Search Results (1,186)

Background: Dragon’s blood (dried resin of Dracaena cochinchinensis (Lour.) S.C.Chen) is a classic traditional medicine for treating ischemic stroke, yet its bioactive components capable of penetrating the blood–brain barrier (BBB) remain ill-defined. This study aims to elucidate its material basis and the synergistic mechanism of Borneol as a “guide drug.” Methods: A systematic strategy integrating UHPLC-Q-TOF-MS/MS and metabolomics was employed to map the chemical profile of dragon’s blood and identify its migrating constituents in rats. Results: A total of 96 compounds were characterized in vitro. In vivo analysis of the cerebrospinal fluid (CSF) revealed a brain-penetrating profile that was significantly enriched by Borneol, with the number of detected constituents increasing from 11 in the DB group to 16 in the DB + B group. The results demonstrated that demethylation, glycoside hydrolysis, and oxidation are primary metabolic pathways, validating a “pro-drug” mechanism where aglycones and hydroxylated derivatives act as the central effectors. Notably, Borneol not only enhanced the BBB permeability of lipophilic flavonoids but also facilitated unique metabolic transformations, such as the cyclization of berberrubine to coptisine. Conclusions: This study elucidates the brain-penetrating material basis of dragon’s blood and reveals the dual synergistic mechanism of Borneol involving both physical permeation enhancement and metabolic modulation, offering scientific evidence for its clinical application in central nervous system diseases. Full article

Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is a chronic inflammatory disorder of the gastrointestinal tract that imposes an increasing global health burden. Conventional pharmacological treatments are often limited by systemic side effects and insufficient drug accumulation at inflamed intestinal sites. Enzyme-responsive polymeric drug delivery systems have emerged as a promising strategy to overcome these limitations by enabling site-specific and controlled drug release within the pathological microenvironment of the colon. This review summarizes recent advances in enzyme-responsive polymeric platforms designed for IBD therapy. We first discuss the altered enzymatic landscape in the intestinal microenvironment of IBD, including host-derived inflammatory enzymes such as esterases, matrix metalloproteinases, and hyaluronidase, as well as microbiota-derived enzymes such as azoreductase, cellulase, and amylase. These enzymes provide intrinsic biological triggers for selective polymer degradation and drug release. We then categorize enzyme-responsive polymeric delivery systems according to the enzymes involved and highlight representative material design strategies, including polymer prodrugs, core–shell nanocarriers, enzyme-degradable hydrogels, and polysaccharide-based carriers. Particular emphasis is placed on the multifunctional roles of polymers that enable targeted delivery, mucosal adhesion, and therapeutic synergy through bioactive degradation products. Finally, current challenges and future directions toward multi-stimuli-responsive systems and clinically translatable polymeric nanomedicine for precision IBD therapy are discussed. Full article

In this study, the native activity of an arabinogalactan endo-β-1,4-galactanase from Aspergillus niger (AnGal) was evaluated under different reaction conditions, and in the presence of various acceptor molecules during the cleavage of the β-1,4-glycosidic linkage of a chromogenic compound and lupin galactan. A combination of spectrophotometric assays, mass spectrometry and chromatography techniques provided insights into the reaction mechanism of the enzyme and its use in the synthesis of galactosides and galactooligosaccharide derivatives. In reactions containing 2-nitrophenol galactopyranoside, AnGal promoted transglycosylation, generating longer galactooligosaccharide derivatives of 2-nitrophenol that have not previously been reported for GH53 enzymes. Furthermore, new alcoholysis products have been detected when AnGal acted on lupin galactan in the presence of benzyl alcohol. To the best of our knowledge, we are first to report the synthesis of galactotriose and galactotetraose derivatives formed by endo-β-1,4-galactanase alcoholysis. This work showcases the potential of utilizing galactanases in the synthesis of valuable galactosides and galactooligosaccharides, under mild conditions from sustainable biomass sources. Potential beneficial applications may be found in several industrial fields such as in the preparation of prodrugs and prebiotics. Full article

