Front Pharmacol. 2025 Feb 11;16:1525029. doi: 10.3389/fphar.2025.1525029. eCollection 2025.

ABSTRACT

Computational drug repositioning, serving as an effective alternative to traditional drug discovery plays a key role in optimizing drug development. This approach can accelerate the development of new therapeutic options while reducing costs and mitigating risks. In this study, we propose a novel deep learning-based framework KGRDR containing multi-similarity integration and knowledge graph learning to predict potential drug-disease interactions. Specifically, a graph regularized approach is applied to integrate multiple drug and disease similarity information, which can effectively eliminate noise data and obtain integrated similarity features of drugs and diseases. Then, topological feature representations of drugs and diseases are learned from constructed biomedical knowledge graphs (KGs) which encompasses known drug-related and disease-related interactions. Next, the similarity features and topological features are fused by utilizing an attention-based feature fusion method. Finally, drug-disease associations are predicted using the graph convolutional network. Experimental results demonstrate that KGRDR achieves better performance when compared with the state-of-the-art drug-disease prediction methods. Moreover, case study results further validate the effectiveness of KGRDR in predicting novel drug-disease interactions.

PMID:40008124 | PMC:PMC11850324 | DOI:10.3389/fphar.2025.1525029

Heliyon. 2025 Feb 5;11(3):e42476. doi: 10.1016/j.heliyon.2025.e42476. eCollection 2025 Feb 15.

ABSTRACT

Predicting drug-target binding affinity via in silico methods is crucial in drug discovery. Traditional machine learning relies on manually engineered features from limited data, leading to suboptimal performance. In contrast, deep learning excels at extracting features from raw sequences but often overlooks essential biological context features, hindering effective binding prediction. Additionally, these models struggle to capture global and local feature distributions efficiently in protein sequences and drug SMILES. Previous state-of-the-art models, like transformers and graph-based approaches, face scalability and resource efficiency challenges. Transformers struggle with scalability, while graph-based methods have difficulty handling large datasets and complex molecular structures. In this paper, we introduce InceptionDTA, a novel drug-target binding affinity prediction model that leverages CharVec, an enhanced variant of Prot2Vec, to incorporate both biological context and categorical features into protein sequence encoding. InceptionDTA utilizes a multi-scale convolutional architecture based on the Inception network to capture features at various spatial resolutions, enabling the extraction of both local and global features from protein sequences and drug SMILES. We evaluate InceptionDTA across a range of benchmark datasets commonly used in drug-target binding affinity prediction. Our results demonstrate that InceptionDTA outperforms various sequence-based, transformer-based, and graph-based deep learning approaches across warm-start, refined, and cold-start splitting settings. In addition to using CharVec, which demonstrates greater accuracy in absolute predictions, InceptionDTA also includes a version that employs simple label encoding and excels in ranking and predicting relative binding affinities. This versatility highlights how InceptionDTA can effectively adapt to various predictive requirements. These results emphasize the promise of our approach in expediting drug repurposing initiatives, enabling the discovery of new drugs, and contributing to advancements in disease treatment.

PMID:40007773 | PMC:PMC11850134 | DOI:10.1016/j.heliyon.2025.e42476

Cell J. 2025 Feb 23;26(10):619-621. doi: 10.22074/cellj.2025.2037024.1635.

ABSTRACT

Endometriosis, a benign gynecological disorder affecting 10-15% of women during their reproductive years, is characterized by the growth of endometrial tissue outside the uterus. Despite its prevalence, the exact pathophysiology of this disease remains poorly understood. Current treatments, including surgery and hormonal therapies, often have limited efficacy and may be associated with significant side effects. In recent years, drug repurposing has emerged as a promising strategy for managing endometriosis. This approach capitalizes on the molecular similarities between endometriosis and certain cancers, particularly the role of proteins such as fibronectin. By targeting these shared molecular pathways, researchers are exploring the potential of repurposing existing drugs, especially anticancer agents, to treat endometriosis. This strategy promises to provide more effective and less invasive treatment options for patients with endometriosis. Preliminary studies have shown the potential of anticancer drugs in inhibiting disease progression and alleviating symptoms. However, further clinical trials are necessary to confirm these findings and establish the precise role of anticancer drugs in the management of endometriosis.

