Neuromolecular Med. 2025 Feb 27;27(1):18. doi: 10.1007/s12017-025-08840-6.

ABSTRACT

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common genetic form of stroke. It is caused by a cysteine-altering variant in one of the 34 epidermal growth factor-like repeat (EGFr) domains of Notch3. NOTCH3 pathogenic variants in EGFr 1-6 are associated with high disease severity, whereas those in EGFr 7-34 are associated with late stroke onset and increased survival. However, whether and how the position of the NOTCH3 variant directly affects the disease severity remains unclear. In this study, we aimed to generate human-induced pluripotent stem cells (hiPSCs) from patients with CADASIL with EGFr 1-6 and 7-34 pathogenic variants to evaluate whether the NOTCH3 position affects the cell phenotype and protein profile of the generated hiPSCs lines. Six hiPSCs lines were generated: two from patients with CADASIL with EGFr 1-6 pathogenic variants, two from patients with EGFr 7-34 variants, and two from controls. Notch3 aggregation and protein profiles were tested in the established six hiPSCs lines. Cell analysis revealed that the NOTCH3 variants did not limit the cell reprogramming efficiency. However, EGFr 1-6 variant position was associated with increased accumulation of Notch3 protein in pluripotent stem cells and proteomic changes related with cytoplasmic reorganization mechanisms. In conclusion, our analysis of hiPSCs derived from patients with CADASIL support the clinical association between the NOTCH3 variant position and severity of CADASIL.

PMID:40016442 | DOI:10.1007/s12017-025-08840-6

Chem Biol Interact. 2025 Feb 25:111448. doi: 10.1016/j.cbi.2025.111448. Online ahead of print.

ABSTRACT

A comprehensive understanding of isoniazid (INH)-mediated hepatotoxic effects is essential for developing strategies to predict and prevent severe liver toxicity in tuberculosis treatment. In this study, we used multi-omics profiling in vitro to investigate the toxic effects of INH, revealing significant involvement of endoplasmic reticulum (ER) stress, mitochondrial impairment, redox imbalance, and altered metabolism. Additional analysis using transcriptomics data from repeated time-course INH treatments on human-specific hepatic microtissues revealed that cellular responses to ER stress and oxidative stress happened prior to disturbances in mitochondrial complexes. Mechanistic validation studies using time-lapse measurements of cytosolic and mitochondrial reactive oxygen species (ROS) revealed that INH initially triggered cytosolic ROS increasement and Nrf2 signaling pathway activation before mitochondrial ROS accumulation. Molecular imaging showed that INH subsequently disrupted mitochondrial function by impairing respiratory complexes I-IV and caused mitochondrial membrane proton leakage without affecting mitochondrial complex V, leading to mitochondrial depolarization and reduced ATP production. These disturbances enhanced mitochondrial fission and mitophagy. Our findings highlight the potential of inhibiting ER stress during early INH exposure to mitigate cytosolic and mitochondrial oxidative stress. We also revealed the critical role of Nrf2 signaling in protecting hepatocytes under INH-induced oxidative stress by maintaining redox homeostasis and enabling metabolic reprogramming through regulating antioxidant gene expression and cellular lipid abundance. Alternative antioxidant pathways, including selenocompound metabolism, HIF-1 signaling, and the pentose phosphate pathway-also responded to INH-induced oxidative stress. Collectively, our study emphasizes the importance of ER stress, redox imbalance, metabolic changes, and mitochondrial dysfunction that underlie INH-induced hepatotoxicity.

PMID:40015660 | DOI:10.1016/j.cbi.2025.111448

Pharmacogenet Genomics. 2025 Apr 1;35(3):116-118. doi: 10.1097/FPC.0000000000000557. Epub 2024 Dec 19.