Human serum albumin (HSA), as a natural protein carrier, possesses excellent biocompatibility and drug binding capacity. Due to the synergistic effects of the enhanced permeability and retention (EPR) effect and Gp60/SPARC-mediated active targeting, this drug carrier demonstrates favorable tumor selectivity and can be enriched in tumor tissues to achieve long-term therapeutic effects. Particularly, HSA undergoes pH-dependent recycling through the neonatal Fc receptor (FcRn), which significantly prolongs its half-life and enhances its feasibility as a drug delivery platform. In practical clinical applications, the regulation of HSA release rates requires multiple strategies to work synergistically. Additionally, the targeting efficiency of delivery systems due to tumor heterogeneity remains a major bottleneck limiting its universality. This article systematically reviews the unique advantages, clinical applications, challenges, and future perspectives of HSA as a prodrug carrier in tumor therapy. Full article

Ovarian cancer is the most lethal gynaecological cancer, largely because it is often diagnosed late and shows strong tumour heterogeneity, therapy resistance, and rapid metastatic spread. A key driver of this aggressive behaviour is the tumour’s ability to reshape its surrounding microenvironment to support invasion, angiogenesis, and escape from treatment. Cathepsin L (CTSL), a lysosomal cysteine protease, has emerged as an important mediator of these processes and is gaining attention as both a prognostic marker and a potential therapeutic target. This review examines the diverse roles of CTSL in ovarian cancer progression, focusing on how its expression, localisation, and extracellular release are altered within the hypoxic and acidic conditions typical of the tumour microenvironment. It also outlines emerging therapeutic strategies aimed at targeting CTSL, including selective inhibitors, multi-cathepsin approaches, CTSL-activated prodrugs and antibody-drug conjugate linkers, and nanomedicine systems designed for tumour-specific delivery. Overall, the evidence highlights CTSL as a central regulator of invasion, angiogenesis, and relapse in ovarian cancer, underscoring its potential as a target for new therapies in aggressive disease. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest cancers, with a 5-year survival rate of 13% and broad resistance to therapy. It is driven by severe tumor hypoxia from desmoplasia, aberrant vasculature, and high interstitial pressure. Hypoxia stabilizes hypoxia-inducible factors (HIFs), reshaping the tumor microenvironment (TME) into a nutrient-poor, acidic milieu that fosters immune exclusion and suppression. While immune checkpoint inhibitors (ICIs) have revolutionized treatment, PDAC responses have been negligible. As hypoxia centrally drives PDAC’s ICI-refractory TME, targeted alleviation could offer synergy with ICIs; however, no such combination is being applied in the clinic. One impediment could be the one-size-fits-all approach when investigating hypoxia-modifying therapy. Indeed, using hypoxia gene signatures, we and others have shown that PDAC tumors are not equally hypoxic, with patients having more hypoxic tumors experiencing worse survival and immunosuppressed TME. This review dissects hypoxia’s mechanistic role in PDAC immune evasion and gives an update on the therapeutic advances that directly or indirectly target hypoxia, such as the inhibition of HIFs, hypoxia-activated prodrugs, and vascular and oxygen delivery approaches, with emphasis on their potential to enhance responses to ICIs. It further evaluates the need for hypoxia biomarkers and proposes gene signatures as detection tools to enable precision hypoxia modulation, potentially converting immune-cold PDAC into an ICI-responsive disease. Full article

Cancer remains one of the leading causes of morbidity and mortality worldwide, and despite major advances in surgery, chemotherapy, radiotherapy, and immunotherapy, important therapeutic limitations persist, including systemic toxicity, therapeutic resistance, and poor drug penetration into hypoxic tumor regions. These challenges have renewed interest in alternative biological strategies, particularly the use of bacteria and bacterial toxins as antitumor agents. Certain bacterial species possess intrinsic tumor-targeting properties, including the ability to selectively colonize hypoxic and necrotic regions of solid tumors that are poorly accessible to conventional therapies. This review provides a comprehensive analysis of the mechanisms underlying bacteria-mediated anticancer activity, including selective tumor colonization, direct oncolysis, immune activation, and toxin-mediated cytotoxicity. Both obligate anaerobes (e.g., Clostridium and Bifidobacterium) and facultative anaerobes (e.g., Salmonella, Escherichia coli, and Listeria monocytogenes) are examined for their tumor-targeting potential. In addition, we discuss the oncological applications of several bacterial toxins and toxin-derived therapeutic constructs, including Cytolysin A (ClyA), Clostridium difficile toxin B (TcdB), diphtheria toxin, Pseudomonas aeruginosa exotoxin A, and Clostridium perfringens enterotoxin (CPE). Emerging strategies such as recombinant immunotoxins and bacterial-directed enzyme prodrug therapy (BDEPT) are also reviewed. Finally, current translational challenges, including pharmacokinetic limitations, immune clearance, and biosafety considerations, are analyzed, highlighting future directions for integrating bacteria-based platforms into next-generation cancer therapies. This approach reflects the growing interest in microbial strategies for oncology and underscores the potential of bacteria and their toxins as innovative tools in the development of targeted anticancer therapies. Full article

