Drug metabolism and personalized therapy最新文献

Objectives: Defined by their unique covalently closed loop, circular RNAs (circRNAs) are a specific class of noncoding RNAs known for their stability and resilience against degradation. They act as microRNA sponges, transcriptional regulators, and modulators of protein interactions. Withania somnifera (WS), a prominent member of the Solanaceae family, is renowned for its anti-oxidative and neuroprotective properties. Although circRNAs are recognized as critical regulators in neurological disorders, their putative roles in eliciting the health-beneficial effects of WS, also known as Ashwagandha, are still unexplored.

Methods: This study investigates WS-modulated global circRNA expression profiles in the SK-N-SH human neuroblastoma cell line, a widely used model for brain-related diseases. We conducted whole genome circRNA profiling using sequencing to identify differentially expressed circRNAs upon WS treatment.

Results: A total of 26,489 circRNAs were detected, out of which 1,515 were novel. Dose-dependent and temporal differential gene expression analysis found 26 upregulated and 20 downregulated circRNAs which were linked to pathways relevant to neuroinflammation, synaptic plasticity and neuronal survival through functional and pathway enrichment analysis.

Conclusions: This study sheds light on the regulatory roles of circRNAs in WS's therapeutic effects, suggesting that modulating circRNA expression may be a key mechanism by which it exerts its benefits. These findings open new avenues for WS-based therapeutic strategies for brain-related diseases, thereby highlighting the therapeutic utility of circRNAs in neurological contexts.

Background: Selinum is an important genus in the Apiaceae family, known for its essential oil-bearing medicinal properties. Selinum vaginatum C. B. Clarke and Ligusticopsis wallichiana (DC.) Pimenov & Kljuykov (Syn. Selinum wallichianum (DC.) Raizada & H. O. Saxena and Selinum tenuifolium Wall. ex DC.) are the two important species found in Himachal Pradesh, India.

Content: The primary objective of this review is to present an updated report on the phytochemistry, traditional knowledge, and pharmacological profile of two species of the genus Selinum that are found in the Western Himalayas.

Summary: The genus Selinum is commonly referred to as Bhutakeshi or Bhootkeshi. Strong evidence supports Selinum's claims for its traditional ethnomedical importance and is used to treat cardiovascular diseases, asthma, toothache, mental disorders and diabetes. It is also used as an insect repellent and in magico-religious practices. The plant has antioxidant, anti-inflammatory, anticancer, anticonvulsant, and antimicrobial activities. The plant is rich in phenols, flavonoids, alkaloids, and terpenoids that contribute to its bioactivities.

Outlook: This review outlines the important phytochemicals, traditional uses, and potential pharmacological properties of Selinum species. Further investigation is needed to elucidate the mechanistic importance of its bioactive components in drug development processes and to investigate the therapeutic potential at the clinical level.

The identification of genetic markers that will enable accurate diagnosis and prediction of the therapy outcome is a crucial step in managing rheumatologic and autoimmune diseases. Low-dose methotrexate is a mainstay therapeutic agent for treatment. The objective of this review is to summarize the data on candidate single nucleotide polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and solute carrier family 19 member 1 (SLC19A1) genes involved in methotrexate pathways. Over the past decade, several functional polymorphisms affecting methylenetetrahydrofolate reductase activity have been studied in the context of low-dose methotrexate therapy. The most frequently investigated polymorphisms are rs1801133 (c.665C>T) and rs1801131 (c.1286A>C) in MTHFR gene and rs1051266 (c.80A>G) in SLC19A1 gene. Although the effects of these polymorphisms are remaining unclear, several studies have shown association with adverse effect while fewer studies have demonstrated association with remission or positive response to methotrexate. However, there is scarcity research in Latin American population assessing the influence of genetic variants in the pharmacokinetics and pharmacodynamics of methotrexate in the context of interethnic admixture. There is an urgent need of to expand these studies and to support the development of clinical pharmacogenomics guidelines.