ABSTRACT

This short communication serves as an update to previously published pilot study results on bronchodilator response (BDR) in children with asthma. We expanded our cohort from 54 to 165 pediatric patients seeking emergency department care for an asthma exacerbation. We obtained measured BDR before and after albuterol administration using the Pediatric Asthma Severity Score and collected genomic DNA. Based on a literature review, we analyzed whether 21 candidate single-nucleotide polymorphisms (SNPs) were associated with BDR. Among the three SNPs initially reported in our pilot study as significantly associated with BDR (rs912142, rs7081864, and rs7903366), we confirmed that rs7081864 was still significantly associated with suboptimal BDR (odds ratio, 0.47; confidence interval, 0.24-0.92). If externally validated in broader studies, simple outpatient testing for that SNP variant could help guide pharmacologic therapy for acute asthma symptoms.

PMID:40014467 | DOI:10.1097/FPC.0000000000000557

Toxicol Res. 2024 Dec 21;41(2):123-129. doi: 10.1007/s43188-024-00271-y. eCollection 2025 Mar.

ABSTRACT

This review investigates the correlation between prenatal tobacco exposure and the risk of liver diseases in offspring. By synthesizing data from clinical trials and animal studies, it provides a comprehensive overview of the potential mechanisms underlying this association. This review begins by analyzing the prevalence of maternal smoking and its impact on fetal development. It then discusses specific liver diseases observed in offspring exposed prenatally to tobacco, such as acute liver injuries and metabolic dysfunction-associated fatty liver disease, and discusses the underlying pathophysiological pathways. Current evidence indicates that altered fetal liver development, oxidative stress, and genetic modifications may predispose offspring to liver diseases. Furthermore, this review highlights the gaps in current research and the need for longitudinal studies to better understand the long-term effects of prenatal tobacco exposure on the liver. The review concludes with recommendations for public health policies aimed at enhancing our understanding of maternal smoking and mitigating its adverse effects on offspring, emphasizing the importance of smoking cessation during pregnancy.

PMID:40013082 | PMC:PMC11850666 | DOI:10.1007/s43188-024-00271-y

J Transl Gastroenterol. 2024 Jun;2(2):125-130. doi: 10.14218/JTG.2024.00017. Epub 2024 Jun 28.

ABSTRACT

The brain-gut axis represents a bidirectional communication network that integrates neural, hormonal, and immunological signaling between the central nervous system and the gastrointestinal tract. Adverse childhood experiences (ACEs) have increasingly been recognized for their profound impact on this axis, with implications for both mental and physical health outcomes. This mini-review explores the emerging field of epigenomics-specifically, how epigenetic modifications incurred by ACEs can influence the brain-gut axis and contribute to the pathophysiology of various disorders. We examine the evidence linking epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNAs to the modulation of gene expression involved in stress responses, neurodevelopment, and immune function-all of which intersect at the brain-gut axis. Additionally, we discuss the emerging potential of the gut microbiome as both a target and mediator of epigenetic changes, further influencing brain-gut communication in the context of ACEs. The methodological and therapeutic challenges posed by these insights are significant. The reversibility of epigenetic marks and the long-term consequences of early life stress require innovative and comprehensive approaches to intervention. This underscores the need for comprehensive strategies encompassing psychosocial, pharmacological, neuromodulation, and lifestyle interventions tailored to address ACEs' individualized and persistent effects. Future directions call for a multi-disciplinary approach and longitudinal studies to uncover the full extent of ACEs' impact on epigenetic regulation and the brain-gut axis, with the goal of developing targeted therapies to mitigate the long-lasting effects on health.

PMID:40012740 | PMC:PMC11864786 | DOI:10.14218/JTG.2024.00017

J Cereb Blood Flow Metab. 2025 Feb 27:271678X251322032. doi: 10.1177/0271678X251322032. Online ahead of print.