Protein turnover and extracellular proteolysis continuously generate diverse peptide fragments within biological systems, yet the metabolic and pharmacological implications of these peptides remain incompletely understood. Among these transporters, members of the solute carrier family 15 (SLC15), including peptide transporter 1 (PEPT1/SLC15A1) and peptide transporter 2 (PEPT2/SLC15A2), mediate the proton-coupled uptake of dipeptides, tripeptides, and structurally related compounds across cellular membranes. While these transporters have been extensively studied in the context of intestinal peptide absorption and drug delivery, their potential roles in cancer biology remain incompletely understood. Tumor microenvironments are characterized by extensive proteolysis and dynamic metabolic remodeling, processes that can generate diverse peptide fragments derived from extracellular matrix proteins and intracellular protein turnover. These peptides may accumulate locally and potentially serve as substrates for cellular peptide transport systems. Once internalized through peptide transporters, dipeptides are typically hydrolyzed into free amino acids that can support biosynthetic pathways, energy metabolism, and cellular growth. In addition to their potential metabolic roles, certain endogenous dipeptides have also been reported to influence cellular signaling pathways and redox homeostasis. The broad substrate specificity of peptide transporters has also attracted significant interest in pharmacology because numerous clinically used drugs exploit these transport systems for efficient cellular uptake. This property raises the possibility that peptide transporters may be utilized for transporter-mediated drug delivery strategies, including the development of peptide-modified prodrugs or dipeptide–drug conjugates. In this review, we summarize the molecular characteristics and physiological functions of dipeptide transport systems with a particular focus on the SLC15 transporter family. We then discuss emerging evidence linking peptide transporters to tumor metabolism and the tumor microenvironment. Finally, we highlight current progress and future perspectives in exploiting peptide transport systems for transporter-mediated drug delivery and therapeutic targeting in cancer. Full article

Tumor oxygenation is a key determinant of cancer biology and treatment response, correlating with angiogenesis, recurrence, and malignant progression. Hypoxia is a defining feature of glioblastoma (GBM) and adult diffuse gliomas, generating low-oxygen niches that promote invasion, stem-like states, immune suppression, and resistance to radiotherapy and temozolomide, contributing to poor outcomes. Measuring tissue partial pressure of oxygen (pO₂) and mapping its spatial heterogeneity can, therefore, inform mechanistic understanding and therapeutic development, including hypoxia-activated prodrugs, hypoxia-responsive gene therapy, and optimized radiotherapy planning. Although direct pO₂ assessment is challenging, invasive probes and multimodal imaging can characterize regional hypoxia pre-operatively, support patient stratification, monitor treatment effects, and improve outcome prediction. This review summarizes oxygen dynamics in GBM; analyzes causes of hypoxia (rapid growth outpacing supply, diffusion-limited hypoxia, and abnormal/chaotic vasculature); compares methods to quantify oxygenation from direct measurements to noninvasive imaging surrogates; and evaluates preclinical and clinical strategies that target hypoxia to enhance standard therapy, including barriers to translation. We further integrate oxygenation with cell signaling and redox biology: oxygen gradients are transduced via hypoxia-inducible factor programs and redox-sensitive pathways (NRF2/KEAP1, NOX-derived ROS, nitric oxide/S-nitrosylation, and sulfur metabolic routes), shaping mesenchymal-like transitions and cell-death programs such as ferroptosis. Framing oxygenation as both a microenvironmental and redox-signaling variable positions oxygen imaging as an entry point to biomarker-guided therapies that exploit oxidative vulnerabilities. Full article