Objectives: The increasing resistance of human infections to pharmaceutical treatments represents a critical global health challenge. Traditional herbs may complement modern antibacterial strategies. This study investigates the antimicrobial, antioxidant, and immunomodulatory properties of Eugenol extracted from Syzygium aromaticum.

Methods: The essential oil was achieved through hydro distillation and analyzed using HPLC. Antioxidant capabilities were assessed using the DPPH radical scavenging assay and reducing power. MTT assays revealed the viability percentages of A549 and MRC5 cell lines after 48 h of exposure to methanolic extract and valerianic acid. Minimum inhibitory concentration (MIC) and broth microdilution methods were utilized to test antibiotic activity against Staphylococcus aureus, Escherichia coli, and Candida albicans. Finally, the essential oil (average concentration 13.1 % ± 0.23, with major components Eugenol, β-caryophyllene, and Eugenol Acetate) was orally administered to rats for 14 days. In vivo safety and immunomodulatory effects were assessed through histopathological, hematological, and hepatic enzyme analyses, as well as cytokine profiling.

Results: The essential oil, rich in Eugenol, β-caryophyllene, and Eugenol acetate, demonstrated strong antioxidant activity. It exhibited significant antimicrobial effects at concentrations≥5 mg/mL, with inhibition zones comparable to standard antibiotics. Cytotoxicity remained low, and in vivo analysis revealed no adverse effects. The extract also increased IFN-γ and IL-4 levels, indicating immunomodulatory potential.

Conclusions: The study indicated an immunomodulatory impact by increasing IFN-γ and IL-4 levels, with no negative effects on hepatic enzymes, hematological parameters, or histopathology. In summary, this research demonstrates that Eugenol, even at low concentrations, exhibits promising antioxidant and antimicrobial activities against common pathogens.

Objectives: Pharmacogenomics (PGx) testing optimizes drug efficacy and minimizes adverse effects, yet its implementation in Iraq remains limited. This study assessed Iraqi pharmacists' attitudes toward PGx testing to identify gaps in education and clinical readiness.

Methods: A cross-sectional survey of 99 Iraqi pharmacists was conducted (June-August 2020). The 20-item questionnaire evaluated demographics, PGx education exposure, attitudes, and self-reported competence using a three-point Likert scale. Data were analyzed descriptively via SPSS.

Results: Most participants were young (83 % aged 21-30), held bachelor's degrees (87.88 %), and supported PGx integration into curricula (80.81 %). While 95 % believed pharmacists should possess PGx knowledge, self-reported competency was low (35-54 %).

Conclusions: Despite strong support for PGx, limited educational exposure and low confidence in applying PGx testing highlight the need for curriculum enhancements and targeted training programs in Iraq. Iraqi pharmacists recognize PGx's clinical value but require further education to bridge competence gaps. Policymakers should prioritize PGx training to facilitate implementation.

Objectives: Diabetes mellitus is a complex metabolic disease characterised by chronic hyperglycaemia, which triggers a cascade of pathological changes in the body. Contemporary methods for developing antidiabetic drugs are often lengthy, expensive, and not always effective. The use of neural networks for modelling diabetes opens up new possibilities for accelerating research and increasing the accuracy of predicting the effectiveness of novel therapeutic strategies. The aim of this study was to develop and validate a neural network for studying experimental diabetes and assessing the efficacy of new antidiabetic drugs, as well as to explore the potential of combined therapeutic strategies.

Methods: The empirical investigation was conducted using laboratory models of diabetes induced in rats with streptozotocin. Three groups were formed: a control group, a diabetic group without treatment, and a diabetic group treated with experimental drugs.

Results: A neural network, based on multilayer perceptrons and recurrent architectures, was trained to predict changes in glucose levels, oxidative stress markers, and the condition of pancreatic tissues. The developed model demonstrated high predictive accuracy of metabolic changes, with an average accuracy of 92.3 %. As a result of treatment with experimental drugs, blood glucose levels in rats decreased by 25-30 % over 28 days, accompanied by a 26 % reduction in oxidative stress markers and partial restoration of pancreatic β-cell function in 30 % of cases. Histological analysis confirmed reduced fibrosis and improved tissue condition in the treatment group. The model also identified that combined therapeutic strategies - for example, the combination of antioxidants with gluconeogenesis inhibitors - had a synergistic effect, lowering glucose levels by up to 40 %.

