Archives of Pharmacal Research最新文献

Antibody-drug conjugates (ADCs) have rapidly developed over the past two decades as a class of targeted anticancer agents. These drugs deliver highly cytotoxic payloads conjugated to specific antibodies, targeting cancer cells and releasing the payload intracellularly to selectively kill tumor cells. However, in clinical practice, the therapeutic efficacy of ADCs is often inconsistent due to factors such as off-target effects, limited endocytosis rates, and the narrow specificity of the target. Bispecific antibody-drug conjugates (BsADCs) combine the characteristics of bispecific antibodies and ADCs, offering enhanced recognition capabilities and facilitating faster drug internalization, thereby potentially improving the therapeutic index and addressing some of the limitations of traditional ADCs. Moreover, BsADCs have the potential to treat not only cancer but also other diseases, positioning them as a future direction for ADC development.This review provides a brief overview of the structure of ADCs and current clinical research results. It focuses on the "toolbox" components of BsADCs and highlights examples of how each component is applied in the construction of BsADCs. This review also summarizes the key characteristics required for bispecific antibodies used in BsADC construction. Finally, a detailed analysis of the advantages of BsADCs over traditional ADCs is presented, along with a discussion of their future development. This paper aims to provide researchers interested in ADCs and BsADCs with detailed information on the composition, structure, and applications (including clinical data) of both ADCs and BsADCs, helping readers quickly understand the features and research progress of BsADCs and paving the way for further exploration in this field.

Autosomal dominant polycystic kidney disease (ADPKD) affects approximately 12.5 million individuals globally and is one of the most common causes of end-stage renal disease. It is typically associated with a gradual increase in the volume of numerous cysts in both kidneys. Recent studies have highlighted the critical role of signal transducer and activator of transcription 3 (STAT3) in ADPKD pathogenesis, as it is highly expressed and persistently activated in ADPKD kidneys. Through screening of our in-house compound library, we identified compound WR-S-647 (4e) as a potent and specific inhibitor of STAT3 with a binding affinity of 34 nM to STAT3. WR-S-647 suppressed the phosphorylation activation and nuclear localization of STAT3. In vitro, WR-S-647 remarkably suppressed cyst formation and expansion in a Madin-Darby canine kidney (MDCK) cyst model. Meanwhile, it effectively diminished cyst growth in an ex vivo embryonal renal cyst model and an in vivo Pkd1 knockout ADPKD mouse model. Our study identifies WR-S-647 as a potent STAT3-mediated inhibitor and provides preclinical proof-of-concept for its efficacy in reducing cyst growth in ADPKD models.

Mitophagy dysfunction is a critical contributor to retinal pigment epithelial (RPE) cell damage during the progression of retinal degenerative diseases, including age-related macular degeneration (AMD). In this study, we investigated the effects of paeoniflorin (PF) on mitophagy in RPE cells, with a particular focus on the CUL3/LKB1/AMPK/ULK1 signaling pathway. ARPE-19 cells were treated with different concentrations of PF to evaluate cytotoxicity, and its protective effects were further examined in H₂O₂-induced oxidative stress models in vitro and in sodium iodate (NaIO₃)-induced RPE injury models in vivo. Protein levels of CUL3, apoptosis-related factors, mitophagy markers, and components of the LKB1/AMPK/ULK1 pathway were assessed by western blotting, and mitophagy was visualized using MitoTracker labeling. Cycloheximide (CHX) and coimmunoprecipitation (Co-IP) assays were performed to analyze the interaction between CUL3 and LKB1. PF treatment enhanced mitophagy in H₂O₂-stimulated ARPE-19 cells, whereas Parkin knockdown markedly attenuated this effect. In oxidatively damaged cells, PF promoted AMPK and ULK1 phosphorylation, increased mitophagy-associated protein expression, and alleviated mitochondrial dysfunction; these protective effects were abolished by pharmacological inhibition of AMPK or ULK1. In addition, CUL3 overexpression significantly attenuated PF-induced mitophagy activation and reduced PF-associated phosphorylation of LKB1, AMPK, and ULK1. Mechanistically, PF downregulated CUL3 expression, while CUL3 promoted the ubiquitination and degradation of LKB1. Silencing CUL3 induced mitophagy in H₂O₂-treated cells, whereas concurrent knockdown of CUL3 and LKB1 abolished this effect. In vivo, PF mitigated RPE cell loss, enhanced mitophagy, and activated the CUL3/LKB1/AMPK/ULK1 signaling pathway in the retinal tissues of NaIO₃-induced mice. Collectively, these findings indicate that PF protects against RPE injury in an NaIO₃-induced AMD-like model by downregulating CUL3 expression and activating LKB1/AMPK/ULK1-mediated mitophagy.

Despite extensive research defining the molecular cascades of ischemic stroke, including excitotoxicity, oxidative stress, inflammation, blood-brain barrier disruption, and regulated cell death, translation of neuroprotective strategies into effective clinical therapies has remained largely unsuccessful. Growing evidence suggests that this gap reflects recurring limitations in translational design rather than insufficient mechanistic insight, including phase-inappropriate intervention, narrow therapeutic windows, inadequate brain exposure, and lack of target engagement in heterogeneous patient populations. In this review, we critically examine why biologically plausible targets have failed to produce clinical benefit by synthesizing lessons from preclinical and clinical studies. We identify common patterns of translational failure and propose a phase-resolved, biomarker-anchored framework that prioritizes therapeutic actionability according to disease stage and neurovascular context. By repositioning biomarkers as tools for patient stratification, risk prediction, and confirmation of target engagement, this framework supports rational sequencing from hyperacute reperfusion support to stage-matched neurovascular and immune modulation and subsequent neurorestorative strategies. This decision-oriented perspective aims to guide more effective trial design and improve translational success in ischemic stroke.

