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

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

Biomedicines. 2025 Jan 24;13(2):291. doi: 10.3390/biomedicines13020291.

ABSTRACT

Background: Resistin (RETN), an inflammatory cytokine exhibiting multifaceted roles in cancer progression, has emerged as a plausible mediator between inflammation and oncogenesis. Prior research from our group has highlighted the pivotal role of resistin in carcinogenesis and its impact on drug responsiveness. The present study delves into the relationship between resistin expression and genetic polymorphisms with cancer risk and clinical outcomes among lung cancer patients undergoing platinum-based chemotherapy. Methods: Immunohistochemical analysis was conducted to assess resistin expression levels in 104 tumor tissues derived from lung adenocarcinoma patients. Additionally, 498 lung cancer patients and 213 healthy controls were recruited for this study, with 467 patients undergoing at least two cycles of platinum-based chemotherapy. Unconditional logistical regression analysis was employed to evaluate the associations between RETN polymorphisms and lung cancer risk, as well as clinical outcomes. Genotyping of RETN polymorphisms (rs1862513 and rs3745367) was performed using the Sequenom MassARRAY System. Results: The findings revealed a positive correlation between resistin expression in tumor tissues and metastasis (particularly distant metastasis) and overall survival in lung adenocarcinoma. However, RETN polymorphisms were not significantly associated with overall survival in lung cancer patients. No substantial association was observed between RETN polymorphisms and lung cancer risk, chemotherapy response, or toxicities, except for rs1862513, which showed a link with severe gastrointestinal toxicity. Meta-analysis results further confirmed the absence of a significant association between RETN polymorphisms and cancer risk. Conclusions: Despite the pivotal role of resistin in carcinogenesis, only the RETN rs1862513 polymorphism emerges as a potential biomarker for gastrointestinal toxicity in lung cancer patients undergoing platinum-based chemotherapy. However, these findings necessitate validation through well-designed studies with larger sample sizes.

PMID:40002704 | DOI:10.3390/biomedicines13020291

Diagnostics (Basel). 2025 Feb 7;15(4):404. doi: 10.3390/diagnostics15040404.

ABSTRACT

Background/Objectives: Lipoprotein (a) [Lp(a)] plays a significant role in atherosclerosis and cardiovascular disease (CVD). Genetic regulation of Lp(a) involves variations in the apo(a) LPA gene, as specific polymorphisms like rs10455872 and rs3798220, both linked to higher Lp(a) levels and CVD. CVD remains the leading global cause of death, with high Lp(a) levels increasingly recognized as a significant factor in younger patients with no other CVD risk factors. We aimed to evaluate the association of LPA genetic variations with Lp(a) levels and its effect on cardiovascular risk as there are existing inconsistent findings. Methods: This case-control study included 251 subjects with a median age of 52 years (interquartile range, IQR = 17) and elevated Lp(a) levels. Cases were subjects who experienced early cardiovascular incidents (women < 65, men < 55 years old), and the control group included subjects without such history. Genotyping of LPA gene polymorphisms (rs10455872 and rs3798220) was performed, and demographic data with Lp(a) levels were collected. To evaluate the association between the LPA genotypes and the risk of cardiovascular incidents (CVI), several logistic regression models were performed. The cut-off points for Lp(a) levels were determined using diagnostic test accuracy measures. Results: The rs3798220-C allele was associated with higher Lp(a) levels (288 ± 166 nmol/L in cases vs. 189 ± 102 nmol/L in controls, p < 0.001) and myocardial infarction (53% in cases vs. 36% in controls, p = 0.036). Among cases, 28.9% carried the rs3798220-C allele, compared to 18.7% in controls. The rs10455872-G allele was slightly more prevalent in controls (34.15% vs. 29.69%) but without further significant associations. In this study, the cut-off Lp(a) value of 151 nmol/L, for patients with a positive family history of early CVD, is associated with a higher chance of developing CVI. Conclusions: This study demonstrates an association between the LPA rs3798220-C allele and higher Lp(a) levels, as well as an increased risk of early onset myocardial infarction. However, the obtained association should further be evaluated at a much larger scale.

PMID:40002555 | DOI:10.3390/diagnostics15040404

Antibiotics (Basel). 2025 Feb 16;14(2):204. doi: 10.3390/antibiotics14020204.

