1. Solute carrier (SLC) transporters are key players in drug pharmacokinetics and are notably involved in drug-drug interactions; their potential interactions with new molecular entities must be evaluated during pharmaceutical development for regulatory purposes. 2. Various fluorescent probes substrates for SLCs have been characterized. This review summarizes the nature of these dyes and their application in vitro for investigating interactions between drugs or other chemicals and main “regulatory” SLCs that handle anionic or cationic compounds. The advantages and limitations of using fluorescent probes for SLC studies are discussed. 3. Fluorescent probe-based SLC assays enable the identification and characterization of xenobiotic-mediated inhibition of SLC activity through cis-inhibition assays. They also facilitate the study of fundamental properties, polymorphisms, and regulatory pathways of SLCs, as well as the characterization of SLC substrates via trans-stimulation or competitive counterflow assays. 4. Dye-based SLC activity assays are more cost-effective and less labor-intensive than conventional methods relying on radiolabeled substrates or liquid chromatography–tandem mass spectrometry. They are also fully compatible with high-throughput screening. 5. Limitations of fluorescent dye-based SLC assays include the relatively low specificity of fluorescent probes, substrate-dependent variability in SLC inhibition, and limited performance of trans-stimulation or competitive counterflow assays for identifying SLC substrates.

Tacrolimus is a novel immunosuppressor for its significant anti-inflammation and immune activity, which would induce hyperglycaemia, increasing its combination with hypoglycaemic drugs. Pachymic acid has been demonstrated to possess the pharmacological activity of anti-hyperglycaemia. Tacrolimus combining pachymic acid was investigated, aiming to guide the prescription of patients taking tacrolimus. In rats, 1.2 mg/kg tacrolimus was combined with three dosages of pachymic acid (50, 100, and 200 mg/kg) with the single dosage of tacrolimus as control. The blood glucose of rats with different medications was monitored and the pharmacokinetic changes of tacrolimus were assessed. Tacrolimus significantly increased the blood glucose of rats. Pachymic acid increased Cmax, AUC, and t1/2 and reduced the clearance rate of tacrolimus in rats, and the effects were promoted by its increasing dosage. The metabolic stability of tacrolimus in rat liver microsomes was also improved by pachymic acid, both of which enhanced its hyperglycaemic effect in rats. Significant inhibition of CYP3A1/2 by pachymic acid was observed with the IC50 value of 12.25μM. Co-administration of tacrolimus with pachymic acid induced adverse interactions, suppressing the metabolism and enhancing the hyperglycaemic effect of tacrolimus through inhibiting CYP3A1/2.

: 1.Objective To investigate the protective mechanism of Astragaloside IV(AS-IV) in diabetic retinopathy(DR). 2.Methods A streptozotocin-induced diabetic rat model was established and divided in to three groups: control, DR, and DR + AS-IV. Retinal injury was assessed using optical coherence tomography(OCT). Retinal proteomes were profiled using 4D-DIA proteomics. Candidate genes were validated using quantitative PCR(qPCR). 3.Results 302 differentially expressed proteins were detected. Venn diagram analysis revealed three down-regulated proteins in the DR group: Gnal, Dennd1a, and Snx13, and two up-regulated proteins: Ogn and Mylpf. AS-IV treatment reversed the expression of Dennd1a and Gnal while downregulating Ogn, Mylpf, and Snx13. PPI analysis revealed limited direct connectivity among the five proteins but identified 10 additional interactors, including MYLK, ADCY9, and RAB35. GO analysis indicated involvement in muscle contraction, muscle myosin complex, and phosphatidylinositol phosphate binding and structural molecule activity. KEGG analysis highlighted calcium signaling as a key pathway. Molecular docking demonstrated stable interactions between AS-IV and Dennd1a, Ogn, and Snx13 proteins. qPCR vconfirmed significant regulation of Dennd1a and Ogn, while Snx13 and Mylpf changes were not significant. 4.Conclusion AS-IV exhibited protective effects against diabetic retinal injury by modulating Dennd1a and Ogn, implicating calcium signaling and structural pathways in its therapeutic mechanism.

