Archives of biochemistry and biophysics最新文献

{"title":"Identification of residues mediating homotropic regulation in human hexokinase 3 reveals a common allosteric interface shared with hexokinase 1","authors":"Carolin Freye,&nbsp;Brian G. Miller","doi":"10.1016/j.abb.2025.110517","DOIUrl":"10.1016/j.abb.2025.110517","url":null,"abstract":"<div><div>Vertebrate hexokinases (HKs) display a variety of allosteric phenomena, including activation and inhibition by both homotropic and heterotropic ligands. The extent to which these homologs share a common allosteric mechanism is unknown. A unique trait of the vertebrate hexokinase 3 (HK3) orthologs is substrate inhibition by glucose. Here, we demonstrate that the isolated, regulatory N-terminal domain of human HK3 contains a low affinity glucose binding site whose dissociation constant (3.2 ± 0.4 mM) approximates the <em>K</em>_<em>i</em> value for glucose (11 ± 2 mM) observed in assays of the full-length enzyme. The isolated, catalytic C-terminal domain harbors a high affinity glucose binding site whose dissociation constant (6.2 ± 0.6 μM) resembles the <em>K</em>_<em>m</em> value for glucose (53 ± 1 μM). Substitution of Asn221 in full-length HK3, which lies within the N-terminal glucose binding site, reduces substrate inhibition by 30-fold while leaving other steady-state kinetic parameters unchanged. Homotropic inhibition of HK3 is largely independent of ATP concentrations, in contrast to heterotropic inhibition of hexokinase 1 (HK1) by glucose 6-phosphate, which is competitive with respect to ATP. Adding a 10-fold molar excess of the N-terminal domain to the C-terminal domain fails to alter substrate inhibition, suggesting that interdomain communication in HK3 requires their physical connection. Disrupting a coulombic interaction between N-terminal residue Asp264 and C-terminal residue Arg807, two conserved residues previously shown to participate in HK1 regulation, attenuates glucose inhibition of HK3. Our data support a common allosteric interface in HK1 and HK3, wherein effector binding at spatially distinct sites within the regulatory N-terminus is communicated to the catalytic C-terminus via conserved coulombic residues.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"771 ","pages":"Article 110517"},"PeriodicalIF":3.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Shear-induced fibronectin fibrillogenesis: Differential mechanisms under high and low shear stress conditions","authors":"Quang Phuc Le ,&nbsp;Hoang Huy Mai ,&nbsp;Thao Nghi Nguyen Hoang ,&nbsp;Hanh Thu Thi Tran ,&nbsp;Duy Phuoc Tran ,&nbsp;Khon Huynh","doi":"10.1016/j.abb.2025.110518","DOIUrl":"10.1016/j.abb.2025.110518","url":null,"abstract":"<div><div>Fibrillogenesis of plasma fibronectin (FN) can be triggered by shear stress, even in the absence of cells. While high shear stress is known to promote FN fibril formation, recent evidence suggests that low shear conditions also contribute to FN assembly. It is likely that distinct molecular mechanisms govern fibril formation under different flow regimes. In this study, we investigated FN fibril formation under high shear (2000-5000 s⁻¹) and low shear (50 s⁻¹) conditions which correspond to 7–17.5 Pa and 0.175 Pa, respectively. Morphological analysis showed that high shear rapidly induced thick, interconnected fibrils, whereas low shear led to the gradual formation of thin, sparse fibrils. Molecular dynamic simulations indicated that shear stress alone did not unfold FN in suspension; however, surface-adsorbed FN enabled shear-driven interaction with soluble FN. Under low shear, fibrillogenesis proceeded via slow FN accumulation and weak intermolecular binding, while high shear promoted strong domain-domain interactions. Molecular docking identified top-ranked <em>trans</em>-binding interfaces between FNI1–5 and FNIII1–3 regions, stabilized by salt bridges (e.g., Glu92-Arg694) and hydrogen bonds involving residues such as Lys149-Gly713 and Tyr265-Ser864. These interdomain interactions provide a structural basis for shear-induced fibril assembly.