Archives of biochemistry and biophysics最新文献

{"title":"MXene-encapsulated ZIF-8@Liposomes for NIR-enhanced photothermal therapy in hepatocellular carcinoma treatment: In vitro, in vivo, and in silico study","authors":"Shehab Elbeltagi ,&nbsp;Nawal Madkhali ,&nbsp;Hanan M. Alharbi ,&nbsp;Zienab E. Eldin","doi":"10.1016/j.abb.2024.110256","DOIUrl":"10.1016/j.abb.2024.110256","url":null,"abstract":"<div><div>Photothermal therapy (PTT) utilizes near-infrared (NIR) light to enhance localized, non-invasive cancer treatments and drug delivery systems (DDS). Combination chemotherapy with PTT (chemo-PTT) offers multiple therapeutic advantages, involving synergistic effects, reduced side effects, and decreased drug toxicity. In this study, 2D titanium carbide (Ti₃C₂T_x) MXene nanosheets were encapsulated in a zeolitic imidazolate framework-8 (ZIF-8) to form (MX-ZIF-8) nanoparticles (NPs) for PTT applications. Sorafenib (SB), an anticancer drug was loaded onto MX-ZIF-8 and further modified with a liposomes (LPs) lipid bilayer to create (SB-MX-ZIF-8@LPs) nanocomposites. TEM imaging revealed that SB-MX-ZIF-8@LPs had a lamellar structure and spherical shape, with an average diameter of 75.2 nm and a zeta potential (ZP) of −8.4 ± 4.5 mV. Additionally, the PT stability, drug encapsulation, and in-vitro release kinetics of SB-MX-ZIF-8@LPs were assessed. These nanocomposites exhibited an impressive PT conversion efficiency of 55 % at 50 μg/mL under NIR irradiation. The cumulative release of SB from SB-MX-ZIF-8@LPs reached 86.15 % at pH 7.4 and 89.3 % at pH 4.8 under NIR over a period of 72 h, with an encapsulation efficiency of 87.34 %. MTT assays revealed strong cytotoxicity against HepG2 cells, with SB-MX-ZIF-8@LPs showing an IC₅₀ value of 2.7 μg/mL and inducing approximately 96 % total apoptosis. The SB-MX-ZIF-8@lip nanocomposite demonstrated excellent biological stability in a serum environment, retaining over 98 % of sorafenib and maintaining consistent particle size (∼347 nm) over 30 days. An in vivo xenograft study in BALB/c mice further demonstrated the efficacy of SB-MX-ZIF-8@LPs, with this treatment group showing the smallest tumor volume compared to other groups and a significantly higher tumor volume reduction than SB alone. Molecular docking studies indicated that SB exhibited strong binding affinities particularly with ABL1 (−8.7 kcal/mol) and EGFR (−9.3 kcal/mol). Docking interactions between MXene and SB, conducted using the Hdock Server, resulted in a docking score of −10.53, with one bond forming at a distance of 4 Å. These findings were consistent with experimental results, highlighting the favorable interaction between MXene and SB. ADMET analysis confirmed that MX-ZIF-8@LPs possessed favorable drug carrier properties, including high intestinal absorption (96.6 %), and low toxicity supporting its potential as an effective DDS for cancer therapy.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"764 ","pages":"Article 110256"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783938","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":"Cuproptosis regulation by long noncoding RNAs: Mechanistic insights and clinical implications in cancer","authors":"Nahla E. El-Ashmawy ,&nbsp;Eman G. Khedr ,&nbsp;Mariam A. Abo-Saif ,&nbsp;Sara M. Hamouda","doi":"10.1016/j.abb.2025.110324","DOIUrl":"10.1016/j.abb.2025.110324","url":null,"abstract":"<div><div>Although survival rates have been improved in recent years, the prognosis of many cancer types remains inadequate, mostly owing to treatment resistance. Moreover, there is a continued need for exploring novel and reliable tumor markers to achieve accurate diagnosis. Understanding the molecular complexity of cancer allows for the development of more effective and personalized treatments and facilitates the discovery of biomarkers that surpass traditional ones and assist in cancer diagnosis and monitoring disease progression and response to treatment. Recent studies exploring the complexity of cancer biology have identified a new form of cell death, known as cuproptosis, which is driven by