Ceftobiprole is a fifth-generation beta-cephalosporin with high inter-individual pharmacokinetic variability in critically ill patients. However, data on its pharmacokinetics and central nervous system (CNS) penetration are limited. This study developed and validated a rapid LC-MS/MS method for quantifying ceftobiprole in human plasma and CSF. Sample preparation involved protein precipitation of 50 µL aliquots. Analysis used gradient elution on an ACQUITY UPLC^® HSS T3 column (2.1 × 100 mm, 1.8 µm) with 0.2% formic acid and acetonitrile and was detected by positive ion electrospray, achieving a 3.5 min run time. The method was linear from 0.100 to 25.0 mg/L in plasma and 0.0500 to 15.0 mg/L in CSF. Intra- and inter-run precision and accuracy were within ±15% at all quality control levels. All validation parameters, including selectivity, matrix effects, recovery, and stability under various conditions, met acceptance criteria. Potential interference from the prodrug ceftobiprole medocaril was evaluated and found to be negligible. The method was successfully applied to samples from three patients, revealing a CSF penetration range of 11.9% to 36.5%. This validated LC-MS/MS method enables simple and rapid quantification of ceftobiprole in plasma and cerebrospinal fluid, filling the gap in data on its CNS penetration and supporting routine drug concentration monitoring in critically ill patients. Full article

Triptolide (TPL), a diterpenoid derived from the Chinese medicinal plant Tripterygium wilfordii, exhibits broad-spectrum biological and pharmacological activities, although its clinical translation is limited by systemic toxicity. Recent advances in the development of TPL derivatives have created new therapeutic opportunities. This review summarizes current knowledge of triptolide, with a focus on TPL’s toxicity profile, derivative strategies, and antitumor mechanisms across different tumor types, including glioma, pancreatic tumor, leukemia, lung cancer, gastric cancer and others. We also summarize the plant’s origin and traditional uses, TPL’s pharmacokinetics (PKs), and relevant clinical trials against tumors. The main mechanism of the TPL antitumor effect is to interfere with ATPase of XPB by covalently binding to it, as well as inducing the rapid depletion of RPB1 via hyperphosphorylation and ubiquitination. We also reviewed systemic toxicity including neuro-, cardio-, oto-, nephron-, hepato-, and hemato-toxicity, as well as digestive and reproductive toxicity. Finally, we searched clinical trial databases across three platforms for tumors and concluded that Minnelide has strong clinical potential for solid tumors. By critically evaluating TPL from multiple dimensions, specifically its traditional use, chemical derivatization, pharmacokinetics, antitumor mechanisms, toxicity, and clinical trials, this review aims to inform future strategies that maximize therapeutic efficacy while minimizing adverse effects. Full article

Cisplatin [cis-diamminedichloroplatinum(II)] is a widely used chemotherapeutic agent that induces cytotoxicity primarily through DNA damage; however, drug resistance severely limits its efficacy. Cisplatin resistance is complex and multifactorial, involving DNA repair via nucleotide excision repair (NER), increased detoxification activities, and overexpression of lysine deacetylases (KDACs), which reduce chromatin accessibility and alter transcriptional regulation. Combining cisplatin with KDAC inhibitors has shown promise, often attributed to increased drug sensitivity through higher chromatin accessibility; however, this hypothesis has not been validated. Here, we synthesized a novel Pt(IV) derivative, ctc-[Pt(NH₃)₂(VPA)(PhB)Cl₂] (cPVP), which combines cisplatin with two KDAC inhibitors, phenylbutyrate and valproic acid. Compared with cisplatin, cPVP induced significantly greater cytotoxicity, and increased DNA damage formation. High-resolution mapping of genomic cisplatin damage and repair indicated that enhanced sensitivity resulted not from altered chromatin accessibility, but from increased drug uptake and the inhibition of NER. Moreover, cPVP prevented the development of resistance to both cisplatin and itself in cancer cells. Together, these results establish the inhibition of nucleotide excision repair, rather than enhanced damage sensitivity due to chromatin accessibility, as the primary mechanism by which KDAC-targeting cisplatin prodrugs overcome resistance to platinum-based therapies. Full article

