Search Results (3,728)

The intra-articular application of drugs has gained considerable interest with regard to formulations for advanced drug delivery systems. It has been identified as a potential route for local drug delivery. A drug agent is usually incorporated into the hydrogel to prolong and control the drug release. This study aimed to design and evaluate an intra-articular hydrogel based sodium hyaluronate, which was modified with an additional polymer to enable the sustained release of the incorporated anti-inflammatory agent, diclofenac sodium (NaDic). Viscosity studies, drug release tests and FTIR−ATR measurements, as well as DSC analysis, were carried out to evaluate the obtained formulations. The viscosity measurements were performed using a rotational viscometer. The drug release was carried out by employing the apparatus paddle over the disk. The concentration of the released drug was obtained spectrophotometrically. The results revealed that the addition of the second polymer to the matrix influenced the dynamic viscosity of the hydrogels. The highest viscosity of (25.33 ± 0.55) × 10³ cP was observed when polyacrylic acid (PA) was doped in the formulation. This was due to the hydrogen bond formation between both polymers. The FTIR−ATR investigations and DSC study revealed the hydrogen bond formation between the drug and both polymers. The drug was released the slowest from hydrogel doped with PA and 17.2 ± 3.7% of NaDic was transported to the acceptor fluid within 8 h. The hydrogel based on hyaluronan sodium doped with PA and containing NaDic is a promising formulation for the prolonged and controlled intra-articulate drug delivery of anti-inflammatory agents. Full article

Background: Drug–drug interactions (DDIs) may occur when two or more drugs are taken together, leading to undesired side effects or potential synergistic effects. Most clinical effects of drug combinations have not been assessed in clinical trials. Therefore, predicting DDIs can provide better patient management, avoid drug combinations that can negatively affect patient care, and exploit potential synergistic combinations to improve current therapies in women’s healthcare. Methods: A DDI prediction model was built to describe relevant drug combinations affecting reproductive treatments. Approved drug features (chemical structure of drugs, side effects, targets, enzymes, carriers and transporters, pathways, protein–protein interactions, and interaction profile fingerprints) were obtained. A unified predictive score revealed unknown DDIs between reproductive and commonly used drugs and their associated clinical effects on reproductive health. The performance of the prediction model was validated using known DDIs. Results: This prediction model accurately predicted known interactions (AUROC = 0.9876) and identified 2991 new DDIs between 192 drugs used in different female reproductive conditions and other drugs used to treat unrelated conditions. These DDIs included 836 between drugs used for in vitro fertilization. Most new DDIs involved estradiol, acetaminophen, bupivacaine, risperidone, and follitropin. Follitropin, bupivacaine, and gonadorelin had the highest discovery rate (42%, 32%, and 25%, respectively). Some were expected to improve current therapies (n = 23), while others would cause harmful effects (n = 11). We also predicted twelve DDIs between oral contraceptives and HIV drugs that could compromise their efficacy. Conclusions: These results show the importance of DDI studies aimed at identifying those that might compromise or improve their efficacy, which could lead to personalizing female reproductive therapies. Full article

The Caco-2 in vitro model of the intestinal barrier is a well-established system for the investigation of the intestinal fate of orally ingested chemicals and drugs, and it has been used for over ten years by pharmaceutical industries as a model for absorption in preclinical studies. The Caco-2 model shows a fair correlation with in vivo drug absorption, though some inherent biases remain unresolved. Its main limitation lies in the lack of structural complexity, as it does not replicate the diverse cell types and mucus layer present in the human intestinal epithelium. Consequently, the development of advanced in vitro models of the intestinal barrier, that more structurally resemble the human intestinal epithelium physiology, has increased the potential applications of these models. Recently, Caco-2-based advanced intestinal models have proven effective in predicting nanomaterial uptake and transport across the intestinal barrier. The aim of this review is to provide a state-of-the-art of human in vitro intestinal barrier models for the study of translocation/uptake of nanoparticles relevant for oral exposure, including inorganic nanomaterials, micro/nano plastic, and fiber nanomaterials. The main effects of the above-mentioned nanomaterials on the intestinal barrier are also reported. Full article

