Abdullah Biçer , Cüneyt Çağlayan , Yeliz Demir , Cüneyt Türkeş , Ramazan Altundaş , Hasan Akyıldız , Şükrü Beydemir
{"title":"Synthesis of N-substituted 4-phenyl-2-aminothiazole derivatives and investigation of their inhibition properties against hCA I, II, and AChE enzymes","authors":"Abdullah Biçer , Cüneyt Çağlayan , Yeliz Demir , Cüneyt Türkeş , Ramazan Altundaş , Hasan Akyıldız , Şükrü Beydemir","doi":"10.1016/j.abb.2024.110159","DOIUrl":"10.1016/j.abb.2024.110159","url":null,"abstract":"<div><div>In this study, thiazole derivatives containing sulphonamide, amide, and phenyl amino groups were synthesized to protect the free amino groups of 5-methyl-4-phenyl-2-aminothiazole and 4-phenyl-2-aminothiazole. Halogenated reactions of N-protected thiazole derivatives have been investigated. LCMS, FT-IR, <sup>1</sup>H NMR, and <sup>13</sup>C NMR spectroscopy techniques were used to elucidate the structures of the synthesized compounds. Inhibition effects of the N-protected thiazole derivatives against human carbonic anhydrase I, II (<em>h</em>CA I, <em>h</em>CA II), and acetylcholinesterase (AChE) were investigated. The best results among the synthesized N-protected thiazole derivatives showed K<sub>i</sub> values in the range of 46.85–587.53 nM against <em>h</em>CA I, 35.01–578.06 nM against <em>h</em>CA II, and in the range of 19.58–226.18 nM against AChE. Furthermore, in silico studies with the target enzyme of the thiazole derivatives <strong>(9</strong> and <strong>11)</strong>, which showed the best results experimentally, have examined the binding interactions of the related compounds at the enzyme active site.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"761 ","pages":"Article 110159"},"PeriodicalIF":3.8,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323449","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":"Probing the site of glutathione reduction by thioredoxin/glutathione reductase from Schistosoma mansoni under anaerobic conditions","authors":"Tyler B. Alt, Madison M. Smith, Graham R. Moran","doi":"10.1016/j.abb.2024.110162","DOIUrl":"10.1016/j.abb.2024.110162","url":null,"abstract":"<div><div>Thioredoxin/glutathione reductase from <em>Schistosoma mansoni</em> (SmTGR) is a multifunctional enzyme that catalyzes the reduction of glutathione (GSSG) and thioredoxin, as well as the deglutathionylation of peptide and non-peptide substrates. SmTGR structurally resembles known glutathione reductases (GR) and thioredoxin reductases (TrxR) but with an appended N-terminal domain that has a typical glutaredoxin (Grx) fold. Despite structural homology with known GRs, the site of GSSG reduction has frequently been reported as the Grx domain, based primarily on aerobic, steady-state kinetic measurements and x-ray crystallography. Here, we present an anaerobic characterization of a series of variant SmTGRs to establish the site of GSSG reduction as the cysteine pair most proximal to the FAD, Cys154/Cys159, equivalent to the site of GSSG reduction in GRs. Anaerobic steady-state analysis of U597C, U597S, U597C + C31S, and I592STOP SmTGR demonstrate that the Grx domain is not involved in the catalytic reduction of GSSG, as redox silencing of the C-terminus results in no modulation of the observed turnover number (∼0.025 s<sup>−1</sup>) and redox silencing of the Grx domain results in an increased observed turnover number (∼0.08 s<sup>−1</sup>). Transient-state single turnover analysis of these variants corroborates this, as the slowest rate observed titrates hyperbolically with GSSG concentration and approaches a limit that coincides with the respective steady-state turnover number for each variant. Numerical integration fitting of the transient state data can only account for the observed trends when competitive binding of the C-terminus is included, indicating that the partitioning of electrons to either substrate occurs at the Cys154/Cys159 disulfide rather than the previously proposed Cys596/Sec597 sulfide/selenide. Paradoxically, truncating the C-terminus at Ile592 results in a loss of GR activity, indicating a crucial non-redox role for the C-terminus.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"761 ","pages":"Article 110162"},"PeriodicalIF":3.8,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142315168","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":"Niacin-induced flushing: Mechanism, pathophysiology, and future perspectives","authors":"Aaqib Javaid , Shyam Lal Mudavath","doi":"10.1016/j.abb.2024.110163","DOIUrl":"10.1016/j.abb.2024.110163","url":null,"abstract":"<div><div>Flushing is a typical physiological reaction to high emotional reactions. It is characterized by cutaneous vasodilation and a feeling of warmth and skin redness, especially in the face areas. Flushing is frequently linked to social anxiety, but it can also be a sign of a number of benign and malignant medical disorders. The study focuses on niacin-induced flushing, a well-researched side effect of the