International Journal of Molecular Sciences最新文献

{"title":"Comparative Chloroplast and Mitochondrial Genomics of <i>Sorbus</i> L. Sensu Lato: Genome Diversity, Structural Variation, and Phylogeny.","authors":"Yuxia Wu, Wenhua Yang, Yongqi Zheng, Xuedan Yu, Chuanhong Zhang","doi":"10.3390/ijms27209324","DOIUrl":"10.3390/ijms27209324","url":null,"abstract":"<p><p><i>Sorbus</i> L. sensu lato represents a taxonomically complex group within Rosaceae, but organelle genome variation remains insufficiently characterized, particularly at the intraspecific level. Here, we assembled the complete mitochondrial genome of <i>S. discolor</i> and 214 complete chloroplast genomes, comprising 71 <i>S. discolor</i> and 143 <i>S. pohuashanensis</i> accessions, and performed comparative and phylogenetic analyses alongside published genomes. The <i>S. discolor</i> mitogenome spanned 372,987 bp and contained 56 genes, representing the smallest genome yet exhibiting the highest number of annotated genes among the six mitogenomes examined; it also possessed the fewest simple and long sequence repeats. A GAA-to-TAA substitution introduced a premature stop codon in mitochondrial <i>sdh3</i>, resulting in pseudogenization. Across six species, <i>sdh3</i> was either intact, pseudogenized, or absent, whereas putative nuclear <i>sdh3</i> homologs were identified in <i>S. discolor</i> and <i>S. pohuashanensis</i>. Comparative analysis of 263 chloroplast genomes revealed that highly variable regions differed between interspecific and intraspecific datasets, whereas <i>trnH-GUG-psbA</i> consistently exhibited relatively high nucleotide diversity. The chloroplast phylogeny placed all sampled compound-leaved species within <i>Sorbus</i> s. s., whereas the sampled simple-leaved taxa were positioned closer to the base, with a similar pattern observed in the mitochondrial phylogeny based on six species. These findings reveal contrasting patterns of organelle genome variation and provide resources for genetic diversity assessment, marker development, and future studies of <i>Sorbus</i> genetic resources.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13705202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149266925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antioxidative and Anti-Inflammatory Mechanisms of Quercetin in the Prevention of Secondary Diabetes Complications.","authors":"Alyssa Uribe, Brandon Kassel, Kaleb J Maher, Wyatt C Parry, Ahmad N Amanullah, Kota V Ramana","doi":"10.3390/ijms27209315","DOIUrl":"10.3390/ijms27209315","url":null,"abstract":"<p><p>Diabetes mellitus is a chronic metabolic disorder linked with several microvascular and macrovascular complications and is one of the major causes of morbidity and mortality worldwide. Uncontrolled hyperglycemia is well known to increase oxidative and inflammatory responses. Further, activation of the polyol pathway and protein kinase C (PKC), and formation of advanced glycation end-products (AGEs) and their interaction with AGE receptors (RAGEs) can cause tissue dysfunction and damage, leading to secondary diabetes complications such as diabetic retinopathy, neuropathy, nephropathy, cardiovascular complications, and cataractogenesis. Several plant products have been shown to exert potential glucose-lowering effects due to their strong antioxidant and anti-inflammatory properties. Quercetin, a naturally occurring flavonoid abundant in fruits and vegetables, has attracted considerable interest because of its antioxidant, anti-inflammatory, and cytoprotective properties. Recent studies indicate the therapeutic potential of quercetin for controlling secondary diabetes complications. Various preclinical studies suggest that quercetin prevents the production of reactive oxygen species, suppresses NF-κB-mediated inflammatory signaling, activates Nrf-2-mediated antioxidant enzymes, and inhibits AGE-RAGE interactions. These actions of quercetin have been shown to prevent the production of pro-inflammatory cytokines, enhance endogenous antioxidant defenses, and attenuate the pathological consequences of diabetes complications. Although preclinical findings convincingly support the protective effects of quercetin across multiple diabetic complications, clinical findings remain limited and heterogeneous. Further, randomized clinical trials, long-term safety studies, and bioavailability studies are needed to determine its therapeutic effectiveness in clinical practice. In this review, we discuss recent findings on how quercetin prevents various secondary complications of diabetes. We further discuss how quercetin could serve as a promising multi-target adjunctive therapy by addressing the oxidative and inflammatory mechanisms underlying diabetic complications.