Molecular subtype–guided therapy for breast cancer (BC) remains limited in a subset of patients by suboptimal efficacy, acquired resistance, and the presence of “undruggable” targets. Proteolysis-targeting chimeras (PROTACs) represent a targeted protein degradation (TPD) strategy that differs fundamentally from conventional occupancy-driven inhibition. By inducing ubiquitination of a protein of interest and subsequent proteasomal degradation, PROTACs can directly reduce pathogenic protein abundance and potentially abrogate non-catalytic or scaffolding functions, thereby enabling more durable pathway suppression in selected resistance contexts. This review comprehensively summarizes the mechanisms of action, key molecular design elements, and the developmental landscape of PROTACs, and maps target selection and research progress across BC molecular subtypes. In hormone receptor–positive/HER2-negative BC, clinical translation is most advanced for estrogen receptor alpha-directed PROTACs; Phase III evidence indicates biomarker-dependent efficacy, with clearer benefit signals in resistant subgroups such as estrogen receptor 1 mutations, suggesting that the net clinical benefit of TPD is more likely to be realized through precision stratification. In contrast, in solid-tumor settings, including human epidermal growth factor receptor 2 (HER2)-positive BC and triple-negative breast cancer, PROTAC translation is more frequently constrained by an “exposure–selectivity–therapeutic window” trade-off driven by physicochemical liabilities, insufficient tumor penetration, and broad target expression. Accordingly, engineering strategies—such as antibody/aptamer-mediated targeted delivery, stimulus-responsive prodrugs, nanocarriers, and local administration—are emerging as decisive approaches to enable safe and effective clinical implementation. Looking forward, further progress of PROTACs in BC will depend on expanding the spectrum of E3 ubiquitin ligases and recruitment modalities, establishing predictable and dynamically monitorable biomarker systems, optimizing rational combination/sequencing regimens with exposure- and schedule-guided dosing, and advancing scalable manufacturing and quality control capabilities, thereby translating mechanistic advantages of TPD into verifiable precision-therapy applications. Full article

Azobenzene derivatives constitute a prototypical class of photoresponsive molecular switches with broad utility in synthetic chemistry and biomedical research, owing to their distinctive physicochemical properties. Recent molecular engineering has enabled red-shifted photoisomerization into the visible biological window, thereby enhancing tissue penetration and reducing phototoxicity. This review systematically surveys contemporary advances in azobenzene-based photoswitchable systems with a specific focus on medicinal chemistry and photopharmacology. Emphasis is placed on rational design strategies—including ortho-functionalization, heteroaryl substitution, and bridged diazocine scaffolds—that improve photophysical properties, thermal stability, and photostationary state distributions. Particular attention is devoted to the integration of these novel azobenzene motifs as privileged pharmacophores, highlighting their emerging therapeutic applications in neurological modulation, enzyme inhibition, receptor targeting, and oncology, as well as their translational potential in drug discovery and photodynamic therapy. Full article

Background: Primary dysmenorrhea is a common gynecologic condition that frequently requires pharmacologic treatment. Pelubiprofen, a 2-arylpropionic acid-derived prodrug with relatively selective cyclooxygenase-2 inhibitory activity, has demonstrated analgesic efficacy in acute pain conditions. Methods: This multicenter, randomized, double-blind, placebo-controlled, crossover phase 3 trial randomized 120 women aged 19–44 years with primary dysmenorrhea to one of two treatment sequences over two menstrual cycles. Pelubiprofen at 45 mg or a matching placebo was administered at the onset of moderate or severe menstrual pain. The co-primary endpoints were time-weighted sums of the total pain relief (TOTPAR-8) and pain intensity difference (SPID-8) during the first 8 h after dosing. Results: Of 120 randomized women, 115 comprised the modified intention-to-treat population and 116 comprised the safety population. Pelubiprofen demonstrated significantly greater analgesic efficacy than placebo, with least-squares mean TOTPAR-8 values of 22.17 versus 15.50 and SPID-8 values of 10.00 versus 6.17 (both p < 0.0001). Significant between-treatment differences were also observed at 12 h (TOTPAR-12 and SPID-12). Treatment-emergent adverse events occurred in 9/113 (8.0%) pelubiprofen treatment periods and 10/112 (8.9%) placebo treatment periods; all events were mild to moderate, and the only serious adverse event occurred during a placebo treatment period and was judged to be unrelated to study treatment. Conclusions: Pelubiprofen at 45 mg provided superior short-term analgesic efficacy compared with placebo and was generally well tolerated in women with primary dysmenorrhea. Full article