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"771 ","pages":"Article 110518"},"PeriodicalIF":3.8,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of COX-2 and its use as a therapeutic target in IBD and related colorectal cancer","authors":"Lulu Yang ,&nbsp;Francis Atim Akanyibah ,&nbsp;Dongming Yao ,&nbsp;Tao Jin ,&nbsp;Fei Mao","doi":"10.1016/j.abb.2025.110516","DOIUrl":"10.1016/j.abb.2025.110516","url":null,"abstract":"<div><div>Inflammatory bowel disease (IBD) is a persistent inflammation of the gastrointestinal tract with a significant risk of progression to colorectal cancer (CRC). IBD and CRC have increased cyclooxygenase-2 (COX-2) levels, which is important in these conditions. In IBD, COX-2 contributes to intestinal inflammation, mucosal injury, and immune response dysregulation, while in CRC, it contributes to carcinogenesis and influences tumor microenvironment and angiogenesis. COX-2 may also facilitate its harmful function via prostanoids. Research suggests that COX-2 polymorphisms in IBD and CRC elevate the chance of developing both conditions. Researchers have recognized COX-2 as a biomarker for CRC. Consequently, inhibiting COX-2 may aid in the prevention of IBD and CRC. Non-selective and selective COX-2 inhibitors have demonstrated the ability to mitigate IBD and CRC; however, their efficacy and safety diminish. Nanoparticles, prodrugs, small molecules, and polymeric substrates can deliver COX-2 inhibitors to specific tissues, which makes therapy more effective and safer. Consequently, their application for administering COX-2 inhibitors may herald a new era of improved effectiveness and reduced side effects. Molecular investigations have identified new compounds as potential COX-2 inhibitors. Extracts, microRNAs, and mesenchymal stem cells also help target COX-2 to prevent IBD and CRC.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"771 ","pages":"Article 110516"},"PeriodicalIF":3.8,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144366844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New 1,2,3-triazole derivatives as acetylcholinesterase and carbonic anhydrase inhibitors: Synthesis, molecular docking, and solubility","authors":"Cagla Efeoglu ,&nbsp;Yeliz Demir ,&nbsp;Cüneyt Türkeş ,&nbsp;Erdal Yabalak ,&nbsp;Zeynel Seferoglu ,&nbsp;Yahya Nural","doi":"10.1016/j.abb.2025.110515","DOIUrl":"10.1016/j.abb.2025.110515","url":null,"abstract":"<div><div>In this study, a series of new 1,2,3-triazole derivatives were synthesized in 84–93 % yield using copper-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry and characterized by ¹H/¹³C NMR, FT-IR, and HRMS analyses. The synthesized compounds (<strong>4a–h</strong>) were evaluated for their inhibitory activities against human carbonic anhydrase isoforms I and II (<em>h</em>CA I and <em>h</em>CA II) and acetylcholinesterase (AChE), which are clinically relevant targets in neurological and metabolic disorders. Among them, compounds <strong>4f</strong> and <strong>4g</strong> exhibited the most potent dual inhibitory activities. Compound <strong>4f</strong> showed <em>K</em>_I values of 144.30 nM for <em>h</em>CA II and 205.10 nM for AChE, while compound <strong>4g</strong> exhibited <em>K</em>_I values of 239.10 nM for <em>h</em>CA II and 125.90 nM for AChE. These values demonstrate that <strong>4f</strong> and <strong>4g</strong> are more effective than the reference drugs acetazolamide (<em>h</em>CA II, <em>K</em>_I = 381.44 nM) and tacrine (AChE, <em>K</em>_I = 255.44 nM). Structure-activity relationship (SAR) analysis revealed that hydrophobicity, steric bulk, and aromaticity significantly influenced enzyme affinity. <em>In silico</em> docking confirmed strong interactions with key active site residues. Furthermore, ethanol solubility profiling revealed that polar and hydrogen-bonding groups significantly improved solubility, while bulky or aromatic hydrophobic substituents reduced it. The combined biological activity and solubility data emphasize the potential of these triazole derivatives particularly <strong>4f</strong> and <strong>4g</strong> as promising candidates for multitarget drug design and further preclinical development.