Drug metabolism and personalized therapy最新文献

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.

Objectives: Ginger, scientifically known as Zingiber officinale, is a plant root that has a variety of therapeutic applications, including the treatment of nausea, inflammation, digestive problems, and management of renal function in chronic kidney disease (CKD). CKD is a life-threatening condition that, if untreated, leads to organ damage and is acknowledged as a global health concern. The present study aims at predicting bioactive compounds from Z. officinale that were identified through gas chromatography-mass spectroscopy (GC-MS), with the potential against a selected target of CKD, and was investigated using a pharmaco-informatics approach.

Methods: The compounds from GC-MS analysis were screened, and the structures of identified compounds were drawn through ACD/Chemsketch 2021.2.1. Based on graph theoretical network analysis, forkhead box protein (FOXO6) was chosen as a potential target for CKD. The Swiss model was used to predict the structure of FOXO6, and the active site details were obtained. Docking was performed against the active sites of FOXO6 using 22 compounds, along with the standard drug, dapagliflozin. Pharmacokinetic, physicochemical and toxicity parameters were predicted for the selected high binders and dapagliflozin. The stability and intermolecular interactions of high binders and dapagliflozin protein-ligand complexes were studied using molecular dynamics simulation.

Results: The binding affinity ranges from -3.5 to -6.7 kcal × mol^-1. Abietic acid and dehydroabietic acid had a higher binding affinity with a score of -6.7 kcal × mol^-1, similar to the standard drug, dapagliflozin (-6.4 kcal × mol^-1). Both abietic acid and dehydroabietic acid also have good bioavailability scores. MD simulation studies indicated greater stability for abietic acid-FOXO6 and dehydroabietic acid-FOXO6 complexes.

Conclusions: This investigation has shed light on the significance of the compounds of Z. officinale R. as potential FOXO6 inhibitors, which could further be used as a lead compound for developing alternative therapy for CKD.

Objectives: Vanari Gutika (VG) is an ayurvedic formulation that has been traditionally utilized for the treatment of various male sexual problems. The primary components of VG include Mucuna pruriens, honey, and clarified butter, which are recognized for their aphrodisiac properties. However, currently, there is no scientific evidence supporting the use of this formulation as a drug for enhancing male fertility or elucidating its mechanism for improving testicular physiology. This study aimed to examine the effect of VG on spermatogenesis.

Methods: Adult male mice received oral administration of VG at doses of 75, 150, and 300 mg/kg body weight daily for 35 days (one spermatogenic cycle). Parameters such as histomorphology of testes, daily sperm production, sperm parameters, activity of antioxidant enzymes (SOD and catalase), and immunoblotting of BTB marker proteins (N-cadherin, connexin 43, β-catenin) were assessed.

Results: VG treatment markedly improves relative testis weight, DSP, and sperm count compared to control. The administration of VG resulted in significant improvements in testis histomorphology, germ cell proliferation, and anti-oxidant enzymes (increased catalase and SOD activities) when compared to control mice. Additionally, there was also a dose-dependent increase in the expression of BTB junctional proteins. VG treatment (150 and 300 mg/kg BW) showed a significant beneficial impact on spermatogenesis in adult male mice.

Conclusions: Thus, our findings strongly support the potent therapeutic potential of Vanari Gutika as an ayurvedic aphrodisiac in enhancing testicular function.

Objectives: Thiopurine S-methyltransferase (TPMT) polymorphisms are associated with low or absent enzyme activity and, consequently, increased myelosuppression risk after conventional doses of azathioprine. The distribution of frequencies for deficient TPMT genotypes differs between ethnic groups. Due to limited data in Tunisia, we aimed to detect TPMT variant alleles (TPMT*2, *3B, *3C, *4) in Tunisian patients on azathioprine, and to investigate the concordance between TPMT phenotyping and genotyping for common TPMT alleles.

Methods: We conducted a total of 32 genotyping assays in patients treated with azathioprine, who were referred to the Clinical Pharmacology Department for therapeutic monitoring of azathioprine metabolites from 2021 to 2024. TPMT phenotyping was performed by measuring azathioprine metabolites (6-TGN and 6-MMP) in patients' red blood cells using HPLC method. TPMT genotyping was performed using next generation sequencing to detect the following nucleotide substitutions: c.238G>C, c.460G>A, c.719A>G and c.626-1G>A.

Results: Twenty-eight patients (87.5 %) were homozygous for the wild type. Four individuals (12.5 %) were TPMT deficient subjects and all carriers for TPMT *3C allele. No individual was carrier of the TPMT *2 or *4 allele. The overall concordance between genotyping and phenotyping in this population was 68.8 %.

Conclusions: Overall, 12.5 % of the Tunisian subjects were found to carry the TPMT *3C allele. However, detecting novel and rare TPMT alleles within a larger cohort essential for more accurate estimation of genotype-phenotype correlation in our population. Combining genotyping and phenotyping is likely represents the most effective approach to prevent life-threatening myelosuppression associated with thiopurines.