1 Objective We aimed to expound the effects of different doses of dexmedetomidine (Dex) combined with stellate ganglion block (SGB) on postoperative pain, sleep quality, and serum orexin A levels in patients undergoing general anesthesia for laparoscopic radical resection for colorectal cancer (CRC). 2 Methods This prospective randomized controlled trial enrolled 320 CRC patients, randomly assigned to four groups (n = 80): control (0.9% NaCl + SGB), and three Dex groups receiving low, medium, or high Dex infusion (0.2, 0.4, and 0.6 mcg/kg·h, respectively) combined with SGB. Postoperative pain [Visual Analogue Scale (VAS), postoperative days 1–3], insomnia [Athens Insomnia Scale (AIS), before and after surgery], serum orexin-A levels (enzyme-linked immunosorbent assay), and adverse events were assessed and compared. 3 Results All Dex groups showed lower VAS scores (postoperative days 1–3), postoperative AIS scores, and serum orexin-A levels than the control group (P < 0.05). These improvements were dose-dependent, with the high-dose group demonstrating the most significant effects. The incidence of adverse events was lower in the Dex groups, with no significant differences across dosage levels (P > 0.05). 4 Conclusion Dex at 0.6 mcg/kg·h combined with SGB provides optimal postoperative analgesia, improves sleep quality, lowers serum orexin-A, and does not significantly increase adverse events.

1. Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a novel class of oral hypoglycemic agents that selectively inhibit glucose reabsorption in the renal proximal tubules, thereby promoting urinary glucose excretion and reducing blood glucose levels. In recent years, accumulating evidence from large-scale clinical trials has demonstrated that SGLT2i not only exert robust glucose-lowering effects but also confer significant protective benefits on the cardiovascular, renal, and nervous systems. However, the precise molecular mechanisms underlying these multi-system benefits remain incompletely understood. 2. Rationale: Mitochondria are central organelles responsible for cellular energy metabolism, redox homeostasis, and calcium handling, and they play a pivotal role in the pathogenesis and progression of various chronic diseases. 3. Mechanisms: Emerging studies indicate that SGLT2i can markedly improve mitochondrial function through multiple mechanisms, including enhancement of mitochondrial quality control, modulation of mitochondrial energy metabolism, reinforcement of antioxidant defenses, and improvement of calcium homeostasis. 4. Conclusions: These mitochondria-centered mechanisms may underlie the protective effects of SGLT2i on the cardiovascular, renal, and neurological systems. In this review, we systematically summarize the regulatory effects of SGLT2i on mitochondrial function and discuss their potential therapeutic implications in related diseases, aiming to provide novel insights and a theoretical foundation for future basic research and clinical applications.

Zinc oxide (ZnO) nanomaterials, acting as engineered xenobiotic-like agents, can induce complex cellular stress and defense responses. This study reports a novel green synthesis of ZnO nanoflowers using Camellia sinensis leaf extract, resulting in a biocompatible nanostructure with a distinctive flower-like morphology. The C. sinensis-mediated synthesis provides a sustainable and reproducible approach for producing stable ZnO nanoflowers. The nanoparticles were thoroughly characterised (hydrodynamic assembly size: 259.3 nm; zeta potential: −32.35 mV; individual nanostructure physical dimensions: ∼38.8 × 138.7 nm), and their biological interactions were evaluated in L929 fibroblasts to assess xenobiotic-like cellular responses. Cytotoxicity was dose- and time-dependent (IC50 = 52.3 µg/mL at 24 h, 14.1 µg/mL at 48 h, and 10.5 µg/mL at 72 h). At a non-toxic IC50 concentration, the nanoflowers induced a transient adaptive stress response, characterised by significant yet reversible upregulation of inflammatory cytokines (IL-1β, IL-10) and key apoptotic regulators (Bax, Bcl-2, and p53). Collectively, this study demonstrates that green-synthesised ZnO nanoflowers trigger moderate, self-resolving apoptotic and inflammatory signalling consistent with a xenobiotic-like adaptive cellular response. These findings highlight the potential of plant-mediated synthesis to engineer ZnO nanostructures with controlled bioactivity, supporting their safer application in biomedical contexts.