PMID:40007448 | DOI:10.22074/cellj.2025.2037024.1635

Pharmaceutics. 2025 Feb 14;17(2):255. doi: 10.3390/pharmaceutics17020255.

ABSTRACT

Background/Objectives: Drug repurposing explores new applications for approved medications, such as simvastatin (SV), a lipid-lowering drug that has shown anticancer potential but is limited by solubility and side effects. This study aims to enhance SV delivery and efficacy against lung cancer cells using bioactive lipid nanoparticles formulated with plant-derived monoterpenes as both nanostructuring agents and anticancer molecules. Methods: Lipid nanoparticles were produced by ultrasonication and characterized for morphology, size, zeta potential, and polydispersity index (PDI). Monoterpenes (linalool-LN-, limonene, 1,8-cineole) or Crodamol® were used as liquid lipids. Encapsulation efficiency (EE), release profiles, stability, biocompatibility, protein adsorption, cytotoxicity, and anticancer effects were evaluated. Results: The nanoparticles exhibited high stability, size: 94.2 ± 0.9-144.0 ± 2.6 nm, PDI < 0.3, and zeta potential: -4.5 ± 0.7 to -16.3 ± 0.8 mV. Encapsulation of SV in all formulations enhanced cytotoxicity against A549 lung cancer cells, with NLC/LN/SV showing the highest activity and being chosen for further investigation. Sustained SV release over 72 h and EE > 95% was observed for NLC/LN/SV. SAXS/WAXS analysis revealed that LN altered the crystallographic structure of nanoparticles. NLC/LN/SV demonstrated excellent biocompatibility and developed a thin serum protein corona in vitro. Cellular studies showed efficient uptake by A549 cells, G0/G1 arrest, mitochondrial hyperpolarization, reactive oxygen species production, and enhanced cell death compared to free SV. NLC/LN/SV more effectively inhibited cancer cell migration than free SV. Conclusions: NLC/LN/SV represents a promising nanocarrier for SV repurposing, combining enhanced anticancer activity, biocompatibility, and sustained stability for potential lung cancer therapy.

PMID:40006622 | DOI:10.3390/pharmaceutics17020255

Pharmaceutics. 2025 Feb 12;17(2):241. doi: 10.3390/pharmaceutics17020241.

ABSTRACT

Background/Objective: World Health Organization latest statistics state that 17% of infectious diseases are transmitted by vectors, causing more than 700,000 deaths each year. Particularly, dengue (DENV), Zika (ZIKV) and yellow fever (YFV) viral infections have generated international awareness due to their epidemic proportion and risks of international spread. In this framework, the repositioning strategy of Efavirenz (EFV) represents a key clinical feature to improve different antiviral therapies. Therefore, the development of Soluplus®-based nanomicelles (NMs) loaded with EFV (10 mg/mL) for optimized oral pharmacotherapy against ZIKV, DENV and YFV infections was investigated. Methods: EFV-NMs were obtained by an acetone diffusion technique. Micellar size and in vitro micellar interaction with mucin were assessed by dynamic light scattering. In vitro cytocompatibility was investigated in A549 and Vero cells and micellar in vitro antiviral activity against ZIKV, DENV and YFV was evaluated. In vivo oral bioavailability and histological studies were assessed in Wistar rats. Results: EFV encapsulation within Soluplus® NMs increased the drug's apparent aqueous solubility up to 4803-fold with a unimodal micellar size distribution and a micellar size of ~90 nm at 25 and 37 °C. Micellar in vitro interaction with mucin was also assessed in a pH range of 1.2-7.5 and its storage micellar physicochemical stability at 4 °C was confirmed over 2 years. In vitro cytocompatibility assays in A549 and Vero cells confirmed that EFV micellar dispersions resulted in safe nanoformulations. Interestingly, EFV-loaded NMs exhibited significantly higher in vitro antiviral activity compared with EFV solution for all the tested flaviviruses. In addition, the selectivity index (SI) values reveal that EFV-loaded NMs exhibited considerably more biological efficacy compared to EFV solution in A549 and Vero cell lines and for each viral infection (SI > 10). Further, the drug pharmacokinetics parameters were enhanced after the oral administration of EFV-loaded NMs, being biocompatible by not causing damage in the gastrointestinal segments. Conclusions: Overall, our EFV nanoformulation highlighted its potential as a novel drug delivery platform for optimized ZIKV, DENV and YFV antiviral therapy.

