Search Results (5,712)

Background: High-dose melphalan 140–200 mg/m² (HDM) with autologous stem cell transplant (ASCT) is standard first-line treatment in multiple myeloma (MM), yet standard BSA-based dosing results in wide variation in systemic exposure (AUC). We developed a pharmacokinetic (PK)-guided dosing strategy using a 100 mg/m² first dose, enabling real-time PK assessment and individualized adjustment for the second dose. We report final results of Phase A of our multi-center Phase 1 trial (NCT04483206, MyMel) evaluating feasibility and accuracy of this personalized approach. Methods: Patients received melphalan 100 mg/m² on Day −3, and seven PK samples were collected and shipped overnight for LC-MS/MS analysis. Real-time AUC estimation using noncompartmental analysis (NCA) guided Day −1 dosing to achieve pre-specified AUC targets (13.5 or 14.5 mg × h/L). For comparison, post hoc Bayesian estimation using a nonlinear mixed effects (NLME) model was performed. Sparse sampling designs were evaluated using NONMEM. Results: All 20 patients successfully received PK-guided dosing, with Day −1 doses determined within 48 h. PK-guided dosing reduced AUC variability (CV 4.20–5.62%), with 19 of 20 achieving AUCs within ±10% of the target, compared to what would have been achieved by BSA dosing (CV 9.74–15.34%). NLME improved accuracy, particularly in patients with missing samples, and maintained performance using only four PK time points. Conclusions: This study demonstrates that PK-guided dosing is accurate and feasible with HDM-ASCT. NLME enhances accuracy and enables simplified sampling. Phase B will identify maximum tolerated systemic exposure of seven additional AUC cohorts using the NLME model and a four-sample design. Full article

Background/Objectives: Ulcerative colitis (UC) is a relapsing colonic disorder in which persistent immune-mediated inflammation is accompanied by oxidative imbalance and deterioration of the protective intestinal mucosal barrier. Due to disease complexity and limitations of current therapies, alternative and adjunctive treatments are needed. This study investigated the phytochemical profiles and anti-UC activities of Commiphora gileadensis, Salsola incanescens, and Savignya parviflora. Methods: The methanolic extracts of aerial parts (AMEs) were characterized using LC-MS/MS and evaluated for their protective effects against acetic acid (AA)-induced UC in female Sprague Dawley rats. Animals were treated orally once daily for 14 days with extract doses of 250 and 500 mg/kg prior to colitis induction. In vitro anti-inflammatory and NO scavenging activities were also evaluated. Molecular docking was performed to explore the potential mechanisms of action by predicting the interactions of key compounds with COX-1 and 2 and the TLR4/MD-2 complex. Results: LC-MS/MS analysis revealed flavonoid-rich extracts with characteristic metabolites, including triterpenes in C. gileadensis, phenolic amides in S. incanescens, and amino acids in S. parviflora. C. gileadensis exhibited the strongest in vitro anti-inflammatory activity, showing marked suppression of interleukin-6 and tumor necrosis factor-α production in lipopolysaccharide (LPS)-induced RAW264.7 macrophages, selective COX-2 inhibition, and potent NO scavenging activity comparable to celecoxib. The extracts significantly attenuated AA-induced colonic injury in a dose-dependent manner. C. gileadensis at 500 mg/kg exhibited the highest protective efficacy by reducing disease activity index, colonic edema, oxidative stress, and inflammatory mediators, while restoring mucosal architecture. It downregulated TLR4 and attenuated NF-κB-dependent inflammatory and iNOS pathways. Histopathological examination and mucin expression results were consistent with these findings. Molecular docking was utilized as a hypothesis-generating tool to provide an in silico insight into the anti-inflammatory activity of C. gileadensis, suggesting potential multi-target interactions with COX-1, COX-2, and the TLR4/MD-2 complex, likely attributable to its unique triterpenoid and flavonoid constituents. Conclusions: C. gileadensis emerged as the most promising extract for UC management, exhibiting marked antioxidant and anti-inflammatory effects. Further mechanistic, pharmacokinetic, and clinical investigations are required to establish its translational potential for the treatment of UC. Full article

