Drug Design, Development and Therapy最新文献

Background: Significant variability in the metabolism of midazolam (MDZ) exists among mechanically ventilated (MV) patients in the intensive care unit (ICU) due to complex clinical conditions and genetic factors. The NR1I2 gene (PXR), which encodes a nuclear receptor that regulates drug-metabolizing enzymes like CYP3A4, plays a critical role in MDZ metabolism. Polymorphisms in NR1I2, along with variations in genes such as CYP3A4, CYP3A5, and ABCB1, may influence enzyme activity and MDZ pharmacokinetics (PK). Understanding these factors is essential for optimizing MDZ dosing in high-risk patient populations.

Methods: We studied 61 MV ICU patients receiving continuous MDZ infusion. A population pharmacokinetic (PopPK) model was used to assess MDZ PK, with genetic factors (NR1I2 rs2461817, CYP3A4, CYP3A5, ABCB1, and other PXR polymorphisms) and clinical covariates (body weight (BW), aspartate aminotransferase (AST) levels) evaluated for their impact on MDZ clearance (CL).

Results: The PK of MDZ and its metabolite, 1-hydroxymidazolam (1-OH-MDZ), were accurately described using a one-compartment model. The estimated population means for MDZ and 1-OH-MDZ CL were 22.6 L/h (inter-individual variability [IIV] 59.4%) and 67.1 L/h (IIV 57.7%), respectively. MDZ CL was significantly associated with the NR1I2 rs2461817 polymorphism and AST levels, accounting for 11.3% of the variability. MDZ CL decreased by 32.7% as AST increased from 22 IU/L to 60 IU/L, and by 40.7% in patients homozygous for the NR1I2 rs2461817 variant. BW also influenced the CL of 1-OH-MDZ, demonstrating a 34.2% increase as weight increased from 54 kg to 65 kg. Simulations confirmed the significant impact of NR1I2 rs2461817 on MDZ CL.

Conclusion: The PopPK model highlights the significant impact of NR1I2 rs2461817 polymorphism on MDZ CL in Chinese MV patients, emphasizing the need to consider genetic and clinical factors for optimizing MDZ dosing in ICU settings.

Global climate change threatens the production, growth, and sustainability of plants. Crop wild relatives (CWRs) offer a practical and sustainable solution to these climatic issues by boosting genetic diversity and crop resilience. Even though CWRs are wild relatives of domesticated plants, they are nevertheless mostly neglected. This review focuses on the possible application of CWRs, which are found in the United Arab Emirates (UAE) and are known for their abiotic stress tolerance and potential medicinal properties. In olden days, traditionally, CWRs has been used as medicine for various ailments as they are rich in phytochemical compounds. However, the medicinal potential of these wild plant species is decreasing at an alarming rate due to climate change stress factors. The medicinal potential of these native crop wild plant species must be investigated because they could be a useful asset in the healthcare sector. Research on pangenomics studies of certain CWRs is also highlighted in the review, which reveals genetic variability caused due to climate change stress factors and how these genetic variability changes affect the production of secondary metabolites that have potent medicinal value. This provides insights into developing personalized medicine, in which particular CWRs plant species can be chosen or modified to generate medicinal compounds. Despite their superior medicinal properties, many CWRs in the UAE are still not well understood. Finding the desired genes coding for the biosynthesis of specific phytochemicals or secondary metabolites may help us better understand how these substances are synthesized and how to increase their production for a range of treatments.

Background: With the advancements in medical technology, the death rate from myocardial infarction (MI), a prevalent heart illness, has gradually decreased; however, treatment hurdles and diagnostic issues remain. Mogrol is a naturally occurring plant extract with specific biological activities such as antioxidant, anti-inflammatory, antitumor, and hypoglycemic effects. These biological activities make it a potential therapeutic drug or research subject; however, its function in MI remains unclear.

Methods: Potential targets of mogrol were searched using the MI Disease Database through online databases. Among the three intersecting genes, we focused on ATPase Na+/K+ transporting subunit 3A3, which is expressed at low levels in patients with MI. The preventive effect of mogrol against MI was investigated using cardiac ultrasonography, Western blotting, qPCR assay, Cell counting kit-8, Ca2+ concentration measurement, Na+/K+-ATPase, and flow cytometry.