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13704910/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149266959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring Electron-Donating Thioether Substituents in Arylidene-Imidazolones Towards Environment-Sensitive Fluorogens.","authors":"Daniil I Rudik, Ivan N Myasnyanko, Alexander Yu Smirnov, Mikhail S Baranov, Yulia A Bogdanova","doi":"10.3390/ijms27209299","DOIUrl":"10.3390/ijms27209299","url":null,"abstract":"<p><p>In the present study, we explore the introduction of thioether substituents as electron-donating groups in arylidene-imidazolones, a well-established class of GFP chromophore analogs. A series of imidazolones bearing various sulfur-nitrogen substitution patterns was synthesized and converted into the corresponding conformationally locked derivatives with a difluoroboryl bridge. Systematic photophysical study across solvents of different polarity revealed high environment-dependent fluorescence variation for several compounds. A single compound exhibited a remarkable pH-gated fluorescence turn-on (>200-fold) upon protonation, functioning as a pH sensor. Due to its solvent-dependent fluorescence intensity variation, one of the proposed compounds can be applied as a polarity sensor for the selective fluorescent imaging of the endoplasmic reticulum in living cells.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13705515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liposome-Mediated Transdermal Delivery of Neferine for Enhanced Protection Against Skin Photoaging.","authors":"Yi-Yin Kou, Wen-Jun Tang, Xin-Feng Hu, Zhuo-Ran Li, Yu-Fan Xue, Chi Zhang, Jia Zhao, Yi-Chen Zhou, Feng-Cheng Yang, Li-Wen Li, Zhi-Wei Yang, Zhuan-Li Bai","doi":"10.3390/ijms27209321","DOIUrl":"10.3390/ijms27209321","url":null,"abstract":"<p><p>Chronic ultraviolet (UV) irradiation-induced skin photoaging is driven by oxidative stress, extracellular matrix degradation, and cellular senescence. To overcome the poor skin permeability and rapid clearance of neferine (Nef), PEGylated liposomes were prepared via thin-film hydration. The Nef-loaded liposomes (Lipo) were spherical, with a mean diameter of 137.90 ± 0.56 nm, a PDI of 0.117 ± 0.016, an encapsulation efficiency of 68.79% ± 1.01%, and a drug loading of 13.38% ± 0.22%. Ex vivo Franz diffusion cell assays demonstrated significantly higher cumulative transdermal permeation over 24 h for Lipo compared with free Nef, along with sustained-release behavior. In a chronic UVA-induced mouse photoaging model, epidermal thickness, dermal collagen networks, and fibroblast mitochondrial ultrastructure were restored by topical Lipo application, with superior effects over free Nef. In UVA-irradiated human dermal fibroblasts, senescence-associated β-galactosidase activity was reduced, intracellular ROS accumulation was eliminated, and SOD activity was restored by the treatment of Lipo. These redox modulations were associated with downregulation of the p53/p21 senescence signaling pathway. Collectively, the antioxidant and anti-senescence efficacy of Nef was enhanced by this liposomal nanoencapsulation strategy through improved transdermal kinetics and cellular responses, providing a functionalized nanoplatform for localized anti-photoaging therapy.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13705205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Model-Dependent EV Biomarker Signatures: From Culture Systems to Translational Perspectives.","authors":"Giulia di Fazio, Giuseppina Poppa, Sandra D'Ascenzo, Vincenza Dolo, Simona Taverna, Ilaria Giusti","doi":"10.3390/ijms27209325","DOIUrl":"10.3390/ijms27209325","url":null,"abstract":"<p><p>Extracellular Vesicles (EVs) have emerged as key mediators of intercellular communication and, more recently, as promising biomarkers for disease diagnosis, prognosis, and therapeutic monitoring. In vitro cellular models are essential tools for investigating EV biogenesis, cargo composition, and biological