This study summarizes the chemical features, pharmacological effects, pharmacokinetic profiles, and current limitations arising from the limited natural distribution of Jujuboside A (JuA). Since demand for JuA is increasing while natural resources are scarce, our review focuses is its biosynthetic pathway and production challenges. Recent advances and perspectives on alternatives for production are also discussed, such as directed glycosylation based on structurally related homologs, metabolic pathway regulation of sour jujuba (Ziziphus jujububa var. spinosa (Bunge) Hu ex H.F.Chou), microbial cell factory development, and plant callus culture. This review summarizes the pharmacological activities, pharmacokinetics, and biosynthesis of JuA, and discusses current limitations and potential production strategies. Collectively, these insights highlight the pharmacological potential of JuA and provide a theoretical basis for future mechanistic studies and sustainable large-scale production.
Drug-induced liver injury remains a principal trigger of acute hepatic failure, late-stage drug attrition, and post-marketing withdrawal, reflecting persistent limitations in mechanistic prediction and translational safety assessment. Owing to its central role in xenobiotic biotransformation, the liver is highly vulnerable to metabolic bioactivation and reactive intermediate formation. This review presents a metabolism-centered; systems level framework that integrates Phase-I and Phase-II enzymatic processes with downstream cellular stress responses governing hepatocellular fate. Cytochrome 450-mediated oxidation and subsequent conjugative pathways determine the balance between detoxification and electrophilic burden; disruption of this equilibrium initiates oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, bile-acid transport impairment, immune-inflammatory activation, and regulated cell death. Emphasis is placed on the dynamic crosstalk among these pathways, which explains interindividual variability, idiosyncratic susceptibility and preclinical-clinical discordance. Emerging insights from network toxicology, transcriptomics, metabolomics and computational modelling have enhanced mechanistic resolution beyond conventional biomarkers. Concurrently, advanced experimental systems including three-dimensional hepatic cultures, organoids, micro-physiological liver-on-chip platforms, humanized animal models and integrative in vitro-in silico approaches are improving translational fidelity. Collectively, this synthesis advances a cohesive mechanistic perspective and highlights integrative strategies to strengthen early risk stratification, mechanistically informed evaluation and predictive safety assessment in drug development.
Bioactivation and clearance of anticancer agents are crucial factors in the efficacy and toxicity of anticancer drugs. Exosomes are membrane-bound vesicles secreted by tumor cells and the tumor microenvironment. These vesicles contain drug-metabolizing enzymes, transporters, and RNA. Exosomes can be non-invasively collected from the blood. This article has been prepared by combining the evidence of the role of exosomal cytochrome P450 isoforms, such as cytochrome P450 family 2 subfamily C member 19, cytochrome P450 family 2 subfamily D member 6, and cytochrome P450 family 3 subfamily A member 5, in the oxi-dation of anticancer drugs in the first phase of drug metabolism. Exosomal UDP-glucuronosyl-transferase 1A1 has been found to help in the conjugation of anticancer drugs in the second phase of drug metabolism. Exosomal ATP-binding cassette transporters, P-glycoprotein, mul-tidrug resistance-associated protein 1, and breast cancer resistance protein have been found to act as intercellular conveyors of drug efflux capacity. These transporters can modulate the ef-ficacy of chemotherapy. Exosomal microRNAs, such as microRNA-21, microRNA-155, and microRNA-1246, have been found to modulate apoptosis, DNA repair, metabolic adaptation, and chemotherapy resistance through the PI3K/AKT pathway, EZH2/STAT3 pathway, and PDCD4 pathway. Long non-coding RNAs, such as UCA1 and HOXA antisense RNA, can reprogram the chromatin structure. These long non-coding RNAs can suppress tumor suppres-sor genes, thus leading to chemotherapy resistance. Bioinformatics pipelines have been de-signed to bridge the gap between exosomal RNA and protein levels in the profile of dynamic metabolic states. The challenges in the field of exosomal therapy drug monitoring have been discussed in the article. The article has recommended the use of artificial intelligence in the integration of omics with microfluidic technology for the improvement of exosomal therapy drug monitoring.
