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Search Results (723)

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20 pages, 3136 KiB  
Review
The Role of Genomic Islands in the Pathogenicity and Evolution of Plant-Pathogenic Gammaproteobacteria
by Yuta Watanabe, Yasuhiro Ishiga and Nanami Sakata
Microorganisms 2025, 13(8), 1803; https://doi.org/10.3390/microorganisms13081803 - 1 Aug 2025
Viewed by 132
Abstract
Genomic islands (GIs) including integrative and conjugative elements (ICEs), prophages, and integrative plasmids are central drivers of horizontal gene transfer in bacterial plant pathogens. These elements often carry cargo genes encoding virulence factors, antibiotic and metal resistance determinants, and metabolic functions that enhance [...] Read more.
Genomic islands (GIs) including integrative and conjugative elements (ICEs), prophages, and integrative plasmids are central drivers of horizontal gene transfer in bacterial plant pathogens. These elements often carry cargo genes encoding virulence factors, antibiotic and metal resistance determinants, and metabolic functions that enhance environmental adaptability. In plant-pathogenic species such as Pseudomonas syringae, GIs contribute to host specificity, immune evasion, and the emergence of novel pathogenic variants. ICEclc and its homologs represent integrative and mobilizable elements whose tightly regulated excision and transfer are driven by a specialized transcriptional cascade, while ICEs in P. syringae highlight the ecological impact of cargo genes on pathogen virulence and fitness. Pathogenicity islands further modulate virulence gene expression in response to in planta stimuli. Beyond P. syringae, GIs in genera such as Erwinia, Pectobacterium, and Ralstonia underpin critical traits like toxin biosynthesis, secretion system acquisition, and topoisomerase-mediated stability. Leveraging high-throughput genomics and structural biology will be essential to dissect GI regulation and develop targeted interventions to curb disease spread. This review synthesizes the current understanding of GIs in plant-pathogenic gammaproteobacteria and outlines future research priorities for translating mechanistic insights into sustainable disease control strategies. Full article
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22 pages, 83520 KiB  
Article
The Kinase Inhibitor GNF-7 Is Synthetically Lethal in Topoisomerase 1-Deficient Ewing Sarcoma
by Carly M. Sayers, Morgan B. Carter, Haiyan Lei, Arnulfo Mendoza, Steven Shema, Xiaohu Zhang, Kelli Wilson, Lu Chen, Carleen Klumpp-Thomas, Craig J. Thomas, Christine M. Heske and Jack F. Shern
Cancers 2025, 17(15), 2475; https://doi.org/10.3390/cancers17152475 - 26 Jul 2025
Viewed by 368
Abstract
Background/Objectives: Ewing sarcoma (ES), a highly aggressive bone and soft tissue cancer occurring in children and young adults, is defined by the ETS fusion oncoprotein EWS::FLI1. Although event-free survival rates remain high in ES patients with localized disease, those with metastatic or relapsed [...] Read more.
Background/Objectives: Ewing sarcoma (ES), a highly aggressive bone and soft tissue cancer occurring in children and young adults, is defined by the ETS fusion oncoprotein EWS::FLI1. Although event-free survival rates remain high in ES patients with localized disease, those with metastatic or relapsed disease face poor long-term survival odds. Topoisomerase 1 (TOP1) inhibitors are commonly used therapeutics in ES relapse regimens. Methods: In this work, we used a genome-wide CRISPR knockout library screen to identify the deletion of the TOP1 gene as a mechanism for resistance to topoisomerase 1 inhibitors. Using isogenic cell line models, we performed a high-throughput small-molecule screen to discover a small molecule, GNF-7, which had an IC50 that was 10-fold lower in TOP1-deficient cells when compared to the wild-type cells. Results: The characterization of GNF-7 demonstrated the molecule was highly active in the inhibition of CSK, p38α, EphA2, Lyn, and ZAK and specifically downregulated genes induced by the EWS::FLI1 fusion oncoprotein. Conclusions: Together, these results suggest that GNF-7 or small molecules with a similar kinase profile could be effective treatments for ES patients in combination with TOP1 inhibitors or for those patients who have developed resistance to TOP1 inhibitors. Full article
(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors (2nd Edition))
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16 pages, 1234 KiB  
Article
Genomic Insights of Emerging Multidrug-Resistant OXA-48-Producing ST135 Proteus mirabilis
by Angeliki Mavroidi, Elisavet Froukala, Nick Spanakis, Aikaterini Michelaki, Maria Orfanidou, Vasiliki Koumaki and Athanasios Tsakris
Antibiotics 2025, 14(8), 750; https://doi.org/10.3390/antibiotics14080750 - 25 Jul 2025
Viewed by 296
Abstract
Background/Objectives: Among Enterobacterales, OXA-48-like-producing Proteus mirabilis strains have been scarcely detected. Herein, we characterized a blaOXA-48-harbouring P. mirabilis strain recovered from Greece (Pm GR-1), while phylogenomics and comparative genomics analyses with previously published blaOXA-48 carriers were also assessed. [...] Read more.
