Journal of Biochemical and Molecular Toxicology最新文献

{"title":"Apelin-13 Protects Against Myocardial Hypoxia/Reoxygenation (H/R) Injury by Inhibiting Ferroptosis Via Nrf2 Activation","authors":"Fan Liang,&nbsp;Chen Li,&nbsp;Yumiao Liu,&nbsp;Yanbo Sui","doi":"10.1002/jbt.70223","DOIUrl":"https://doi.org/10.1002/jbt.70223","url":null,"abstract":"<div>\u0000 \u0000 <p>Ischemia-reperfusion (IR)-induced myocardial damage represents <i>a major</i> pathological event in coronary artery disease (CAD). Effective therapeutic strategies are urgently needed to improve clinical outcomes for CAD patients. Apelin-13, primarily produced by magnocellular neurons, exhibits diverse biological functions across various cell types and tissues. However, its role in myocardial IR injury remains unexplored. In this study, we utilized an in vitro model of myocardial IR injury using H9c2 cardiomyocytes to investigate the potential protective effects of Apelin-13. Our findings reveal that Apelin-13 protects against hypoxia/reoxygenation (H/R)-induced oxidative stress in H9c2 cells by reducing mitochondrial reactive oxygen species (ROS) and malondialdehyde (MDA) levels, while enhancing superoxide dismutase (SOD) activity. Additionally, Apelin-13 alleviates H/R-induced mitochondrial dysfunction, as evidenced by increased mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) production. Crucially, Apelin-13 mitigates H/R-induced cardiomyocyte injury, as shown by reduced levels of creatine kinase-myocardial band (CK-MB), cardiac troponin I (cTnI), and lactate dehydrogenase (LDH). Remarkably, Apelin-13 also counteracts ferroptosis during H/R by decreasing ferrous iron (Fe²⁺) concentrations, increasing glutathione (GSH) levels, and suppressing glutathione peroxidase 4 (GPX4) and ferritin heavy chain 1 (FTH1) expression. These protective actions were negated by the ferroptosis inducer Erastin. Further investigation revealed that Apelin-13 activates the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) through enhanced nuclear translocation and upregulation of heme oxygenase-1 (HO-1). Conversely, Nrf2 knockdown nullified the protective effects of Apelin-13 against ferroptosis and cardiomyocyte injury, underscoring the critical involvement of Nrf2 in mediating these benefits. Collectively, our results highlight the promising therapeutic potential of Apelin-13 in managing CAD.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sevoflurane Mediates LINC00339/miR-671-5p/PSMB2 Axis to Improve Cardiomyocytes Against Hypoxia/Reoxygenation Injury","authors":"Juan Li,&nbsp;Chuan Mou,&nbsp;Yawei Yuan,&nbsp;Long Wang,&nbsp;Caihong Wu","doi":"10.1002/jbt.70234","DOIUrl":"https://doi.org/10.1002/jbt.70234","url":null,"abstract":"<div>\u0000 \u0000 <p>Ischemia/reperfusion (I/R) causes a deterioration in heart function, leading to myocardial infarction. It is aimed at investigating the protective mechanism of sevoflurane (Sevo) on cardiomyocytes by constructing a cellular model of hypoxic/reoxygenation (H/R) in this study.[Human hybrid] epithelioid cells (AC16) were induced by H/R to establish a model of myocardial I/R injury and Sevo postconditioning. The expression of long intergenic non-protein coding RNA 339 (LINC00339), microRNA-671-5p (miR-671-5p) and proteasome 20S subunit beta 2 (PSMB2) was detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Viability and apoptosis of AC16 cells were detected by cell counting kit-8 (CCK-8) assay and flow cytometry, respectively. The levels of interleukin-6 (IL-6), IL-10, tumor necrosis factor-a (TNF-a), reactive oxygen species (ROS), malondialdehyde (MDA), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD), were detected. LINC00339 expression was upregulated in H/R cardiomyocytes relative to the Control group, whereas Sevo decreased LINC00339 expression in H/R cardiomyocytes. The viability of AC16 cells were increased, and apoptosis, oxidative stress, and inflammatory responses decreased in the Sevo postconditioning group relative to the H/R group, but the protective effect of Sevo on H/R cardiomyocytes was partially reversed by LINC00339 overexpression. LINC00339 negatively regulated miR-671-5p, and miR-671-5p upregulation could alleviate the damage of LINC00339 on H/R cardiomyocytes. PSMB2, a downstream target gene of miR-671-5p, could inhibit the protective effect of Sevo on H/R cardiomyocytes. Sevo postconditioning exerts a protective effect in H/R-induced cardiomyocyte injury, which may be achieved by interfering with LINC00339/miR-671-5p/PSMB2 expression.