Photodynamic therapy (PDT) is a minimally invasive therapeutic modality based on the interaction between a photosensitizer (PS), light, and molecular oxygen to generate reactive oxygen species (ROS) capable of inducing localized cytotoxicity. Natural products provide a chemically diverse source of photosensitizers, including curcumin, hypericin, hypocrellin, chlorin derivatives, alkaloids, flavonoids, anthraquinones, and other photoactive scaffolds. However, their translational development remains limited by poor solubility, aggregation, instability, variable purity, limited tissue penetration, suboptimal pharmacokinetics, and insufficient formulation readiness. In parallel, artificial intelligence (AI), including machine learning (ML), deep learning (DL), quantitative structure–activity relationship (QSAR) and quantitative structure–property relationship (QSPR) modeling, radiomics, and predictive analytics, is increasingly being applied to photosensitizer discovery, molecular property prediction, nanoformulation optimization, treatment planning, and precision PDT. This critical review evaluates the intersection between AI, natural photosensitizers, nanopharmaceutical development, and PDT, with emphasis on methodological strengths, current limitations, and translational priorities. A PRISMA 2020-inspired search strategy identified 27 studies for qualitative synthesis, comprising 11 review articles and 16 original investigations, while additional seminal references were used for historical and mechanistic contextualization. The analysis indicates that current AI applications in PDT are concentrated around molecular property prediction, QSAR/QSPR modeling, phototoxicity assessment, radiomics, image-guided therapy, and treatment-response prediction, whereas AI-guided exploration of natural photosensitizer chemical space and AI-assisted nanoformulation design remain comparatively underdeveloped. Key barriers include heterogeneous datasets, limited natural-product representation in predictive models, insufficient external validation, weak integration between formulation variables and photodynamic outcomes, and limited consideration of manufacturing and regulatory requirements. This review proposes an integrated AI-enabled translational framework connecting natural-product chemical diversity, photochemical prediction, nanocarrier optimization, precision PDT validation, and clinical implementation. Full article

To overcome the challenges of low water solubility, nonspecific biodistribution, limited tumor penetration, and easy inactivation of bortezomib (BTZ) under physiological conditions, we designed and synthesized a novel methoxypolyethylene glycol-modified bortezomib prodrug (mPEG₂₀₀₀-DEA-BTZ). This prodrug employs diethanolamine as a linker and mPEG₂₀₀₀ as the polymer chain, synthesized through a three-step reaction, with its chemical structure confirmed by ¹H NMR. Solubility studies demonstrated that in PBS buffer at pH 7.4, the solubility of mPEG₂₀₀₀-DEA-BTZ was ≥436.0 mg/mL, corresponding to a bortezomib solubility of ≥66.7 mg/mL, over 167-fold higher than that of free BTZ (399 μg/mL). In vitro release experiments showed that only approximately 2% of BTZ was released from the prodrug within 24 h at pH 7.4, indicating excellent physiological stability. In contrast, drug release was significantly accelerated under acidic conditions (pH 6.5 and pH 5.0), with the cumulative release exceeding 90% at pH 5.0 within 4 h and approaching complete release at 24 h. Compared to the previously reported mPEG₅₀₀₀-CA-BTZ prodrug, the lower molecular weight mPEG₂₀₀₀ and diethanolamine linker employed in this study significantly improved the drug release rate and completeness. This pH-sensitive prodrug is expected to enhance the pharmacokinetic profile of bortezomib and achieve acidic tumor microenvironment-triggered targeted release, demonstrating significant potential for clinical translation. Full article