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"771 ","pages":"Article 110515"},"PeriodicalIF":3.8,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144366845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Organosilicon molecules bind to the intrinsically disordered protein NUPR1 by clamping its hot-spots","authors":"Laura F. Peña ,&nbsp;Matías Estaras ,&nbsp;Paula González-Andrés ,&nbsp;Carlos Díez-Poza ,&nbsp;Bruno Rizzuti ,&nbsp;Olga Abian ,&nbsp;Adrian Velazquez-Campoy ,&nbsp;Juan L. Iovanna ,&nbsp;Patricia Santofimia-Castaño ,&nbsp;José L. Neira ,&nbsp;Asunción Barbero","doi":"10.1016/j.abb.2025.110513","DOIUrl":"10.1016/j.abb.2025.110513","url":null,"abstract":"<div><div>The nuclear protein 1, or NUPR1, is an intrinsically disordered protein (IDP) involved in the development and progression of pancreatic ductal adenocarcinoma (PDAC). We have previously developed drugs capable of binding at the two hot-spot regions of NUPR1, around residues Ala33 and Thr68, hampering its interactions <em>in cellulo</em>. In this work, we synthesized new organosilicon molecules targeting those key hot-spots. The compounds were obtained by an acid-catalyzed intramolecular cyclization of a starting alkenol that contains a silyl group attached to the double bond. Binding between the silyl compounds and NUPR1 involved the two hot-spots, as shown by 2D ¹H–¹⁵N HSQC NMR. Molecular simulations clarified that the binding relies on a loose clamp mechanism of the ligands towards the hot-spots. The dissociation constants (<em>K</em>_d) were around 20 μM, as measured by several biophysical techniques. However, studies <em>in cellulo</em> with PDAC cells did not show a decrease of cell viability upon treatment with the compounds; furthermore, proximity ligation assays <em>in cellulo</em> with a natural partner protein of NUPR1, G3BP, did not show a significant level of interfering in such interaction when silyl compounds were present, probably due to the high hydrophobicity of the designed compounds. Thus, in the case of NUPR1, moderate-to-high drug binding affinities (<em>K</em>_d &lt; 10 μM) <em>in vitro</em> and a higher hydrophilicity are necessary to hamper protein-protein interactions <em>in cellulo</em>. As a more general conclusion, <em>in vitro</em> binding of ligands to the protein hot-spots is a necessary condition in the drug design targeting IDPs, but it is not enough to guarantee inhibition of their interactions <em>in cellulo</em>.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"771 ","pages":"Article 110513"},"PeriodicalIF":3.8,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-asthmatic effects of andrographolide on OVA-stimulated mice via Th17 cell differentiation-mediated glycolytic pathway","authors":"Qian Yu ,&nbsp;XuChun Ding ,&nbsp;ChunXiu Xu ,&nbsp;LiHong Zhu ,&nbsp;YaFang Lou","doi":"10.1016/j.abb.2025.110514","DOIUrl":"10.1016/j.abb.2025.110514","url":null,"abstract":"<div><h3>Background</h3><div>Asthma has always been considered a major global health issue. Despite the significant efficacy of the established treatment, the incidence of exacerbation and mortality remains alarmingly high. Andrographolide (AG), extracted from the traditional Chinese herb Andrographis paniculate, has been proved to be anti-asthmatic with different mechanisms. But there have been no studies involving the regulatory function of AG in asthma through glycolysis. Herein, we aim to explore the potential effects and mechanism of glycolytic pathway in AG inhibition of asthma.</div></div><div><h3>Methods</h3><div>Animals were randomly divided into 6 groups: a control group, an OVA model group, AG (0.1 mg/kg) group, AG (0.5 mg/kg) group, AG (1 mg/kg) group and DEX (2 mg/kg) group. The OVA models were established and the BALF, serum and lung tissue of the mice were collected separately for the administration of ELISA, rt-PCR, Western blot and immunofluorescence staining. Network pharmacology and flow cytometry were also utilized to analyze and verify the potential targets of AG in treatment of asthma by glycolysis.