ABSTRACT

Background/Objectives: Studies show that SNPs in ABCB1 rs2032582 and SLCO1B1 rs4149015 affect the PK profile of moxifloxacin, a key drug for MDR-TB. This study aimed to assess the genotype frequencies of ABCB1 rs2032582 and SLCO1B1 rs4149015; describe moxifloxacin AUC0-24 and Cmax; and evaluate the association between genotype variations and moxifloxacin AUC0-24 and Cmax, corrected for the effect of other determinants in MDR-TB patients in Indonesia. Methods: The genotypes were identified using DNA sequencing. Plasma samples for PK analysis were collected at either two or four timepoints post-dose, at steady state. AUC0-24 values were assessed with a limited sampling formula. A multivariate linear regression analysis identified the determinants for moxifloxacin AUC0-24 and Cmax. Results: We recruited 204 MDR-TB patients for PG analysis, with 80 providing PK samples. The majority of the ABCB1 and SLCO1B1 genotypes were wildtype (GG), 41.7% and 93.6%, respectively. The geometric mean AUC0-24 for moxifloxacin was 78.6 mg·h/L and that for Cmax was 6.1 mg/L. No statistically significant difference in exposure to moxifloxacin could be shown between the genotypes. Sex, age, and dose in mg/kg/body weight were significant determinants of the AUC0-24 of moxifloxacin. Conclusions: The major genotype of ABCB1 rs2032582 and SLCO1B1 rs4149015 was wildtype, and the exposure to moxifloxacin was high but not related to the studied genotype in an Indonesian population.

PMID:40001447 | DOI:10.3390/antibiotics14020204

Br J Clin Pharmacol. 2025 Feb 25. doi: 10.1002/bcp.70026. Online ahead of print.

ABSTRACT

AIMS: The influence of CYP2C19 polymorphisms on voriconazole plasma concentrations is recognized, but its extent, other contributing factors and risks for adverse reactions remain under-explored.

METHODS: This study focused on Japanese paediatric patients recruited between 2020 and 2022 treated with voriconazole. We specifically investigated the occurrence of cholestasis and thrombocytopenia as adverse reactions of voriconazole. Voriconazole plasma levels were modelled in a previous study using a population pharmacokinetics approach. Missing values were estimated with a Bayesian method in Phoenix NLME. We analysed CYP2C19*2, CYP2C19*3 and CYP2C19*17. Clinical and laboratory data were collected before and after voriconazole treatment.

RESULTS: Among the 60 patients (mean age: 6.5 years; 53.3% male), 38 had haematological malignancies, 18 inborn errors of immunity, 2 solid tumours and 2 other diseases. Adverse reactions occurred in 12 patients. The voriconazole plasma concentrations were significantly higher in those experiencing these adverse reactions (mean normalized concentrations: 0.66 in cases vs. -0.16 in controls, P = .025), with a trend towards higher concentrations in carriers of the CYP2C19*2 or *3 alleles (mean normalized concentrations: 0.98 in carrier cases vs. 0.016 in noncarrier cases, P = .14). A predictive model for voriconazole concentrations, incorporating carriership of CYP2C19*2 or *3, C-reactive protein levels, and platelet counts, showed a summed variance explained of 23.6% with the variance attributable to CYP2C19*2 or *3 carrier status alone was 2.6%. Including carrier status improved the area under the receiver operating characteristic curve for predicting adverse reactions to 0.70.

CONCLUSIONS: Our findings underscore the role of the CYP2C19 polymorphism in voriconazole-induced thrombocytopenia and cholestasis.

PMID:40001258 | DOI:10.1002/bcp.70026

Reprod Biol Endocrinol. 2025 Feb 25;23(Suppl 1):29. doi: 10.1186/s12958-025-01359-2.

ABSTRACT

Luteinizing hormone (LH) is fundamental to support development and reproduction. It acts through a receptor expressed in the gonads, modulating mitogenic, anti-apoptotic, and steroidogenic signals. LH is also marketed as a drug for controlled ovarian stimulation (COS), where it is administered to women to support the action of follicle-stimulating hormone and can lead to specific responses, depending on the individual genetic background. These concepts underline the relevance of a pharmacogenetic approach to COS, in the attempt to optimize clinical outcomes and avoid adverse events. However, knowledge is currently limited by the paucity of clinical studies. This review aims to provide a comprehensive overview of LH and its receptor activity, starting from the description of their molecular pathways from in vitro studies. Data on LH action from in vivo studies were described, as well as the impact of LH and LH/choriogonadotropin (hCG) receptor genetic variants on folliculogenesis and its association with infertility or polycystic ovarian syndrome. Finally, evidence from clinical studies evaluating genetic polymorphisms in the context of assisted reproductive technology treatments and its implications for a pharmacogenomic approach were discussed.

PMID:40001128 | DOI:10.1186/s12958-025-01359-2