Current drug metabolism最新文献

Pancreatic cancer is a highly lethal malignancy with a low 5-year survival rate. This review focuses on natural compounds as potential therapeutics for it. Different types of natural compounds, such as polyphenols, saponins, and alkaloids, have shown anti-pancreatic cancer effects, including inhibiting tumor cell growth, inducing apoptosis, and preventing angiogenesis. They also have indirect impacts on pancreatic cancer through influencing the gut microbiota, glucose and lipid metabolism, and the endocrine system. Additionally, Chinese herbal medicines containing these compounds show promise in clinical applications. However, challenges such as target identification and low bioavailability persist. Future research trends involve interdisciplinary collaboration and the use of advanced technologies to overcome these issues.

Background: Diabetes mellitus, a widespread and chronic metabolic condition, creates significant challenges for healthcare systems due to complications from inadequate glycemic control, patient non-compliance, and the invasive nature of traditional treatments, including oral medications and insulin injections, which often lead to discomfort, variability in blood glucose levels, and low adherence.

Objective: To explore the potential of Transdermal Drug Delivery Systems (TDDS) as a non-invasive and effective alternative for diabetes management, highlighting their advantages, recent technological advancements, and associated challenges.

Methods: This review examines the role of TDDS in diabetes treatment, with an emphasis on recent innovations, including microneedles, hydrogels, and sonophoresis. The study also discusses the benefits of TDDS in maintaining stable plasma drug levels, reducing first-pass metabolism, and integrating with continuous glucose monitoring systems.

Results: Emerging TDDS technologies improve drug permeability, enhance bioavailability, and offer sustained drug release, potentially addressing limitations of conventional delivery methods. However, barriers such as skin permeability, high manufacturing costs, and patient variability remain significant challenges.

Discussion: Multi-drug patches and microneedle-based systems represent innovative approaches that enhance therapeutic efficacy and patient compliance by enabling painless, targeted, and combination drug delivery. With support from nanotechnology and pharmacogenomics, these platforms are evolving toward personalized medicine, offering optimized dosing and reduced side effects.

Conclusion: TDDS presents a promising alternative for diabetes management by improving patient adherence, ensuring controlled drug release, and reducing discomfort associated with injections. While further research is required to overcome existing limitations, advancements in biomaterials and personalized medicine approaches hold the potential to optimize TDDS for widespread clinical application. This research aims to summarize the advancements and address existing challenges for future development.

Background: Tetrandrine (TET) demonstrates therapeutic potential for hypoxic pulmonary hypertension (HPH); however, its precise pharmacological mechanisms remain unclear. In this study, we aimed to investigate the effects of TET on pulmonary vascular remodeling (PVR) in HPH and elucidate the molecular pathways through which TET ameliorates HPH.

Methods: We established a rat model of HPH and evaluated the therapeutic effects of TET by measuring hemodynamic parameters, assessing right ventricular hypertrophy, and analyzing pathological changes in lung tissue. To explore the molecular mechanisms, we carried out comprehensive analyses using transcriptome and untargeted metabolomics technologies to examine the impact of TET on gene expression and metabolite profiles in the lung tissue of HPH rats. Using data from these multiomics analyses, we performed biochemical assays, immunofluorescence staining, and Western blotting to validate the effects of TET on vasoconstriction and angiogenesis-related factors. These experiments provide further evidence of the anti-HPH and anti-PVR properties of TET.

Results: TET intervention significantly reduced hemodynamic parameters, including mean pulmonary arterial pressure (mPAP) and right ventricular systolic pressure (RVSP), as well as right ventricular hypertrophy indices, such as the right ventricular hypertrophy index (RVHI) and right ventricle-to-body weight ratio (RV/BW), in HPH rats. TET inhibited smooth muscle cell proliferation and alleviated pathological changes in lung tissue. Transcriptome and metabolome analyses revealed that genes affected by TET intervention were enriched in pathways related to PVR, including those involved in endothelial and smooth muscle cell proliferation, angiogenesis, and blood vessel morphogenesis. Metabolites were predominantly associated with the arachidonic acid (AA) metabolism pathway. Differentially expressed genes included Cyp4a1, Cyp4a3, Cyp2u1, and Alox15. Validation experiments demonstrated that TET upregulated ALOX15 protein expression and downregulated CYP4A and CYP2U1 proteins, modulating levels of arachidonate metabolites 20-HETE and 15(S)-HPETE. We further observed that TET reduced the levels of PVR markers, including endothelin-1 (ET-1) secretion, while increasing nitric oxide (NO) release. TET also decreased the expression of cell proliferation markers PCNA and Ki-67 and elevated the endothelial marker CD31. Moreover, TET intervention suppressed angiogenic and vasoconstrictive factors, such as MMP-9, TGF-β1, IGF2, and PDGF-B, while enhancing levels of FGF9 and NOS3.