Introduction: Type 2 diabetes management remains challenging because of low bioavailability, side effects, and poor compliance with oral therapies. Transdermal delivery methods offer a non-invasive therapeutic approach with sustained delivery, which avoids first-pass metabolism. Methods: A total of 207 different phytochemicals were virtually screened using i-dock against the diabetic target, PPAR-γ. Subsequently, three matrix-type transdermal patches were developed: a patch containing pure baicalin, a standard patch containing metformin, and a baicalin-loaded phytosomal patch. Phytosomes loaded with baicalin were optimized by using Central Composite Design and evaluated for their physicochemical properties, drug content, physical strength, in vitro, and ex vivo studies. In vivo antidiabetic efficacy was also studied in diabetic Wistar rats over 21 days, followed by a comparison of all formulations, including histopathological analysis of pancreatic tissue. Results: Molecular docking studies showed promising results; baicalin has a high binding affinity for PPAR-γ (-9.8 kcal/mol). The optimized phytosomal patch confirmed a uniform drug content (91.4 ± 0.12 %) and showed sustained release over 12 hours. The ex vivo permeation study showed a significantly higher skin flux for the phytosomal patch (83.6%). In vivo studies confirmed that baicalin-loaded phytosomal patches showed significant blood glucose reductions (223 ± 0.32 to 96 ± 0.38 levels by Day 21), a comparable efficacy to standard metformin patches (224 ± 0.37mg/dL to 94 ± 0.34 mg/dL by Day 21). Discussion: The enhanced skin permeation, penetration, and sustained-release exhibited by the phytosomal transdermal patch can be explained by the phospholipid-based shell structure, leading to better affinity with the skin, facilitating retention of the drug. The comparable glycemic control observed with metformin indicates that baicalin-loaded phytosomal transder-mal patches can achieve effective therapeutic concentrations via transdermal delivery, which is corroborated across two studies. These observations are consistent with previous literature documenting improved solubility and bioavailability of plant-derived actives utilizing phyto-some-based systems, which have applicability for chronic metabolic diseases such as T2DM. Conclusion: The developed phytosomal transdermal patch showed sustained release, better permeation, and potent antidiabetic activity; thus, it offers an alternative to conventional T2DM therapies.
Introduction: Chiglitazar was approved by the China National Medical Products Administration (NMPA) in 2021 for the treatment of patients with type 2 diabetes mellitus, and may also benefit from metabolic dysfunction-associated steatohepatitis (MASH). Methods: To characterise the role of Chiglitazar in MASH, in vitro experiments examining monocyte activation and migration were conducted, alongside liver and stellate cell proliferation assays. Three distinct MASH animal models (db/db mouse model, MCD model, CCl4 model) for conducting in vivo studies were established. Results: The results indicated that Chiglitazar reduced MCP-1-induced THP-1 migration and down-regulated TNF-α and MCP-1 expression. It also blocked TGF-β-driven proliferation in dermal fibroblasts and hepatic stellate cells while suppressing α-SMA and CTGF expression. In vivo, Chiglitazar alleviates hepatic steatosis and inflammation in the MCD model, whilst improving hepatic inflammation and fibrosis in both the CCL4 and HFD+CCL4 models. Discussion: In the study, it has been demonstrated that chiglitazar suppresses monocyte activation and chemotaxis, thereby attenuating chronic inflammation-elicited vascular and tissue damage. It also blocks fibroblast proliferation and differentiation, curbing toxin- or metabolite-induced inflammation and fibrosis. Although CCl4, MCD, and HFD+CCl4 models were used, they only partially reproduce human MASH pathology. Future work should employ more physiologically faithful systems. Conclusions: As the world's first pan-PPAR agonist approved for the treatment of Type 2 Diabetes Mellitus (T2DM), Chiglitazar has also demonstrated potential for treating MASH by modulating steatosis, inflammation, and fibrosis. This potential may be translatable into clinical treatments in the foreseeable future.
