Pub Date : 2025-01-25DOI: 10.1016/j.abb.2025.110321
Jessica Georgina Filisola-Villaseñor , Beatriz Irene Arroyo-Sánchez , Luis Janiel Navarro-González , Edgar Morales-Ríos , Viridiana Olin-Sandoval
Cancer is among the leading causes of death worldwide. The effectiveness of conventional chemotherapy has some drawbacks, therefore, there is an urgency to develop novel strategies to fight this disease. Ornithine decarboxylase (ODC) is the most finely tuned enzyme of the polyamine (PA) biosynthesis pathway as it is regulated at different levels: transcriptional, translational, post-translational, and by feedback inhibition. In cancer, this enzyme is overexpressed due to its regulation by the protooncogene c-Myc, thus it has been proposed as a drug target against this disease. This review describes information regarding the biochemistry and regulation of the ODC at different levels and its role in cancer. Moreover, we discuss the molecules aiming on the inhibition of the ODC activity that have been tested as therapeutic options. ODC remains as a therapeutic opportunity that needs to be more explored.
{"title":"Ornithine decarboxylase and its role in cancer","authors":"Jessica Georgina Filisola-Villaseñor , Beatriz Irene Arroyo-Sánchez , Luis Janiel Navarro-González , Edgar Morales-Ríos , Viridiana Olin-Sandoval","doi":"10.1016/j.abb.2025.110321","DOIUrl":"10.1016/j.abb.2025.110321","url":null,"abstract":"<div><div>Cancer is among the leading causes of death worldwide. The effectiveness of conventional chemotherapy has some drawbacks, therefore, there is an urgency to develop novel strategies to fight this disease. Ornithine decarboxylase (ODC) is the most finely tuned enzyme of the polyamine (PA) biosynthesis pathway as it is regulated at different levels: transcriptional, translational, post-translational, and by feedback inhibition. In cancer, this enzyme is overexpressed due to its regulation by the protooncogene c-Myc, thus it has been proposed as a drug target against this disease. This review describes information regarding the biochemistry and regulation of the ODC at different levels and its role in cancer. Moreover, we discuss the molecules aiming on the inhibition of the ODC activity that have been tested as therapeutic options. ODC remains as a therapeutic opportunity that needs to be more explored.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"765 ","pages":"Article 110321"},"PeriodicalIF":3.8,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143050999","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}
Pub Date : 2025-01-25DOI: 10.1016/j.abb.2025.110319
Kaylen R. Meeks , Juan Ji , Gary K. Scott , Ashley C. Campbell , Jay C. Nix , Ada Tadeo , Lisa M. Ellerby , Christopher C. Benz , John J. Tanner
The mitochondrial flavoenzymes proline dehydrogenase (PRODH) and hydroxyproline dehydrogenase (PRODH2) catalyze the first steps of proline and hydroxyproline catabolism, respectively. The enzymes are targets for chemical probe development because of their roles in cancer cell metabolism (PRODH) and primary hyperoxaluria (PRODH2). Mechanism-based inactivators of PRODH target the FAD by covalently modifying the N5 atom, with N-propargylglycine (NPPG) being the current best-in-class of this type of probe. Here we investigated a close analog of NPPG, but-3-yn-2-ylglycine (B32G), distinguished by having a methyl group adjacent to the ethynyl group of the propargyl warhead. UV–visible spectroscopy shows that a bacterial PRODH catalyzes the oxidation of the S-enantiomer of B32G, a necessary first step in mechanism-based inactivation. In contrast, the enzyme does not react with the R-enantiomer. Enzyme activity assays show that S–B32G inhibits bacterial PRODH in a time-dependent manner consistent with covalent inactivation; however, the inactivation efficiency is ∼600-times lower than NPPG. We generated the crystal structure of PRODH inactivated by S–B32G at 1.68 Å resolution and found that inactivation induces a covalent link between the FAD N5 and the ε-nitrogen of an active site lysine, confirming that S–B32G follows the same mechanism as NPPG. Despite its lower inactivation efficiency at the purified bacterial enzyme, S–B32G exhibited comparable activity to NPPG against PRODH and PRODH2 in human cells and mouse livers. Molecular modeling is used to rationalize the stereospecificity of B32G.