Conclusion: Our findings highlight the protective effects of TET on lung tissue in HPH mediated through the regulation of 15(S)-HPETE and 20-HETE within the arachidonic acid metabolism pathway. This regulation inhibits pulmonary angiogenesis and vasoconstriction, ultimately improving PVR in HPH.

In the article titled "Establishment of a High Content Image Platform to Measure NF-κB Nuclear Translocation in LPSinduced RAW264.7 Macrophages for Screening Anti-inflammatory Drug Candidates" published in Current Drug Metabolism, Volume 23, No. 5, 2022, pp. 394-414 [1], the authors have identified error in Fig. (8C). They request correction to this figure to ensure accuracy in the representation of their findings. We regret the error and apologize to readers. The original article can be found online at: https://www.eurekaselect.com/article/122464.

Aims: To explore the relationship between oxidative stress biomarkers and the occurrence of acute kidney injury (AKI) alongside notable liver function disturbances in preterm neonates.

Background: Given the immaturity of kidneys and incomplete liver development in preterm neonates, oxidative stress poses a considerable threat to their renal and hepatic health.

Objective: To find out the association between various oxidative stress biomarkers and polymorphisms of antioxidant enzymes with renal and live functions.

Methods: In this cross-sectional study, we gathered umbilical cord blood and peripheral blood samples for assessing oxidative stress biomarkers and identifying single nucleotide polymorphisms (SNPs) in antioxidant enzymes. Utilizing enzyme-linked immunosorbent assay kits, we quantified these oxidative stress biomarkers. Receiver-operating characteristics curve analysis was employed to ascertain the predictive capacity of these biomarkers, denoted by the area-under-the-curve (AUC).

Results: Our findings revealed that umbilical cord heat-shock proteins emerged as robust predictors of neonatal AKI (AUC: 0.92; 95% CI: 0.8-1) with a defined cut-off concentration of 1.8 ng/mL. Likewise, umbilical cord 8-hydroxy-2-deoxy guanosine demonstrated significant predictability for liver function alterations (AUC: 0.7; 95% CI: 0.6-0.9) at a cut-off concentration of 2487.6 pg/mL.

Conclusions: We observed significant associations between SNPs in endothelial nitric oxide synthase and catalase with both AKI and impaired liver functions. Prospective studies are warranted to validate these findings, with a particular focus on exploring potential antioxidant interventions aimed at mitigating AKI and liver function abnormalities.

Introduction: CYP1B1, a crucial drug-metabolizing enzyme, metabolizes both endogenous compounds and clinical drugs. The present study investigated the effects of CYP1B1 on the proliferation, migration, apoptosis, and ferroptosis of HCC cells. It further elucidated the regulatory role of m⁶A modification particularly via the methyltransferase METTL14 in regulating CYP1B1 mRNA stability and translation efficiency.

Methods: CCK-8, colony formation, wound healing, and transwell assays were employed to assess the role of CYP1B1 in HCC cell proliferation and migration. Ferroptosis-related assays, Western blot analysis, RNA immunoprecipitation, and RNA stability assays were conducted to elucidate the underlying molecular mechanisms. The Hepatocellular Carcinoma Database (HCCDB) was utilized for gene expression analysis of CYP1B1 and METTL14.

Results: Upregulated CYP1B1 in HCC inhibits ferroptosis and promotes cell proliferation by mediating GPX4, without significantly affecting HCC cell migration or apoptosis. METTL14-mediated m⁶A modification negatively regulates CYP1B1 expression in HCC. Specifically, METTL14 (downregulated in HCC) catalyzes m⁶A methylation of CYP1B1 mRNA, reducing its stability, while YTHDF3 binds to CYP1B1 mRNA to decrease its expression.

Discussion: These findings established a functional link between drug metabolism, m⁶A epigenetics, and iron-dependent cell death in HCC, highlighting CYP1B1 and its upstream m⁶A machinery as potential targets for developing precision therapies that enhance ferroptosis sensitivity in HCC. The clinical relevance of the identified molecular mechanisms necessitates additional in-depth exploration.

Conclusion: CYP1B1 promotes HCC cell proliferation by regulating GPX4-mediated ferroptosis resistance, while METTL14-mediated m⁶A modification serves as a key negative regulatory mechanism for CYP1B1. Targeting CYP1B1 as a therapeutic strategy holds substantial promise for future drug development in HCC.

Background: The use of computer-aided toxicity and Pharmacokinetic (PK) prediction studies are of significant interest to pharmaceutical industries as a complementary approach to traditional experimental methods in predicting potential drug candidates.