This paper focuses on the numerical modeling of drug diffusion in biological tissues using fractional time-dependent parabolic equations with non-local boundary conditions. The model includes a Caputo fractional derivative to capture the non-local effects and memory inherent in biological processes, such as drug absorption and transport. The theoretical framework of the problem is based on the work of Alhazzani, et al.,which demonstrates the solution’s goodness, existence, and uniqueness. Building on this foundation, we present a robust numerical method designed to deal with the complexity of fractional derivatives and non-local interactions at the boundaries of biological tissues. Numerical simulations reveal how fractal order and non-local boundary conditions affect the drug concentration distribution over time, providing valuable insights into drug delivery dynamics in biological systems. The results underscore the potential of fractal models to accurately represent diffusion processes in heterogeneous and complex biological environments. Full article

Background: The candidate therapeutic peptide TnP demonstrates broad, system-level regulatory capacity, revealed through integrated network analysis from transcriptomic data in zebrafish. Our study primarily identifies TnP as a multifaceted modulator of drug metabolism, wound healing, proteolytic activity, and pigmentation pathways. Results: Transcriptomic profiling of TnP-treated larvae following tail fin amputation revealed 558 differentially expressed genes (DEGs), categorized into four functional networks: (1) drug-metabolizing enzymes (cyp3a65, cyp1a) and transporters (SLC/ABC families), where TnP alters xenobiotic processing through Phase I/II modulation; (2) cellular trafficking and immune regulation, with upregulated myosin genes (myhb/mylz3) enhancing wound repair and tlr5-cdc42 signaling fine-tuning inflammation; (3) proteolytic cascades (c6ast4, prss1) coupled to autophagy (ulk1a, atg2a) and metabolic rewiring (g6pca.1-tg axis); and (4) melanogenesis-circadian networks (pmela/dct-fbxl3l) linked to ubiquitin-mediated protein turnover. Key findings highlight TnP’s unique coordination of rapid (protease activation) and sustained (metabolic adaptation) responses, enabled by short network path lengths (1.6–2.1 edges). Hub genes, such as nr1i2 (pxr), ppara, and bcl6aa/b, mediate crosstalk between these systems, while potential risks—including muscle hypercontractility (myhb overexpression) or cardiovascular effects (ace2-ppp3ccb)—underscore the need for targeted delivery. The zebrafish model validated TnP-conserved mechanisms with human relevance, particularly in drug metabolism and tissue repair. TnP’s ability to synchronize extracellular matrix remodeling, immune resolution, and metabolic homeostasis supports its development for the treatment of fibrosis, metabolic disorders, and inflammatory conditions. Conclusions: Future work should focus on optimizing tissue-specific delivery and assessing genetic variability to advance clinical translation. This system-level analysis positions TnP as a model example for next-generation multi-pathway therapeutics. Full article

Prostate cancer continues to be the most common cause of cancer-related disease and mortality among men worldwide, especially in the advanced stages, notably metastatic castration-resistant prostate cancer (mCRPC), which poses significant treatment challenges. Docetaxel, a widely used chemotherapeutic agent, has long served as the standard treatment, offering survival benefits and mitigation. However, its clinical impact is frequently undermined by the development of chemoresistance, which is a formidable challenge that leads to treatment failure and disease progression. The mechanisms driving docetaxel resistance are diverse and complex, encompassing modifications in androgen receptor signaling, drug efflux transporters, epithelial-mesenchymal transition (EMT), microtubule alterations, apoptotic pathway deregulation, and tumor microenvironmental influences. Recent evidence suggests that extracellular RNAs influence drug responses, further complicating the resistance landscape. This review offers a broad discussion on the mechanisms of resistance and explores novel therapeutic approaches to address them. These include next-generation taxanes, targeted molecular inhibitors, immunotherapies, and combination regimens that can be designed to counteract specific resistance pathways. By broadening our understanding of docetaxel resistance, this review highlights potential strategies to improve therapeutic efficacy and the potential to enhance outcomes in patients with advanced treatment-resistant prostate cancer. Full article

The ATP-binding cassette transporter ABCG2 plays a critical role in drug pharmacokinetics and multidrug resistance in cancer therapy. Two common nonsynonymous polymorphisms, rs2231137 (V12M) and rs2231142 (Q141K), are associated with altered ABCG2 function, drug response, and disease susceptibility. However, the functional impact of their haplotype remains poorly understood. In this study, we established Flp-In™-293 cell lines stably expressing ABCG2 (12M/141K) and systematically compared their expression and drug resistance profiles with those of cells expressing ABCG2 (12V/141Q) (WT), ABCG2 (12M/141Q), and ABCG2 (12V/141K). The mRNA of ABCG2 (12M/141K) was expressed at levels comparable to those of the other variants in cells. Cells expressing ABCG2 (12M/141K) exhibited significantly higher resistance to mitoxantrone (10.7-fold) and SN-38 (5.99-fold) than the mock cells. While ABCG2 (12M/141Q) conferred the highest resistance among the tested variants, the ABCG2 (12M/141K) haplotype showed a trend toward higher mitoxantrone resistance than the ABCG2 (12V/141Q) (WT) (p = 0.066), suggesting a haplotype-specific effect. These findings provide novel insights into haplotype-based modulation of ABCG2 function and its contribution to multidrug resistance, with potential implications for optimizing personalized chemotherapy strategies. Full article