In the article titled "Nanocochleates in Clinical Trials: A Review of Current Status, Challenges, and Future Directions", published in Current Drug Metabolism, 2025, 26(6), 390-401 [1], the in-text citation of references [100, 101] was inadvertently included in Table 2 of the original version of the manuscript. The original article can be found online at: https://www.eurekaselect.com/article/150830.
Introduction/Objectives Procyanidins are abundant dietary flavonoids with diverse pharmacological activities; however, their Absorption, Distribution, Metabolism, and Excretion (ADME) remain incompletely characterized. MT-8, a procyanidin B3 derivative with an ethyl group at the C8 position of the A-ring, is a promising preclinical candidate for cerebral ischemia treatment and is currently in the Investigational New Drug (IND) application stage. This study aimed to systematically characterize the ADME profile of MT-8 in male Sprague-Dawley (SD) rats following intravenous administration to provide a reference for ADME studies of procyanidin-related compounds. Methods A single intravenous dose of 24 mg/kg (100 mu Ci/kg) [C-14]MT-8 was administered to male SD rats. Given the observed instability of MT-8 in plasma due to catechol oxidation, 10 mM tris(2-carboxyethyl) phosphine hydrochloride (TCEP) was employed as a stabilizer in all sample preparations. Pharmacokinetics, tissue distribution, mass balance, metabolite profiling, and metabolic enzyme phenotyping were comprehensively evaluated. Results Pharmacokinetic analysis revealed rapid elimination of [C-14]MT-8-related substances, with a terminal half-life of 1.77 hours. The blood-to-plasma radioactivity ratio (1.68) indicated preferential distribution into blood cells. Tissue distribution revealed the highest radioactivity concentrations in the small intestine, kidneys, and liver. Mass balance analysis showed total radioactive recovery of 95.49% within 168 hours, with clearance of >90% of drug-related substances within 24 hours, predominantly via feces (85.57%) and bile (62.78% in bile duct-cannulated rats), with only 9.91% in urine. Metabolite profiling identified 32 metabolites in plasma, urine, feces, and bile, with methylation and glucuronidation as the major metabolic pathways. In vitro phenotyping referred to catechol-O-methyltransferase (COMT) involvement in methylation and UDP-glucuronosyltransferase 1A1 (UGT1A1) and 1A9 (UGT1A9) in glucuronidation. Discussion After verifying the mechanism of the instability of MT-8 in plasma, we tracked the in vivo disposition of MT-8 via radioisotope labeling technique and acquired credible pharmacokinetic, mass balance, tissue distribution, and metabolite identification results. Phenotypes of two enzymes were determined to further the investigation of the methylation and glucuronidation process of in vivo clearance of MT-8. Conclusion Collectively, MT-8 undergoes rapid clearance, broad distribution, extensive metabolism, and predominant biliary/fecal excretion. These findings provide critical support for MT-8's IND application and subsequent clinical development.
Impairment or irreversible loss of bone tissue function remains a prevalent clinical challenge, frequently compounded by donor scarcity, perioperative infection, and immune-mediated rejection, which collectively constrain therapeutic success rates. Novel functional nanomaterials based on nucleic acids-endowed with superior biocompatibility, predictable biodegradability, negligible systemic toxicity, and an abundance of programmable modification sites-have emerged as versatile platforms in bone tissue engineering. Currently, these materials are principally exploited across four interrelated domains: sustained release, bone targeting, scaffold materials for bone regeneration, and bioimaging, all aimed at orchestrating efficient bone regeneration. Recent mechanistic investigations into nano-bio interactions reveal that autophagy, a conserved catabolic pathway in eukaryotes that maintains energetic and metabolic homeostasis, critically governs skeletal repair by directing the timely degradation of intracellular cargo and the turnover of damaged organelles. Through direct modulation of osteoclast and osteoblast differentiation, autophagy fine-tunes the coupled process of bone remodeling. Concurrently, it shapes the regenerative milieu by reprogramming immune cell responses. Consequently, targeted modulation of autophagy represents a rational and promising strategy through which nucleic acid nanomaterials can accelerate bone regeneration. This review synthesizes current knowledge on the contributions of nucleic acid nanomaterials to bone healing, delineates the regulatory functions of autophagy in skeletal regeneration, and explains how these nanomaterials exploit autophagy as a mechanistic lever to enhance bone repair.