Background/Objectives: Among Enterobacterales, OXA-48-like-producing Proteus mirabilis strains have been scarcely detected. Herein, we characterized a blaOXA-48-harbouring P. mirabilis strain recovered from Greece (Pm GR-1), while phylogenomics and comparative genomics analyses with previously published blaOXA-48 carriers were also assessed. Methods: Characterization of Pm GR-1 was performed by the Vitek® Compact and Mass Spectrometry systems, antimicrobial susceptibility testing, detection of beta-lactamases, multilocus-sequence typing (MLST), and whole-genome sequencing (WGS). In silico prediction of mobile genetic elements (MGEs), genomic islands (GIs), antimicrobial resistance genes (ARGs) and virulence factors (VFs), and phylogenetic, core-genome SNP and comparative genomics analyses were executed using bioinformatic tools. Results: Pm GR-1 was isolated from a urine sample of an outpatient in a Greek hospital. It exhibited a multidrug-resistant phenotype, being susceptible only to amikacin and ceftazidime/avibactam. It co-carried several beta-lactamase genes on the chromosome (blaOXA-48, blaCTX-M-14, blaTEM-1) and a plasmid (blaTEM-2) and several other ARGs, but also mutations associated with quinolone resistance in the DNA gyrase and topoisomerase IV subunits. It belonged to the international clone ST135 that has also been detected among OXA-48-producing P. mirabilis strains from Germany and the USA. Pm GR-1 was genetically related to those from Germany, sharing highly similar MGEs, GIs, ARGs and VFs, including the chromosomal blaOXA-48 genetic structure, the O-antigen locus, the flagella locus, the MR/P fimbriae operon, and the urease gene cluster. Conclusions: To our knowledge, this is the first report from Greece of a blaOXA-48-possessing P. mirabilis strain. The emergence of blaOXA-48 among P. mirabilis strains of the international clone ST135 in different geographical regions is worrying. Close monitoring of these strains is required in One Health settings. Full article
(This article belongs to the Special Issue Antimicrobial Resistance Genes: Spread and Evolution)
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24 pages, 855 KiB  
Review
Antibody–Drug Conjugates Powered by Deruxtecan: Innovations and Challenges in Oncology
by Jung Yoon Jang, Donghwan Kim, Na Kyeong Lee, Eunok Im and Nam Deuk Kim
Int. J. Mol. Sci. 2025, 26(13), 6523; https://doi.org/10.3390/ijms26136523 - 7 Jul 2025
Viewed by 1286
Abstract
Antibody–drug conjugates (ADCs) have revolutionized precision oncology by enabling targeted drug delivery with improved therapeutic indices. Among these, deruxtecan (DXd)-based ADCs have demonstrated remarkable efficacy across a range of cancers, particularly in tumors expressing human epidermal growth factor receptor 2 (HER2), human epidermal [...] Read more.