PMID:40006610 | DOI:10.3390/pharmaceutics17020241

Pharmaceuticals (Basel). 2025 Feb 7;18(2):224. doi: 10.3390/ph18020224.

ABSTRACT

Background/Objectives: Voglibose, an α-glucosidase inhibitor commonly prescribed to manage postprandial hyperglycemia in diabetes mellitus, demonstrates potential for repurposing as an anti-melanogenic agent. This study aims to explore the inhibitory effects of voglibose on melanogenesis and elucidate its molecular mechanisms, highlighting its possible applications in treating hyperpigmentation disorders. Methods: The anti-melanogenic effects of voglibose were investigated using B16F10 melanoma cells. Cell viability, melanin content, and tyrosinase activity were assessed following voglibose treatment. Western blot analysis was performed to examine changes in melanogenic proteins and transcription factors. The role of signaling pathways, including PKA/CREB, MAPK, PI3K/AKT, and GSK3β/β-Catenin, was analyzed. Primary human skin irritation tests were conducted to evaluate the topical safety of voglibose. Results: Voglibose significantly reduced melanin synthesis and tyrosinase activity in B16F10 cells in a dose-dependent manner. Western blot analysis revealed decreased expression of MITF, TRP-1, and TRP-2, indicating the inhibition of melanogenesis. Voglibose modulated key signaling pathways, including the suppression of PKA/CREB, MAPK, and AKT activation, while restoring GSK3β activity to inhibit β-catenin stabilization. Human skin irritation tests confirmed voglibose's safety for topical application, showing no adverse reactions at 50 and 100 μM concentrations. Conclusions: Voglibose demonstrates anti-melanogenic properties through the modulation of multiple signaling pathways and the inhibition of melanin biosynthesis. Its safety profile and efficacy suggest its potential as a repurposed drug for managing hyperpigmentation and advancing cosmeceutical applications.

PMID:40006038 | DOI:10.3390/ph18020224

Pathogens. 2025 Feb 1;14(2):127. doi: 10.3390/pathogens14020127.

ABSTRACT

Chagas disease, caused by the protozoan Trypanosoma cruzi, affects millions globally, with limited treatment options available. Current therapies, such as benznidazole and nifurtimox, present challenges, including their toxicity, side effects, and inefficacy in the chronic phase. This study explores the potential of drug repurposing as a strategy to identify new treatments for T. cruzi, focusing on compounds from the Medicines for Malaria Venture (MMV) COVID Box. An initial screening of 160 compounds identified eight with trypanocidal activity, with almitrine and bortezomib showing the highest efficacy. Both compounds demonstrated significant activity against the epimastigote and amastigote stages of the parasite and showed no cytotoxicity in murine macrophage cells. Key features of programmed cell death (PCD), such as chromatin condensation, mitochondrial membrane potential disruption, and reactive oxygen species accumulation, were observed in T. cruzi treated with these compounds. The potential to induce controlled cell death of these two compounds in T. cruzi suggests they are promising candidates for further research. This study reinforces drug repurposing as a viable approach to discovering novel treatments for neglected tropical diseases like Chagas disease.

PMID:40005505 | DOI:10.3390/pathogens14020127

Molecules. 2025 Feb 15;30(4):900. doi: 10.3390/molecules30040900.

ABSTRACT

Drug repurposing is a cost-effective and innovative strategy for identifying new therapeutic applications for existing drugs, thereby shortening development timelines and accelerating the availability of treatments. Applying this approach to the development of cosmeceutical ingredients enables the creation of functional compounds with proven safety and efficacy, adding significant value to the cosmetic industry. This study evaluated the potential of rifampicin, a drug widely used for the treatment of tuberculosis and leprosy, as a cosmeceutical agent. The anti-melanogenic effects of rifampicin were assessed in B16F10 melanoma cells, showing no cytotoxicity at concentrations up to 40 µM and a significant reduction in intracellular tyrosinase activity and melanin content. Mechanistically, rifampicin reduced the expression of melanogenic enzymes, including tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2, via a protein kinase A (PKA)-dependent pathway, leading to the suppression of microphthalmia-associated transcription factor (MITF), which is a key regulator of melanogenesis. Additionally, rifampicin inhibited the p38 signaling pathway but was independent of the PI3K/protein kinase B (Akt) pathway. Furthermore, it decreased Ser9 phosphorylation, enhancing glycogen synthase kinase-3β (GSK-3β) activity, promoted β-catenin phosphorylation, and facilitated β-catenin degradation, collectively contributing to the inhibition of melanin synthesis. To evaluate the topical applicability of rifampicin, primary human skin irritation tests were conducted, and no adverse effects were observed at concentrations of 20 µM and 40 µM. These findings demonstrate that rifampicin inhibits melanogenesis through multiple signaling pathways, including PKA, MAPKs, and GSK-3β/β-catenin. This study highlights the potential of rifampicin to be repurposed as a topical agent for managing hyperpigmentation disorders, offering valuable insights into novel therapeutic strategies for pigmentation-related conditions.