ABSTRACT

The impact of DNA methylation (DNAm) on epigenetics has gained prominence in recent years due to its potential influence on ischemic stroke (IS) and treatment outcomes. DNAm is reversible and a better understanding of its role in IS could help identify novel therapeutic targets. The aim of this systematic review was to compile the available data on DNAm in the risk and prognosis of IS and to explore its therapeutic potential. The review process followed the PRISMA criteria. We searched the Pubmed and Cochrane databases to identify studies that used hypothesis free methodological approaches. Of the 459 studies identified, 34 met the inclusion criteria. The studies were categorized as follows: risk of IS; outcomes; and DNAm age. Most studies used genotyping array technology rather than whole-genome sequencing. DNAm testing was mainly based on blood samples. Most studies involved European cohorts. Most of the studies were performed at a single-center with recruitment at the time of stroke. In a few studies, health status was determined longitudinally. This systematic review shows that IS patients are biologically older than expected and present characteristic DNAm patterns related to stroke risk and outcomes. These patterns could be used to develop new treatments with epidrugs.

PMID:40012472 | DOI:10.1177/0271678X251322032

Nature. 2025 Feb 26. doi: 10.1038/s41586-025-08622-x. Online ahead of print.

ABSTRACT

Human accelerated regions (HARs) are conserved genomic loci that have experienced rapid nucleotide substitutions following the divergence from chimpanzees1,2. HARs are enriched in candidate regulatory regions near neurodevelopmental genes, suggesting their roles in gene regulation3. However, their target genes and functional contributions to human brain development remain largely uncharacterized. Here we elucidate the cis-regulatory functions of HARs in human and chimpanzee induced pluripotent stem (iPS) cell-induced excitatory neurons. Using genomic4 and chromatin looping information, we prioritized 20 HARs and their chimpanzee orthologues for functional characterization via single-cell CRISPR interference, and demonstrated their species-specific gene regulatory functions. Our findings reveal diverse functional outcomes of HAR-mediated cis-regulation in human neurons, including attenuated NPAS3 expression by altering the binding affinities of multiple transcription factors in HAR202 and maintaining iPS cell pluripotency and neuronal differentiation capacities through the upregulation of PUM2 by 2xHAR.319. Finally, we used prime editing to demonstrate differential enhancer activity caused by several HAR26;2xHAR.178 variants. In particular, we link one variant in HAR26;2xHAR.178 to elevated SOCS2 expression and increased neurite outgrowth in human neurons. Thus, our study sheds new light on the endogenous gene regulatory functions of HARs and their potential contribution to human brain evolution.

PMID:40011774 | DOI:10.1038/s41586-025-08622-x

Basic Clin Pharmacol Toxicol. 2025 Apr;136(4):e70013. doi: 10.1111/bcpt.70013.

ABSTRACT

The aim of the present study was to investigate the effect of CYP2D6 genotypes on mirtazapine and mianserin serum concentrations. Patients were included retrospectively from a therapeutic drug monitoring service. Multiple linear regression analysis was used to investigate the effect of CYP2D6 genotype, age and sex on mirtazapine and mianserin concentration-to-dose (C/D) ratio. The study included 2315 mirtazapine patients and 474 mianserin patients who were assigned to the genotype-predicted phenotype groups of CYP2D6 poor metabolizers (PMs), intermediate metabolizers (IMs), normal metabolizers (NMs) and ultrarapid metabolizers (UMs). Multiple linear regression analysis revealed 18% and 14% higher mirtazapine C/D ratio in CYP2D6 PMs and IMs, respectively, compared with NMs (p ≤ 0.004). For mianserin, the C/D ratio was 80% and 45% higher in PMs and IMs, respectively, compared with NMs (p < 0.001). The C/D ratio in UMs did not differ from NMs for either drug (p ≥ 0.3). In conclusion, CYP2D6 genotype was only associated with a minor change in mirtazapine serum concentration. The association between CYP2D6 genotype and mianserin serum concentration was greater, with 80% higher mianserin C/D ratio in CYP2D6 PMs compared with NMs.

PMID:40010695 | DOI:10.1111/bcpt.70013

Pharmaceutics. 2025 Jan 21;17(2):144. doi: 10.3390/pharmaceutics17020144.