Antibody–drug conjugates (ADCs) have revolutionized precision oncology by enabling targeted drug delivery with improved therapeutic indices. Among these, deruxtecan (DXd)-based ADCs have demonstrated remarkable efficacy across a range of cancers, particularly in tumors expressing human epidermal growth factor receptor 2 (HER2), human epidermal growth factor receptor 3 (HER3), and trophoblast cell surface antigen 2 (TROP2), including breast, lung, gastric, and other solid tumors. DXd, a potent topoisomerase I inhibitor, enhances the cytotoxic potential of ADCs through a cleavable and stable linker and a high drug-to-antibody ratio that ensures optimal drug release. The clinical success of trastuzumab DXd (Enhertu®) and datopotamab DXd (Datroway®), along with the ongoing development of patritumab DXd, has expanded the therapeutic potential of ADCs. However, challenges remain, including toxicity, resistance, and manufacturing scalability. This review discusses the mechanisms of action, clinical progress, and challenges of DXd-based ADCs, highlighting their transformative role in modern oncology and exploring future directions to optimize their efficacy and accessibility. Full article
(This article belongs to the Special Issue New Wave of Cancer Therapeutics: Challenges and Opportunities)
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19 pages, 719 KiB  
Article
Redefining Systemic Sclerosis Classification: Anti-Topoisomerase Antibody as a Superior Predictor of Interstitial Lung Disease and Skin Progression Compared to Limited Cutaneous Systemic Sclerosis Subset
by Chana Chaovanitkul, Tippawan Onchan, Patnarin Pongkulkiat, Ajanee Mahakkanukrauh, Siraphop Suwannaroj and Chingching Foocharoen
Life 2025, 15(7), 1067; https://doi.org/10.3390/life15071067 - 4 Jul 2025
Viewed by 542
Abstract
Background: Currently, no information exists on the clinical course of anti-topoisomerase I antibody (ATA)-positive limited cutaneous systemic sclerosis (lcSSc). We aimed to evaluate the incidence of and time to the development of interstitial lung disease (ILD), pulmonary hypertension (PHT), scleroderma renal crisis (SRC), [...] Read more.
Background: Currently, no information exists on the clinical course of anti-topoisomerase I antibody (ATA)-positive limited cutaneous systemic sclerosis (lcSSc). We aimed to evaluate the incidence of and time to the development of interstitial lung disease (ILD), pulmonary hypertension (PHT), scleroderma renal crisis (SRC), and maximal modified Rodnan skin score (max-mRSS) in patients with lcSSc and dcSSc, with and without ATA. Methods: This cohort study included 522 patients with systemic sclerosis (SSc). The incidence of and time to the development of ILD, PHT, SRC, and max-mRSS were assessed. Results: ATA-positive dcSSc (dcSSc-posATA) was the most common presentation among Thai patients (321 cases; 61.5%). The median time to the development of ILD was shorter than that in lcSSc-posATA, comparable to that in dcSSc-posATA (1.0 vs. 1.8 years, p = 0.21), and shorter than that in ATA-negative dcSSc (dcSSc-negATA) (1.0 vs. 4.8 years, p = 0.001). The time to max-mRSS in lcSSc-posATA was comparable to that in dcSSc-posATA (p = 0.17) but shorter than that in dcSSc-negATA (p < 0.001). Conclusions: Patients with lcSSc-posATA had a similar risk of ILD development and time to reach max-mRSS as those with dcSSc, regardless of the presence of ATA, but had earlier ILD development and max-mRSS compared to those with dcSSc-negATA. Their prognosis appeared to be better than that of dcSSc-posATA. Full article
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15 pages, 2600 KiB  
Article
Substituted Triazole-3,5-Diamine Compounds as Novel Human Topoisomerase III Beta Inhibitors
by Yasir Mamun, Somaia Haque Chadni, Ramanjaneyulu Rayala, Hasham Shafi, Shomita Ferdous, Rudramani Pokhrel, Adel Nefzi, Prem Chapagain and Yuk-Ching Tse-Dinh
Int. J. Mol. Sci. 2025, 26(13), 6193; https://doi.org/10.3390/ijms26136193 - 27 Jun 2025
Viewed by 469
Abstract
Human topoisomerase III beta (hTOP3B) is a unique and important enzyme in human cells that plays a role in maintaining genome stability, affecting cellular aging, and potentially impacting viral replication. Its dual activity on both DNA and RNA makes it a valuable target [...] Read more.