PMID:40005210 | DOI:10.3390/molecules30040900

Int J Mol Sci. 2025 Feb 14;26(4):1619. doi: 10.3390/ijms26041619.

ABSTRACT

Globally, bladder cancer is the sixth most frequently diagnosed cancer among men. Despite the increasing availability of immunomodulatory treatments for bladder cancer, the survival rates are still low, which calls for potential new drug-repurposing targets. This study aimed to investigate the effects of cromolyn, a mast cell (MC) stabilizer in allergic reactions, on a subcutaneous tumor model with a syngeneic mouse MB49 bladder cancer cell line. A concentration of 50 mg/kg of cromolyn was daily administered intraperitoneally in a 4-day therapeutic protocol to mice with established tumors and in a continuous 11-day protocol which started one day prior to the subcutaneous injection of tumor cells. Therapeutic treatment demonstrated a marked downregulation of genes related to angiogenesis and upregulation of genes related to cytotoxic T-cell and NK cell activity. Conversely, continuous cromolyn treatment suppressed genes involved in immune cell recruitment and activation, as well as apoptotic and necroptotic pathways, leading to a greater tumor burden (+142.4 mg [95CI + 28.42, +256.4], p = 0.0158). The same pro-tumorigenic effect was found in mast cell-deficient mice (KitW-sh/W-sh + 301.7 mg [95CI + 87.99, 515.4], p = 0.0079; Cpa3Cre/+ +107.2 mg [95CI - 39.37, +253.57], p = 0.1423), indicating that continuous cromolyn treatment mostly acts through the inhibition of mast cell degranulation. In summary, our results demonstrate the distinct effects of cromolyn on tumor progression, which depend on the protocol of cromolyn administration.

PMID:40004083 | DOI:10.3390/ijms26041619

Orphanet J Rare Dis. 2025 Feb 25;20(1):86. doi: 10.1186/s13023-025-03595-6.

ABSTRACT

BACKGROUND: Rare diseases are conditions that have a low prevalence in the population and a high disease burden and are often chronic and progressive. International evidence concerning the experience of people and families living with rare diseases is scarce, leading to late and erroneous diagnoses, as well as non-specific treatments. This study explored the therapeutic trajectories of people and families living with rare diseases within Chile's public and private healthcare systems from the perspective of patients, caregivers, and medical teams, including the initial symptoms, first consultation, testing, diagnosis, treatment, and follow-up.

METHODS: A qualitative exploratory study was conducted through multiple case studies. Sixty participants were interviewed in person and/or virtually: patients (n = 16), caregivers (n = 22), healthcare workers (n = 20), and two patient organisation leaders. The material was analysed using thematic analysis. The project was approved by the Scientific Ethics Committee of Facultad de Medicina Clínica Alemana, Universidad del Desarrollo.

RESULTS: After similar initial symptoms and first consultation, three main types of trajectories were identified: (i) the path taken by those who reach a diagnosis for a disease that has specific treatment available; (ii) the journey of those who reach a diagnosis for their health condition, but their disease does not have a specific treatment available; and (iii) the trajectory of those who have not reached a diagnosis and receive symptomatic treatments for symptoms.

CONCLUSIONS: The therapeutic trajectories of patients with rare symptoms are similar in terms of initial symptoms and first consultation. However, their paths diverge at the diagnostic stage, with diverse experiences related to these journeys, largely based on having a diagnosis and whether there is a specific treatment. Rare conditions in Chile requires further attention and urgent action that considers those who live with them and their families.

PMID:40001237 | DOI:10.1186/s13023-025-03595-6

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