the accumulation of copper and subsequent stress induced by dysregulation of copper homeostasis. Increased copper level enables cancer cells to maintain their accelerated growth rates and metastatic potential, yet these cells can evade cuproptosis. Long noncoding RNAs (lncRNAs) have been recognized for their pivotal role in different hallmarks of cancer, including resistance to cell death. They have been found to be implicated in controlling copper balance and cuproptosis. Besides, lncRNAs associated with cuproptosis pathway have demonstrated their potential as diagnostic and prognostic cancer biomarkers as well as indicators of treatment response. Our review aims to summarize recent studies focusing on the intricate relationship between lncRNAs and cuproptosis and explore the mechanisms by which lncRNAs can modulate copper homeostasis and regulate cuproptosis pathway. We also highlight recent discoveries concerning the role of cuproptosis-related lncRNAs in diagnosis, prognosis, and therapy of different types of cancer. By elucidating the significance of cuproptosis-related lncRNAs, this review provides insights into how these lncRNAs can be used to develop new therapeutic strategies to improve treatment outcomes.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"765 ","pages":"Article 110324"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143104586","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":"PROTAC-attractive site as a new target for suppressing P-glycoprotein activity","authors":"Tatyana A. Grigoreva,&nbsp;Aleksandra Sagaidak,&nbsp;Daria S. Novikova,&nbsp;Vyacheslav G. Tribulovich","doi":"10.1016/j.abb.2024.110258","DOIUrl":"10.1016/j.abb.2024.110258","url":null,"abstract":"<div><div>P-glycoprotein (P-gp) plays an important role in the rapid release of various small molecule substances from the cell. In turn, inhibition of this efflux transporter is an attractive strategy for both overcoming chemoresistance and facilitating oral absorption of drugs or CNS drug delivery. In this work, we adopt an approach typical for PROteolysis Targeting Chimera (PROTAC), which is based on the artificial drawing together of the target protein to E3 ubiquitin ligase, to P-gp. Forced ubiquitinylation of a transmembrane protein will provoke its removal from the cell membrane and promote its subsequent degradation. Within this concept, we investigated the possibility of P-gp ubiquitinylation by a number of PROTAC-specific E3 ligases using several approaches. We also identified the most promising site for the development of P-gp ligands. By screening a diversified library of compounds, we not only identified a number of scaffolds suitable for the construction of specific ligands, but also proposed dorsomorphin as a convenient platform for creating the constituent of a bifunctional chimera. We show that dorsomorphin both has the structural characteristics necessary to develop a PROTAC-like molecule and exhibits P-gp inhibitory activity. In conclusion, the proposed approach is universal and can be applied to other transmembrane proteins associated with the pathogenesis of certain diseases.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"764 ","pages":"Article 110258"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783939","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 primary studies of epigallocatechin-3-gallate in improving brain injury induced by chronic high-altitude natural environment in rats by 7.0T high-field MR imaging","authors":"Chen Chen ,&nbsp;Haotian Chen ,&nbsp;Duojie Dingda ,&nbsp;Lei Wang ,&nbsp;Fabao Gao","doi":"10.1016/j.abb.2024.110224","DOIUrl":"10.1016/j.abb.2024.110224","url":null,"abstract":"<div><h3>Background</h3><div>Epigallocatechin-3-gallate (EGCG) is one of the most abundant and important bioactive polyphenolic compounds in green tea. However, despite its potent antioxidant effects, its neuroprotective effects on chronic high altitude (HA)-induced nerve damage have not been reported. The purpose of this study is to use quantitative susceptibility mapping (QSM) with pathology to dynamically evaluate the status of brain damage and the effect of EGCG.