</div></div><div><h3>Results</h3><div>AG attenuated the OVA-induced production of HK2, lactate and PKM2 in lung tissue and the production of IL-1β in serum and lung tissue; AG restrained the OVA-stimulated expression of mRNA of Glut-1, LDHA and PKM2 in lung tissue; AG inhibited the OVA-mediated protein expression of HK2, Glut-1, LDHA, phosphorylation of PKM2, IL-17 in lung tissue; AG also alleviated the expression of PKM2 in lung tissue. Network pharmacology revealed 36 target genes including IL-1β and potential mechanism Th17 cell differentiation which was suppressed by AG.</div></div><div><h3>Conclusions</h3><div>We conclude that AG inhibits the inflammatory response of asthma in OVA-stimulated mice by blocking the activation of glycolytic pathway, especially by targeting Th17 cell differentiation.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"771 ","pages":"Article 110514"},"PeriodicalIF":3.8,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Semicarbazone and thiosemicarbazone derivatives associated with antibiotics inhibit β-lactamases and efflux pumps in Staphylococcus aureus strains","authors":"Débora Feitosa Muniz ,&nbsp;Raimundo Luiz Silva Pereira ,&nbsp;Priscilla Ramos Freitas ,&nbsp;Ana Carolina Justino de Araújo ,&nbsp;Cristina Rodrigues dos Santos Barbosa ,&nbsp;Irwin Rose Alencar de Menezes ,&nbsp;Henrique Douglas de Melo Coutinho ,&nbsp;Saulo Relison Tintino ,&nbsp;Victor Hugo Nunes Soares Costa ,&nbsp;Lucas Oliveira da Silva ,&nbsp;Dalci José Brondani ,&nbsp;Cícera Datiane de Morais Oliveira-Tintino ,&nbsp;Teresinha Gonçalves da Silva","doi":"10.1016/j.abb.2025.110512","DOIUrl":"10.1016/j.abb.2025.110512","url":null,"abstract":"<div><div>The production of the β-lactamase enzyme and the presence of efflux pumps in <em>Staphylococcus aureus</em> represent crucial mechanisms in antibiotic resistance. This microorganism constitutes a serious public health problem, triggering hospital-acquired infections and, in extreme cases, resulting in the death of the host. Thus, the development of an effective medication against multidrug-resistant bacteria becomes imperative, minimizing side effects. In this study, six semicarbazone and thiosemicarbazone derivatives (3a, 3b, 3c, 3d, 3e and 3f) were evaluated against the strains K4414, K4100, and K2068, which have QacA/B, QacC, and MepA efflux systems, respectively, with K4414 and K4100 producing β-lactamases. Direct antibacterial activity and β-lactamase inhibition were analyzed using the broth microdilution method, determining the minimum inhibitory concentration (MIC). The ability to inhibit efflux pumps was assessed using the MIC of substances at sub-inhibitory concentrations, in combination with the antibiotics ampicillin, oxacillin, ciprofloxacin, and the DNA intercalating dye, ethidium bromide. Although all compounds showed MIC values &gt; 1024 μg/mL, considered inactive, in combination with antibiotics, a significantly enhancing activity of MIC was observed, especially for the compounds 3d and 3e. These results indicate that 3d and 3e have the potential to act as antibiotic enhancers. Subsequent studies can be conducted to elucidate their specific mechanisms of action, paving the way for considering these compounds as valuable alternatives in the pharmaceutical industry.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"771 ","pages":"Article 110512"},"PeriodicalIF":3.8,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144306303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The E3 ubiquitin ligase SMURF2 protects against atherosclerosis by inhibiting endothelial inflammation","authors":"Xiangjun Liang ,&nbsp;Zhiwei Xue ,&nbsp;Yanzhao Wu ,&nbsp;Wenchen Xing ,&nbsp;Feiyu Mu ,&nbsp;Zhihan Zhang ,&nbsp;Lu Ling ,&nbsp;Tao Sun ,&nbsp;Donghai Wang","doi":"10.1016/j.abb.2025.110508","DOIUrl":"10.1016/j.abb.2025.110508","url":null,"abstract":"<div><div>Endothelial dysfunction is a key driver