The cytochromes P450 (P450 or CYP), a family of drug-metabolising enzymes, are important in drug development and drug therapy. In tree shrews, a range of P450s, including CYP1A, CYP2A, CYP2B, CYP2C, CYP2D, CYP2E, CYP3A, CYP4A, and CYP4F, have been identified and analysed. In general tree shrew P450s have enzymatic characteristics similar to those of human P450s. In the present study, the cDNAs of five novel tree shrew P450s homologous to human CYP2J2, namely, CYP2J104, CYP2J105, CYP2J106, CYP2J107, and CYP2J108, were identified. The deduced amino acid sequences (500–502 residues) were highly homologous (79–87%) to human CYP2J2 and were closely related to human CYP2J2 in a phylogenetic tree. All five novel tree shrew CYP2J genes contained nine coding exons and formed a gene cluster at a genomic region corresponding to human CYP2J2. Except for CYP2J104 mRNA, expression of all tree shrew CYP2J2 mRNAs was detected in liver. All five tree shrew CYP2Js metabolised ebastine and astemizole, typical substrates of human CYP2J2, and thus were functional enzymes with characteristics similar to human CYP2J2.

Case reports of adverse event and loss of efficacy in individuals are the primary source of natural product drug interactions (NPDIs). Given the fundamental constraints, there is clear need for prospective and systematic study as foolproof methodology to understand NPDIs. Although human trials are confirmatory, an integrative physiologically-based pharmacokinetic (PBPK) modelling approach can be considered, despite challenges associated with NP data availability, variability and complexity. To explore the applicability of this approach, glycyrrhizin (GL) and its active metabolite glycyrrhetinic acid (GA) were identified as an NP with numerous pharmacological benefits and a potential likelihood of concomitant administration with narrow therapeutic antipsychotic drug quetiapine. Numerous serious case reports of quetiapine toxicity in combination with NPs support the proposed hypothesis. Simcyp® simulator was used to develop and validate quetiapine PBPK model followed by its utilisation for the evaluation of NPDI risk. PBPK modelling data indicated ∼ three-fold increase in quetiapine area under the curve (AUC) and peak plasma concentration (Cmax) in the presence of GA, signifying moderate increase in exposure which implies the need for further clinical assessment. This study successfully demonstrated the translation of in vitro information into helpful risk predictions for in vivo NPDIs by PBPK modelling.

A five-compartment hybrid model that simulates the pharmacokinetic behaviour of methyl mercury (MeHg) and its biotransformation (demethylation) product inorganic mercury (Hg(II)) in humans is described. This model accounts for demethylation of MeHg at two sites: one which is within the body and a second which is extracorporeal (presumably the gut lumen). Simulations indicate that approximately 85% of demethylation occurs in the gut lumen and 15% in body tissues. The two-compartment model for Hg(II) pharmacokinetics developed by Farris et al. serves as the basis for the five-compartment model and is embedded within its structure. Parameters from the two-compartment model are used to describe Hg(II) pharmacokinetics in the current model. The model is validated against previously published experimental data for two human subjects dosed with MeHg. Model simulations showing the effects of decreased biotransformation of MeHg in the gastrointestinal lumen are discussed.

This study investigated the synergistic effect of l-arginine [inducible nitric oxide synthase (iNOS) substrate] combined with 5-fluorouracil (5-FU, iNOS inducer) on epithelial–mesenchymal transition (EMT) in hepatocellular carcinoma (HCC). In vitro, the combination significantly inhibited HCC cell proliferation, invasion, migration, and upregulated iNOS. It also decreased mesenchymal markers (N-cadherin, vimentin, Snail, Slug) and increased epithelial E-cadherin. In vivo, using diethylnitrosamine-induced HCC rats, the combination group showed extensive tumour necrosis, reduced mitoses, enhanced iNOS, reduced mesenchymal markers, elevated E-cadherin, fewer pseudopodia, and increased cytoplasmic vacuolation compared to the model group. Thus, l-arginine + 5-FU synergistically inhibits HCC metastasis by suppressing EMT via iNOS upregulation.