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the Role and Regulatory Mechanisms of the Histone Deacetylase 4 Gene in Chondrocyte Differentiation Impairments Associated With Kashin–Beck Disease","authors":"Lei Yang,&nbsp;Chaowei Wang,&nbsp;Jie Zhou,&nbsp;Feihong Chen,&nbsp;Lian Liu,&nbsp;Lulu Bai,&nbsp;Xi Wang,&nbsp;Xiong Guo,&nbsp;Shuangqiang Yi","doi":"10.1002/jbt.70231","DOIUrl":"https://doi.org/10.1002/jbt.70231","url":null,"abstract":"<div>\u0000 \u0000 <p>This study aimed to investigate the role of the HDAC4 gene in the pathogenesis of Kashin–Beck disease (KBD) cartilage injury and chondrocyte differentiation induced by T-2 toxin. Immunohistochemistry was used to compare HDAC4 and PTHrP protein expression levels in cartilage from children and adults who have KBD and from respective controls, as well as in cartilage from a rat model exposed to T-2 toxin and selenium deficiency. A KBD cell model was established by exposure to T-2 toxin, and RNA interference was employed to silence HDAC4. Expression levels of mRNA and protein expression levels were subsequently measured before and after HDAC4 gene silencing for genes related to the PTHrP–HDAC4 signaling pathway and cartilage differentiation by real-time quantitative reverse transcription PCR and western blotting. We found that HDAC4 expression levels were not consistent between adult and child chondrocytes. Silencing of HDAC4 resulted in a significant increase in the mRNA expression of Runx2 and PTHrP, and elevated the levels of both the mRNA and protein of MMP13, and increased both the mRNA and protein levels of MEF2C. Notably, following the addition of T-2 toxin, there was a significant increase in Runx2 expression, whereas the levels of MEF2C and MMP13 were markedly decreased in comparison to pre-silencing conditions. These findings indicate that T-2 toxin may influence HDAC4 expression, and the role and regulatory mechanisms of this gene in impairing the differentiation of KBD chondrocytes were explored, thereby offering novel insights into the pathogenesis of KBD.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Promotion of Autophagy and Apoptosis in Colorectal Cancer Exposed to Imatinib and Thymoquinone","authors":"Dalia El-Khouly,&nbsp;Nadia A. Thabet,&nbsp;Mohamed Sayed-Ahmed,&nbsp;Mervat M. Omran","doi":"10.1002/jbt.70238","DOIUrl":"https://doi.org/10.1002/jbt.70238","url":null,"abstract":"<p>Cancer cells possess high proliferative ability and usually override apoptosis and metastasize to distant lesions. Autophagy in cancer cells is a double-edged weapon where a cross-regulation postulation between apoptosis and autophagy exists. The aim of the present study was to investigate the effect of adding Thymoquinone (TQ) to Imatinib (IM) in HCT₁₁₆ human colorectal cancer cell line model on various apoptotic and autophagy markers. The combination doses of IM and TQ were selected according to our previous study concerned with cytotoxicity and uptake/efflux genes modulation. In the current study, the combination induced autophagy in HCT₁₁₆ cell line which in turn enhanced apoptosis. Moreover, early apoptosis was evidenced. The induction of both autophagy and apoptosis resulted in programmed cell death. The assessment of AMPK, Par-4, apoptosis markers, colony formation assays, flow cytometry and autophagy detection by acridine orange proved this rapport.