ABSTRACT

Background/Objectives: Oxidative stress significantly impacts skin health, contributing to conditions like aging, pigmentation, and inflammatory disorders. Curcumin, with its potent antioxidant properties, faces challenges of low solubility, stability, and bioavailability. This study aimed to encapsulate curcumin in three lipid nanocarriers-solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), and nanoemulsions (NEs)-to enhance its stability, bioavailability, and antioxidant efficacy for potential therapeutic applications in oxidative-stress-related skin disorders. Methods: The lipid nanocarriers were characterized for size, polydispersity index, ζ-potential, and encapsulation efficiency. Stability tests under various conditions and antioxidant activity assays (DPPH and FRAP methods) were conducted. Cytotoxicity in human dermal fibroblasts was assessed using MTT assays, while the expression of key antioxidant genes was evaluated in human dermal fibroblasts under oxidative stress. Skin penetration studies were performed to analyze curcumin's distribution across the stratum corneum layers. Results: All nanocarriers demonstrated high encapsulation efficiency and stability over 90 days. NLCs exhibited superior long-term stability and enhanced skin penetration, while NE formulations facilitated rapid antioxidant effects. Antioxidant assays confirmed that curcumin encapsulation preserved and enhanced its bioactivity, particularly in NLCs. Gene expression analysis revealed upregulation of key antioxidant markers (GPX1, GPX4, SOD1, KEAP1, and NRF2) with curcumin-loaded nanocarriers under oxidative and non-oxidative conditions. Cytotoxicity studies confirmed biocompatibility across all formulations. Conclusions: Lipid nanocarriers effectively enhance curcumin's stability, antioxidant activity, and skin penetration, presenting a targeted strategy for managing oxidative stress in skin applications. Their versatility offers opportunities for tailored therapeutic formulations addressing specific skin conditions, from chronic disorders like psoriasis to acute stress responses such as sunburn.

PMID:40006512 | DOI:10.3390/pharmaceutics17020144

Pharmaceuticals (Basel). 2025 Feb 6;18(2):220. doi: 10.3390/ph18020220.

ABSTRACT

Background/Objectives: Pain management in colorectal cancer is influenced by genetic variability in opioid receptor genes (OPRM1 and OPRD1), potentially affecting opioid efficacy and adverse drug reactions (ADRs). This study evaluated the association of OPRM1 (rs1799971 and rs510769) and OPRD1 (rs2236861) polymorphisms with pain severity, opioid efficacy, and ADRs in Chilean colorectal cancer patients. Methods: The genotypes of OPRM1 and OPRD1 polymorphisms and clinical data from 69 colorectal cancer patients were analyzed. Associations between genotypes, ADRs, and pain severity (maximum Visual Analog Scale, VAS) were evaluated under inheritance models. Results: The OPRM1 rs1799971 G allele was significantly associated with pain presence (p = 0.008), while OPRD1 rs2236861 was linked to ADR risk (p = 0.042). Allelic distribution analysis revealed higher frequencies of the OPRD1 G allele and OPRM1 rs510769 T allele in patients with ADRs and pain, respectively. For OPRM1 rs510769, the dominant model showed a significant association with pain severity (p = 0.033), while the overdominant model revealed a trend toward significance (p = 0.0504). Logistic regression model tests showed no significant predictive associations for the maximum VAS or ADRs under inheritance models. Conclusions: Genetic variations in OPRM1 and OPRD1 may play a role in pain perception and ADRs in colorectal cancer patients. These findings contribute to the understanding of pharmacogenomic factors in opioid therapy, emphasizing the need for further research to validate the clinical utility of these genetic markers.

PMID:40006034 | DOI:10.3390/ph18020220

Pharmaceuticals (Basel). 2025 Jan 23;18(2):151. doi: 10.3390/ph18020151.