Human topoisomerase III beta (hTOP3B) is a unique and important enzyme in human cells that plays a role in maintaining genome stability, affecting cellular aging, and potentially impacting viral replication. Its dual activity on both DNA and RNA makes it a valuable target for therapeutic interventions. hTOP3B has been shown to be required for the efficient replication of certain positive-sense ssRNA viruses including Dengue. We performed in silico screening of a library comprising drugs that are FDA-approved or undergoing clinical trials as potential drugs to identify potential inhibitors of hTOP3B. The topoisomerase activity assay of the identified virtual hits showed that bemcentinib, a compound known to target the AXL receptor tyrosine kinase, can inhibit hTOP3B relaxation activity. This is the first small molecule shown to inhibit the complete catalytic cycle of hTOP3B for the potential interference of the function of hTOP3B in antiviral application. Additional small molecules that share the N5,N3-1H-1,2,4-triazole-3,5-diamine moiety of bemcentinib were synthesized and tested for the inhibition of hTOP3B relaxation activity. Five compounds with comparable IC50 to that of bemcentinib for the inhibition of hTOP3B were identified. These results suggest that the exploration of tyrosine kinase inhibitors and their analogs may allow the identification of novel potential topoisomerase inhibitors. Full article
(This article belongs to the Special Issue Small Molecule Drug Design and Research: 3rd Edition)
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11 pages, 2358 KiB  
Communication
Quinaldehyde o-Nitrobenzoylhydrazone: Structure and Sensitization of HepG2 Cells to Anti-Cancer Drugs
by Valeri V. Mossine, Steven P. Kelley and Thomas P. Mawhinney
Compounds 2025, 5(3), 24; https://doi.org/10.3390/compounds5030024 - 25 Jun 2025
Viewed by 372
Abstract
A quinoline unit is present in many natural products and is an attractive pharmacophore for the development of clinical drugs, including antineoplastics. The title compound (QN) was synthesized via the condensation reaction between quinoline-2-carboxaldehyde and 2-nitrobenzhydrazide. QN’s structure was examined by X-ray diffraction [...] Read more.
A quinoline unit is present in many natural products and is an attractive pharmacophore for the development of clinical drugs, including antineoplastics. The title compound (QN) was synthesized via the condensation reaction between quinoline-2-carboxaldehyde and 2-nitrobenzhydrazide. QN’s structure was examined by X-ray diffraction and features extensive stacking interactions in the crystal. The compound is weakly toxic to HepG2 cells, with an IC50 exceeding 400 μM for 48 h exposure. QN at 50 μM, with the dose reduction index in the range of 1.9–4.4, potentiated the cytotoxicity of several clinical chemotherapeutic drugs, including doxorubicin and other topoisomerase inhibitors, vincristine, and carboplatin, but not cisplatin or 5-fluorouracil. The calculated ADME parameters predict satisfactory drug-like properties for QN. Full article
(This article belongs to the Special Issue Organic Compounds with Biological Activity)
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18 pages, 2254 KiB  
Article
Didemnosides A and B: Antiproliferative Nucleosides from the Red Sea Marine Tunicate Didemnum Species
by Lamiaa A. Shaala, Diaa T. A. Youssef, Hadeel Almagthali, Ameen M. Almohammadi, Wafaa T. Arab, Torki Alzughaibi, Noor M. Bataweel and Reham S. Ibrahim
Mar. Drugs 2025, 23(7), 262; https://doi.org/10.3390/md23070262 - 23 Jun 2025
Viewed by 606
Abstract
Marine tunicates are a very attractive and abundant source of secondary metabolites with chemical diversity and biological activity. Fractionation and purification of the organic extract of the Red Sea tunicate Didemnum species resulted in the isolation and identification of three new compounds, didemnosides [...] Read more.