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbt.70238","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sulfo-N-Succinimidyl Oleate Sodium as CD36 Inhibitor: Dose Optimization and Its Effects on FFA Uptake, Inflammation, and ER Stress in HepG2 Cells","authors":"Widya Wasityastuti,&nbsp;Shabrina Farras Tsany,&nbsp;Hanif Shidqi Pasaribu,&nbsp;Rahmalia Diani Saffana,&nbsp;Daniel Saputra Wahyudi,&nbsp;Dwi Aris Agung Nugrahaningsih","doi":"10.1002/jbt.70243","DOIUrl":"https://doi.org/10.1002/jbt.70243","url":null,"abstract":"<div>\u0000 \u0000 <p>The risk of metabolic disorders is increasing due to high-fat diets. An imbalance between the absorption and utilization of fatty acids results in lipid accumulation. CD36 is a scavenger receptor involved in fatty acid uptake and immunity. Theoretically, CD36 inhibition will prevent lipid accumulation. CD36 has several known inhibitors, such as sulfo-N-succinimidyl oleate sodium (SSO). Therefore, this study aimed to find the optimal concentration of SSO on HepG2 cells and its effects on FFA uptake, ER stress, and inflammation. HepG2 cell viability assay against various concentrations of SSO was conducted to determine the 50% cell growth inhibition (IC50). The cultures were given SSO in IC50, ½ IC50, ¼ IC50, and 1/8 IC50 concentrations and treated with palmitic acid. Cell morphology was observed. FFA uptake was evaluated. Real-time PCR was used to determine <i>CHOP</i>, <i>IL-8</i>, and <i>TNFα</i> mRNA expressions. The ¼ IC50 of SSO is effective in inhibiting FFA uptake without causing a decrease in cell viability. Downregulation of <i>CHOP</i>, <i>IL-8</i>, and <i>TNFα</i> was seen after SSO administration, especially at ¼ IC50. In conclusion, the ¼ IC50 SSO concentration was the safest and most optimal concentration in reducing FFA uptake and the expressions of <i>IL-8</i>, <i>TNFα</i>, and <i>CHOP</i> in HepG2 cells.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dimethyl Fumarate Protects Diabetes-Induced Testicular Toxicity in Rats: Investigations on Nrf-2/HO-1 and β-Catenin/OCT-4 Signalling Pathways","authors":"Asutosh Pattnaik,&nbsp;Girija Prasanna Sahoo,&nbsp;Vaishali Maurya,&nbsp;Archna Panghal,&nbsp;Vinod Kumar,&nbsp;Gopabandhu Jena","doi":"10.1002/jbt.70209","DOIUrl":"https://doi.org/10.1002/jbt.70209","url":null,"abstract":"<div>\u0000 \u0000 <p>Type 1 Diabetes Mellitus (T1DM) is associated with the destruction of insulin-producing β-cells and is characterized by prolonged hyperglycemia. This can increase oxidative stress which eventually damages the male reproductive system, disturbs the production of testosterone, alters semen quality and histological architecture, and increases testicular apoptosis. Dimethyl Fumarate (DMF) is an Nrf-2 activator that has been explored as possible protective agent in several preclinical studies, although its exact role in germ-cell toxicity is still not well-known. In the present study, an attempt has been made to elucidate the role of DMF in testicular toxicity in Sprague-Dawley (SD) rats. Animals having fasting blood glucose &gt;250 mg/dl after treatment with Streptozotocin (STZ; 55 mg/kg, i.p) were considered diabetic. Three doses of DMF (12.5, 25, and 50 mg/kg) were administered to the diabetic animals for 4 consecutive weeks. The testicular damage was characterized by evaluating organ index, biochemical and histological parameters, sperm-related indices, DNA strand breaks, and expression of different proteins. The results revealed that treatment with DMF ameliorated diabetes-induced testicular damage by decreasing testicular oxidative stress and apoptosis, increasing testosterone production, and upregulating the expressions of Nrf-2, HO-1, IL-10, β-Catenin, OCT-4, 3β-HSD, Bcl-2 and downregulating NF-κB, Bax. The present finding suggests that DMF has a protective effect against diabetes-induced testicular damage in SD rat.