</div></div><div><h3>Methods</h3><div>A model of HA environments-induced brain injury was established of Sprague-Dawley (SD) rats in a natural plateau environment for 4 weeks, 8 weeks, 12 weeks and 20 weeks. Behavioral alterations were then observed and assessed with the open field test (OFT) and Morris water maze (MWM) test. The microglial activation, nissl staining and neural degeneration by Fluoro Jade B in the hippocampus of the rats were observed by immunohistochemistry. In the rats, serum erythropoietin (EPO), hippocampal inflammatory cytokines (interleukin-1β [IL-1β], interleukin-6 [IL-6] and tumor necrosis factor-α [TNF-α]), ferritin, oxidative stress (superoxide dismutase [SOD], glutathione peroxidase [GSH-Px], catalase [CAT] and malondialdehyde [MDA]) were detected using ELISA kits and biochemical methods. Iron accumulation was observed by QSM and colorimetry. Iron metabolisms (ceruloplasmin [Cp], transferrin [Tf], divalent metal transport1 [DMT1] and hepcidin [Hep]) were detected using qPCR. Neural ultrastructural changes were evaluated with electron microscope. Salidroside treatment was chosen as the positive control group in ELISA, biochemical detection and electron microscopy.</div></div><div><h3>Results</h3><div>The susceptibility values in the left and right hippocampus, the hippocampal ferritin, serum and hippocampal iron content increased significantly after HA exposure. The expression of hippocampal Cp and Hep decreased and the expression of Tf increased. Nissl staining revealed that the neurons of hippocampal CA1 region of h-20w group were small and irregular, atrophied, and nuclear shrinkage. Tissue oxidative stress and inflammatory indicators (MDA, TNF-α, IL-1β, IL-6) increased while antioxidant enzymes (SOD, CAT, GSH-Px) decreased. EGCG attenuated HA environments-induced cognitive impairment, iron accumulation, microglial activation and neural degeneration. The effects of EGCG in reducing EPO and the metal chelating property with respect to iron were dose-dependent, with effects of EGCG (50 mg/kg) being similar to those of salidroside (50 mg/kg).</div></div><div><h3>Conclusions</h3><div>EGCG can act as a neuroprotective agent against chronic HA environments-mediated neural injuries. QSM provides a potential complementary imaging technique to detect the effect of treating HA diseases.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"764 ","pages":"Article 110224"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715160","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":"Kinetic studies of bifurcating flavoproteins","authors":"Russ Hille ,&nbsp;Dimitri Niks ,&nbsp;Wayne Vigil Jr. ,&nbsp;Jessica Tran ,&nbsp;Steve Ortiz ,&nbsp;Kevin Menjivar ,&nbsp;Derek Nguyen","doi":"10.1016/j.abb.2024.110278","DOIUrl":"10.1016/j.abb.2024.110278","url":null,"abstract":"<div><div>Since their original proposal in 2008, a number of broadly distributed flavoprotein systems catalyzing electron bifurcation have been identified that play key roles in the bioenergetics of anaerobic bacteria and archaea. While the overall thermodynamics of flavin-based electron bifurcation are now quite well-understood, the same cannot be said of their kinetic behavior. The present account represents a summary of results obtained with several electron-electron bifurcating systems, shamelessly focusing on work done in the authors’ laboratory.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"764 ","pages":"Article 110278"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871095","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":"New metal complexes of 1H-benzimidazole-2-yl hydrazones: Cytostatic, proapoptotic and modulatory activity on kinase signaling pathways","authors":"Maria Argirova ,&nbsp;Emiliya Cherneva ,&nbsp;Rositsa Mihaylova ,&nbsp;Georgi Momekov ,&nbsp;Denitsa Yancheva","doi":"10.1016/j.abb.2024.110245","DOIUrl":"10.1016/j.abb.2024.110245","url":null,"abstract":"<div><div>The copper complexes of two 1<em>H</em>-benzimidazole-2-yl hydrazones were obtained by complexation with copper chloride. The molecular structure of the complexes was studied by microchemical analysis, SEM-EDX, IR and micro-Raman spectroscopy and DFT calculations. It was found that both ligands form 1:1 complexes with the copper, where the Cu ions are coordinated by N-atom from the benzimidazole ring, N-atom of the azomethine bond, O-atom from the <em>ortho</em>-OH group of the aromatic ring and one chlorine atom. The coordination process significantly affected their cytotoxicity profile. The conversion of 2-(2-hydroxybenzylidene)-1-(1<em>H</em>-benzimidazol-2-yl)hydrazine <strong>1.1.