFD group, the glycogen area within the visual field exhibited a significant increase to 18.250%. However, the administration of AEE resulted in a notable reduction in the glycogen area to 13.314%. Liver and serum metabolomics results show that AEE can reverse the metabolite changes caused by a HFD. The major metabolites were involved in seven pathways, including riboflavin metabolism, glycerophospholipid metabolism, tryptophan metabolism, primary bile acid biosynthesis, biosynthesis of unsaturated fatty acids, nicotinate and nicotinamide metabolism, and tryptophan metabolism. In conclusion, AEE had a positive regulatory effect on NAFLD. Full article

Background and Clinical Significance: Gliomas diagnosed during pregnancy are rare, and there are no established guidelines for their management. Effective treatment requires a multidisciplinary approach to balance maternal health and pregnancy preservation. Case Presentation: We here present a case of rapidly progressing glioma in a 33-year-old pregnant woman. The patient initially presented with a generalized tonic–clonic seizure at 21 weeks’ gestation. Imaging revealed a tumor in the right cerebral lobe, involving both cortical and subcortical structures, while magnetic resonance spectroscopy suggested a low-grade glioma. The patient remained clinically stable for two months but then developed severe headaches; MRI showed a worsening mass effect. At 34 weeks’ gestation, an emergency and premature caesarean section was performed under general anesthesia. The patient then underwent a craniotomy for maximal tumor resection, which was histologically and molecularly diagnosed as IDH wild-type glioblastoma (GB). Using qPCR, we found that the GB tissue showed upregulated expression of genes involved in cell structure (GFAP, VIM) and immune response (SSP1, TSPO), as well as increased expression of genes related to potential hormone response (AR, CYP19A1, ESR1, GPER1). After surgery, the patient showed resistance to Stupp protocol therapy, which was substituted with lomustine and bevacizumab combination therapy. Conclusions: This case illustrates that glioma may progress rapidly during pregnancy, but a favorable obstetric outcome is achievable. Management of similar cases should respect both the need for timely treatment and the patient’s informed decision. Full article

Droughts are predicted to intensify with climate change, posing a serious threat to global crop production. Increasing drought tolerance in plants requires an understanding of the underlying mechanisms. This study measured the physiological, phytohormonal and transcriptomic responses to drought in two apple rootstocks to identify drought ‘biomarkers’ and investigated whether the application of acibenzolar-S-methyl (ASM) to the roots could enhance drought tolerance. Two potted-plant trials were conducted on dwarfing (M9) and semi-dwarfing (CG202) apple rootstocks. In both trials, the response patterns in the roots and leaves were compared between irrigated and non-irrigated plants over a 14-day period. In trial 2, ASM was applied 14 days before and immediately before withdrawing irrigation. Drought induced significant decreases in transpiration, photosynthesis and stomatal conductance in both trials. This was accompanied by the accumulation of abscisic acid (ABA) metabolites and the upregulation of ABA pathway transcripts (CYP707A1/A2 and NCED3), a decrease in 12-oxophytodienoic acid (cis-OPDA) and the downregulation of ABA receptor genes (PYL4). The responses to drought were greater in the roots than the leaves, broadly similar across both rootstocks, but differed in strength and timing between the rootstocks. The application of ASM to the roots did not significantly affect the responsiveness to drought in either rootstock. The identified phytohormonal and transcriptomic biomarkers require further validation across a broader range of genotypes. Full article

Background: Sirolimus (SRL, rapamycin) is a clinically important mTOR inhibitor used in immunosuppression, oncology, and cardiovascular drug-eluting devices. Despite its long-standing FDA approval, the human metabolic profile of SRL remains incompletely characterized. SRL is primarily metabolized by CYP3A enzymes in the liver and intestine, but the diversity, pharmacokinetics, and biological activity of its metabolites have been poorly explored due to the lack of structurally identified standards. Methods: To investigate SRL metabolism, we incubated SRL with pooled human liver microsomes (HLM) and isolated the resulting metabolites. Structural characterization was performed using high-resolution mass spectrometry (HRMS) and ion trap MSⁿ. We also applied Density Functional Theory (DFT) calculations to assess the energetic favorability of metabolic transformations and conducted molecular dynamics (MD) simulations to model metabolite interactions within the CYP3A4 active site. Results: We identified 21 unique SRL metabolites, classified into five major structural groups: O-demethylated, hydroxylated, didemethylated, di-hydroxylated, and mixed hydroxylated/demethylated derivatives. DFT analyses indicated that certain demethylation and hydroxylation reactions were energetically preferred, correlating with metabolite abundance. MD simulations further validated these findings by demonstrating the favorable orientation and accessibility of key sites within the CYP3A4 binding pocket. Conclusions: This study provides a comprehensive structural map of SRL metabolism, offering mechanistic insights into the formation of its metabolites. Our integrated approach of experimental and computational analyses lays the groundwork for future investigations into the pharmacodynamic and toxicodynamic effects of SRL metabolites on the mTOR pathway. Full article