Marine tunicates are a very attractive and abundant source of secondary metabolites with chemical diversity and biological activity. Fractionation and purification of the organic extract of the Red Sea tunicate Didemnum species resulted in the isolation and identification of three new compounds, didemnosides A and B (1 and 2) and 1,1′,3,3′-bisuracil (3), together with thymidine (4), 2′-deoxyuridine (5), homarine (6), and acetamide (7). Planar structures of the compounds were explained through analyses of their 1D (1H and 13C) and 2D (1H–1H COSY, HSQC, and HMBC) NMR spectra and high-resolution mass spectral determinations. Compound 1 exhibited the highest growth inhibition toward the MCF-7 cancer cell line with IC50 values of 0.597 μM, while other compounds were inactive (≥50 μM) against this cell line. On the other hand, compounds 1, 2, and 47 moderately inhibited SW-1222 and PC-3 cells with IC50 values ranging between 5.25 and 9.36 μM. Molecular docking analyses of the top three active compounds on each tested cell line exposed stable interactions into the active pockets of estrogen receptor alpha (ESR1), human topoisomerase II alpha (TOP2A), and cyclin-dependent kinase 5 (CDK5) which are contemplated as essential targets in cancer treatments. Thus, compound 1 represents a scaffold for the development of more effective anticancer drugs. Full article
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18 pages, 6004 KiB  
Article
Targeting Topoisomerase I and DNA with LCS1269 Drives Glioblastoma Cell Death Despite ATM/Chk1/BRCA1/RAD51 Signaling Pathway Activation
by Nikolay Kalitin, Ekaterina Savchenko, Nadezhda Samoylenkova, Natalia Koroleva, Anna Lushnikova, Aida Karamysheva and Galina Pavlova
Int. J. Mol. Sci. 2025, 26(13), 6014; https://doi.org/10.3390/ijms26136014 - 23 Jun 2025
Viewed by 363
Abstract
Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. The success of modern multimodal standards approved in anti-glioblastoma therapy remains limited. Consequently, new therapeutics are urgently needed. In this study, utilizing ex vivo, in silico, and in vitro approaches, we investigated [...] Read more.
Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. The success of modern multimodal standards approved in anti-glioblastoma therapy remains limited. Consequently, new therapeutics are urgently needed. In this study, utilizing ex vivo, in silico, and in vitro approaches, we investigated the LCS1269 effects on two potential targets, DNA and Top I. We also elucidated the influence of LCS1269 on signaling pathways and GBM cell viability. Based on our docking data and competition studies results, we demonstrated that LCS1269 may bind to DNA, demonstrating selectivity toward AT-rich regions. We also showed that LCS1269 could dock both Top I/DNA binary complex and Top I active sites. LCS1269 caused Top I dysfunction and downregulated the expression of Top I. Moreover, the LCS1269 treatment of GBM cells facilitated DNA damage and the activation of the ATM/Chk1/BRCA1/Rad51 pathway. Meanwhile, DNA damage response induction and ATM/Chk1/BRCA1/Rad51 pathway activation were insufficient to prevent GBM cell death triggered by LCS1269 treatment. Our work shows that DNA and Top I are promising molecular targets of LCS1269, thus providing insight on several novel mechanisms of its anti-tumor activity. Nonetheless, we did not perform a biophysical validation of the LCS1269–DNA interaction, which is a limitation of our study. Full article
(This article belongs to the Special Issue Molecular Modeling: Latest Advances and Applications)
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25 pages, 2579 KiB  
Article
Exploring Carboxamide Derivatives as Promising Anticancer Agents: Design, In Vitro Evaluation, and Mechanistic Insights
by Manal M. Al-Najdawi, Maysaa M. Saleh, Dima A. Sabbah, Rima Hajjo, Hiba Zalloum, Suha M. Abudoleh, Duaa A. Abuarqoub, Yusuf M. Al-Hiari, Mohammad Yasin Mohammad, Husam ALSalamat, Hebah Mansour, Nawzat D. Aljbour and Aktham H. Mestareehi
Int. J. Mol. Sci. 2025, 26(12), 5903; https://doi.org/10.3390/ijms26125903 - 19 Jun 2025
Viewed by 742
Abstract
Carboxamide derivatives are a promising class of compounds in anticancer drug discovery, owing to their ability to interact with multiple oncogenic targets and their favorable pharmacological profiles. In this study, we report the design, synthesis, and biological evaluation of a series of N [...] Read more.