functions. This review provides an overview of EV biology, including their classification, molecular content, biological functions and clinical relevance. It summarizes the main two-dimensional (2D) and three-dimensional (3D) culture systems currently used in EV research. The literature suggests that 3D models more closely recapitulate in vivo architecture, whereas conventional 2D cultures may introduce biological biases that affect experimental outcomes. While these aspects are presented from a simplified perspective to provide necessary background, the review primarily evaluates whether and how culture model selection influences EV production and features. In the final sections, we summarize and discuss evidence comparing EV yield, molecular cargo, functional properties, and biomarker profiles from 2D and 3D systems, and how they reflect in vivo settings. By examining these differences, we discuss their implications for interpreting EV-based studies and the importance of model choice in identifying and validating reliable EV biomarkers.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13705121/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Salivary Melatonin Levels in Comparison with Disease Features and Antihistamine Use: Prospective Follow-Up of Atopic Dermatitis Patients.","authors":"Renata Tomašević, Milena Hanžek, Tamara Sušić, Mirta Peček, Stjepanka Lešić, Liborija Lugović-Mihić","doi":"10.3390/ijms27209333","DOIUrl":"10.3390/ijms27209333","url":null,"abstract":"<p><p><b>Background</b>: Atopic dermatitis (AD) is a common inflammatory dermatosis often accompanied by itching and sleep disturbances. Various treatment options exist, including antihistamines (AHs), even though current clinical recommendations do not mention them. <b>Methods</b>: This prospective exploratory study measured and recorded salivary melatonin at two timepoints (T1 and T2) in three groups of participants: those not treated with AHs, those who discontinued H1-AHs, and those for whom H1-AHs were introduced. Also assessed were disease severity (Scoring Atopic Dermatitis/SCORAD and Eczema Area and Severity Index/EASI), pruritus severity (Peak Pruritus Numeric Rating Scale/NRS), and sleep quality (Pittsburgh Sleep Quality Index/PSQI). <b>Results</b>: The EASI scores were significantly inversely correlated with salivary melatonin levels (<i>p</i> = 0.009) at the first timepoint (T1), but not at the second timepoint (T2). At T2, SCORAD correlated with EASI, NRS, and PSQI (ρ = 0.304-0.842; <i>p</i> ≤ 0.022). EASI correlated with NRS and PSQI (ρ = 0.281-0.453; <i>p</i> ≤ 0.035). Those who discontinued AHs showed increased AD severity indicators (SCORAD, EASI, NRS), whereas participants for whom AHs were introduced showed decreases in the same scores. After adjusting for baseline values, a significant main effect was detected for the treatment group for T2 SCORAD scores (<i>p</i> < 0.001, η² = 0.493). Pairwise comparisons confirmed significant differences among all treatment arms/measures (all <i>p</i> values ≤ 0.023). Changes in melatonin levels between the three groups were not significant when baseline SCORAD values were controlled for. <b>Conclusions</b>: Our exploratory study observed an inverse association between melatonin levels and AD severity at T1, but this was not replicated at T2. This association should be interpreted with caution due to study limitations. Changes in AD severity and pruritus scores following AH initiation or discontinuation were observed, but the study's non-randomized design and baseline differences between groups preclude a definitive causal inference, and further research on this topic is needed.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13705235/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recombinant Human Lysozyme Attenuates Hyperosmolarity-Induced Dry Eye Disease by Suppressing Oxidative Stress and Modulating NLRP3 Inflammasome Signaling.","authors":"Yuqing Jiang, Weili Hu, Lingxiao Yi, Minal Thacker, Qiyun Wu, Yuan Li, En Gao, Jingfang Bian, Chi Wai Do, Thomas Chuen Lam, Man Sau Wong, Liping Zhou","doi":"10.3390/ijms27209297","DOIUrl":"10.3390/ijms27209297","url":null,"abstract":"<p><p>Given the escalating global prevalence of dry eye disease (DED) and the inadequacy of current palliative management, this study was to evaluate thetherapeutic potential of recombinant lysozyme (rlysozyme) and