niacin, a drug which increases cholesterol levels. Niacin-induced flushing occurs when the hydroxycarboxylic acid receptor 2 (HCA2 or GPR109A) is activated. This starts a signaling cascade that releases prostaglandins, especially PGD2, which causes cutaneous vasodilation. Furthermore, niacin directly interacts with the transient receptor potential (TRP) channel TRPV1, offering a different, non-prostaglandin-based explanation for flushing brought on by niacin, highlighting the intricate physiological mechanisms behind this widespread occurrence. The review delves deeper into the advantages of niacin treatment for the cardiovascular system, highlighting how it can improve lipid profiles and lower cardiovascular events when used with statins. To sum it up, this study offers a thorough understanding of flushing, including its physiological foundation, many etiologies, diagnostic difficulties, and the subtleties of flushing caused by niacin. The investigation of innovative dose forms and nanomedicine highlights the continuous endeavors to improve patient compliance and reduce side effects, laying the groundwork for further developments in flushing treatment.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"761 ","pages":"Article 110163"},"PeriodicalIF":3.8,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142318921","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":"Aldose reductase with quinolone antibiotics interaction: In vitro and in silico approach of its relationship with diabetic complications","authors":"Cüneyt Türkeş","doi":"10.1016/j.abb.2024.110161","DOIUrl":"10.1016/j.abb.2024.110161","url":null,"abstract":"<div><div>Aldose reductase (AR, EC1.1.1.21), a member of the aldo-keto reductase family, is critically implicated in the pathogenesis of chronic complications associated with diabetes mellitus, including neuropathy, nephropathy, and retinopathy. Hyperglycemia-induced AR overactivity results in intracellular sorbitol accumulation, NADPH depletion, and oxidative stress. Consequently, AR is recognized as a key mediator of oxidative and inflammatory signaling pathways involved in diverse human pathologies such as cardiovascular diseases, inflammatory disorders, and cancer. This has sparked renewed interest in developing novel AR inhibitors (ARIs) with enhanced therapeutic profiles. In this study, we evaluated the inhibitory potential of five quinolone antibiotics-gatifloxacin, lomefloxacin, nalidixic acid, norfloxacin, and sparfloxacin-as ARIs relevant to various physiological and pathological conditions. Through comprehensive <em>in vitro</em> and <em>in silico</em> analyses, we explored these antibiotics' binding interactions and affinities within the AR active site. Our findings reveal that these quinolones moderately inhibit AR at micromolar concentrations, with inhibition constants (<em>K</em><sub>I</sub>s) ranging from 1.03 ± 0.13 μM to 4.12 ± 0.51 μM, compared to the reference drug epalrestat (<em>K</em><sub>I</sub> of 0.85 ± 0.06 μM). The combined <em>in vitro</em> and <em>in silico</em> results underscore significant interactions between these drugs and AR, suggesting their potential as therapeutic agents against the aforementioned pathological conditions. Furthermore, these insights will aid in optimizing clinical dosing regimens and mitigating unexpected drug-drug interactions when these antibiotics are co-administered with other treatments.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"761 ","pages":"Article 110161"},"PeriodicalIF":3.8,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307021","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":"SHIN-2 exerts potent activity against VanA-type vancomycin-resistant Enterococcus faecium in vitro by stabilizing the active site loop of serine hydroxymethyltransferase","authors":"Hironori Hayashi , Erika Saijo , Kazushige Hirata , Shumei Murakami , Haruka Okuda , Eiichi N. Kodama , Kazuya Hasegawa , Kazutaka Murayama","doi":"10.1016/j.abb.2024.110160","DOIUrl":"10.1016/j.abb.2024.110160","url":null,"abstract":"<div><div>Novel classes of antibiotics are needed to improve the resilience of the healthcare system to antimicrobial resistance (AMR), including vancomycin resistance. <em>vanA</em> gene cluster is a cause of vancomycin resistance. This gene cluster is transferred and spreads vancomycin resistance from <em>Enterococcus</em> spp. to <em>Staphylococcus aureus</em>. Therefore, novel antibacterial agents are required to combat AMR, including <em>vanA</em>-type vancomycin resistance. Serine hydroxymethyltransferase (SHMT) is a key target of antibacterial agents. However, the specific binding mechanisms of SHMT inhibitors remain unclear. Detailed structural information will contribute to understanding these mechanisms. In this study, we found that (+)–SHIN–2, the first <em>in vivo</em> active inhibitor of human SHMT, is strongly bound to the <em>Enterococcus faecium</em> SHMT (<em>efm</em>SHMT). Comparison of the crystal structures of apo- and (+)–SHIN–2-boud <em>efm</em>SHMT revealed that (+)–SHIN–2 stabilized the active site loop of <em>efm</em>SHMT <em>via</em> hydrogen bonds, which are critical for <em>efm</em>SHMT inhibition. Additionally, (+)–SHIN–2 formed hydrogen bonds with serine, forming the Schiff's base with pyridoxal 5′-phosphate, which is a co-factor of SHMT. Furthermore, (+)–SHIN–2 exerted biostatic effects on vancomycin-susceptible and <em>vanA</em>-type vancomycin-resistant <em>E. faecium in vitro</em>, indicating that SHMT inhibitors do not induce cross-resistance to <em>vanA</em>-type vancomycin. Overall, these findings can aid in the design of novel SHMT inhibitors to combat AMR, including vancomycin resistance.