{"title":"Biochemical, structural, and cellular characterization of S-but-3-yn-2-ylglycine as a mechanism-based covalent inactivator of the flavoenzyme proline dehydrogenase","authors":"Kaylen R. Meeks , Juan Ji , Gary K. Scott , Ashley C. Campbell , Jay C. Nix , Ada Tadeo , Lisa M. Ellerby , Christopher C. Benz , John J. Tanner","doi":"10.1016/j.abb.2025.110319","DOIUrl":"10.1016/j.abb.2025.110319","url":null,"abstract":"<div><div>The mitochondrial flavoenzymes proline dehydrogenase (PRODH) and hydroxyproline dehydrogenase (PRODH2) catalyze the first steps of proline and hydroxyproline catabolism, respectively. The enzymes are targets for chemical probe development because of their roles in cancer cell metabolism (PRODH) and primary hyperoxaluria (PRODH2). Mechanism-based inactivators of PRODH target the FAD by covalently modifying the N5 atom, with N-propargylglycine (NPPG) being the current best-in-class of this type of probe. Here we investigated a close analog of NPPG, but-3-yn-2-ylglycine (B32G), distinguished by having a methyl group adjacent to the ethynyl group of the propargyl warhead. UV–visible spectroscopy shows that a bacterial PRODH catalyzes the oxidation of the S-enantiomer of B32G, a necessary first step in mechanism-based inactivation. In contrast, the enzyme does not react with the R-enantiomer. Enzyme activity assays show that S–B32G inhibits bacterial PRODH in a time-dependent manner consistent with covalent inactivation; however, the inactivation efficiency is ∼600-times lower than NPPG. We generated the crystal structure of PRODH inactivated by S–B32G at 1.68 Å resolution and found that inactivation induces a covalent link between the FAD N5 and the ε-nitrogen of an active site lysine, confirming that S–B32G follows the same mechanism as NPPG. Despite its lower inactivation efficiency at the purified bacterial enzyme, S–B32G exhibited comparable activity to NPPG against PRODH and PRODH2 in human cells and mouse livers. Molecular modeling is used to rationalize the stereospecificity of B32G.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"765 ","pages":"Article 110319"},"PeriodicalIF":3.8,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051016","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}
Pub Date : 2025-01-25DOI: 10.1016/j.abb.2025.110320
Daniel Eggerichs , Heiner G. Weddeling , Laura Alvigini , Tobias Rapsch , Nils Weindorf , Andrea Mattevi , Dirk Tischler
4-Phenol oxidases are proposed to be involved in the utilization of lignin-derived aromatic compounds. While enzymes with selectivity towards 4-hydroxyphenyl and guaiacyl motifs are well described, we identified the first syringyl-specific oxidase from Streptomyces cavernae (Sc4ASO) only very recently. Here, in-depth studies were conducted to unravel the molecular origins of the outstanding selectivity of Sc4ASO. Kinetic experiments revealed high activities on dimethoxylated substrates (up to 2.9 ± 0.1 s−1), but also strong cooperativity between both protein subunits, as well as substrate inhibition in dependency of ortho methoxylation and chain length of the para substituent. Rapid mixing kinetics in combination with the determination of the crystal structure in complex with three substrates allowed to connect the kinetic behavior with never-observed positioning of the conserved residue Y471. Ultimately, the catalytic potential of Sc4ASO was investigated in a 100 mL scale cascade reaction to produce the natural product syringaresinol.
{"title":"Kinetic and structural investigation of the 4-allyl syringol oxidase from Streptomyces cavernae","authors":"Daniel Eggerichs , Heiner G. Weddeling , Laura Alvigini , Tobias Rapsch , Nils Weindorf , Andrea Mattevi , Dirk Tischler","doi":"10.1016/j.abb.2025.110320","DOIUrl":"10.1016/j.abb.2025.110320","url":null,"abstract":"<div><div>4-Phenol oxidases are proposed to be involved in the utilization of lignin-derived aromatic compounds. While enzymes with selectivity towards 4-hydroxyphenyl and guaiacyl motifs are well described, we identified the first syringyl-specific oxidase from <em>Streptomyces cavernae</em> (<em>Sc</em>4ASO) only very recently. Here, in-depth studies were conducted to unravel the molecular origins of the outstanding selectivity of <em>Sc</em>4ASO. Kinetic experiments revealed high activities on dimethoxylated substrates (up to 2.9 ± 0.1 s<sup>−1</sup>), but also strong cooperativity between both protein subunits, as well as substrate inhibition in dependency of <em>ortho</em> methoxylation and chain length of the <em>para</em> substituent. Rapid mixing kinetics in combination with the determination of the crystal structure in complex with three substrates allowed to connect the kinetic behavior with never-observed positioning of the conserved residue Y471. Ultimately, the catalytic potential of <em>Sc</em>4ASO was investigated in a 100 mL scale cascade reaction to produce the natural product syringaresinol.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"765 ","pages":"Article 110320"},"PeriodicalIF":3.8,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051018","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}
Pub Date : 2025-01-24DOI: 10.1016/j.abb.2025.110322
Huayu Ling , Yuling Li , Panjun Wang , Zhengxiang Zhang , Zhong Yang
Background
Diffuse large B-cell lymphoma (DLBCL) is a prevalent and aggressive form of non-Hodgkin's lymphoma with a complex etiology. NOP2/Sun domain 2 (NSUN2) is an RNA methyltransferase that has been linked to the regulation of gene expression in various cancers. However, the function of NSUN2 in DLBCL, specifically its contribution to exosome-driven tumor progression, remains to be thoroughly elucidated.