Conclusions: The study confirmed the effectiveness of the developed neural network for analysing therapeutic strategies and predicting metabolic changes in diabetes models. The proposed neural network represents a promising tool for investigating new antidiabetic drugs, including efficacy assessment within personalised medicine. Its application may accelerate preclinical research, optimise therapeutic approaches, and contribute to reducing drug development costs.

Fluoropyrimidines are chemotherapy treatments widely used in chemotherapeutic regimens for different types of cancer. Adverse effects produced by dihydropyrimidine dehydrogenase (DPD) enzyme deficiency due to single nucleotide variants (SNVs) in the limiting enzyme of fluoropyrimidine catabolism occur with a high frequency in the world population; however, clinical recommendation guidelines focus mainly on variants of DPD gene (DPYD), which are highly prevalent in European populations. The aim of this review is to identify clinically relevant DPYD variants considering ethnic origin in order to develop population-specific genotyping panels for Afro-Latin Americans. Current recommendations from clinical guidelines and scientific literature in populations of African origin, including Dominican, have been reviewed. Based on the high reported frequency, the inclusion of the c.557A>G variant (which leads to a decrease in DPD enzyme activity) in populations of Afro-Latin American ancestry is proposed.

The ESR1 gene encodes estrogen receptor alpha (ERα), whose central role in breast tumorigenesis has supported the development of endocrine therapies, including selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs). Despite their proven efficacy, resistance, relapse, and treatment-limiting toxicity remain frequent, underscoring interindividual and interpopulation variability in therapeutic outcomes. Allelic diversity within ESR1 is a key determinant of these differences, as variant frequencies and distributions vary substantially across populations and ethnic groups. Associating ESR1 variants with genomic ancestry can help anticipate variability in drug response, thereby reducing adverse events and facilitating the clinical implementation of pharmacogenetics. Investigating population-specific differences that shape drug efficacy and toxicity not only generates evidence for groups historically underrepresented in genomic studies but also enhances the equity and global applicability of personalized medicine. In conclusion, genetic variation in ESR1 may modulate both the efficacy and safety of breast cancer therapies. Understanding the genetic diversity of populations worldwide is therefore essential for minimizing adverse effects, improving treatment outcomes, and advancing the implementation of pharmacogenetics in clinical practice.

Objectives: Antibiotic resistance is a global health concern, prompting exploration of alternative therapies, including medicinal herbs. Glycyrrhiza glabra (licorice) contains saponins, which may possess antibacterial and antioxidant properties. This study aims to evaluate the antibacterial and antioxidant activities of saponin extracted from G. glabra and assess its safety and immunomodulatory effects in vivo.

Methods: Saponin was isolated from licorice roots using a Soxhlet apparatus with 70 % ethanol as the extraction solvent over 168 h. Antioxidant activity of the extract was evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH)-free radical scavenging assay and ferric reducing antioxidant power (FRAP) assay. Antibacterial activity toward Streptococcus pneumoniae was detected using broth microdilution method to evaluate minimum inhibitory concentration (MIC). In vivo safety and immunomodulatory effects were assessed in mice.

Results: Saponin exhibited an IC₅₀ of 20.16 ± 0.21 μg/mL in the DPPH assay. Inhibition zones against S. pneumoniae were observed at concentrations of 10 μg/mL (6.4 mm), 20 μg/mL (17.6 mm), and 50 μg/mL (21.9 mm). In vivo, treatment with 20 μg/mL saponin resulted in a 0.06 μg/mL fold increase in IFN-γ levels compared to control without adverse effects on hepatic enzymes, hematological parameters, or histopathology.

Conclusions: Saponin from G. glabra demonstrates promising in vitro antioxidant and antibacterial activities against S. pneumoniae, with favorable safety and immunomodulatory profiles in vivo, supporting its potential as a natural therapeutic candidate.