INTRODUCTION:The purpose of this systematic review was to assess the expression of nicotinamide N-methyltransferase (NNMT), its mechanistic value, and clinical importance in Hepatocellular Carcinoma (HCC). METHODS:A search was conducted in PubMed, Scopus, Web of Science, Google Scholar, and the Cochrane Library in accordance with PRISMA guidelines. Studies published between 2010 and 2024 that evaluated NNMT expression and its functional implications in HCC were included. Data extraction, synthesis, and qualitative analysis were performed according to standardized criteria. RESULTS:Sixty studies were included in this review. Most studies reported significantly higher NNMT overexpression in liver tumor tissue compared to non-tumor liver tissue. High NNMT levels were associated with aggressive tumor behavior, poor prognosis, and disruptions in methylation and energy metabolism. However, comparability across studies was limited due to heterogeneity in detection methods and small cohort sizes. DISCUSSION:The findings indicate that NNMT plays a crucial role in hepatocarcinogenesis by regulating methyl-donor balance and epigenetic remodeling. Although NNMT shows strong diagnostic and therapeutic potential, the current evidence is largely preclinical, high-lighting the need for multicenter validation. CONCLUSION:NNMT is a promising biomarker and therapeutic target for HCC. Future research should include quantitative assessment of NNMT expression, mechanistic validation, and clinical studies exploring NNMT inhibition strategies.
INTRODUCTION:Cytochrome P450 2E1 (CYP2E1) plays a crucial role in metabolism and disease, making it highly significant to establish a simpler, sensitive method for evaluating its in vivo activity compared to traditional pharmacokinetic (PK) parameters. METHODS:A high-performance liquid chromatography-ultraviolet (HPLC-UV) method was developed and validated for determining chlorzoxazone (CZX) and its metabolite 6-hydroxy CZX (6-OH CZX) in plasma. Four mouse models with distinct CYP2E1 activity were constructed: high activity induced by isoniazid, and low activity via Q11 (a CYP2E1 inhibitor), Cyp2e1 knockout, or carbon tetrachloride (CCl₄). PK experiments were conducted, with activity changes verified by in vitro CYP2E1 protein expression and microsomal activity. Additionally, the sensitivity of PK parameters and the plasma 6-OH CZX/CZX ratio (metabolite ratio, MR) for characterizing CYP2E1 activity, as well as correlations between MR at different time points and both microsomal CYP2E1 activity and CZX half-life (t₁/₂), were analyzed. RESULTS:The HPLC-UV method met analytical requirements in terms of specificity, linearity, and intra-day and inter-day precision. Microsomal activity and protein expression experiments confirmed the successful establishment of the four models. For CYP2E1 activity characterization, CZX t₁/₂ was more sensitive than its area under the curve (AUC) and clearance (CL); MR values at 15 and 7 minutes outperformed those at 2 minutes, with 15-minute MR showing stronger correlations with microsomal activity (r = 0.57, P = 0.007) and CZX t₁/₂ (r = 0.83, P < 0.01). DISCUSSION:This study addresses limitations of traditional PK parameters (multiple samplings, non-metabolic interference) and existing MR methods (unclear optimal time points). The 15-min MR and CZX t₁/₂ offer simplified evaluation, with CZX's high CYP2E1 specificity enhancing translation. Limitations include focus on male C57BL/6J mice and single-point MR's inability to reflect dynamic activity. CONCLUSION:Four representative mouse models with distinct CYP2E1 activity were successfully constructed. CZX t₁/₂ exhibits higher sensitivity and applicability in characterizing in vivo CYP2E1 activity changes, while the 15-minute MR better represents activity changes. This research lays a foundation for characterizing CYP2E1 variations in disease and pathological processes.