Androgenetic alopecia (AGA) is the most prevalent form of alopecia areata. Traditional treatment options, including minoxidil, finasteride, and hair transplantation, have their limitations, such as skin irritation, systemic side effects, invasiveness, and high costs. The transdermal drug delivery system (TDDS) offers an innovative approach for treating AGA by administering medications through the skin to achieve localized and efficient delivery while overcoming the skin barrier. This review systematically explores the application of TDDS in AGA treatment, highlighting emerging technologies such as microneedles (MNs), liposomes, ionic liquids (ILs), nanostructured lipid carriers (NLCs), and transporters (TFs). It analyzes the underlying mechanisms that enhance drug penetration through hair follicles. Finally, this review presents a forward-looking perspective on the future use of TDDS in the management of AGA, aiming to provide insights and references for designing effective transdermal drug delivery systems for this condition. Full article

Background: Salmonella infections pose a serious threat to both animal and human health worldwide. Notably, there is an increasing trend in the resistance of Salmonella to fluoroquinolones, the first-line drugs for clinical treatment. Methods: Utilizing Salmonella Typhimurium CICC 10420 as the test strain, ciprofloxacin was used for in vitro induction to develop the drug-resistant strain H1. Changes in the minimum inhibitory concentrations (MICs) of various antimicrobial agents were determined using the broth microdilution method. Transcriptomic and metabolomic analyses were conducted to investigate alterations in gene and metabolite expression. A combined drug susceptibility test was performed to evaluate the potential of exogenous metabolites to restore antibiotic susceptibility. Results: The MICs of strain H1 for ofloxacin and enrofloxacin increased by 128- and 256-fold, respectively, and the strain also exhibited resistance to ceftriaxone, ampicillin, and tetracycline. A single-point mutation of Glu469Asp in the GyrB was detected in strain H1. Integrated multi-omics analysis showed significant differences in gene and metabolite expression across multiple pathways, including two-component systems, ABC transporters, pentose phosphate pathway, purine metabolism, glyoxylate and dicarboxylate metabolism, amino sugar and nucleotide sugar metabolism, pantothenate and coenzyme A biosynthesis, pyrimidine metabolism, arginine and proline biosynthesis, and glutathione metabolism. Notably, the addition of exogenous glutamine, in combination with tetracycline, significantly reduced the resistance of strain H1 to tetracycline. Conclusion: Ciprofloxacin-induced Salmonella resistance involves both target site mutations and extensive reprogramming of the metabolic network. Exogenous metabolite supplementation presents a promising strategy for reversing resistance and enhancing antibiotic efficacy. Full article

Ulcerative colitis (UC), a subtype of inflammatory bowel disease (IBD), is a chronic, relapsing inflammatory condition that significantly impairs the patient’s quality of life. While biologics have transformed disease management, a substantial number of patients remain unresponsive or lose efficacy over time. Tofacitinib (TOFA), an oral Janus kinase (JAK) inhibitor, introduces a novel therapeutic class of small-molecule drugs with a unique oral administration route, offering enhanced patient convenience and broader accessibility compared to parenterally administered biologics. As the first oral treatment approved for moderate to severe UC in years, TOFA acts by modulating the JAK/STAT pathway, influencing critical inflammatory mediators such as IL-6, IL-17, and IFN-γ. However, response rates are variable and appear dose-dependent, with up to 60% of patients showing inadequate therapeutic outcomes. This review represents the first comprehensive synthesis focused specifically on biomarkers of TOFA response in UC. Drawing on multi-omics data—epigenomics, transcriptomics, proteomics, and cellular profiling, we highlight emerging predictors of responsiveness, including CpG methylation signatures (e.g., LRPAP1 and FGFR2), transcriptomic regulators (e.g., REG3A and CLDN3), immune and epithelial cell shifts, and the cationic transporter MATE1. TOFA demonstrates a dual mechanism by modulating immune responses while supporting epithelial barrier restoration. Despite being promising, TOFA’s dose-dependent efficacy and interpatient variability underscore the critical need for non-invasive, predictive biomarkers to guide personalized treatment. As the first review of its kind, this work establishes a basis for precision medicine approaches to optimize the clinical utility of TOFA in UC management. Full article