Methods
Quantitative real-time polymerase chain reaction was used to analyze the expression of NSUN2 and programmed death ligand 1 variant (PDL1). Western blotting assay was performed to detect the protein levels of NSUN2, PDL1 and Y-box binding protein 1 (YBX1). Cell proliferation was analyzed by cell counting kit-8 and 5-Ethynyl-2′-deoxyuridine assays. Cell apoptosis and CD206-positive cells were quantified by flow cytometry. The levels of tumor necrosis factor-alpha and interferon-γ in cell supernatant were analyzed by enzyme-linked immunosorbent assays. m6A RNA immunoprecipitation and RNA pull-down assays were performed to determine the association between NSUN2 and PDL1. An RNA immunoprecipitation assay was used to analyze the association of YBX1 and PDL1. In vitro findings were validated in a mouse model.
Results
NSUN2 was overexpressed in DLBCL tissues and cells. DLBCL cell-derived exosomes facilitated the transfer of NSUN2 to DLBCL cells, which in turn promoted tumor cell proliferation, M2 macrophage polarization, and immune escape and inhibited cell apoptosis. In addition, NSUN2 stabilized PDL1 mRNA through an m5C-dependent mechanism and a YBX1-dependent pathway. Moreover, the suppression of PDL1 significantly mitigated the effects induced by NSUN2 within DLBCL cell-derived exosomes on cellular proliferation, apoptosis, M2 macrophage polarization, and immune evasion. Further, DLBCL cell-derived exosomal NSUN2 promoted tumor growth by regulating PDL1.
Conclusion
NSUN2 in DLBCL cell-derived exosomes stabilized PDL1 in a YBX1-dependent manner and thus promoted tumor immune escape and M2 macrophage polarization. These findings highlight the potential of targeting the NSUN2-PDL1 axis as a novel therapeutic strategy for DLBCL.
{"title":"Diffuse large B-cell lymphoma cell-derived exosomal NSUN2 stabilizes PDL1 to promote tumor immune escape and M2 macrophage polarization in a YBX1-dependent manner","authors":"Huayu Ling , Yuling Li , Panjun Wang , Zhengxiang Zhang , Zhong Yang","doi":"10.1016/j.abb.2025.110322","DOIUrl":"10.1016/j.abb.2025.110322","url":null,"abstract":"<div><h3>Background</h3><div>Diffuse large B-cell lymphoma (DLBCL) is a prevalent and aggressive form of non-Hodgkin's lymphoma with a complex etiology. NOP2/Sun domain 2 (NSUN2) is an RNA methyltransferase that has been linked to the regulation of gene expression in various cancers. However, the function of NSUN2 in DLBCL, specifically its contribution to exosome-driven tumor progression, remains to be thoroughly elucidated.</div></div><div><h3>Methods</h3><div>Quantitative real-time polymerase chain reaction was used to analyze the expression of NSUN2 and programmed death ligand 1 variant (PDL1). Western blotting assay was performed to detect the protein levels of NSUN2, PDL1 and Y-box binding protein 1 (YBX1). Cell proliferation was analyzed by cell counting kit-8 and 5-Ethynyl-2′-deoxyuridine assays. Cell apoptosis and CD206-positive cells were quantified by flow cytometry. The levels of tumor necrosis factor-alpha and interferon-γ in cell supernatant were analyzed by enzyme-linked immunosorbent assays. m6A RNA immunoprecipitation and RNA pull-down assays were performed to determine the association between NSUN2 and PDL1. An RNA immunoprecipitation assay was used to analyze the association of YBX1 and PDL1. <em>In vitro</em> findings were validated in a mouse model.</div></div><div><h3>Results</h3><div>NSUN2 was overexpressed in DLBCL tissues and cells. DLBCL cell-derived exosomes facilitated the transfer of NSUN2 to DLBCL cells, which in turn promoted tumor cell proliferation, M2 macrophage polarization, and immune escape and inhibited cell apoptosis. In addition, NSUN2 stabilized PDL1 mRNA through an m5C-dependent mechanism and a YBX1-dependent pathway. Moreover, the suppression of PDL1 significantly mitigated the effects induced by NSUN2 within DLBCL cell-derived exosomes on cellular proliferation, apoptosis, M2 macrophage polarization, and immune evasion. Further, DLBCL cell-derived exosomal NSUN2 promoted tumor growth by regulating PDL1.