Carboxamide derivatives are a promising class of compounds in anticancer drug discovery, owing to their ability to interact with multiple oncogenic targets and their favorable pharmacological profiles. In this study, we report the design, synthesis, and biological evaluation of a series of N-substituted 1H-indole-2-carboxamides as potential anticancer agents. The synthesized compounds were assessed for antiproliferative activity using the MTT assay against MCF-7 (breast cancer), K-562 (leukemia), and HCT-116 (colon cancer) cell lines, with normal human dermal fibroblasts included as a non-cancerous control. Several compounds demonstrated notable cytotoxicity and selectivity. Compounds 12, 14, and 4 exhibited potent activity against K-562 cells, with IC50 values of 0.33 µM, 0.61 µM, and 0.61 µM, respectively. Compound 10 showed the most significant activity against HCT-116 cells (IC50 = 1.01 µM) with a high selectivity index (SI = 99.4). Moderate cytotoxicity was observed against MCF-7 cells. To elucidate the mechanism of action, molecular docking and induced-fit docking studies were conducted against key cancer-related targets, including topoisomerase–DNA (PDB ID: 5ZRF), PI3Kα (4L23), and EGFR (3W32), revealing favorable binding interactions. Additionally, principal component analysis of molecular descriptors indicated that the compounds possess promising drug-like and lead-like properties, particularly compound 10. Overall, this study highlights N-substituted indole-2-carboxamides as promising scaffolds for further optimization. The integration of synthetic chemistry, biological assays, and computational modeling provides a robust foundation for the continued development of these compounds as potential anticancer agents. Full article
(This article belongs to the Special Issue Biological Hallmarks and Therapeutic Strategies in Cancer)
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21 pages, 1771 KiB  
Article
Total Synthesis and Biological Evaluation of 22-Hydroxyacuminatine and the Related Natural Products Norketoyobyrine and Naucleficine
by Shohta Mizuno, Takashi Nishiyama, Hana Bessho, Tetsuya Nakamura, Tomoki Oe, Nanako Hayashi, Yuhzo Hieda, Toshio Motoyashiki, Toshiyuki Hata, Noriyuki Hatae and Tominari Choshi
Molecules 2025, 30(12), 2650; https://doi.org/10.3390/molecules30122650 - 19 Jun 2025
Viewed by 454
Abstract
Aromathecin compounds—which contain the same indolizine core structure as camptothecin-like compounds—are expected to show anticancer activity. Among them, 22-hydroxyacuminatine—which has a substituent on the E-ring of the pentacyclic scaffold—exhibits topoisomerase 1 inhibitory activity; therefore, the development of efficient methods for its synthesis has [...] Read more.