ABSTRACT

Background/Objectives: Pregabalin is a useful therapeutic option for patients with anxiety or neuropathic pain. Genetic variants in certain genes encoding for transporters related to absorption and distribution could have an impact on the efficacy and safety of the drug. Furthermore, extreme phenotypes in metabolic enzymes could alter pregabalin-limited metabolism. Methods: In this study, we included 24 healthy volunteers participating in a bioequivalence clinical trial and administered pregabalin 300 mg orally; 23 subjects were genotyped for 114 variants in 31 candidate genes, and we explored their impact on pregabalin pharmacokinetics and safety. Results: The uncorrected mean (±SD) of AUC∞ and Cmax were 61,097 ± 14,762 ng*h/mL and 7802 ± 1659 ng/mL, respectively, which were significantly higher in females than in males (p = 0.002 and p = 0.001, respectively), with no differences in dose/weight (DW)- corrected exposure metrics. NAT2 slow acetylators (SAs) showed a 16-18% increase in exposure compared to intermediate (IAs) and normal (NAs) acetylators; NAT2 SAs exhibited a 25% higher t1/2 as compared with NAT2 IAs and 58% higher compared to NAT2 NAs. In contrast, neither the NAT2 phenotype nor other genetic variants were related to pregabalin adverse drug reaction (ADR) occurrence. On the contrary, sex and sex-related exposure differences (i.e., females and their higher exposure compared to males) were the main predictors of ADR occurrence. Conclusions: Our findings suggest that NAT2 could be partially responsible for the minor proportion of pregabalin metabolism, but the effect of NAT2 phenotype does not seem clinically relevant. Therefore, pharmacogenetic biomarkers appear to play a restrained role in pregabalin pharmacotherapy.

PMID:40005966 | DOI:10.3390/ph18020151

Pathogens. 2025 Feb 3;14(2):140. doi: 10.3390/pathogens14020140.

ABSTRACT

Ovarian cancer (OC) remains the most lethal gynecologic malignancy with limited effective treatment options. Oncolytic viruses (OVs) have emerged as a promising therapeutic approach for cancer treatment, capable of selectively infecting and lysing cancer cells while stimulating anti-tumor immune responses. Preclinical studies have demonstrated significant tumor regression and prolonged survival in OC models using various OVs, such as herpes simplex. Early-phase clinical trials have shown a favorable safety profile, though the impact on patient survival has been modest. Current research focuses on combining OVs with other treatments like immune checkpoint inhibitors to enhance their efficacy. We provide a comprehensive overview of the current understanding and future directions for utilizing OVs in the management of OC.

PMID:40005517 | DOI:10.3390/pathogens14020140

Molecules. 2025 Feb 18;30(4):936. doi: 10.3390/molecules30040936.

ABSTRACT

Nasturtium officinale R. Br. (watercress) is an endangered species with valuable pharmaceutical, cosmetic, and nutritional properties. The purpose of this work was to evaluate the phytochemical profile and biological activity of extracts from microshoot cultures grown in PlantForm bioreactors and the parent plant material. After 20 days of cultivation, the cultures achieved the best results both in terms of key active ingredient content and biological activity. The glucosinolates (GSL) profile by the UHPLC-DAD-MS/MS method showed that the dominant compounds were glucobrassicin (493.00 mg/100 g DW, 10 days) and gluconasturtiin (268.04 mg/100 g DW, 20 days). The highest total polyphenol content (TPC) was obtained after a 20-day growth period (2690 mg GAE/100 g DW). Among polyphenols, the dominant compounds in the extracts from in vitro cultures were sinapinic acid (114.83 mg/100 g DW, 10 days) and ferulic acid (87.78 mg/100 g DW, 20 days). The highest antioxidant potential assessed by ABTS and DPPH assays was observed for ethanol extracts. The best results for inhibiting hyperpigmentation (18.12%) were obtained for ethanol extracts and anti-elastase activity (79.78%) for aqueous extract from N. officinale microshoot cultures. The extracts from microshoot cultures inhibited the growth of bacteria, including Cutibacterium acnes (MIC = 0.625 mg/mL). Antioxidant tests and the chelating capacity of iron ions Fe2+ of the face emulsion with N. officinale extracts showed higher results than the control.