Bacteria-mediated cancer therapy represents a novel and promising strategy for targeted drug delivery to solid tumors. Multiple studies have demonstrated that various Bifidobacterium species can selectively colonize the hypoxic microenvironments characteristic of solid tumors. Leveraging this property, Bifidobacterium has been explored as a delivery vector for a range of anti-cancer approaches such as immunotherapy, nanoformulated chemotherapeutics, and gene therapy. Notably, anti-angiogenic genes such as endostatin and tumstatin have been successfully delivered to colorectal tumors using Bifidobacterium infantis and Bifidobacterium longum, respectively. Additionally, Bifidobacterium bifidum has been employed to transport doxorubicin and paclitaxel nanoparticles to breast and lung tumor sites. Furthermore, both Bifidobacterium longum and Bifidobacterium bifidum have been utilized to deliver nanoparticles that act as synergistic agents for high-intensity focused ultrasound (HIFU) therapy, significantly enhancing tumor ablation, particularly in triple-negative breast cancer (TNBC) models. While these pre-clinical findings are highly encouraging, further clinical research is essential. Specifically, studies are needed to investigate the colonization dynamics of different Bifidobacterium species across various tumor types and to evaluate their potential in delivering diverse cancer therapies in human patients. Full article

Background and Objectives: Colorectal cancer (CRC) is one of the most frequently diagnosed malignancies worldwide. Although chemotherapy is an effective treatment for colorectal cancer (CRC), its effectiveness is frequently hindered by the emergence of resistant cancer cells. Studies have demonstrated a linkage between drug resistance and the pregnane X receptor (PXR), which influences the metabolism and the transport of chemotherapeutic agents. Likewise, autophagy is also a well-established mechanism that contributes to chemotherapy resistance, and it is closely tied to tumor progression. This pre-clinical study aims to investigate the role of mtKRAS-dependent autophagy with PXR expression after treatment with Irinotecan in colorectal cancer. Methods: CRC lines were treated with specific inhibitors, such as 3-methyladeninee, hydroxychloroquine PI-103, and irinotecan hydrochloride, and subjected to various assays, including MTT for cell viability, Western blot for protein expression, siRNA-mediated PXR knock-out, and confocal microscopy for autophagic vacuole visualization. Protein quantification, gene knockdown, and subcellular localization studies were performed under standardized conditions to investigate treatment effects on autophagy and apoptosis pathways. Conclusions: Our experiments showed that PXR knockdown does not alter autophagy levels following Irinotecan treatment, but it promotes apoptotic cell death despite elevated autophagy. Moreover, late-stage autophagy inhibition reduces PXR expression, whereas induction through PI3K/AKT/mTOR inhibition leads to increased expression of PXR. Our experiments uncover a mechanism by which autophagy facilitates the nuclear translocation of the PXR, thereby promoting resistance to Irinotecan across multiple cell lines. Full article

In this work, the thermodynamics of molecular transport between two compartments connected by a nanochannel is investigated through an analysis of internal energy and entropy changes, with a focus on how these changes depend on intermolecular interaction strength. When interactions are weak, resembling gas-like behavior, entropy dominates and favors configurations in which molecules are evenly distributed between the two compartments, despite an increase in internal energy. In contrast, strong interactions, characteristic of liquid-like behavior, lead to dominant energetic contributions that favor configurations with molecules localized in a single compartment, despite entropy loss. Intermediate interaction strengths yield comparable entropic and energetic contributions that cancel each other out, resulting in oscillatory behavior between evenly distributed and localized configurations, as observed in previous work. This thermodynamic analysis reveals energy–entropy compensation, in which entropic and energetic contributions offset each other across different interaction strengths; notably, this compensatory relationship exhibits a linear trend. These findings provide insight into the thermodynamic origins of molecular transport behavior and highlight fundamental parallels between molecular transport and molecular binding, the latter being particularly relevant to molecular recognition and drug design. Full article