Aromathecin compounds—which contain the same indolizine core structure as camptothecin-like compounds—are expected to show anticancer activity. Among them, 22-hydroxyacuminatine—which has a substituent on the E-ring of the pentacyclic scaffold—exhibits topoisomerase 1 inhibitory activity; therefore, the development of efficient methods for its synthesis has been actively pursued. Herein, we report a versatile synthetic methodology for introducing various substituents on the E-ring, leading to the total synthesis of 22-hydroxyacuminatine as a model compound of the aromathecin family. The synthesis comprises the following key steps: the synthesis of an isoquinoline N-oxide via the thermal cyclization of 2-alkynylbenzaldehyde oxime, the subsequent Reissert–Henze-type reaction to yield an isoquinolone, and the construction of the indolizine moiety (CD-ring) through C–N bond formation via the Mitsunobu reaction. Consequently, a pentacyclic benz[6,7]indolizino[1,2-b]quinolin-11(13H)-one framework is obtained. Using this methodology, the total synthesis of the natural products norketoyobyrine and naucleficine and an intermediate of the latter, which are indoloquinolizidine-type alkaloids, was achieved, and their antiproliferative activity against HCT-116 human colon cancer cells and HepG2 human liver cancer cells was assessed. Naucleficine and its intermediate exhibited moderate antiproliferative activity against HCT-116 cells, with IC50 values of 55.58 and 41.40 μM, respectively. Full article
(This article belongs to the Special Issue Exclusive Feature Papers in Synthetic Medicinal Chemistry)
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21 pages, 2243 KiB  
Review
Top2b-Regulated Genes and Pathways Linked to Retinal Homeostasis and Degeneration
by Merna M. Ibrahim and Li Cai
Cells 2025, 14(12), 887; https://doi.org/10.3390/cells14120887 - 12 Jun 2025
Viewed by 497
Abstract
Retinal homeostasis and degeneration are significant contributors to global vision loss, with retinal health primarily assessed by the count and function of photoreceptor cells, the most abundant cells in the retina. Genomic studies have identified topoisomerase II beta (Top2b), an enzyme that untangles [...] Read more.
Retinal homeostasis and degeneration are significant contributors to global vision loss, with retinal health primarily assessed by the count and function of photoreceptor cells, the most abundant cells in the retina. Genomic studies have identified topoisomerase II beta (Top2b), an enzyme that untangles DNA supercoils to facilitate gene expression, as a critical transcriptional regulator for retinal health. This review aims to uncover and categorize genes linked to Top2b that are dynamically expressed during retinal degeneration, revealing shared and overlooked regulatory pathways. RNA sequencing data from wild-type and Top2b knockout mice revealed thousands of differentially expressed genes regulated by Top2b. By cross-referencing these genes with retinal degeneration datasets, including RetNet and the Gene Ontology Browser, we identified 44 Top2b-linked genes associated with retinal degeneration. These genes were grouped into fourteen functional categories: ciliary function and trafficking, metabolism, synaptic transmission, transcription factors and regulation, visual cycle, retinoids, and more. Key genes such as Bbs7, Ubb, Rbp4, Cetn2, Pik3r1, and Crx were explored, and their critical pathways for retinal health were outlined. This comprehensive catalog of 44 Top2b-linked retinal homeostatic genes will serve as a valuable resource for researchers. It provides new insights into the regulatory mechanisms underlying retinal homeostasis, setting the framework for the development of targeted therapeutic approaches and early intervention strategies for preventing photoreceptor loss. Full article
(This article belongs to the Special Issue Advances in the Discovery of Retinal Degeneration)
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32 pages, 4898 KiB  
Review
A Review of Natural and Synthetic Chalcones as Anticancer Agents Targeting Topoisomerase Enzymes
by François-Xavier Toublet, Aurélie Laurent and Christelle Pouget
Molecules 2025, 30(12), 2498; https://doi.org/10.3390/molecules30122498 - 6 Jun 2025
Viewed by 875
Abstract
Cancer remains one of the leading causes of morbidity and mortality worldwide, driving the search for innovative and selective therapeutic agents. Topoisomerases I and II are essential enzymes involved in key cellular processes such as DNA replication and transcription. They have emerged as [...] Read more.