of sustained and chronic vascular inflammation, which plays a critical role in the progression of atherosclerotic disease. Despite its significance, the molecular mechanisms underlying vascular endothelial inflammation remain poorly understood. Ubiquitination, a widespread post-translational modification, regulates a wide range of biological processes and is essential for maintaining cellular homeostasis in both physiological and pathological conditions. Numerous studies have highlighted the intricate interplay between vascular endothelial inflammation and ubiquitination. In this study, we identified a novel function for the HECT-type E3 ubiquitin ligase SMURF2 in modulating endothelial inflammation and atherosclerosis. Endothelial-specific overexpression of SMURF2 in mice significantly attenuated vascular endothelial inflammation and slowed atherosclerosis progression, a result that was further corroborated through in vitro experiments. At the mechanistic level, we demonstrated that HMGB1 is a novel substrate of SMURF2, with this interaction being enhanced under inflammatory conditions. Moreover, the WW domain of SMURF2 interacts with the HMG-B box domain of HMGB1, promoting its K48-linked ubiquitination and subsequent proteasomal degradation. In conclusion, our findings emphasize the pivotal role of endothelial SMURF2 and the SMURF2-HMGB1 regulatory axis in controlling vascular endothelial inflammation and atherosclerosis, suggesting that SMURF2 represents a promising therapeutic target for atherosclerotic disease.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"771 ","pages":"Article 110508"},"PeriodicalIF":3.8,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Indanone-based Mannich bases: Design, synthesis, in-silico molecular docking, ADME predictions and biological evaluation including carbonic anhydrases, acetylcholinesterase inhibition and cytotoxicities","authors":"Mehtap Tugrak Sakarya ,&nbsp;Halise Inci Gul ,&nbsp;Hiroshi Sakagami ,&nbsp;Yusuf Sert ,&nbsp;Parham Taslimi ,&nbsp;Ilhami Gulcin","doi":"10.1016/j.abb.2025.110511","DOIUrl":"10.1016/j.abb.2025.110511","url":null,"abstract":"<div><div>This study examined the rational design, synthesis, carbonic anhydrases (CAs), acetylcholinesterase (AChE) inhibitory effects, and cytotoxicity of 2-(2-hydroxy-3-(aminomethyl))benzylidene)-2,3-dihydro-1<em>H</em>-inden-1-one (<strong>1–6</strong>) and 2-(2-hydroxy-3,5-bis(aminomethyl))benzylidene)-2,3-dihydro-1<em>H</em>-inden-1-one (<strong>7–11</strong>). All compounds exhibited significant inhibitory activity against hCA I, hCA II, and AChE enzymes. Among them, compound <strong>9</strong> demonstrated potent inhibition of hCA I (Ki = 46.828 ± 11.32 nM) and AChE (Ki = 0.9820 ± 0.402 nM), while compound <strong>11</strong> showed strong inhibition against hCA II (Ki = 24.683 ± 6.216 nM). For comparison, the reference compound acetazolamide (AZA) inhibited hCA I and hCA II with Ki values of 183.390 ± 19.71 nM and 104.60 ± 27.60 nM, respectively. Regarding AChE inhibition, the reference drug Tacrine exhibited a Ki value of 58.85 ± 12.1 nM. These results indicate that compound <strong>9</strong> is significantly more potent than AZA against hCA I and markedly outperforms tacrine in inhibiting AChE. Similarly, compound <strong>11</strong> shows superior inhibitory activity compared to AZA against hCA II. The compounds' cytotoxicity against four human oral squamous cell carcinoma (OSCC) cell lines was compared to that of three normal oral cells. The compound <strong>3</strong>, 2-(2-hydroxy-3-(piperidin-1-ylmethyl)benzylidene)-2,3-dihydro-1<em>H</em>-inden-1-one, stood out for its promising selectivity in cytotoxicity, demonstrating the highest SI (9.5 toward HSC-2), TS1 (4.8), and PSE (4.8) compared to other studied compounds. Compound <strong>3</strong> showed 5-fold higher tumor specificity than 5-FU when using epithelial normal (human oral keratinocyte) and four human OSCC cell lines. Molecular docking results demonstrated that molecule <strong>9</strong> exhibited a strong binding affinity to