</strong> into a Cu complex <strong>2.1.</strong> led to a 2.4-fold increase in its antileukemic activity against <em>AR-230</em> cells and an 8-fold increase in the cytostatic activity against <em>MCF-7</em> breast cancer cell line. The growth-inhibitory effect of the Cu complex of 2-(2-hydroxy-4-methoxybenzylidene)-1-(1<em>H</em>-benzimidazol-2-yl)hydrazine <strong>2.2.</strong> on the MCF-7 cells was comparable to that of the respective ligand, however lacked towards the leukemic AR-230 cell population. Regarding their cytotoxic potential towards <em>CCL-1</em> cells, both Cu complexes exhibited a weaker selectivity pattern as compared to their ligands. The proapoptotic and modulatory activity of <strong>1.1</strong> and <strong>2.1.</strong> on key kinase signaling pathways was further studied in the ER + breast cancer (MCF-7) and bcr-abl + leukemic (AR-230) <em>in vitro</em> tumor models in a comparative manner to the reference drugs tamoxifen and imatinib, respectively. Inhibition of the JAK/STAT signaling pathway was outlined as a prominent mechanism in the antileukemic activity against the Ph + <em>AR-230 in vitro</em> model, whereas recruitment and activation of the extrinsic apoptotic pathway was established in the <em>MCF-7</em> cells.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"764 ","pages":"Article 110245"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765720","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":"FFA intervention on LO2 cells mediates SNX-10 synthesis and regulates MMP9 secretion in LX2 cells via TGF-β1","authors":"Jianhui Xie ,&nbsp;Shiyan Chen ,&nbsp;Yangli Chen ,&nbsp;Junlu Tong ,&nbsp;Huijie Huang ,&nbsp;Jingwen Liao ,&nbsp;Jixin Sun ,&nbsp;Li Cong ,&nbsp;Yingjuan Zeng","doi":"10.1016/j.abb.2024.110255","DOIUrl":"10.1016/j.abb.2024.110255","url":null,"abstract":"<div><h3>Background</h3><div>Metabolic-associated fatty liver disease (MAFLD) is a public health concern. Transforming growth factor-β1(TGF-β1) plays an important regulatory role in multiple MAFLD stages, as it can promote the expression of matrix metalloproteinase-9 (MMP9) and promote liver fibrosis. Sorting nexin protein-10 (SNX-10) may be involved in the occurrence and development of fatty liver disease.</div></div><div><h3>Methods</h3><div>Free fatty acids (FFA) treatment was used to simulate the cellular lipid deposition stage of MAFLD and the interactions between cells were simulated via LX2 and LO2 coculture. The molecular interaction between the two cell types was studied via ELISA, immunoprecipitation, qPCR, and western blotting.</div></div><div><h3>Results</h3><div>In FFA-treated LO2 cells, intracellular TGF-β1 expression increased as lipid deposition increased. FFA-treated LO2 cells promoted the expression and secretion of MMP9 by LX2 cells through paracrine pathways. MMP9 secretion decreased with decreasing SNX-10 expression in LX2 cells. The interaction between MMP9 and SNX-10 was confirmed by coimmunoprecipitation. TGF-β1 promoted the synthesis of SNX-10 through the p38 MAPK pathway, and SNX-10 affected the secretion of MMP9 through protein interactions, thereby affecting the development of liver fibrosis.</div></div><div><h3>Conclusions</h3><div>FFA induced lipid deposition in LO2 cells, and TGF-β1 mediated the p38 MAPK pathway to promote SNX-10 synthesis and stimulate MMP9 secretion, thereby regulating the involvement of LX2 in the process of liver fibrosis.