Antimicrobial resistance (AMR) among pathogens involved in intra-abdominal infections (IAIs) represents a critical and escalating clinical challenge. The interconnected nature of antimicrobial resistance, spanning human medicine, veterinary practice, agricultural use and environmental reservoirs, has required coordinated international responses based on the ‘One Health’ principle. This study presents an update on efforts underway worldwide to develop new antibiotics, novel combined antimicrobial agents, and alternatives to classic therapies for IAIs. New antibiotics or compounds with antibacterial activity are currently in various stages of clinical trials, including several fluoroquinolones, beta-lactamase inhibitors, and polymyxin analogues. To reduce the risk of bacterial resistance, various additions to antimicrobial treatments are being explored, such as nanoparticles (NPs), antimicrobial peptides (AMPs), bacteriophages, the CRISPR/Cas system, and probiotics. Each modality offers distinct mechanisms that circumvent established resistance pathways, including multi-target membrane disruption, sequence-specific gene editing, and microbiome restoration. Current preclinical and clinical evidence is synthesized, and key translational barriers, including delivery challenges, safety concerns, regulatory complexity, and the need for IAI-specific pharmacokinetic data are critically examined. In conclusion, the convergence of novel antibiotic agents and non-traditional antimicrobial strategies reviewed herein provides the foundation for a new paradigm in the management of drug-resistant IAIs. The transition from a monotherapy-centric approach to an integrated, multi-modal treatment framework, guided by rapid diagnostics and informed by antimicrobial stewardship, will be essential to preserve therapeutic efficacy against AMR threats of the coming decades. Full article

Background: Calcium formulations are important nutritional interventions for improving insufficient calcium intake and assisting in the prevention and treatment of osteoporosis. In vitro and in vivo performance may be influenced by dosage form, calcium source, and formulation composition. In this study, an integrated approach combining in vitro dissolution, pharmacokinetic, and pharmacodynamic evaluations was used to compare the comprehensive performance of nine calcium formulations and related functional components. Methods: The nine samples were coded as CS-1 to CS-9 according to a predefined order. Calcium release characteristics were determined under simulated gastrointestinal pH conditions using a flow-through cell system. Calcium concentrations in rat plasma, feces, and urine were measured by inductively coupled plasma optical emission spectrometry (ICP-OES) to evaluate calcium exposure, excretion, and retention. Meanwhile, the bone-protective effects of different calcium preparations were assessed in a retinoic acid-induced osteoporotic ICR mouse model, and the pharmacodynamic performance of calcium citrate and various bone-derived peptide preparations was investigated in a calcium-deficient female Sprague–Dawley (SD) rat model. Results: CS-1 exhibited rapid and nearly complete calcium release in simulated gastric fluid and showed a relatively favorable dissolution profile under sequential gastrointestinal pH conditions. Calcium balance analysis indicated that calcium retention in rats was relatively higher after administration of CS-1. Animal experiments showed that different calcium sources and bone-derived peptide preparations improved bone-related parameters to varying degrees, among which CS-1 produced relatively consistent improvements in bone microarchitecture and biomechanical properties. As a functional component of the CS-1 formulation, salmon bone-derived ingredients showed activity in the comparative pharmacodynamic evaluation, suggesting that they may contribute to the overall bone-protective effect. Conclusions: Different calcium formulations showed distinct profiles in dissolution behavior, calcium retention, and bone-protective effects. Among the tested samples, CS-1 demonstrated relatively favorable overall performance, which may be related to its liquid dosage form and salmon bone-derived functional components. Full article

Imperatorin (IPT) is a naturally occurring coumarin with recognized antioxidant and anti-aging properties; unfortunately, its poor water solubility and low oral bioavailability severely limit its practical use. To get around these issues, we formulated IPT-loaded NLCs using grape seed oil and glyceryl monostearate—both food-grade excipients—with the goal of enhancing oral absorption. Optimized IPT@NLCs were prepared by high-pressure homogenization, featuring uniform spherical morphology, an average particle size of 186.63 ± 1.65 nm, a PDI of 0.188 ± 0.008, an encapsulation efficiency of 99.54 ± 0.10%, and a drug loading capacity of 9.08 ± 0.23%. IPT@NLCs remained stable in SGF, while their cumulative in vitro release over 48 h reached 90.56 ± 3.12% in SIF. We established a Caco-2/HT29-MTX-E12 co-culture monolayer to examine mucus penetration, cellular uptake, and transcellular transport routes. In parallel, oxidative stress experiments using 3T3-L1 cells, along with in vivo pharmacokinetic and gastrointestinal safety evaluations, were conducted to provide complementary evidence. Our results indicate that NLC encapsulation significantly improves both the dissolution and intestinal uptake of IPT, primarily by shifting the absorption mechanism from passive diffusion to energy-dependent active transport. In addition, IPT@NLCs effectively reduce intracellular oxidative damage through modulation of endogenous antioxidant enzyme activities. Animal studies further reveal an approximately 9-fold increase in relative oral bioavailability, with no notable irritation to gastrointestinal tissues. Overall, GSO-based NLCs offer safe and efficient oral delivery, enhancing IPT bioavailability and antioxidant activity, providing a strategy for developing natural-product-based formulations. Full article