Background/Objectives: Hypertension is a pathological condition characterized by elevated systolic and/or diastolic blood pressure. A range of pharmacotherapeutic agents are available to treat this condition and prevent complications, including the angiotensin II AT1-receptor blocker losartan. Following oral administration, losartan is exposed to a variety of enzymes that facilitate its metabolism or transportation. The structural characteristics of the genes that encode the enzymes may potentially impact the pharmacokinetics and pharmacodynamics of losartan, thereby modulating its effects on the treatment process. Methods: In this study, a computational model of losartan pharmacokinetics was developed, taking into account the influence of different alleles of the CYP2C9 gene, which plays a pivotal role in losartan metabolism, and the ABCB1 gene, which is responsible for losartan transport. Results: Alterations in the modeled activities of the enzymes encoded by CYP2C9 and ABCB1 result in changes in the losartan and its metabolite profiles that are consistent with known experimental data in real patients with different CYP2C9 and ABCB1 genotypes. Conclusions: The findings of the modeling can potentially be used to personalize drug therapy for arterial hypertension. Full article

The significant burden of polypharmacy in clinical settings contrasts sharply with the narrow research focus on drug–drug interactions (DDIs), revealing an important gap in understanding the complexity of real-world multi-drug regimens. The present study addresses this gap by conducting a high-resolution, multidimensional bibliometric and network analysis of 19,151 DDI publications indexed in the Web of Science Core Collection (1975–2025). Using advanced tools, including VOSviewer version 1.6.20, Bibliometrix 5.0.0, and AI-enhanced terminology normalization, global research trajectories, knowledge clusters, and collaborative dynamics were systematically mapped. The analysis revealed an exponential growth in publication volume (from 55 in 1990 to 1194 in 2024), with output led by the United States and a marked acceleration in Chinese contributions after 2015. Key pharmacological agents frequently implicated in DDI research included CYP450-dependent drugs such as statins, antiretrovirals, and central nervous system drugs. Thematic clusters evolved from mechanistic toxicity assessments to complex frameworks involving clinical risk management, oncology co-therapies, and pharmacokinetic modeling. The citation impact peaked at 3.93 per year in 2019, reflecting the increasing integration of DDI research into mainstream areas of pharmaceutical science. The findings highlight a shift toward addressing polypharmacy risks in aging populations, supported by novel computational methodologies. This comprehensive assessment offers insights for researchers and academics aiming to navigate the evolving scientific landscape of DDIs and underlines the need for more nuanced system-level approaches to interaction risk assessment. Future studies should aim to incorporate patient-level real-world data, expand bibliometric coverage to underrepresented regions and non-English literature, and integrate pharmacogenomic and time-dependent variables to enhance predictive models of interaction risk. Cross-validation of AI-based approaches against clinical outcomes and prospective cohort data are also needed to bridge the translational gap and support precision dosing in complex therapeutic regimens. Full article

Korean rockfish, Sebastes schlegeli, a coastal species, is vulnerable to pollutants such as microplastics and bacteria. While interactions between microplastics and other pollutants have been studied, little is known about microplastic and bacteria interactions. This study examined the effects of combined exposure to polystyrene microplastics in the form of microbeads (MB; 0.2 µm, 5 and 50 beads/L) and Streptococcus iniae (1 × 10⁵ and 1 × 10⁷ CFU/mL) for five days on oxidative stress and apoptosis in Korean rockfish. We assessed the mRNA expression and activity of oxidative stress markers (SOD, CAT, H₂O₂, NO, CYP1A1, GST), plasma LPO levels, and caspase-3 expression in liver tissue. Co-exposure to high MB and S. iniae concentrations significantly elevated oxidative stress and apoptosis markers, suggesting enhanced toxicity. This may result from MB facilitating pathogen transport into the fish, indicating microplastics can act as vectors for bacterial infection in aquatic environments. Full article

Background/Objectives: Polycystic ovary syndrome (PCOS) is a multifactorial disorder influenced by both environmental and genetic factors. The aim of this study was to evaluate associations between selected polymorphisms (CYP19, INSR, FTO, MC4R) and the clinical manifestations of PCOS in a Polish female population. Methods: A total of 50 women (25 with PCOS and 25 healthy controls) were included. Genetic variants were identified using Polymerase Chain Reaction (PCR)-based methods. The frequencies of genotypes and alleles were compared between groups. Clinical symptoms such as irregular menstruation, hirsutism, acne, androgenetic alopecia, and overweight were assessed in relation to genotype. Results: No significant differences were found in genotype distributions for CYP19, FTO, INSR, or MC4R between PCOS and control groups. The MC4R polymorphisms showed deviations from Hardy–Weinberg equilibrium, possibly reflecting population-specific effects. Conclusions: Although most analyzed variants were not directly associated with PCOS in this cohort, the observed link between INSR rs1799817 and acne suggests a role in androgen-related symptoms. These findings contribute new insights to the genetic background of PCOS in Polish women and support the need for further studies combining genetic and phenotypic data in diverse populations. Full article