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"764 ","pages":"Article 110255"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812036","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":"Decoding KRAS dynamics: Exploring the impact of mutations and inhibitor binding","authors":"Divya Pandey,&nbsp;Kuldeep K. Roy","doi":"10.1016/j.abb.2024.110279","DOIUrl":"10.1016/j.abb.2024.110279","url":null,"abstract":"<div><div>KRAS (Kirsten rat sarcoma viral oncogene homologue), the most common mutated protein in human cancers, is the leading cause of morbidity and mortality. Before Sotorasib (AMG-510) was approved for non-small cell lung cancer treatment in 2020, the oncogenic KRAS mutations were believed to be non-druggable. High-resolution X-ray crystal structures of GDP-bound KRAS mutants with and without inhibitor are resolved and deposited in the Protein Data Bank (PDB). Nevertheless, to develop inhibitors targeting oncogenic KRAS mutants, understanding the dynamics of protein conformations and respective binding sites is crucial. In the present study, multiple molecular dynamics (MD) simulations were conducted on wild-type and mutant KRAS structures to understand how G12C or G12D mutations lead to the stabilization of the active state and how KRAS inhibitors lock the mutated conformations in their inactive state. The study found that the guanosine diphosphate (GDP)-bound KRAS mutants, G12C and G12D, were locked in the inactive state, in terms of stability, when the KRAS inhibitors, AMG-510 and MRTX1133, respectively, bind to the respective Switch-II (S-II) pocket. Covalent inhibitor AMG-510 locked the inactive GDP-bound KRAS^G12C mutant more efficiently when compared to the non-covalent inhibitor MRTX1133. The Cα atom distance between key highly dynamic amino acids from P-loop, Switch-I, and Switch-II domains, lying within 4 Å of the inhibitor, were stable in the KRAS mutant with bound inhibitors (AMG-510 or MRTX1133), but were varying largely in the absence of any inhibitor throughout the microsecond simulation. According to the per-residue energy decomposition results, S-II amino acids in inhibitor-free KRAS^G12C and KRAS^G12D mutants showed larger variations in energy values as compared to AMG-510-bound KRAS^G12C and MRTX1133-bound KRAS^G12D, respectively. For example, the inhibitor-free KRAS^G12C exhibited larger variations in energy values in the S-II residues, namely, Thr58, Gln61, Glu63, and Arg68, as compared to the AMG-510-bound KRAS^G12C. The study found that the higher stability of AMG-510 in torsion angles was due to its covalent nature of binding to the KRAS^G12C mutant. The S-II amino acids, namely, Thr58, Glu63, and Arg68 remained stable in AMG-510-bound KRAS^G12C. The study showed that AMG-510 binding significantly stabilizes the amino acids surrounding it, surpassing that of MRTX1133. The insights gained in the present study is expected to be useful in the design and development of new KRAS-targeted drugs.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"764 ","pages":"Article 110279"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875601","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":"In silico based re-engineering of a computationally designed biosensor with altered signalling mode and improved dynamic range","authors":"Dustin D. Smith ,&nbsp;D. Wade Abbott ,&nbsp;Hans-Joachim Wieden","doi":"10.1016/j.abb.2024.110275","DOIUrl":"10.1016/j.abb.2024.110275","url":null,"abstract":"<div><div>A current challenge in the rational design of biomolecular sensors is the ability to custom design binding affinities and detection mode <em>in silico</em>. To this end, we re-engineered a previously reported computationally-designed fluorescent maltooligosaccharide (MOS)-detecting biosensor to both alter its ligand-binding affinity and to analyse the underlying sensing mechanism. The dynamic range of the biosensor was expanded through the computer aided introduction of a series of amino acid substitutions in the starting protein scaffold (MalX from <em>Streptococcus pneumoniae</em>), which generated a biosensor set with binding affinities spanning over five orders of