Tinospora crispa (Menispermaceae) has been traditionally consumed as a functional food and herbal remedy in Southeast Asia, notably in Thailand and India. cis-Clerodane-type diterpenoids represent the characteristic and predominant metabolites of the genus Tinospora. Chemical investigation of a MeOH extract of T. crispa leaves, guided by LC/MS analysis coupled with an in-house UV spectral library, led to the isolation of five compounds (1-5), including four new cis-clerodane-type diterpenoids (1-4). Their structures were elucidated by 1D and 2D NMR spectroscopy, high-resolution mass spectrometry (HR-ESIMS), interproton distance analysis using NOE peak amplitude normalization for improved cross-relaxation (PANIC), Snatzke's method, and computational ECD and DP4⁺ probability calculations. The isolated compounds (1-5) were evaluated for their anticancer potential in both liver (Hepa1c1c7, Hepa1-6) and lung (LLC1, A549) cancer cell lines. All compounds 1-5 reduced A549 cell viability by approximately 70%, at 200 μM and showing comparable activity in LLC1. Molecular analyses showed that compound 3 affected downstream Hippo signaling components (YAP, TAZ, pan-TEAD) in liver cancer cells and inhibited pro-survival pathways-including phosphorylated AKT-in lung cancer cells, where it also elevated apoptotic markers Bax and cleaved caspase-3 while reducing anti-apoptotic BCL-2. Overall, compound 3 exhibited the most consistent and potent cell-line specific anticancer effects across both models, highlighting its potential as a promising lead candidate for further anticancer drug development. Collectively, these results suggest concentration-dependent anticancer activity of T. crispa diterpenoids in liver and lung cancer models and further support compound 3 as promising leading candidate targeting key survival signaling pathways in cancer.

Drug development is a multifaceted and time-intensive process that spans candidate discovery, formulation, pharmacokinetics (PK), and evaluation of therapeutic efficacy and safety. Nuclear medicine imaging-particularly positron emission tomography (PET) and single-photon emission computed tomography (SPECT)-enables noninvasive, quantitative, and dynamic assessments of drug behavior at the molecular and systemic levels. These modalities visualize real-time biodistribution, tissue PK, target engagement, and treatment response, addressing the limitations of conventional approaches such as plasma sampling and invasive tissue biopsies. This review summarizes the contributions of PET and SPECT across the drug development continuum. Representative case studies illustrate their applications in characterizing molecular kinetics, informing pharmacokinetic and pharmacodynamic (PK/PD) relationships, evaluating target specificity, and detecting early off-target effects. We also discuss how imaging-derived metrics can support earlier go/no-go decisions, enhance preclinical-to-clinical translation through a shared quantitative framework across species and disease models, and inform individualized therapeutic strategies. Overall, PET and SPECT serve as core tools that improve the accuracy, safety, and efficiency of modern drug development for molecularly targeted therapies.

Targeted cancer therapy is often compromised by the development of acquired drug resistance. Beyond genetic mutations, recent studies underscore the role of non-genetic plasticity and adaptive network rewiring in driving this resistance. Overcoming this challenge requires innovative approaches, including the integration of transcriptomics and natural product research. Natural products are chemically diverse agents that can modulate multiple resistance pathways due to their polypharmacological properties. In parallel, transcriptomic profiling of drug-exposed cells provides genome-wide snapshots of resistance states and reveals how candidate compounds remodel these cells. This review summarizes the methods by which transcriptomics facilitates the identification of natural products that overcome resistance to targeted therapies. It outlines the canonical resistance mechanisms and highlights the natural products that reverse these adaptive networks at the molecular level. It then discusses how systematic transcriptomic workflows, including differential expression profiling, pathway analysis, and perturbome matching, elucidate the modes of action of natural compounds. This data-driven framework facilitates the discovery of novel agents, supports drug repurposing, and guides the rational design of combination therapies to restore drug sensitivity. Finally, it addresses clinical translation barriers and emerging computational frontiers, such as multi-omics and artificial intelligence, which will increasingly play vital roles in harnessing the therapeutic potential of natural products in patients with resistant cancers.

The skin is frequently subjected to injuries and disorders encompassing both acute and chronic wounds. Chronic wounds, including diabetic wounds, pose significant clinical problems due to prolonged and ineffective healing processes. Traditional therapies are associated with many limitations. In this regard, nanoparticles (NPs)-based drug delivery systems have emerged as promising solutions for improving chronic wound healing and to overcome the drawbacks of conventional approaches. Furthermore, the functionalization of these NPs through surface modification can increase the overall therapeutic performance. Incorporating them into advanced dosage form maximizes the therapeutic impact. Although their therapeutic promise is high, clinical translation of nanoparticles is hindered by challenges such as manufacturing problems with scaling up production of lipid nanoparticles and the regulatory difficulties related to nanoparticle characterization, such as compliance with FDA criteria for size variation. The current review endeavored to explore the most recently developed nanotechnology-based therapeutic agents that are used in diabetic chronic wound healing, especially SLNs. It also discusses the various surface modification strategies that can enhance therapeutic effectiveness. Further, to maximize the overall efficacy of the drug delivery system and to improve wound healing outcomes, the incorporation of NPs into advanced dosage forms such as thermoresponsive gels has a huge impact. This review also serves as a database for the methodology of collecting the required data, screening, and selection in addition to the pathways from NPs preclinical studies to the stages of clinical approval; moreover, NPs manufacturing and scaling-up feasibility.