Background/Objectives: Preoperative characterization of salivary gland tumors remains challenging because conventional MRI and diffusion-weighted imaging may show overlapping features, particularly between Warthin tumors and malignant lesions. This study evaluated the diagnostic value of quantitative permeability MRI based on dynamic contrast-enhanced pharmacokinetic analysis for differentiating salivary gland tumors. Methods: This retrospective single-center study included 51 patients with 59 histologically confirmed salivary gland lesions examined between January 2022 and November 2024. MRI included diffusion-weighted imaging and dynamic contrast-enhanced MRI (DCE-MRI). Quantitative pharmacokinetic analysis based on the Extended Tofts model provided Ktrans, Kep, Ve, and Vp. Interobserver reproducibility was assessed using the intraclass correlation coefficient, and diagnostic performance was evaluated by receiver operating characteristic analysis. Results: Of 59 lesions, 44 were benign, and 15 were malignant. Warthin tumors showed significantly higher Kep values than malignant lesions (median, 998 vs. 480 × 10⁻³/min; p = 0.002) and lower Ve values (median, 121 vs. 245 × 10⁻³; p = 0.004). ADC values partially overlapped between Warthin tumors and malignant lesions. Interobserver agreement was good, with ICC values ranging from 0.78 to 0.86. Kep showed the highest diagnostic performance in this cohort, with an AUC of 0.96. A Kep threshold of 723 × 10⁻³/min yielded 92.3% sensitivity and 93.3% specificity. Conclusions: Quantitative DCE-MRI, particularly Kep, may provide additional information for differentiating Warthin tumors from malignant salivary gland lesions within a multiparametric MRI assessment. The threshold identified in this cohort is exploratory and requires external validation before routine clinical use. Full article

Alzheimer’s disease (AD) is a complex neurodegenerative disorder with limited effective therapies. In this study, a series of 2-(arylamino)thiazol-4(5H)-one derivatives was synthesized using an efficient microwave-assisted protocol, and evaluated for neuroprotective effects against 6-hydroxydopamine (6-OHDA)-induced oxidative stress (OS) in SH-SY5Y neuronal cells and an Aβ42-expressing Drosophila melanogaster model of AD. Among the synthesized compounds, 3n, 3i, and 3b exhibited low cytotoxicity and significant neuroprotection, as evidenced by increased cell viability, reduced reactive oxygen species (ROS) production, and preserved mitochondrial membrane potential. Notably, compound 3n demonstrated the highest activity and effectively ameliorated Aβ42-induced behavioral deficits in vivo. Molecular docking studies predicted favorable binding affinity within the acetylcholinesterase (AChE) active site, with the thiazol scaffold and aryl substituents stabilizing ligand binding through π–π stacking and hydrophobic interactions; compound 3n also formed additional hydrogen bonds enhancing its affinity. Consistent with the docking predictions, in vitro AChE inhibition studies demonstrated that compounds 3n, 3i, and 3b inhibited AChE in a concentration-dependent manner. Network pharmacology predicted seven potential core targets implicated in AD pathogenesis and related pathways, including OS, neuroinflammation, and synaptic dysfunction. Furthermore, in silico pharmacokinetic analysis indicated compliance with Lipinski’s and Veber’s rules, supporting favorable drug-like properties. While further experimental validation is essential, these findings highlight 2-(arylamino)thiazol-4(5H)-one derivatives, particularly compound 3n, as promising multifunctional candidates for further preclinical development against AD. Full article