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"761 ","pages":"Article 110160"},"PeriodicalIF":3.8,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Discovering potential asthma therapeutics targeting hematopoietic prostaglandin D2 synthase: An integrated computational approach","authors":"Fahad M. Aldakheel","doi":"10.1016/j.abb.2024.110157","DOIUrl":"10.1016/j.abb.2024.110157","url":null,"abstract":"<div><div>Allergic asthma, a chronic inflammatory illness that affects millions worldwide, has serious economic and health consequences. Despite advances in therapy, contemporary treatments have poor efficacy and negative effects. This study investigates hematopoietic prostaglandin D2 synthase (HPGDS) as a potential target for novel asthma therapies. Targeting HPGDS may provide innovative treatment methods. A library of phytochemicals was used to find putative HPGDS inhibitors by structure-based and ligand-based virtual screening. Among the 2295 compounds screened, four compounds (ZINC208828240, ZINC95627530, ZINC14727536, and ZINC14711790) demonstrated strong binding affinities of −10.4, −10.3, −9.2, −9.1 kcal/mol respectively with key residues, suggesting their potential as a highly effective HPGDS inhibitor. Molecular dynamics (MD) simulations and Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) computations were further performed to evaluate the stability and binding affinity of the complexes. MD simulations and MMPBSA confirmed that compound ZINC14711790 showed high stability and binding affinity (binding energy −31.52 kcal/mol) than other compounds, including HQL-79, suggesting that this compound might be used as promising inhibitors to treat asthma. RMSD and RMSF analysis also revealed that ZINC14711790 exhibited strong dynamic stability. The findings of this study show the efficacy of ZINC14711790 as HPGDS inhibitors with high binding affinity, dynamic stability, and appropriate ADMET profile.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"761 ","pages":"Article 110157"},"PeriodicalIF":3.8,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279704","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}
Yuxin Zhang, Lei Liu, Chunyu Yang, Wei Xie, Jianshe Wang
{"title":"Regulation of corticosteroid-binding globulin release in murine leydig tumor cell line mLTC-1 by luteinizing hormone and interleukin-6","authors":"Yuxin Zhang, Lei Liu, Chunyu Yang, Wei Xie, Jianshe Wang","doi":"10.1016/j.abb.2024.110158","DOIUrl":"10.1016/j.abb.2024.110158","url":null,"abstract":"<div><div>Exogenous assaults interfere with homeostatic processes in the body by inducing stress responses. Corticosteroid-binding globulin (CBG) binds to stress hormone glucocorticoids to transport and dynamically control their availability to target tissues. In our previous study, we confirmed that CBG is locally produced by Leydig cells in the testes. Here, we explored the potential regulators of CBG using a murine Leydig tumor cell line (mLTC-1). Results indicated that luteinizing hormone (LH) and interleukin-6 (IL-6) were important factors stimulating the release of CBG from mLTC-1 cells. In addition, IL-6 stimulated mLTC-1 cells to release alpha-1 antitrypsin (AAT), a serine proteinase inhibitor (serpin) that affects CBG conformation. The results implied that any challenge that altered LH or IL-6 levels also changed the release and binding status of CBG with steroid hormones in the testicular microenvironment and modulated cellular responses to these stress hormones. In addition, secretory proteomic analysis indicated that the extracellular matrix (ECM), cytoskeleton, and proteasomes were essentially produced by the mLTC-1 cells, and LH evoked the secretion of proteins involved in binding and metabolism. These results emphasize that Leydig cells may undertake more functions than just steroidogenesis, and the regulation of Leydig cells by LH is versatile.