INTRODUCTION:Rheumatoid Arthritis (RA) is a chronic autoimmune inflammatory disease. Guogong Jiu (GGJ) is a classical traditional Chinese medicine formula that is widely used in clinical treatment of rheumatoid arthritis. Nevertheless, the gut microbiota and metabolic mechanisms have not been fully studied. The objective of this study was to elucidate the gut microbiota-mediated mechanisms by which GGJ alleviates RA using network pharmacology, metabolomics, and experimental approaches. METHODS:A rat model of collagen-induced arthritis was established to assess anti-arthritic effects systemically. The arthritis index, histopathology, inflammatory cytokines, and gut microbiota analysis (16S rRNA) were assessed for their effects. The serum and fecal metabolomics were done using UHPLC-Q-Exactive MS/MS. Moreover, network pharmacology and secondary metabolome analysis were used to identify the active herbal components, potential targets, and pathways, which were validated in Rheumatoid Arthritis Fibroblast-Like Synoviocytes (RA-FLS) as well. RESULTS:GGJ improved the symptoms of Rheumatoid arthritis. GGJ affected pathways involved in amino acid, lipid, and energy metabolism. Moreover, the assessment of gut micro-biota revealed that GGJ helped restore microbial equilibrium by augmenting beneficial bacteria populations, including Lactobacillus and Alloprevotella, alongside diminishing Prevotella abundance. An integrated analysis identified NF-κB, MAPK, and NRF2 as key targets, which were subsequently validated at the cellular level. DISCUSSION:The multi-omics integration reveals that GGJ exerts its therapeutic effects through coordinated regulation of the gut-joint axis, involving microbiota restoration, metabolic reprogramming, and signaling pathways. These findings provide a mechanistic basis for the clinical application of GGJ in RA. CONCLUSION:GGJ is effective in RA through multi-target effects involving modulation of inflammatory signaling pathways, mediation of metabolic reprogramming, and restoration of gut microbiota. The clinical application of GGJ for RA is therefore scientifically supported.
INTRODUCTION:Type 2 Diabetes (T2D) presents a significant global health challenge, characterized by persistent hyperglycemia and insulin resistance, with effective long-term glycemic control remaining a critical unmet need. Geraniol, a naturally occurring monoterpene alcohol, holds promising anti-diabetic potential but is limited by poor water solubility, which restricts its therapeutic application. This study focuses on the formulation and CCD-based optimization of geraniol-loaded niosomes. Additionally, to assess its antidiabetic effect, blood glucose levels were evaluated. METHOD:Geraniol-loaded niosomes were formulated using the thin-film hydration technique. A central composite design was generated using Design Expert software to evaluate the impact of Span 40 and cholesterol concentrations on dependent variables such as particle size and encapsulation efficiency. A streptozotocin-induced diabetic model was used to assess the in vivo antidiabetic effect of the geraniol-loaded niosomes. RESULT:Using the thin-film hydration technique and CCD optimization, the niosomes demonstrated favorable characteristics, including an average particle size of 287.7 nm, an entrapment efficiency of 80.13%, and a zeta potential of -25.46 mV. Geraniol-loaded niosomes produced a notable hypoglycemic effect, reducing blood glucose levels from 275 ± 0.28 mg/dL to 150 ± 0.20 mg/dL by day 21. Although slightly less potent than metformin (117 ± 0.93 mg/dL), the formulation showed significantly better efficacy than both the diabetic control and plain geraniol solution groups. DISCUSSION:Pharmacokinetic analysis revealed that the AUC, AUMC, and MRT of the geraniol-loaded niosomal formulation were approximately 1.5-, 4-, and 3-fold higher, respectively, compared to plain geraniol. These findings indicate that niosomal formulations improve bioavailability while providing sustained and prolonged drug release. CONCLUSION:Overall, these results highlight the potential of geraniol-loaded niosomes as an innovative and effective strategy for managing T2D, supporting further clinical research to explore their therapeutic application in addressing this global health challenge.