Background: Sodium–glucose cotransporter 2 (SGLT2) inhibitors have transformed type 2 diabetes mellitus (T2DM) management by promoting glucosuria, lowering glycated hemoglobin (HbA1c), blood pressure, and weight; however, their use is limited by genitourinary infections and ketoacidosis. Phytocannabinoids—bioactive compounds from Cannabis sativa—exhibit multi-target pharmacology, including interactions with cannabinoid receptors, Peroxisome Proliferator-Activated Receptors (PPARs), Transient Receptor Potential (TRP) channels, and potentially SGLT2. Objective: To evaluate the potential of phytocannabinoids as novel modulators of renal glucose reabsorption via SGLT2 and to compare their efficacy, safety, and pharmacological profiles with synthetic SGLT2 inhibitors. Methods: We performed a narrative review encompassing the following: (1) the molecular and physiological roles of SGLT2; (2) chemical classification, natural sources, and pharmacokinetics/pharmacodynamics of major phytocannabinoids (Δ⁹-Tetrahydrocannabinol or Δ⁹-THC, Cannabidiol or CBD, Cannabigerol or CBG, Cannabichromene or CBC, Tetrahydrocannabivarin or THCV, and β-caryophyllene); (3) in silico docking and drug-likeness assessments; (4) in vitro assays of receptor binding, TRP channel modulation, and glucose transport; (5) in vivo rodent models evaluating glycemic control, weight change, and organ protection; (6) pilot clinical studies of THCV and case reports of CBD/BCP; (7) comparative analysis with established synthetic inhibitors. Results: In silico studies identify high-affinity binding of several phytocannabinoids within the SGLT2 substrate pocket. In vitro, CBG and THCV modulate SGLT2-related pathways indirectly via TRP channels and CB receptors; direct IC₅₀ values for SGLT2 remain to be determined. In vivo, THCV and CBD demonstrate glucose-lowering, insulin-sensitizing, weight-reducing, anti-inflammatory, and organ-protective effects. Pilot clinical data (n = 62) show that THCV decreases fasting glucose, enhances β-cell function, and lacks psychoactive side effects. Compared to synthetic inhibitors, phytocannabinoids offer pleiotropic benefits but face challenges of low oral bioavailability, polypharmacology, inter-individual variability, and limited large-scale trials. Discussion: While preclinical and early clinical data highlight phytocannabinoids’ potential in SGLT2 modulation and broader metabolic improvement, their translation is impeded by significant challenges. These include low oral bioavailability, inconsistent pharmacokinetic profiles, and the absence of standardized formulations, necessitating advanced delivery system development. Furthermore, the inherent polypharmacology of these compounds, while beneficial, demands comprehensive safety assessments for potential off-target effects and drug interactions. The scarcity of large-scale, well-controlled clinical trials and the need for clear regulatory frameworks remain critical hurdles. Addressing these aspects is paramount to fully realize the therapeutic utility of phytocannabinoids as a comprehensive approach to T2DM management. Conclusion: Phytocannabinoids represent promising multi-target agents for T2DM through potential SGLT2 modulation and complementary metabolic effects. Future work should focus on pharmacokinetic optimization, precise quantification of SGLT2 inhibition, and robust clinical trials to establish efficacy and safety profiles relative to synthetic inhibitors. Full article

Hyperlipidemia (HLP) is a disorder of human lipid metabolism or transport, primarily characterized by abnormally elevated levels of total cholesterol (TC), triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C) in the blood. It is a key factor contributing to the development of non-alcoholic fatty liver disease, obesity, diabetes, atherosclerosis, and cardiovascular and cerebrovascular diseases. Statistics show that the prevalence of dyslipidemia among Chinese adults is as high as 35.6%, and it has shown a trend of younger onset in recent years, posing a serious threat to public health. Therefore, the prevention and treatment of dyslipidemia carry significant social significance. The pathogenesis of hyperlipidemia is complex and diverse, and currently used medications are often accompanied by side effects during treatment, making the research and development of new therapeutic approaches a current focus. Numerous studies have shown that flavonoids, which are abundant in most medicinal plants, fruits, and vegetables, exert effects on regulating lipid homeostasis and treating hyperlipidemia through a multi-target mechanism. These compounds have demonstrated significant effects in inhibiting lipid synthesis, blocking lipid absorption, promoting cholesterol uptake, enhancing reverse cholesterol transport, and suppressing oxidative stress, inflammation, and intestinal microbiota disorders. This article reviews the latest progress in the mechanisms of flavonoids in the treatment of hyperlipidemia, providing a theoretical basis for future research on drugs for hyperlipidemia. Full article