Results: The findings demonstrated that mogrol upregulated Ca2+ concentration and ATPase Na+/K+ transporting subunit 3 protein levels in cardiomyocytes and tissues, downregulated the apoptosis-related proteins B-cell lymphoma 2-like protein 4, cleaved-caspase-3, and upregulated B-cell lymphoma 2. These effects enhanced cardiac function, prevented cardiomyocyte apoptosis, encouraged cardiomyocyte proliferation, and protected mice from MI. Knocking down ATP1A3 can reverse the protective effect of Mogrol.

Conclusion: Mogrol may have a protective effect on myocardial infarction by regulating Ca2+ concentration and the level of the ATPase Na+/K+ transport subunit 3 protein, as well as by regulating apoptosis-related proteins. Further revealing the pharmacokinetics of mogrol in vivo is expected to make it a subsequent drug for the treatment of cardiac infarction.

Background: Milvexian is a small molecule, selective factor XIa (FXIa) inhibitor being developed as an oral anticoagulant. This study assessed the pharmacokinetics, pharmacodynamics (activated partial thromboplastin time [aPTT]), and safety of milvexian in healthy Chinese subjects.

Methods: Part 1: Thirty subjects were randomly assigned 1:1:1 to receive milvexian 25 mg on Day 1 followed by 25 mg once daily (QD) on Days 5-12; milvexian 25 mg twice daily at 12-hour intervals (BID) on Days 1-8; or milvexian 100 mg BID on Days 1-8. Part 2: Ten subjects received milvexian 200 mg on Day 1 followed by 200 mg BID on Days 5-12. Plasma samples were collected for pharmacokinetics and aPTT assessments. Safety and tolerability were assessed.

Results: Milvexian was rapidly absorbed (median t_max of 3-4 hours after a single dose and repeated administration). Mean maximum concentrations or area under the concentration-time curve values of milvexian in plasma after single doses or BID administration of 25 mg, 100 mg, or 200 mg increased in a dose-dependent manner. Steady state conditions were achieved within 6 days of repeated administration based on milvexian trough concentration values. Mean terminal half-life values (9-10 hours) were independent of the dose. Milvexian reversibly prolonged aPTT in a manner that was directly related to milvexian dose and exposure. All milvexian regimens were safe and well tolerated, with only mild treatment-emergent adverse events and no clinically significant bleeding events. No new safety signals were identified.

Conclusion: The pharmacokinetic, pharmacodynamic, and safety profiles of milvexian demonstrate suitability for further clinical development in Chinese participants.

Purpose: Osteotoxicity, a common consequence of Methotrexate (MTX) therapy, significantly compromises bone health by inducing oxidative stress and disrupting bone remodeling. This study examines the protective effects of Tempol, a nitroxide compound with antioxidant properties, against MTX-induced osteotoxicity.

Methods: Osteocyte-like MLO-Y4 cells were cultured and treated with Tempol and MTX to evaluate changes in apoptotic mediators, MAPK signaling pathways, and oxidative stress parameters.

Results: MTX treatment significantly increased caspase-3 activity and Bax expression while decreasing Bcl-2 levels, thereby creating a pro-apoptotic environment. It also activated stress-related pathways by elevating JNK and ERK activities. Conversely, Tempol effectively countered these effects by restoring the balance of apoptotic mediators, downregulating MAPK activation, and enhancing Total Antioxidant Status (TAS). Additionally, Tempol reduced Total Oxidant Status (TOS) and improved the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx).

Conclusion: These findings highlight Tempol's potential to mitigate oxidative stress and apoptosis linked to MTX therapy, supporting its use as an adjunctive treatment to protect bone health in patients undergoing MTX therapy. Emphasizing Tempol's clinical implications as a protective agent reinforces the urgency for further research into its long-term effects on cellular viability and bone integrity in the context of chemotherapy.