INTRODUCTION:Reported pharmacokinetic parameters, particularly half-life (t1/2), show substantial variability for phylloquinone, due to the limitations of classical pharmacokinetic models. The study aims to determine the pharmacokinetic parameters of phylloquinone using a Constant-Speed Intravenous Infusion (CSII) strategy, designed to overcome the limitations of the low terminal-phase concentration quality following Intravenous (IV) bolus administration. METHODS:The Sprague-Dawley rats received a constant-rate infusion of phylloquinone for 15 hours. Plasma concentrations were quantified by a validated HPLC method, and pharmacokinetic parameters following CSII were derived by fitting the data to a one-phase exponential association model. RESULTS:Following CSII, phylloquinone exhibited a t1/2 of 4.27 ± 0.47 h, CL of 56.93 ± 9.00 mL/h, and Vd of 321.86 ± 29.25 mL without the limitation of low terminal-phase concentrations. Following IV, the t1/2 and Vd of phylloquinone based on two-compartment analysis were larger than those based on one-compartment analysis. Noncompartmental analysis revealed significant differences in t1/2 and Mean Residence Time (MRT) across varying sampling durations. Meanwhile, the t1/2 of phylloquinone was markedly different from its MRTequated half-life. Additionally, the Vd estimated after CSII was larger than that obtained from the IV bolus. DISCUSSION:The CSII strategy avoids reliance on error-prone terminal-phase data by deriving the pharmacokinetic parameters from the ascending phase of the concentration-time profile. This approach provided robust parameter estimates and helped clarify inconsistencies observed with traditional IV bolus analyses. CONCLUSION:CSII provides a valuable complementary strategy for pharmacokinetic parameter estimation, especially for compounds with problematic terminal-phase analysis or those routinely given by CSII. Its broader applicability warrants further investigation.
BACKGROUND:Cordyceps militaris is a medicinal fungus known for producing bioactive compounds, including cordycepin, adenosine, and polysaccharides, that exhibit antioxidant, immunomodulatory, and anticancer properties. Enhancing production and ensuring the genetic stability of these metabolites are essential for therapeutic development. OBJECTIVE:To evaluate growth characteristics, metabolite yield, antioxidant activity, and genetic stability of 20 C. militaris strains, and to identify high-performing, stable candidates suitable for pharmaceutical applications. METHODS:Twenty C. militaris strains were cultured and analyzed for colony diameter, fruiting body morphology, biomass yield, and bioactive compound content. Antioxidant activity was assessed using the DPPH assay. Genetic stability was monitored over five generations via MAT gene profiling. RESULTS:Strain KTDT8 showed superior performance with the highest levels of cordycepin (469.8 ± 16.4 mg/100 g), adenosine (121.8 ± 7.4 mg/100 g), and polysaccharides (37.0 ± 2.9 mg/g), and the strongest antioxidant activity (IC₅₀ = 31.2 μg/mL). The strain maintained morphological and genetic stability across four generations, with a moderate decline in the fifth. DISCUSSION:KTDT8 consistently demonstrated superior metabolite yield, antioxidant capacity, and morphological stability across generations. Despite a moderate decline in biomass and fruiting body quality in the fifth generation, the strain retained its core phenotypic and genetic traits. These findings support KTDT8 as a viable candidate for long-term cultivation and bioactive compound production. CONCLUSION:KTDT8 represents a genetically stable, high-yielding strain with strong antioxidant properties, supporting its potential for large-scale pharmaceutical and nutraceutical applications.