AChE (−12.3 kcal/mol) with a remarkably low inhibition constant (Ki = 0.963905 nM), suggesting its potential as a potent inhibitor despite the absence of conventional hydrogen bonding. Conversely, molecule <strong>11</strong> showed enhanced selectivity toward hCAII, forming two hydrogen bonds and displaying a binding affinity of 10.4 kcal/mol. These findings indicate that both molecules possess promising inhibitory potential and can serve as valuable candidates for further experimental validation. Overall, this study highlights the effectiveness of molecular docking as a predictive tool in drug discovery and supports the further development of these lead compounds for therapeutic applications. SAR-based structural changes of compounds <strong>3</strong>, <strong>9</strong>, and <strong>11</strong> have the potential to generate novel, highly effective molecules, providing alternative treatments for a wide range of therapeutic areas, including cancer and neurological illnesses.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"771 ","pages":"Article 110511"},"PeriodicalIF":3.8,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144306302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Norcantharidin inhibits the METTL16/MAT2A pathway to induce apoptosis and suppress tumor progression in ovarian cancer","authors":"Yuan-Yuan Zhang ,&nbsp;Qiu-Xia Zeng ,&nbsp;Li Wang ,&nbsp;Kong-Xian Li ,&nbsp;Shun Zhang ,&nbsp;Ping Wan ,&nbsp;Xue-Ming Zhou ,&nbsp;Qi Chen","doi":"10.1016/j.abb.2025.110510","DOIUrl":"10.1016/j.abb.2025.110510","url":null,"abstract":"<div><h3>Objective</h3><div>This study aimed to investigate the antitumor effects of norcantharidin (NCTD) in ovarian cancer and to elucidate its molecular targets and mechanisms of action, with a focus on the methyltransferase-like protein 16 (<em>METTL16</em>)<em>/</em>methionine adenosyl transferase II alpha (<em>MAT2A</em>) signaling axis.</div></div><div><h3>Materials and methods</h3><div>Expression levels of <em>METTL16</em> and <em>MAT2A</em> were analyzed in ovarian cancer tissues and cells using immunohistochemistry, quantitative real-time polymerase chain reaction, and western blotting. Human ovarian cancer cell lines (ES2 and SKOV3) were cultured and subjected to <em>METTL16</em> overexpression via gene recombination. The cytotoxic effects of varying concentrations of NCTD were assessed using the Cell Counting Kit-8 assay. Apoptosis, proliferation, and migration were evaluated through flow cytometry and wound healing (scratch) assays. A subcutaneous xenograft model of human ovarian cancer was established in nude mice to assess in vivo antitumor efficacy. Enzyme-linked immunosorbent assay was used to quantify intracellular levels of S-adenosylmethionine (SAM).</div></div><div><h3>Results</h3><div><em>METTL16</em> and <em>MAT2A</em> gene expression levels were significantly elevated in ovarian cancer tissues and cell lines (<em>p</em> &lt; 0.05). Treatment with NCTD at 10 μg/mL significantly inhibited proliferation and induced apoptosis in ES2 and SKOV3 cells. NCTD also suppressed cellular migration and angiogenic activity, with downregulation of related gene expression, effects that were attenuated by <em>METTL16</em> overexpression (<em>p</em> &lt; 0.05). In the xenograft model, NCTD administration significantly reduced tumor volume and downregulated expression of <em>METTL16</em>, <em>MAT2A</em>, protein phosphatase 2A (PP2A), and vascular endothelial growth factor (<em>p</em> &lt; 0.05).</div></div><div><h3>Conclusions</h3><div>NCTD exerts antineoplastic effects in ovarian cancer by reducing intracellular S-adenosylmethionine levels, promoting PP2A demethylation, and inhibiting the <em>METTL16/MAT2A</em> signaling pathway. These effects contribute to cell cycle arrest, suppressed proliferation, and enhanced apoptosis, supporting the therapeutic potential of NCTD in ovarian malignancies.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"771 ","pages":"Article 110510"},"PeriodicalIF":3.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}