Background: Colquhounia root tablet (CRT) has been in treatment of autoimmune and inflammatory diseases for decades, but large-scale clinical observations are lacking. The novelty of this study lies in providing the first large-scale real-world clinical data to evaluate the effectiveness and safety of CRT on chronic glomerulopathy and to explore potential molecular mechanisms.

Methods: This is a single-arm retrospective study in the real-world. Data analysis included descriptive statistics, t-tests, non-parametric tests, and analysis of variance, with P < 0.05 considered as the standard for statistical significance. Predicting molecular targets and pathways of CRT through network pharmacology and validating through molecular docking.

Results: (1) Among 317 patients, 74.8% experienced a significant decrease in proteinuria (P < 0.001), particularly in IgA nephropathy (IgAN), type 2 diabetes mellitus-related chronic kidney disease (T2DM related-CKD) and membranous nephropathy (MN). (2) CRT works quickly in reducing proteinuria. 76.7% patients had obvious effect at first visit (P < 0.001). (3) CRT had no obvious effect on creatinine and albumin. (4) Subgroup analysis showed regardless of level of proteinuria and eGFR, CRT had significant efficacy. (5) CRT has good security and low incidence of adverse reactions. (6) Bioinformatics analysis suggested that CRT acts on chronic glomerulopathy by infections, metabolism, Th17 cell differentiation and C-type lectin signaling pathways. The core targets are IL-6, TNF, AKT1, IL-1β and ALB.

Conclusion: CRT treatment for chronic glomerulopathy is safe and effective, which can significantly reduce proteinuria. Network pharmacology results suggest the mechanism of CRT in chronic glomerulopathy may involve Th17 cell differentiation and CLR signaling pathway.

Background: KCNH2 encodes the hERG potassium channel, which is associated with drug-induced long QT syndrome. Arsenic trioxide (ATO) is an effective therapeutic agent for acute promyelocytic leukemia; however, its long-term use can lead to cardiotoxicity, particularly in cases of acquired long QT syndrome (acLQTS), which may result in torsade de pointes (TdP). Therefore, it is essential to comprehend the mechanisms behind acLQTS and to develop effective preventive and therapeutic strategies.

Aim: This study sought to investigate the role and molecular mechanism of MALAT1 in ATO-induced acLQTS. Furthermore, it sought to identify pharmacological agents that could mitigate the cardiotoxic effects of ATO and establish viable intervention targets for the prevention and management of acLQTS.

Methods: First, we employed gene chip arrays to identify target long noncoding RNAs (lncRNAs). Subsequently, we performed quantitative qRT-PCR and RNA-binding protein immunoprecipitation (RIP) to assess lncRNA levels. Next, we utilized Western blotting for protein expression analysis, and finally, we conducted whole-cell patch-clamp recordings to evaluate hERG currents.

Results: Our results revealed a significant upregulation of lncRNA MALAT1 expression in HEK293-hERG cells treated with ATO. Mechanistically, MALAT1 interacts with calpain-1, inhibiting its ubiquitin-mediated degradation and enhancing the cleavage activity of calpain-1 on the hERG channel. FEX and TAN were found to mitigate the effects of ATO on the MALAT1/calpain-1 pathway, ultimately restoring hERG protein levels.

Conclusion: This study demonstrated that ATO-induced enhancement of calpain-1 and reduction of hERG may be linked to the aberrant overexpression of lncRNA MALAT1. Tanshinone IIA and fexofenadine restored the hERG protein levels potentially by decreasing MALAT1 expression and counteracting ATO's effects on the MALAT1/calpain-1 pathway. Collectively, our research uncovers a previously unreported regulatory mechanism underlying ATO-induced acLQTS. Moreover, it identifies potential molecular targets and intervention strategies for acLQTS therapy.

Background: Atopic Dermatitis (AD) is a common continuous inflammation dermatosis requiring efficacious therapeutic intervention. Phellodendri Chinensis Cortex-Cnidii Fructus (PC) herb pair has shown effectiveness and security in traditional Chinese medicine (TCM) clinical applications, yet its pharmacological constituents and mechanisms are not fully elucidated.