OBJECTIVE:Baicalin (BA), the primary active component of Scutellaria baicalensis, exhibits anti-tumor potential; however, its multi-target mechanism in the treatment of non-small cell lung cancer (NSCLC) remains poorly understood. METHODS:This study systematically elucidated the anti-NSCLC mechanism of BA through an integrated approach that combined network pharmacology, molecular docking, molecular dynamics simulations, in vivo animal models, and untargeted metabolomics using LC-MS. Potential targets were predicted using SwissTargetPrediction and multiple disease databases. A protein-protein interaction (PPI) network was constructed and analyzed with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Core targets were validated via molecular docking and simulations. The effects of BA on tumor growth and on the expression of EGFR and TNF-α were assessed in an A549 tumor-bearing nude mouse model. Serum metabolite changes were profiled and linked to associated pathways. RESULTS:Sixty overlapping targets were identified, with EGFR, TNF-α, CASP3, PTGS2, EZH2, and IL-2 serving as core nodes. Molecular docking demonstrated strong binding affinity between BA and both EGFR (-9.830 kcal/mol) and PTGS2 (-7.244 kcal/mol). The in vivo xenograft model demonstrated that BA (2.5 mg/kg) significantly inhibited NSCLC tumor growth, with efficacy comparable to paclitaxel. Immunohistochemistry confirmed BA downregulated EGFR and TNF-α expression in tumors. Metabolomics analysis revealed 17 differentially expressed metabolites and four significantly altered metabolic pathways: purine, caffeine, sphingolipid, and pyrimidine metabolism. Purine metabolism exhibited the most pronounced perturbation. DISCUSSION:The integrated analysis reveals that BA exerts its anti-NSCLC effects through a multi-target mechanism involving direct interactions with key signaling proteins, such as EGFR and PTGS2, downregulation of oncogenic and inflammatory pathways, and systemic reprogramming of cancer-associated metabolism, with purine metabolism as a central target. CONCLUSION:BA exerts its anti-NSCLC effects via multi-target regulation of oncogenic signaling and metabolic reprogramming. This offers preliminary insights that could inform future applications in metabolic-targeted therapies and combination treatments.
INTRODUCTION:Oxycodone is frequently co-consumed with xylazine, etizolam, di-azepam, and methamphetamine during clinical and/or illicit use. METHODS:We investigated oxycodone metabolism to its two main metabolites, the active ox-ymorphone and the inactive noroxycodone, and potential interactions with these four drugs, using rat (RLM) and human (HLM) liver microsomes. RESULTS:In RLM, Km values were similar for oxymorphone (115 μM) and noroxycodone (128 μM) formation, whereas in HLM, Km values differed for oxymorphone (146 μM) and noroxycodone (1.23 mM) formation. The CLint of oxycodone to noroxycodone was ~4-fold higher than oxycodone to oxymorphone, in both RLM and HLM. Xylazine inhibits (Ki) ox-ymorphone (1.9 μM) and noroxycodone (4.4 μM) formation in RLM more potently than in HLM (313 μM and 247 μM, respectively). Diazepam inhibits oxymorphone (5.0 μM) and no-roxycodone (5.6 μM) formation in RLM more potently than in HLM (1.8 mM and 163 μM, respectively). Etizolam inhibits oxymorphone (14.2 μM) and noroxycodone (16.1 μM) for-mation in RLM more potently than in HLM (550 μM and 129 μM, respectively). Metham-phetamine is not a potent inhibitor of oxymorphone formation (487 μM in RLM and 352 μM in HLM) or noroxycodone formation (5.8 mM in RLM and 2.7 mM in HLM). Similar inhi-bition patterns in RLM for both oxycodone and dextromethorphan, a probe substrate, con-firmed that CYP2D and CYP3A mediate oxymorphone and noroxycodone formation, respec-tively. DISCUSSION:In summary, xylazine, diazepam, and etizolam may cause pharmacokinetic drug-drug interactions (PK-DDIs) with oxycodone in rats but are unlikely to do so in humans. CONCLUSION:Substantial species differences were observed in both the metabolism of oxyco-done by CYP2D and CYP3A and the inhibition of metabolite formation in RLM versus HLM.
INTRODUCTION/OBJECTIVE:This study evaluates the adverse effects of sodium benzoate on the bone marrow and liver of rats, its potential to form benzene, and the protective role of Atriplex halimus extract. METHODS:Thirty male albino rats were divided into five groups: control, Atriplex halimus extract alone, sodium benzoate alone, sodium benzoate with preventive Atriplex halimus ex-tract, and sodium benzoate with curative Atriplex halimus extract. Sodium benzoate was administered in drinking water at a dose of 100 mg/kg body weight for 15 weeks. Atriplex halimus extract was administered intragastrically either during the final 30 days (curative) or throughout the entire sodium benzoate exposure period (preventive). Phytochemical analysis of the extract was conducted using LC-MS. Biochemical, histopathological, and oxidative stress markers were assessed. RESULTS:Sodium benzoate exposure led to benzene detection in fat tissues, reduced neutrophil counts, altered hepatic enzyme levels (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase), decreased antioxidant defenses (glutathione, catalase, glutathione S-transferase), and increased malondialdehyde levels. Histopathological analysis revealed significant liver degeneration and milder bone marrow damage. Atriplex halimus extract restored biochemical and histological parameters, reversed neutropenia, and reduced benzene accumulation. DISCUSSION:The findings confirm sodium benzoate's toxicity, particularly its oxidative stress and tissue damage effects, and highlight the protective potential of Atriplex halimus extract due to its phenolic compounds and saponins. CONCLUSION:Atriplex halimus extract exhibits preventive and curative effects against sodium benzoate-induced benzene accumulation in fat, as well as bone marrow and liver injuries.