PMID:40005247 | DOI:10.3390/molecules30040936

J Clin Med. 2025 Feb 17;14(4):1333. doi: 10.3390/jcm14041333.

ABSTRACT

Background: Uveal melanoma is the most common primary intraocular cancer in adults; however, it remains rare. Despite its rarity, metastatic uveal melanoma poses significant treatment challenges. Tebentafusp, a T-cell receptor-bispecific molecule targeting glycoprotein 100 and CD3, has shown substantial survival benefits for HLA-A*02:01 positive patients. A notable complication associated with tebentafusp and similar immunotherapies is cytokine release syndrome (CRS), occurring in nearly 90% of tebentafusp-treated patients. Although typically mild, severe CRS (grade 3) affects around 1% of patients. The unpredictable nature of CRS complicates patient management during treatment. Methods: Monitoring cytokine levels, as key indicators of inflammation, may therefore be crucial for understanding and managing CRS. Advanced proteomic technologies enable the simultaneous measurement of multiple cytokines, providing a comprehensive view of inflammatory responses. Results: In this case, a patient with metastatic uveal melanoma developed CRS after tebentafusp treatment. A proteomic analysis tracked the cytokine changes from baseline to post-treatment, revealing significant elevations in inflammatory markers. Conclusions: These findings suggest potential strategies for more personalized CRS management in similar therapies.

PMID:40004863 | DOI:10.3390/jcm14041333

Genes (Basel). 2025 Feb 11;16(2):213. doi: 10.3390/genes16020213.

ABSTRACT

CYP2C9 metabolizes approximately 20% of clinically administered drugs. Several single-nucleotide polymorphisms (SNPs) of CYP2C9 (e.g., *2, *3, *8, and rs12777823) are used as biomarkers to predict CYP2C9 activity. However, a large proportion of variability in CYP2C9 expression remains unexplained.

BACKGROUND/OBJECTIVES: We previously identified a variable number tandem repeat (pVNTR) polymorphism in the CYP2C9 promoter. The short repeat (pVNTR-S) showed reduced transcriptional activity in reporter gene assays and was associated with decreased CYP2C9 mRNA expression. However, because pVNTR-S is in high linkage disequilibrium (LD) with CYP2C9*3 in the European population, whether pVNTR-S directly impacts CYP2C9 expression remains unclear. The objective of this study was to clarify the association between the pVNTR-S and CYP2C9 mRNA expression in human liver samples and to assess its impact on CYP2C9 expression independently of known CYP2C9 biomarkers.

METHODS: Gene expression was measured by real-time qPCR. SNPs and pVNTRs were genotyped using SNapShot assays and fragment analysis, respectively. Associations between CYP2C9 and the pVNTR-S or SNPs were analyzed using multiple linear regression.

RESULTS: Our results showed that pVNTR-S was associated with lower CYP2C9 expression (34% reduction, p-value = 0.032) in human liver samples (n = 247), while the known CYP2C9 biomarkers (CYP2C9*2, *3, *8, or rs12777823) were not. These results suggest that pVNTR-S reduces CYP2C9 expression independently of known biomarkers. Therefore, pVNTR-S may explain additional variability in CYP2C9 expression when present alone or in conjunction with other CYP2C9 alleles.

PMID:40004542 | DOI:10.3390/genes16020213

Int J Mol Sci. 2025 Feb 19;26(4):1760. doi: 10.3390/ijms26041760.