Purpose: This study used serum pharmacochemistry, network pharmacology, and validation experiments to examine the impact of PC in the treatment of AD.

Methods: Initially, ultra performance liquid chromatography-mass spectrometry (UPLC-MS) had been applied to elucidate the components of PC that were absorbed. An integrative approach combining network pharmacology and in vivo research (general index observation, skin pathological tissue staining, ELISA, immunohistochemistry, immunofluorescence, and Western blotting) was employed to validate PC's mechanism in action after 2,4-dinitrochlorobenzene (DNCB) was used to create a mouse model of AD.

Results: Fifty-three compounds and 18 serum prototype components were characterized within PC. The therapeutic efficacy of PC in AD was notably manifested in the alleviation of pruritus, improvement of skin histopathology, and reduction of cytokines involving IgE, IL-4, TNF-α and IL-6. Based on molecular docking studies, pharmacodynamic components such as phellodendrine, xanthotoxin, nomilin, and isopimpinellin strongly favored the main targets. Comprehensive investigations integrating serum pharmacochemistry, network pharmacology, and in vivo studies had revealed that PC prevented DNCB-induced AD through adjusting the TLR4/NF-κB signaling pathway.

Conclusion: The anti-AD effects of PC may be attributed to its modulation of the TLR4/NF-κB signaling pathway, reduction of NF-кB expression in the nucleusim, downregulation of inflammatory cytokine levels, provement of skin histopathological manifestations, and reduction of skin pruritus.

Bone and cartilage diseases are significantly associated with musculoskeletal disability. However, no effective drugs are available to cure them. FOXO3a, a member of the FOXO family, has been implicated in cell proliferation, ROS detoxification, autophagy, and apoptosis. The biological functions of FOXO3a can be modulated by post-translational modifications (PTMs), such as phosphorylation and acetylation. Several signaling pathways, such as MAPK, NF-κB, PI3K/AKT, and AMPK/Sirt1 pathways, have been implicated in the development of bone and cartilage diseases by mediating the expression of FOXO3a. In particular, FOXO3a acts as a transcriptional factor in mediating the expression of various genes, such as MnSOD, CAT, BIM, BBC3, and CDK6. FOXO3a plays a critical role in the metabolism of bone and cartilage. In this article, we mainly discussed the biological functions of FOXO3a in bone and cartilage diseases, such as osteoporosis (OP), osteoarthritis (OA), rheumatoid arthritis (RA), ankylosing spondylitis (AS), and intervertebral disc degeneration (IDD). FOXO3a can promote osteogenic differentiation, induce osteoblast proliferation, inhibit osteoclast activity, suppress chondrocyte apoptosis, and reduce inflammatory responses. Collectively, up-regulation of FOXO3a expression shows beneficial effects, and FOXO3a has become a potential target for bone and cartilage diseases.

Background: The 797S mutation in EGFR disrupts the covalent binding of third-generation inhibitors, causing drug resistance. Currently, no clinically drug fully overcomes this resistance.

Methods: We designed and synthesised a novel EGFR C797S-targeted inhibitor-5d by introducing structures such as cyclopropyl and sulfonamide with Brigatinib as the lead compound; we identified the target of action by ELISA and molecular docking, and tested its anti-tumor activity and safety in vivo and vitro, as well as its effects on cell cycle, apoptosis and DNA damage.

Results: It was found that there were 10 new small-molecule inhibitors and compound 5d was identified as highly selective with low toxicity. WB confirmed 5d's inhibition of EGFR and m-TOR pathways. Mechanistic studies revealed 5d induced cell cycle arrest in G2/M phase caused DNA damage and cell apoptosis, increasing apoptotic protein cleaved caspase-3 levels. It also inhibited growth in PC9 cells with an EGFR^del19 mutation. Importantly, 5d also demonstrated superior anti-tumor activity in vivo and was superior to the positive control Brigatinib.

Conclusion: We concluded that cyclopropylsulfonamide 5d derivatives induce cell cycle arrest, apoptosis, and DNA damage by regulating tumor-related genes, thereby inhibiting the proliferation of C797S mutated lung cancer cells.