Due to adsorption of proteins, abundant protein molecules quickly bind to the nano-particles' (NPs) surface when they enter the bloodstream, forming a "protein corona." The protein corona leads to rapid clearance of NPs, thereby impeding efficient drug delivery. Notably, mi-croneedles (MNs) can reduce protein corona formation by altering the route of drug entry and confining the drug within the local tissue microenvironment. This article outlines the relationship between drug-loaded MNs and the protein corona and proposes strategies to suppress its for-mation. Furthermore, it underscores that the synergy between microneedles and stealth nanocar-riers can minimize the detrimental effects associated with protein corona formation.
Herbal medicines have gained remarkable popularity due to their natural origins and potential medicinal value. Nevertheless, they are chemically complex and pose signifi-cant pharmacological challenges. This review focuses on the key aspects influencing their clinical use: their variable bioavailability, complex pharmacokinetics (ADME), and potential for interactions. A primary concern is herb-drug interactions, with special emphasis on the modulation of drug-metabolizing enzymes by specific phytoconstituents, which can alter drug concentrations to an extent that may be life-threatening, causing either increased toxicity or therapeutic failure. The pharmacological profile is further complicated by the complex effects of constituents, such as synergistic or antagonistic actions, which make predicting therapeutic response and safety difficult. A critical challenge in this field is the frequent dis-connect between in vitro findings and in vivo outcomes, underscoring the importance of phar-macokinetic data, particularly bioavailability, for accurate clinical risk assessment. Safety is a paramount concern, as it is often compromised by inconsistent standardization and quality control, leading to batch-to-batch variability, potential adulteration, and contamination. The absence of stringent regulation impairs therapeutic consistency and introduces health risks. To address these issues, advanced approaches are being employed to improve bioavailability, including novel drug delivery systems that enhance solubility and stability. This review em-phasizes that a rigorous, phytoconstituent-centric approach is essential for navigating the complexities of herbal medicine. By addressing challenges in pharmacokinetics, interactions, safety, standardization, and bioavailability through rigorous scientific investigation and em-bracing future perspectives, such as in silico modeling and improved regulatory frameworks, the quality, safety, and effectiveness of herbal treatments can be ensured, supporting their responsible integration into modern, evidence-based medical systems.
The liver plays a vital role in regulating normal physiological processes in the body. Liver dysfunction can lead to mild to severe pathological conditions and, in some cases, death. To date, more than 900 drugs, toxins, and herbs have been identified with the potential to cause various liver diseases, including acute liver damage, cholestatic jaundice, hepatic granulomas, active chronic hepatitis, and hepatic tumors. A wide range of liver dysfunction results from drug consumption and is referred to as drug-induced liver injury (DILI). DILI significantly contributes to the immediate withdrawal of drugs from the mar-ket. Due to its numerous advantages, the oral route has long been the preferred method of drug administration, although these medicines increase the risk of liver damage. Novel drug delivery approaches, such as the lymphatic drug delivery system and lipid-based nanofor-mulations-including solid lipid nanoparticles (SLNs) and nanostructured lipid carriers-can bypass the liver, reducing the toxic effects of various drugs. Therefore, SLNs represent a promising strategy for lymphatic drug delivery, particularly for hepatocompromised pa-tients and those taking hepatotoxic drugs. This review summarizes how lymphatic drug delivery systems and lipid-based nanoformulations can benefit hepatocompromised pa-tients and individuals on hepatotoxic medications.