Background/Objectives: The chemokine receptor CXCR4 plays a pivotal role in tumor progression, metastasis, and therapy resistance and is frequently overexpressed in hematologic malignancies, including multiple myeloma and lymphoma. This study investigates a CXCR4-targeted theranostic platform comprising a PET imaging agent and two therapeutic radioconjugates derived from the high-affinity CXCR4 antagonist LY2510924. Methods: The PET tracer [¹⁸F]AlF-NOTA-SC and therapeutic radioconjugates [¹⁷⁷Lu]Lu-BL02 and [¹⁶¹Tb]Tb-BL02 were synthesized and evaluated. Radiolabeling efficiency, molar activity, and in vitro binding affinity were assessed. Specificity and uptake were evaluated in CXCR4-expressing U87.CD4.CXCR4 and MM.1S cells, with cytotoxic potential being analyzed via clonogenic survival assays. In vivo biodistribution and pharmacokinetics were evaluated in MM.1S xenograft mouse models, supported by longitudinal SPECT imaging. Results: All radioconjugates were obtained with high radiochemical purity (>98%). The constructs showed nanomolar affinity for human CXCR4; in vitro assays confirmed specific uptake in CXCR4-positive cells, and both therapeutic agents demonstrated dose-dependent cytotoxicity. In vivo, all compounds displayed comparable tumor uptake with low off-target accumulation. Co-injection studies confirmed consistent pharmacokinetics across agents, while SPECT/CT imaging demonstrated gradual tumor clearance of [¹⁷⁷Lu]Lu-BL02 over seven days. Conclusions: The radiopharmaceutical trio [¹⁸F]AlF-NOTA-SC, [¹⁷⁷Lu]Lu-BL02, and [¹⁶¹Tb]Tb-BL02 demonstrates the feasibility of a CXCR4-targeted theranostic approach for imaging and treating hematologic malignancies. The observed tumor washout highlights the need for further structural optimization to enhance tumor retention and therapeutic efficacy, providing a clear direction for future development toward clinical translation. Full article

Cardiovascular disease (CVDs) and atherosclerosis remain a major causes of morbidity and mortality worldwide. Endothelial dysfunction is a central driver of atherosclerosis, which is significantly accelerated in diabetes mellitus through hyperglycemia-induced oxidative stress, oxidized low-density lipoprotein (oxLDL) accumulation, and NLRP3 inflammasome activation. Phenolic acids, a class of plant-derived polyphenols, have gained attention as vasoprotective agents due to their antioxidant and anti-inflammatory properties. Among them, rosmarinic acid and salvianolic acid have gained attention, yet no previous review has systematically compared their distinct molecular mechanisms. This review addresses the gap by summarizing the pathophysiological mechanisms linking endothelial dysfunction to atherosclerotic progression and comparing how rosmarinic acid and salvianolic acid modulate oxidative stress, nitric oxide signaling, inflammatory responses, and NLRP3 inflammasome activation. Rosmarinic acid primarily exerts its effects through the p38 MAPK-FOXO1-TXNIP and AMPK/eNOS pathways, while salvianolic acid mainly acts via the PKM2/PKR and NF-ĸB/NLRP3 signaling pathways. Despite these findings, clinical evidence remains limited, primarily limited to Phase 1 pharmacokinetic studies and mixed-extract trials, leaving compound-specific efficacy in humans unverified. This review highlights these translational gaps and suggests prioritizing clinical trials of purified compounds, bioavailability optimization, and dose-standardization studies to advance rosmarinic acid and salvianolic acid toward clinical application in diabetic atherosclerosis. Full article