ABSTRACT

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders influenced by microbial, environmental, genetic, and immune factors. The introduction of biological agents has transformed IBD therapy, improving symptoms, reducing complications, and enhancing patients' quality of life. However, approximately 30% of patients exhibit primary non-response, and 50% experience a loss of response over time. Genetic and non-genetic factors contribute to variability in treatment outcomes. This systematic review aims to thoroughly analyze and assess existing studies exploring the relationships between genetic variations and individual responses to biologic drugs, in order to identify genetic markers that are predictive of treatment efficacy, risk of adverse effects, or drug toxicity, thereby informing clinical practice and guiding future research. PubMed and EMBASE papers were reviewed by three independent reviewers according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses [PRISMA] guidelines. Of the 883 records screened, 99 met the inclusion criteria. The findings of this review represent an initial step toward personalized medicine in IBD, with the potential to improve clinical outcomes in biological therapy.

PMID:40004223 | DOI:10.3390/ijms26041760

Int J Mol Sci. 2025 Feb 19;26(4):1757. doi: 10.3390/ijms26041757.

ABSTRACT

The extracts from fruits of Chaenomeles japonica (Thunb.) Lindl. ex Spach (CJE), Cornus mas L. (CME), and Hippophaё rhamnoides L. (HRE) are known inhibitors of a variety of eukaryotic hydrolases, engaged in the digestion of fats and polysaccharides. However, there are no data on their potential interaction with the bacterial hydrolases participating in the replication of microbial nucleic acids. This analysis predicted the interaction of the most abundant constituents of HRE, CJE, and CME with the bacterial nucleases. The analysis covered the molecular docking of isorhamnetin glycosides, procyanidins C1 and B2, epicatechin, loganic acid, and cornuside with bacterial enzymes (Escherichia coli endonuclease 1, colicin E9, and ribonuclease H; or Staphylococcus aureus thermonuclease and nuclease SbcCD). The suggested complexes have been subjected to molecular mechanics with generalized Born and surface area solvation (MM/GBSA) calculations. The second aim was the in vitro evaluation of the influence of the CJE, HRE, and CME on the metabolic activity of bacterial biofilm of selected microbial strains, as well as fibroblasts (L929) and adenocarcinoma intestinal cells (Caco-2) toxicity. Among all extracts, CME showed the most relevant effect on the survival of planktonic cells and biofilm of E. coli and Pseudomonas aeruginosa. As a result of in silico studies, most virtual hits were predicted to inhibit the proteins under investigation, except for procyanidin C1. Further research on the direct interaction of phytochemicals and selected enzymes in vitro is required and challenged.

PMID:40004218 | DOI:10.3390/ijms26041757

Int J Mol Sci. 2025 Feb 13;26(4):1571. doi: 10.3390/ijms26041571.

ABSTRACT

(6S,9R)-vomifoliol (VO) is a natural norisoprenoid of the megastigmane type derived from Gaultheria procumbens, an aromatic, evergreen shrub whose leaves, fruits, and aerial parts are used in traditional phytotherapy to treat oxidative stress and inflammation-related disorders. The plant is known as a rich source of essential oil and polyphenols. However, the levels of other constituents of G. procumbens, including VO, have yet to be explored. There is also a knowledge gap in the pharmacological potential of VO in the context of inflammation. Therefore, the present study aimed to investigate the accumulation of VO in leaves, stems, and fruits of G. procumbens and to determine its antioxidant and anti-inflammatory effects in non-cellular in vitro and cell-based models of human immune cells ex vivo. The GC-FID-MS (gas chromatography coupled with flame ionisation detector and mass spectrometer) analysis revealed the leaves as the richest source of VO (0.36 mg/g dw of the plant material) compared to other G. procumbens organs. In non-cellular activity tests, VO showed comparable to positive control anti-inflammatory activity against lipoxygenase, with significantly weaker impact on hyaluronidase and cyclooxygenase-2, and no effect on cyclooxygenase-1 isozyme. VO at 5-75 μM revealed a significant and dose-dependent ability to reduce the reactive oxygen species (ROS) level, downregulate the release of pro-inflammatory cytokines [tumour necrosis factor-α (TNF-α), interleukin-8 (IL-8), IL-6, and IL-1β] and tissue-remodelling enzymes (elastase-2, metalloproteinase-9), and up-regulate the secretion of anti-inflammatory cytokine IL-10 in bacterial lipopolysaccharide (LPS)- and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP)-stimulated human neutrophils and peripheral blood mononuclear cells (PBMCs) ex vivo. Furthermore, a significant reduction in IL-6, lipoxygenase (LOX), nuclear factor κ-light-chain-enhancer of activated B cells 1 (NF-κB1), and NF-κB2 gene expression in LPS-stimulated peripheral blood lymphocytes was demonstrated by real-time PCR. The cellular safety of VO at 5-75 μM was confirmed by flow cytometry, with the viability of neutrophils and PBMCs after incubation with VO at 93.8-98.4%. The results encourage further studies of VO as a promising non-cytotoxic natural anti-inflammatory agent and support the use of leaves of G. procumbens in the adjuvant treatment of oxidative stress and inflammation-related diseases of affluence.