Methods: In the present study, in-silico pharmacokinetic properties (ADME), drug-likeness, and toxicity profiles of valeric acid were examined using SwissADME and ADMETlab web tools.

Results: The drug-likeness prediction results revealed that valeric acid adheres to the Lipinski rule, Pfizer rule, and GlaxoSmithKline (GSK) rule. From a pharmacokinetic perspective, valeric acid is anticipated to have the best absorption profile including cell permeability and bioavailability. Plasma Protein Binding (PPB) and Blood-Brain Barrier (BBB) permeability may have a positive effect on Central Nervous System modulating (CNS). There is a minimal chance of it being a substrate for cytochrome P2D6 (CYP). Except for a "very slight risk" for eye corrosion and eye irritation, none of the well-known toxicities in valeric acid were anticipated, which was compatible with wet-lab data. The molecule possesses no environmental hazard as analyzed with common indicators such as bio-concentration factor and LC₅₀ for fathead minnow and daphnia magna. The toxicity parameters identified valeric acid as nontoxic to androgen receptors, antioxidant response element, mitochondrial membrane receptor, heat shock element, and tumor suppressor protein (p53), except Peroxisome Proliferator-Activated Receptor- gamma (PPAR-γ) was found to be medium toxicity. However, no toxicophores were found out of seven parameters.

Conclusion: Overall, the ADMETLab evaluated that valeric acid has favorable pharmacokinetic and drug-likeness profiles, making it a promising drug candidate for new drug development.

Mycophenolic acid (MPA) is an approved drug widely used as an immunosuppressant agent for the prevention of rejection in organ transplant patients and for managing various autoimmune disorders. Pharmacological studies have shown that the plasma exposure of MPA is critical to maintaining its efficacy, leading to a significant focus on MPA therapeutic drug monitoring (TDM) in clinical practice. Additionally, many papers have been published regarding MPA's absorption, distribution, metabolism, and elimination (ADME) characteristics, which are the key disposition factors affecting the plasma exposure of MPA. In this paper, we review the current data and information in the literature on the ADME properties of MPA and discuss their implications for MPA's TDM. We also analyze the disposition of MPA major metabolites mycophenolic acidglucuronide (MPAG), and acyl-glucuronide (AcMPAG), highlighting the key factors that affect MPA plasma exposure, including the influence of transporters, namely Multidrug Resistance-Associated Protein 2 (MRP2), Breast Cancer Resistance Protein (BCRP), Organic Anion-Transporting Polypeptides (OATPs), metabolic enzymes (i.e., UDP-Glucuronosyltransferases (UGTs)), enterohepatic recycling (EHR), and protein binding. We expect to provide researchers with a comprehensive understanding of factors that could affect MPA's TDM to ensure its efficacy.

Background: As a long-acting DPP-4 inhibitor administered orally once a week, trelagliptin can address the issues of frequent medication and poor compliance associated with traditional hypoglycemic drugs.

Methods: The Hypoxia model in rats was constructed at an altitude of approximately 4300 meters. The plasma concentration of trelagliptin was determined by LC-MS/MS. The biochemical indices and the protein expression levels of P-gp and OCT2 in the kidneys of rats were determined to explain the possible reasons for the pharmacokinetic changes of trelagliptin.

Results: This study demonstrated that the pharmacokinetic parameters of trelagliptin were significantly changed in high-altitude hypoxic environments. Compared with the control group, the AUC, MRT, t1/2, and Vd were remarkably increased during acute and chronic hypoxia, while the CL and Ke were decreased. Additionally, the biochemical indexes and protein expression of P-gp and OCT2 were significantly altered.

Conclusion: The study demonstrated that high-altitude hypoxia significantly altered trelagliptin's pharmacokinetics, slowing clearance, prolonging elimination half-life and residence time, and increasing bioavailability. These changes suggested that the optimal therapeutic dosage of trelagliptin should be reassessed under hypoxic exposure.

Gene silencing is the characteristic that inhibits gene expression afforded by siRNA interference. The efficacy of the delivery system in terms of precision, efficacy, and stability can be enhanced by genebased drug delivery options. The delivery challenges and their associated side effects create a challenge for the delivery of gene-based drug delivery carriers. Nano-based delivery systems were reported to improve the efficacy of therapy. The absence of an efficient delivery mechanism that shields siRNA from nuclease degradation delivers it to cancer cells, and releases it into the cytoplasm of specific cancer cells without causing side effects is currently the greatest obstacle to the practical implementation of siRNA therapy. This article focuses on general aspects of siRNA and various siRNA nanocarrier-based formulations. In the near future, we will move towards the siRNA-based drug delivery approach.