Background/Objectives: 2-(2-Benzofuranyl)-2-imidazoline (2-BFI) is a selective imidazoline I₂-site ligand that has shown neuroprotective and neuromodulatory effects in preclinical central nervous system (CNS) studies. However, the primary preclinical literature remains fragmented across disease models, outcome types, mechanistic endpoints, and cellular targets, making it difficult to define where its therapeutic-development potential is strongest and how disease- or model-specific functional effects relate to molecular, cellular, tissue, and blood–brain barrier/neurovascular unit (BBB/NVU)-related findings. Methods: This systematic review integrated preclinical evidence from 36 original studies identified in the PubMed, Web of Science, Embase, and Scopus databases through searches last updated on May 19, 2026, to evaluate the strength of evidence for 2-BFI across CNS-related models and to connect functional, molecular, cellular, and neurovascular findings. The evidence categories included ischemic stroke/neurovascular outcomes (n = 13), traumatic CNS injury (n = 2), neuroinflammatory/neurodegeneration-related models (n = 9), behavioral pharmacology (n = 8), and cellular mechanisms (n = 4). Eligible studies were original CNS-related animal, cellular, or behavioral/pharmacological studies that directly evaluated 2-BFI and reported neuroprotective, neurological, cellular, molecular, vascular, inflammatory, neurotransmitter-related, or behavioral outcomes. Findings were synthesized qualitatively, and risk of bias in in vivo animal studies was assessed using SYRCLE’s risk-of-bias tool. Results: The most extensive preclinical evidence was found in ischemic stroke and neurovascular injury models, in which 2-BFI attenuated infarct size, neurological deficits, and edema, and suppressed apoptosis-related injury and blood–brain barrier/neurovascular unit (BBB/NVU) disruption. Across models, these effects are best interpreted as modulation of interconnected secondary injury processes involving N-methyl-D-aspartate receptor (NMDAR)/Ca²⁺-dependent excitotoxicity, oxidative and mitochondrial stress, inflammatory amplification, regulated cell death, and neurovascular destabilization. Evidence from traumatic CNS injury, autoimmune neuroinflammation, Alzheimer’s disease-related models, chronic epilepsy, and cellular stress models broadened the CNS relevance of 2-BFI but remained less replicated or more mechanistically indirect than the stroke/neurovascular evidence. Behavioral and pharmacological studies additionally indicated that 2-BFI modulates neurotransmitter-related systems associated with pain-, affective-, addiction-, opioid-, and compulsivity-related outcomes, although these findings should be distinguished from disease-modifying neuroprotective evidence. Conclusions: Meta-analysis was not conducted because of heterogeneity in models, dosing regimens, treatment timing, and outcomes. Overall, the current evidence does not yet support definitive dosing, treatment timing, or clinical development recommendations for 2-BFI. The strongest preclinical therapeutic rationale is currently found in ischemic stroke and neurovascular injury settings, whereas other CNS indications require further validation. Future studies should define dose–response relationships, therapeutic windows, pharmacokinetic and safety profiles, sex- and age-related effects, and efficacy in clinically relevant comorbid models before clinical translation is considered. The review was not prospectively registered. Funding was provided by a National Research Foundation of Korea grant funded by the Korean government. Full article

Alzheimer’s disease (AD) is a complex neurodegenerative condition marked by a gradual decline in cognitive abilities, a reduction in acetylcholine (ACh) levels, and the accumulation of β-amyloid (Aβ) plaques. In a healthy brain, approximately 80% of ACh is broken down by acetylcholinesterase (AChE). Meanwhile, butyrylcholinesterase (BChE) serves a supportive function, gaining significance as AChE activity diminishes during the progression of Alzheimer’s disease. Modern therapeutic approaches focus on creating dual inhibitors of AChE and BChE that also aim to diminish Aβ-amyloidogenesis through interactions with the peripheral anionic site (PAS). This study combined fragment-based molecular design (CReM), AI-assisted retrosynthetic feasibility assessment, and in silico evaluation (docking, molecular dynamics, and ADMET profiling) to identify novel Donepezil derivatives as potential dual AChE/BChE inhibitors. A series of 10,000 derivatives were developed through computational methods and carefully assessed based on stringent drug-likeness, synthetic accessibility, and medicinal chemistry standards. This was succeeded by comprehensive ADMET profiling. Nine candidates were identified with predicted CNS pharmacokinetics, adequate toxicological profiles and reduced cytochrome P450 liabilities. Molecular docking yielded improved predicted binding affinities relative to Donepezil. Several derivatives, particularly D4 and D5, showed dual-site binding poses spanning both the catalytic gorge and the PAS. MD simulations indicated the stability of these poses over 100 ns. These computational results suggest that the proposed derivatives may preserve or improve upon Donepezil’s pharmacokinetic profile while offering potentially balanced AChE/BChE inhibition and anti-amyloidogenic activity, pending experimental validation. Full article