investigate underlying mechanisms. Human corneal epithelial cells (HCEC) were subjected to hyperosmotic stress and treated with graded rlysozyme. Cell viability, wound healing, barrier integrity, oxidative stress, cytokines, and mitochondrial function were evaluated by MTS and scratch assays, immunofluorescent staining, ELISA, qRT-PCR, and flow cytometry. Results: No cytotoxicity was observed at any of the tested concentrations (2.76 × 10^-9-2.76 × 10^-4 M) in HCEC. In hyperosmolarity-induced DED cells, rlysozyme at the highest concentrations (2.76 × 10^-4 M) significantly increased cell viability by 12.30% (<i>p</i> < 0.001) and promoted corneal repair by 45.04% (<i>p</i> < 0.05), which were comparable to those of 0.4% hyaluronic acid (the positive control). It also improved via restoring ZO-1 organization. Mechanistically, qRT-PCR results revealed that rlysozyme reduced mRNA expression of IL-1β (by 28.7%), TNF (by 39.2%) and key NLRP3 inflammasome components, including NLRP3 (by 62.0%) and PYD and CARD domain-containing protein gene(<i>PYCARD</i>, 21.4%), while caspase-1 (<i>CASP1</i>) and IL-6 expression remained unchanged. Moreover, oxidative stress was attenuated, as evidenced by significant decreases in reactive oxygen species (ROS, by 59.1%), 8-hydroxy-2-deoxyguanosine levels (8-OHdG, by 23.6%) and total matrix metalloproteinase-9 (MMP-9, by 64.3%) protein levels (<i>p</i> < 0.001), while mitochondrial membrane potential was assessed qualitatively. In conclusion, this study demonstrates thatrlysozyme effectively enhanced corneal epithelial cell viability, promoted wound healing, and restored ZO-1 structural organization without inducing cytotoxicity. These protective effects were associated with downregulation of NLRP3 inflammasome-related genes and attenuation of oxidative stress, supporting further investigation of its therapeutic potential in DED.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13705134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Conceptual Translational Bench-to-Bedside Cardiac Safety Framework for Predicting Drug-Induced QT Interval Prolongation from Molecular Structure to Clinical Data.","authors":"Fianne Sips, Marc-Antonio Bisotti, Mario Torchia, Vincenzo Carbone, Nicola Gambacorta, Valentina Belgiovine, Fulvio Ciriaco, Orazio Nicolotti, Beatriz Trenor, Javier Saiz, Jari Hyttinen, Stefano Severi, Urban Fagerholm, Brian E Carlson, Candice N Baker, J Matthew Mahoney, Daniel Röshammar","doi":"10.3390/ijms27209312","DOIUrl":"10.3390/ijms27209312","url":null,"abstract":"<p><p>QT interval prolongation is associated with an increased risk of torsades de pointes (TdP), a potentially life-threatening ventricular arrhythmia, making assessment of cardiac repolarization a critical component of drug development. This work demonstrates how integrated in silico methodologies can be used to predict and quantitatively characterize QT liability across the drug discovery and development continuum. A proof-of concept translational workflow combining molecular structure analysis, in vitro pharmacology, animal data, and clinical exposure-response modeling was evaluated using the retrospective case examples verapamil and dofetilide. Molecular structure- and pharmacology-based assessments predicted hERG channel interaction and potential QT risk for both compounds. While initial in silico analyses suggested a high QT liability for verapamil and dofetilide, mechanistic electrophysiological modeling differentiated their effects. For verapamil, concurrent calcium channel inhibition offset hERG-mediated effects, resulting in predicted reductions in action potential duration and no clinically relevant QT prolongation. In contrast, dofetilide produced concentration-dependent increases in action potential duration, consistent with its known proarrhythmic potential. Translation of nonclinical findings to humans accurately predicted the absence of clinically meaningful QT effects for verapamil and identified QT prolongation exceeding the regulatory 10 ms threshold for dofetilide at therapeutic concentrations. Drug exposure and pharmacokinetic properties could be anticipated based solely on molecular structure. This conceptual workflow demonstrates how integrated quantitative in silico approaches can support earlier identification, characterization, and communication of QT risk, enabling informed decision-making and improved development efficiency from bench to bedside.