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antiproliferative and Apoptotic Efficacy of Nano-PLGA Encapsulated Quercetin Molecules by Downregulation of Akt in K-ras Mutated NSCLC Cell Lines, A549 and H460","authors":"Avinaba Mukherjee,&nbsp;Sandip Ghosh,&nbsp;Sayak Ganguli,&nbsp;Jhinuk Basu,&nbsp;Biswarup Basu","doi":"10.1002/jbt.70240","DOIUrl":"https://doi.org/10.1002/jbt.70240","url":null,"abstract":"<div>\u0000 \u0000 <p>To test if encapsulating hydrophobic flavonoids in nanoparticles could offer a new possibility in the therapeutics of non-small cell lung cancer (NSCLC), quercetin was encapsulated in Poly(lactic-co-glycolic acid) (PLGA) nanoparticles by the solvent displacement technique. The synthesized nanoparticles were then characterized by dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR), and atomic force microscopy (AFM). The size of the nanoparticles with smooth surface topology was estimated at 110 nm. Treatment with nano-PLGA encapsulated quercetin (NPEQ) triggered the death of K-ras mutated NSCLC cells, A549 and H460, and showed 50% cell cytotoxicity in them at a dose of 406 and 347 ng/ml respectively. NPEQ was able to block uncontrolled cell proliferation by inducing concomitant destruction of BrdU activity and a lower incidence of cell migrations. Cell death was due to the induction of apoptosis rather than necrosis, as revealed by morphological alterations and phosphatidylserine externalization induced by NPEQ. NPEQ also caused the arrest of A549 and H460 cells at the sub-G1 stage. Through network analysis, AKT was identified as a key gene target of quercetin in NSCLC. Moreover, we found that NPEQ induced downregulation of Akt, which is usually hyperactive in NSCLC due to K-ras mutation. This indicates that NPEQ caused target-specific apoptotic and antiproliferative activity by targeting the downregulation of Akt. Further, when NPEQ was generated in the tumour-bearing mice model, it showed antitumor efficacy also modulating the Akt expression along with upregulation in cleaved caspase 3 activation. Besides this, histological alteration of tissue architecture and reduction in tumor volume was also found. This as a whole indicates the prospects and advantages of nanoparticulate quercetin delivery in therapeutic formulations against cancer.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nano-Encapsulated Coumarin Derivative, CS-QM2 Inhibits Neoplasm Growth: Experimented in Zebrafish Model","authors":"S. Madesh,&nbsp;Raghul Murugan,&nbsp;Avra Sau,&nbsp;S Jubie,&nbsp;Akey Krishna Swaroop,&nbsp;Rajakrishnan Rajagopal,&nbsp;Kathiravan Muthu Kumaradoss,&nbsp;Jesu Arockiaraj","doi":"10.1002/jbt.70239","DOIUrl":"https://doi.org/10.1002/jbt.70239","url":null,"abstract":"<div>\u0000 \u0000 <p>Cancer remains a significant global health challenge with limited therapeutic success, prompting the need for innovative treatment strategies. This study investigates the anticancer potential of nano-encapsulated metal derivatives (CS-QM2) using a zebrafish model with chemically induced cellular neoplasia. Characterization of CS-QM2 nanoparticles revealed successful synthesis with a high entrapment efficiency and enhanced drug release under acidic conditions. Zebrafish embryos exposed to 7,12-Dimethylbenz[a]anthracene (DMBA) exhibited significant malformations, macrophage accumulation, and abnormal tissue growth, which were markedly reduced by CS-QM2 treatment. CS-QM2 significantly increases intracellular ROS, resulting in higher LPO and induces apoptosis in neoplasm tissues. Furthermore, CS-QM2 treatment alters the tumor microenvironment, reducing macrophage accumulation by decreasing neutral lipid droplets, disrupting TAM metabolic support and limiting their protumorigenic activities. Biochemical assays demonstrated restored activities of antioxidant enzymes SOD, CAT, and GSH. Gene expression analysis showed upregulation of apoptosis and tumor suppressor genes (<i>cas3</i>, <i>p53</i>) and downregulation of inflammatory genes (<i>cox-2</i>, <i>nf-kb</i>). Histological assessment and SEM analysis confirmed reduced neoplasm occurrence and tissue abnormalities. These findings suggest that CS-QM2 nanoparticles effectively inhibit neoplasm growth and modulate the tumor microenvironment through oxidative stress induction and gene expression regulation.