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"761 ","pages":"Article 110158"},"PeriodicalIF":3.8,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279706","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":"Serum exosomal miRNA promote glioma progression by targeting SOS1 via abscopal effect of radiation","authors":"Ying Zhang, Jing Xie, Huimin Zhang, Jiacheng Li, Xing Mi, Xuyi Zhou, Zhenhua Ding","doi":"10.1016/j.abb.2024.110138","DOIUrl":"10.1016/j.abb.2024.110138","url":null,"abstract":"<div><h3>Introduction</h3><div>Local exposure to ionizing radiation (IR) can induce changes in biological processes in distant tissues and organs. Exosomes are nanoscale vesicles that transport biomolecules, mediate communication between cells and tissues, and can affect the abscopal effects of radiotherapy.</div></div><div><h3>Methods</h3><div>Mice were treated with 8.0 Gy doses of chest and abdomen IR, after which serum samples were taken 24 h after exposure. Their serum exosomes were then isolated via ultracentrifugation and the small RNA portions were extracted for sequencing and bioinformatic analysis. Exosomes were injected intravenously into the mice to assess their ability to cross the blood-brain barrier (BBB). Glioma cells and glioma stem cells (GSCs) were examined for malignant biological behaviors, stemness, and tumorigenic capacity after co-culturing with different groups of exosomes.</div></div><div><h3>Results</h3><div>We found that serum exosomes crossed the BBB in mice after local IR exposure-which induced decreases in the expression of BBB tight-junction proteins and increased brain endothelial cell apoptosis. Exosomes from the exposed groups promoted malignant biological behaviors, stemness, and tumorigenic capacity in glioma cells and GSCs by upregulating the expression of SOS1. Phospho-MEK1/2 and Phospho-ERK1/2, of the MAPK signaling pathway, were found to be up-regulated in cells that were co-cultured with the exposing groups of the exosomes. Further analyses demonstrated that differentially expressed levels of miR-93–5p in mouse serum exosomes regulated the cellular expression of SOS1.</div></div><div><h3>Conclusion</h3><div>Following local IR exposure, serum exosomes cross the BBB to promote the progression of distant gliomas. Exosomal microRNAs play an important role in this process.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"761 ","pages":"Article 110138"},"PeriodicalIF":3.8,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279709","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":"Structural analysis of the TPI-Manchester, a thermolabile variant of human triosephosphate isomerase","authors":"Jorge Miguel Romero","doi":"10.1016/j.abb.2024.110156","DOIUrl":"10.1016/j.abb.2024.110156","url":null,"abstract":"<div><p>Human triosephosphate isomerase G122R, also known as TPI-Manchester, is a thermolabile variant detected in a screening of more than 3400 individuals from a population in Ann Arbor, Michigan. Here, the crystallographic structure of G122R was solved to determine the molecular basis of its thermal stability. Structural analysis revealed an increase in the flexibility of residues at the dimer interface, even though R122 is about 20 Å away, suggesting that long-range electrostatic interactions may play a key role in the mutation effect.</p></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"761 ","pages":"Article 110156"},"PeriodicalIF":3.8,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142271497","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}
Peiyu Xue , Xinyong You , Li Ren , Weiming Yue , Zheng Ma
{"title":"PPARγ-mediated amelioration of lipid metabolism abnormality by kaempferol","authors":"Peiyu Xue , Xinyong You , Li Ren , Weiming Yue , Zheng Ma","doi":"10.1016/j.abb.2024.110154","DOIUrl":"10.1016/j.abb.2024.110154","url":null,"abstract":"<div><p>Kaempferol can exert biological functions by regulating various signaling pathways. This study evaluated the ameliorative effect of kaempferol on lipid accumulation using oleic acid and palmitic acid-treated HepG2 cells and high-fat diet mice. <em>In vitro</em> oil red O staining showed that kaempferol treatment improved lipid accumulation (<em>p</em> < 0.001 for TG content and <em>p</em> < 0.05 for TC content). Immunofluorescence, Western blot analysis and RT-qPCR showed that kaempferol could promote nuclear translocation of PPARγ and reduce the expression of PPARγ, C/EBPβ, and SREBP-1c. Dietary intervention with kaempferol could reduce the lipid accumulation in hepatocytes and inflammatory cell infiltration, as well as attenuated serum levels of IL-6 and TNF-α in HFD-fed mice (<em>p</em> < 0.001 for IL-6 and <em>p</em> < 0.01 for TNF-α at kaempferol 60 mg/kg/d). Meanwhile, histopathological examination revealed that there was no substantial damage or distinct inflammation lesions in organs at the experimental dose, including the heart, lung, kidney, and spleen. The aforementioned research findings can serve as references for further preclinical investigations on the potential of kaempferol to mitigate lipid accumulation.</p></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"761 ","pages":"Article 110154"},"PeriodicalIF":3.8,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142232844","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}