Objectives: Macrophages play a major role in the inflammation. Recently, the expression of some cytochrome P450 (CYP450) 4 family enzymes was identified in the macrophages including CYP4V2, which metabolizes saturated fatty acids. Lauric acid is unsaturated fatty acid, which can induce inflammation. Its effect on the expression of CYP4V2 and the inflammatory mediators in macrophages is still unknown. This study aims to investigate the effect of lauric acid on the expression of CYP4V2 and cyclo-oxygenase 2 (COX2) in the human monocytes and macrophage THP1 cell line.

Methods: The THP1 monocyte cell line was differentiated into macrophages using 100 ng/mL PMA. Then, the cells were treated with 10 µM lauric acid for 72 h. The mRNA and protein expression of human CYP4V2 and COX2 were analyzed using real-time and western blot techniques, respectively.

Results: It was found that the mRNA and protein expression of CYP4V2 was upregulated after treatment of the macrophages with lauric acid in a dose-dependent manner. This upregulation was correlated with the expression of COX2.

Conclusions: It can be concluded from the results of this study that mRNA and protein expression of CYP4V2 are upregulated by lauric acid in correlation with the induction of inflammation. CYP4V2 can play a role in the inflammation process managed by macrophages.

Objectives: Phosphorus, an essential mineral with diverse biological functions, has recently garnered attention for its potential role in modulating the immune system. However, no study is present regarding the effect of homoepthic preparation of Phosphorus on immune system. Thus, this study aims to investigate the immunomodulatory effects of Phosphorus, shedding light on its impact on Normal and Immunosuppressive conditions in mice.

Methods: The immunomodulatory effect of Phosphorus 6C, 30C, and 200C was tested using Sheep red blood cells on humoral antibody titer and delayed-type hypersensitivity assays. The effect of Phosphorus was investigated in cyclophosphamide induced immune-compromised mice by assessing hematology, organ index, phagocytic index, histology, cytokine level, and their mRNA expression in the spleen.

Results: Phosphorus 6C produced a significant increase in the primary and secondary humoral immune response. While Phosphorus treatment at 6C, 30C, and 200C did not significantly alter hematological and organ index parameters, it considerably enhance the phagocytic index at 30C and 200C, and raise the levels of TNF-α and IL-2 in mice against immunosuppression induced by CPM after the pretreatment with Phosphorus-30C.

Conclusions: The present study shows that Phosphorus 6C potency augment the humoral immunity. In case of immunosuppression, Phosphorus at high dilution might play a significant role but more research is needed to find out the possible effect of Phosphorus preparation.

The review article, "Navigating the Crossroads of Cell Death: Interplay and Intersections Among Ferroptosis, Apoptosis, and Autophagy," delves into the complex interactions between these three key cell death pathways. Understanding how ferroptosis, apoptosis, and autophagy intersect is crucial for maintaining cellular homeostasis. Each pathway represents a unique mechanism of cell death, and recent research highlights their intricate interconnections and mutual influences. Exploring these relationships is vital for comprehending how cells make fate decisions and how these processes are implicated in various diseases. The review's significance lies in elucidating the molecular details of cell death and providing insight into how cells balance survival and death. The interplay among ferroptosis, apoptosis, and autophagy has important implications for developing therapeutic interventions, particularly in diseases where cell death regulation is disrupted. By examining the molecular crosstalk between these pathways, researchers can identify new drug targets and devise strategies to modulate cell fate effectively. This review aims to enhance our understanding of cell biology by offering a detailed perspective on the dynamic and interconnected nature of these cell death mechanisms.

Objectives: Hepatocellular carcinoma (HCC) is a common type of liver cancer that progresses quickly and has limited treatment options. Nutraceutical anacardic acid (AA), a bioactive compound derived from cashew nut shell, has emerged as a potential candidate for HCC treatment owing to its reported anti-inflammatory, anticancer and diverse pharmacological properties. In the present study, we investigate the potential of AA as an HCC inhibitor using molecular docking, gene ontology, and network pharmacology.

Methods: The pharmacokinetic and physicochemical properties of AA were assessed using Swiss ADME. SuperPred, Similarity Ensemble Approach, ChEMBL and Swiss Target Prediction online tools were used for determining molecular targets of AA. In addition, GeneCards, NCBI, DisGeNET and UniProt ID were used to search the targets of HCC and the top 25 hub genes were determined using Cytohubba plugin. A protein protein interaction (PPI) network was constructed through the STRING database. Gene Ontology (GO) biological process and Kyoto Encyclopaedia of Genes and Genes (KEGG) pathway enrichment analysis were performed through FunRich and ShinyGO 0.77. Moreover, molecular docking studies were performed on NF-κB and GSK-3β. The expression levels of the hub genes were also validated by western blotting.

Results: Comprehensive data analysis identified 375 targets for AA and 11,333 for HCC, with 264 targets in common. Network analysis determined 25 key HCC targets, including caspase-3, and NF-κB. Gene ontology and topology analysis highlighted essential pathways implicated in HCC progression such as the renin-angiotensin system, VEGF signalling, and apoptosis. Molecular docking analysis revealed strong binding affinity of HCC proteins with NF-κB and GSK-3β. Upregulation of p-NRF2 and p-GSK-3β, and downregulation of p-NF-κB and caspase-1 expression were validated using western blotting.

Conclusions: Taken together, our study highlights the potential of AA as a promising chemopreventive agent for HCC because of its significant modulatory effects on important regulatory proteins linked to cell division, inflammation, apoptosis, and antioxidant response.