Cancer remains one of the leading causes of morbidity and mortality worldwide, driving the search for innovative and selective therapeutic agents. Topoisomerases I and II are essential enzymes involved in key cellular processes such as DNA replication and transcription. They have emerged as valuable anticancer targets; thus, many inhibitors of topoisomerases have been designed and some of them are considered to be major anticancer agents such as anthracyclines, etoposide or irinotecan. A great deal of attention is currently being paid to chalcones, a class of naturally occurring compounds, since they exhibit a wide range of biological activities, including anticancer properties. These compounds are characterized by an open-chain structure and an α,β-unsaturated carbonyl moiety that enables interaction with cellular targets. Recent studies aiming to design anti-topoisomerase agents have identified both natural and synthetic chalcones, including chalcone-based hybrids. This review highlights the structural diversity of chalcones as topoisomerase inhibitors and particular attention is given to structure–activity relationship studies and molecular hybridization strategies aimed at optimizing the pharmacological profile of chalcones. These findings underline the potential of chalcones as promising scaffolds in the design of next-generation anticancer agents. Full article
(This article belongs to the Special Issue Synthesis and Evaluation of Bioactivity of Enzyme Inhibitors)
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25 pages, 1207 KiB  
Review
The Era of Precision Medicine: Advancing Treatment Paradigms for Small Cell Lung Cancer
by Derek A. Corica, Scott D. Bell, Lei Zhao, Nicholas J. Lawler, McKade A. Poirier, Peyton J. Miller, Mark R. Wakefield and Yujiang Fang
Cancers 2025, 17(11), 1847; https://doi.org/10.3390/cancers17111847 - 31 May 2025
Viewed by 987
Abstract
Small cell lung cancer (SCLC) remains a challenge prognostically. A clinically silent early stage and predilection for early metastasis leads to over half of patients presenting with metastatic disease at the time of diagnosis. Akin to many other cancers, once SCLC metastasizes, current [...] Read more.
Small cell lung cancer (SCLC) remains a challenge prognostically. A clinically silent early stage and predilection for early metastasis leads to over half of patients presenting with metastatic disease at the time of diagnosis. Akin to many other cancers, once SCLC metastasizes, current therapies begin to lose their effectiveness. The future of SCLC rests in innovative treatments aimed at improving patient outcomes. Chemotherapy and radiation remain the backbone treatment for SCLC. Most patients diagnosed with SCLC begin treatment with combination chemotherapy consisting of a platinum analog and topoisomerase inhibitor with or without concurrent radiation. Disease progression or recurrence warrants new treatment approaches. New chemotherapy combinations and advances in radiation precision offer patients novel approaches using the same backbone of treatment used in many other cancers. The introduction of newer therapeutic approaches, such as immune checkpoint inhibitors, small molecule targeted therapies, bispecific antibodies, and antibody–drug conjugates offer a bright future for patients with SCLC who fail first-line therapy. This review will focus on advancing treatment paradigms for SCLC in the era of precision medicine. Such a study might be helpful for pulmonologists and oncologists to manage precisely patients with SCLC. Full article
(This article belongs to the Special Issue Feature Review for Cancer Therapy: 2nd Edition)
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26 pages, 975 KiB  
Review
Doxorubicin-Induced Cardiotoxicity: A Comprehensive Update
by Vasvi Bhutani, Fahimeh Varzideh, Scott Wilson, Urna Kansakar, Stanislovas S. Jankauskas and Gaetano Santulli
J. Cardiovasc. Dev. Dis. 2025, 12(6), 207; https://doi.org/10.3390/jcdd12060207 - 30 May 2025
Cited by 2 | Viewed by 2215 | Correction
Abstract
Doxorubicin is an anthracycline chemotherapeutic that is widely used for treating various malignancies, including breast cancer, lymphomas, and sarcomas. Despite its efficacy, its clinical utility is limited by a well-documented risk of cardiotoxicity, which may manifest acutely or chronically. Doxorubicin works by intercalating [...] Read more.
Doxorubicin is an anthracycline chemotherapeutic that is widely used for treating various malignancies, including breast cancer, lymphomas, and sarcomas. Despite its efficacy, its clinical utility is limited by a well-documented risk of cardiotoxicity, which may manifest acutely or chronically. Doxorubicin works by intercalating DNA and inhibiting topoisomerase II, leading to DNA damage and cell death. However, this mechanism is not selective to cancer cells and can adversely affect cardiac myocytes. The introduction of doxorubicin into oncologic practice has revolutionized cancer treatment, but its cardiotoxic effects remain a significant concern. This systematic review aims to comprehensively examine the multifaceted impact of doxorubicin on cardiac structure and function through both preclinical and clinical lenses. Full article
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