magnitude. The impact of the introduced substitutions on the underlying mode of signal generation was assessed <em>in silico</em> using our previously reported Computational Identification of Non-disruptive Conjugation sites (CINC) pipeline. CINC utilizes molecular dynamics simulations and an in-house developed algorithm to examine and exploit the structural dynamics of a protein at amino acid-level resolution. Using CINC, we demonstrate that re-engineering of the MOS-detecting biosensor set resulted in sensors with two distinct output modes which differed based on local conformational changes at the fluorescently modified reporter position. These output modes were classified as “ligand-sensing”-type biosensors (readout based on the tool sensing a unique conformation in the ligand-bound state), and “<em>apo</em>-sensing”-type biosensors (readout based on the tool sensing a unique conformation in the <em>apo</em> state). Together, these results demonstrate that structural dynamics at the individual amino acid residue level can be used as an engineer-able feature to rationally alter the fluorescence reporting properties of a biosensing device. Moving forward, the CINC workflow can also be adapted for the rational design of protein dynamic properties maximizing its utility as an <em>in silico</em> design platform for custom biomolecular tools.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"764 ","pages":"Article 110275"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851701","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":"Augmenter of liver regeneration inhibits renal fibrosis during acute kidney injury to chronic kidney disease transition by regulating autophagic flux","authors":"Chunxia Wang ,&nbsp;Xujia Zeng ,&nbsp;Pengfei Yang ,&nbsp;Gang Wang ,&nbsp;Zheng Zhang ,&nbsp;Xiaohui Liao","doi":"10.1016/j.abb.2024.110218","DOIUrl":"10.1016/j.abb.2024.110218","url":null,"abstract":"<div><h3>Background</h3><div>Augmenter of liver regeneration (ALR) is believed to protect against acute kidney injury (AKI). The objective of this study was to investigate the mechanisms of ALR in the transition from AKI to chronic kidney disease (CKD).</div></div><div><h3>Methods</h3><div>ALR Conditional Knockout (CKO) mice were bilateral renal artery clamped to induce AKI and CKD. Serum creatinine, blood urea nitrogen, and uric acid were measured to reflect renal function. Renal histology was used to assess kidney damage. Transcriptome sequencing and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to identify differentially expressed genes (DEGs) and related pathways. TUNEL assay was conducted to assess apoptosis. Polymerase chain reaction and immunohistology were used to analyze autophagy-related factors and kidney fibrosis. AAV9-mRFP-GFP-LC3 was injected to observe autophagy flux.</div></div><div><h3>Results</h3><div>In the murine models of AKI and CKD, loss of ALR led to markedly reduced renal function and renal tubular pathology injury. Multiple autophagy-related pathways were found to be enriched in up-regulated DEGs in transcriptome sequencing of ALR CKO and control groups with AKI. Renal fibrosis was evident in ALR CKO mice, with marked suppression of Beclin-1, a factor associated with the initiation phase of autophagy, and ATG5, an important factor in the extension phase of autophagosomes. The marked accumulation of LC3 and SQSTM1/P62, which is associated with the formation of autophagosomes, was also observed, suggesting an impairment of autophagic processes. Correspondingly, the AAV9-mRFP-GFP-LC3 results indicated that decreased ALR led to the accumulation of autophagosomes and impaired autophagic lysosome generation.</div></div><div><h3>Conclusions</h3><div>Collectively, these results suggested that ALR deficiency led to apoptosis and enhanced renal fibrosis by impairing autophagic flux, which in turn led to the transition of AKI to CKD.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"764 ","pages":"Article 110218"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754354","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}