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"METTL3-mediated m6A Modification Promotes miR-221-3p Expression to Exacerbate Ischemia/Reperfusion-Induced Acute Lung Injury","authors":"Yang yang,&nbsp;Chenlu Li,&nbsp;Ziwang Lu,&nbsp;Xiantong Cao,&nbsp;Qifei Wu","doi":"10.1002/jbt.70235","DOIUrl":"https://doi.org/10.1002/jbt.70235","url":null,"abstract":"<div>\u0000 \u0000 <p>Ischemia/reperfusion (I/R)-induced acute lung injury (ALI) represents a prevalent pulmonary pathology. The N6-methyladenosine (m6A) RNA modification is integral in regulating numerous biological processes across various human diseases through the modulation of gene expression. Nevertheless, the precise role and underlying molecular mechanisms of m6A modifications in ALI remain inadequately understood. This study aimed to elucidate the impact of RNA methyltransferase 3 (METTL3)-mediated m6A modification of miR-221-3p on the progression of I/R-induced ALI. Our initial findings demonstrated an upregulation of m6A levels and METTL3 expression in I/R-induced ALI in murine models and hypoxia/reoxygenation (H/R)-induced murine lung epithelial (MLE)-12 cells. Inhibition of METTL3 was observed to reverse H/R-induced apoptotic cell death, oxidative stress, and inflammatory cytokine secretion. Furthermore, METTL3 was found to enhance the expression of miR-221-3p in an m6A-dependent manner, thereby contributing to ALI pathogenesis. In addition, miR-221-3p was shown to negatively regulate PTEN expression, while METTL3 facilitated phosphorylated AKT expression via the miR-221-3p/PTEN axis. Functional experiments further revealed that the downregulation of PTEN negated the inhibitory effects of METTL3 knockdown in H/R-treated MLE-12 cells. In conclusion, our study demonstrates that the METTL3-mediated m6A modification of miR-221-3p exacerbates ALI through modulation of the PTEN/AKT pathway. Therapeutic strategies aimed at targeting the METTL3/m6A/miR-221-3p/PTEN/AKT axis may offer a promising approach to mitigate I/R-induced ALI.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143689763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interaction of Asparagusic Acid, Asparaptines and Related Dithiolane Derivatives With Angiotensin-Converting Enzyme-2 (ACE-2): A Molecular Docking Study","authors":"Gérard Vergoten,&nbsp;Christian Bailly","doi":"10.1002/jbt.70236","DOIUrl":"https://doi.org/10.1002/jbt.70236","url":null,"abstract":"<p>A variety of sulfur-containing small molecules can be found in the spears of asparagus (<i>Asparagus Officinalis</i> L.) including compounds derived from asparagusic acid such as the amino acid derivatives asparaptines A, B, and C. The previous characterization of asparaptine A as an inhibitor of angiotensin-converting enzyme (ACE) prompted us to compare the binding of the three asparaptines to ACE2 using molecular modeling. The lysine conjugate asparaptine B was found to bind better to the enzyme than the arginine (asparaptine A) and histidine (asparaptine C) conjugates. The stability of ACE2-asparaptine B complexes was only a little inferior to that observed with the reference ACE2 inhibitor MLN-4760. On this basis, 20 additional compounds bearing a thiol group or a dithiolane motif were evaluated as potential binders to ACE2 using the same docking methodology. Three compounds emerged as robust ACE2 binders: the natural products isovalthine and N-acetyl-felinine, and the drug candidate CMX-2043. The empirical energy of interaction (ΔE) of N-acetyl-felinine with ACE2 was comparable to that measured with asparaptine B, and a little higher with the thiol metabolite isovalthine. Remarkably, CMX-2043 revealed a high capacity to form stable complexes with ACE2, superior to that of the reference MLN-4760. Both the <span>l</span>-Glu-<span>l</span>-Ala dipeptide motif and the α-lipoic acid moiety of CMX-2043 are implicated in the protein interaction. Our observations pave the way to the design of novel ligands of ACE2 equipped with a dithiolane motif.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbt.70236","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143689765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}