Thromboembolism is a life-threatening complication of nephrotic syndrome, which is treated with oral anticoagulants (warfarin and direct oral anticoagulants [DOACs]) that possess a variety of pharmacokinetic characteristics. This narrative review focused on drug–drug interactions between oral anticoagulants and calcineurin inhibitors (CNIs) (e.g., tacrolimus, cyclosporine, and voclosporin) for the management of thromboembolism in nephrotic syndrome. While warfarin has less potential for interacting with CNIs, DOACs carry a risk of drug–drug interactions with CNIs owing to the inhibition of drug-metabolizing enzymes and transporters, including cytochrome P450 3A4 (CYP3A4) and P-glycoprotein. Specifically, a significant increase in DOAC exposure was observed when DOACs were co-administered with cyclosporine, a more potent P-glycoprotein inhibitor than tacrolimus. Limited evidence suggests that more pronounced drug interactions occur in specific cases: (1) apixaban and CNIs in patients with renal impairment, (2) edoxaban combined with cyclosporine in patients with renal impairment, and (3) a combination of rivaroxaban with dual inhibitors of P-glycoprotein and CYP3A4 (e.g., cyclosporine and fluconazole). From a pharmacological viewpoint, CNI-induced nephrotoxicity and hypertension may increase the risk of critical bleeding in patients receiving DOACs. In addition, the variation factors of pharmacokinetic parameters, such as renal function, pharmacogenomic profiles, and pathophysiological changes directly caused by nephrotic syndrome, may vary between patients, which could potentially augment the magnitude of drug–drug interactions between oral anticoagulants and CNIs. Further studies are required to understand the clinical significance of drug interactions in patients with nephrotic syndrome. Full article

Background/Objectives: Extra virgin olive oil (EVOO), a key component of the Mediterranean diet, has attracted research interest because olive-derived phenolics demonstrate potential anticancer activity in experimental models. This review summarizes evidence concerning whole EVOO, phenolic-enriched EVOO, olive phenolic extracts, and the isolated compounds hydroxytyrosol, oleuropein, oleocanthal, and oleacein. Methods: A structured narrative search of PubMed, Web of Science, ScienceDirect, and Google Scholar was conducted for literature published between 2015 and 2025. Evidence was reviewed for breast, prostate, colorectal, pancreatic, bone, oral, liver, gastric, hematological, and brain cancers. Comparatively limited evidence concerning cervical, endometrial, ovarian, melanoma, non-melanoma skin, and thyroid cancers was summarized separately. Results: The molecular evidence was derived primarily from cell culture and animal studies using isolated phenolics and concentrated extracts. Preclinical studies indicate that EVOO phenolics may demonstrate anticancer activity through multiple mechanisms, including antioxidant activity, anti-inflammatory effects, cell cycle arrest, induction of apoptosis, inhibition of metastasis, anti-angiogenic activity, and modulation of key signaling pathways, such as PI3K/AKT/mTOR, MAPK/ERK, NF-κB, JAK/STAT, Wnt/β-catenin, p53, and epithelial–mesenchymal transition-related pathways. Most molecular and pathway-level evidence was obtained using isolated phenolic compounds in cell culture or animal models, whereas evidence directly examining whole EVOO consumption was largely observational and substantially more limited. Experimental studies also reported that oleocanthal induced lysosomal membrane permeabilization, whereas hydroxytyrosol and oleuropein promoted mitochondria-mediated apoptosis. Furthermore, preclinical combination studies suggested enhanced tumor-cell sensitivity to selected chemotherapeutic, targeted, and immunotherapeutic agents. However, these effects have not been established in patients. Human evidence remains limited mainly to observational dietary associations and small exploratory interventions, with no conclusive demonstration of cancer prevention or therapeutic efficacy. Conclusions: Isolated EVOO-derived phenolic compounds demonstrated promising anticancer mechanisms in preclinical models. However, these results should not be directly extrapolated to dietary EVOO because experimentally administered doses, bioavailability, metabolism, and food-matrix interactions differ substantially from human dietary exposure. Therefore, well-designed studies using chemically characterized EVOO, pharmacokinetic investigations, and controlled human trials are required before dietary or clinical recommendations can be made. Full article