PMID:40004039 | DOI:10.3390/ijms26041571

Life (Basel). 2025 Jan 22;15(2):144. doi: 10.3390/life15020144.

ABSTRACT

Endometriosis afflicts 10% of women in their reproductive years and nearly half of women with infertility, and its etiology is not yet clear. Pharmacological therapy is generally based on progestins like progestogen. This drug binds to progesterone receptors with many known side effects. Here, we describe the case of a 33-year-old woman surgically treated for endometriosis who continued with drug therapy based on estradiol valerate and dienogest. Approximately 21 months after treatment, she reported ocular symptoms with vision alteration, diplopia, and metamorphopsia related to central serous chorioretinopathy (CSC). After the discontinuation of combined progestin-based treatment, the CSC fully subsided. Semeiological, clinical, and laboratory approaches were adopted, and urinary steroids were measured. A slight increase in prolactinemia in the absence of macro-prolactinemia was reported. The steroidal profile appeared without abnormalities, although a slight alteration of estrogen balance was noted. Considering the pharmacodynamics of dienogest versus selective progesterone receptor modulators, it can be assumed that patients' clinical events are related to specific site response to steroids that bind the progesterone receptor. Dienogest may have induced the CSC as a not yet characterized side effect of the drug. Undoubtedly, further specific studies are needed concerning the metabolic and pharmacodynamic aspects that cannot be exhaustively covered here.

PMID:40003553 | DOI:10.3390/life15020144

Biomedicines. 2025 Feb 12;13(2):447. doi: 10.3390/biomedicines13020447.

ABSTRACT

Type 2 diabetes (T2D) is the fastest-growing non-communicable disease worldwide, accounting for around 90% of all diabetes cases and imposing a significant health burden globally. Due to its phenotypic heterogeneity and composite genetic underpinnings, T2D requires a precision medicine approach personalized to individual molecular profiles, thereby shifting away from the traditional "one-size-fits-all" medical methods. This review advocates for a thorough pharmacomultiomics approach to enhance precision medicine for T2D. It emphasizes personalized treatment strategies that enhance treatment efficacy while minimizing adverse effects by integrating data from genomics, proteomics, metabolomics, transcriptomics, microbiomics, and epigenomics. We summarize key findings on candidate genes impacting diabetic medication responses and explore the potential of pharmacometabolomics in predicting drug efficacy. The role of pharmacoproteomics in prognosis and discovering new therapeutic targets is discussed, along with transcriptomics' contribution to understanding T2D pathophysiology. Additionally, pharmacomicrobiomics is explored to understand gut microbiota interactions with antidiabetic drugs. Emerging evidence on utilizing epigenomic profiles in improving drug efficacy and personalized treatment is also reviewed, illustrating their implications in personalized medicine. In this paper, we discuss the integration of these layers of omics data, examining recently developed paradigms that leverage complex data to deepen our understanding of diabetes. Such integrative approaches advance precision medicine strategies to tackle the disease by better understanding its complex biology.

PMID:40002860 | DOI:10.3390/biomedicines13020447