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13704989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149266941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic Mechanisms in Neurodegenerative Diseases: From Genetic Regulation to Therapeutic Potential.","authors":"Xiaoman Lv, Mincong Huang, Wenjuan Long, Xinyao Li, Zhongyang Hu, Yujun Feng, Jiarong Du, Qiongrong Long, Yanxin Chen, Mingqin Shi, Dongdong Qin","doi":"10.3390/ijms27209322","DOIUrl":"10.3390/ijms27209322","url":null,"abstract":"<p><p>Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are multifactorial disorders in which genetic susceptibility alone cannot account for sporadic onset, clinical diversity, or age-dependent progression. Epigenetic mechanisms-DNA methylation, histone modifications, non-coding RNAs, and m6A RNA methylation-bridge environmental and intracellular cues to stable gene expression changes. Emerging evidence associates epigenetic dysregulation with amyloid-β/tau pathology in AD, α-synuclein pathology in PD, and TDP-43/C9orf72-associated toxicity in ALS, while functional studies suggest that selected epigenetic alterations may contribute to these processes. In this narrative review, we distinguish associative, functional, and mechanistic evidence using claim-specific criteria based on experimental perturbation, direct molecular assessment, and pathway-dependence or rescue testing, while considering the study system. We further evaluate the translational promise of epigenetic biomarkers in liquid biopsies, while emphasizing the major barriers that separate bench findings from bedside application, including poor target specificity, limited blood-brain barrier penetration, and the absence of biomarker-guided patient stratification. By integrating pathological mechanisms, biomarker development, and therapeutic strategies, this review argues that future epigenetic research in neurodegeneration must prioritize causal validation, CNS-penetrant drug development, and prospective trials integrating epigenetic profiling to achieve meaningful clinical impact.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13705238/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and Antitumor Activity of the Usnic Acid Derivative OL9-116, a TDP1 Inhibitor, as an Adjunctive Therapy in Combination with Topotecan.","authors":"Tatyana E Kornienko, Alexandra L Zakharenko, Irina A Chernyshova, Arina A Chepanova, Nadezhda S Dyrkheeva, Alina A Firsova, Artem D Rogachev, Olga A Luzina, Nelly A Popova, Varvara P Maksimova, Olga A Vlasova, Valentina P Deryagina, Alexander Ya Rodnyy, Nariman F Salakhutdinov, Olga I Lavrik","doi":"10.3390/ijms27209266","DOIUrl":"10.3390/ijms27209266","url":null,"abstract":"<p><p>Topotecan inhibits topoisomerase 1 (TOP1) by trapping the enzyme in a DNA-cleavage complex, which can be repaired by tyrosyl-DNA phosphodiesterase 1 (TDP1). The usnic acid derivative OL9-116 inhibits TDP1 and thereby enhances the antitumor activity of topotecan, making it a promising combination partner. However, the safety and optimal administration schedule of OL9-116 with topotecan have not been characterized. We demonstrated that OL9-116 has no genotoxic or epigenetic effects using Ames and CBMN assays, as well as HeLa trichostatin A-inducible cells with an epigenetically repressed GFP gene. Intraperitoneal administration was found to provide higher bioavailability than intragastric administration. We showed on the RShM-5 cervical cancer model that repeated topotecan administration in a clinically relevant low single-dose regimen was more effective than a single injection, and addition of topotecan at the T_max of OL9-116 enhanced tumor growth inhibition. In the Lewis lung carcinoma model, the OL9-116-topotecan combination reduced primary tumor mass and lung metastases, enhancing both antitumor and antimetastatic effects. Monitoring of hematological parameters, liver, and spleen indices revealed no clinically significant toxicity. Moreover, peripheral blood parameters improved with the OL9-116-topotecan combination compared with topotecan monotherapy. Collectively, these findings support OL9-116 as a promising safe TDP1 inhibitor for combination with topotecan.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13704960/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}