</div></div><div><h3>Conclusion</h3><div>NSUN2 in DLBCL cell-derived exosomes stabilized PDL1 in a YBX1-dependent manner and thus promoted tumor immune escape and M2 macrophage polarization. These findings highlight the potential of targeting the NSUN2-PDL1 axis as a novel therapeutic strategy for DLBCL.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"766 ","pages":"Article 110322"},"PeriodicalIF":3.8,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045328","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}
Pub Date : 2025-01-23DOI: 10.1016/j.abb.2025.110318
Yanqi Liu , Yu Xin , Mengyao Yuan , Yuhan Liu , Yuchen Song , Lifeng Shen , Yu Xiao , Xinran Wang , Dawei Wang , Linqiong Liu , Yuxi Liu , Yinghao Luo , Pengfei Huang , Qianqian Zhang , Weiting Zhang , Hongxu Li , Yuxin Zhou , Xibo Wang , Kaijiang Yu , Changsong Wang
Background
Ischemia-reperfusion injury (IRI) often results in renal impairment. While the presence of neutrophil extracellular traps (NETs) is consistently observed, their specific impact on IRI is not yet defined. Sivelestat sodium, an inhibitor of neutrophil elastase which is crucial for NET formation, may offer a therapeutic approach to renal IRI, warranting further research.
Methods
A mouse model was established for early-stage renal IRI, confirmed by injury markers and histological assessments. The involvement of NETs in renal I/R was demonstrated using immunofluorescence and Western blot. Renal function and pathology were further evaluated through a comprehensive set of methods, including Periodic Acid-Schiff staining (PAS) and Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling (TUNEL) staining, enzyme-linked immunosorbent assay (ELISA), Real time Glomerular Filtration Rate (RT-GFR) monitoring, Polymerase Chain Reaction (PCR), biochemical analysis, and additional Western blot and immunofluorescence assays.
Results
We firstly quantified NET expression in renal IRI mice, noting a peak at 24 h. Subsequently, sivelestat sodium treatment was administered, resulting in decreased MPO, CitH3, and attenuated tubular damage. Moreover, it resulted in a decrease in serum levels of creatinine, blood urea nitrogen (BUN), as well as neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1). Additionally, it lowered the abundance of renal tissue inflammatory markers interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and mitigated the levels of oxidative stress indicators malondialdehyde (MDA) and 4 Hydroxynonenal (4HNE), accompanied by a decline in renal cell apoptosis and an enhancement of GFR in renal I/R mice.
Conclusion
Sivelestat sodium ameliorates renal IRI by downregulating neutrophil NETs, reducing inflammation, oxidative stress, and apoptosis, thereby enhancing renal function.
{"title":"Sivelestat sodium protects against renal ischemia/reperfusion injury by reduction of NETs formation","authors":"Yanqi Liu , Yu Xin , Mengyao Yuan , Yuhan Liu , Yuchen Song , Lifeng Shen , Yu Xiao , Xinran Wang , Dawei Wang , Linqiong Liu , Yuxi Liu , Yinghao Luo , Pengfei Huang , Qianqian Zhang , Weiting Zhang , Hongxu Li , Yuxin Zhou , Xibo Wang , Kaijiang Yu , Changsong Wang","doi":"10.1016/j.abb.2025.110318","DOIUrl":"10.1016/j.abb.2025.110318","url":null,"abstract":"<div><h3>Background</h3><div>Ischemia-reperfusion injury (IRI) often results in renal impairment. While the presence of neutrophil extracellular traps (NETs) is consistently observed, their specific impact on IRI is not yet defined. Sivelestat sodium, an inhibitor of neutrophil elastase which is crucial for NET formation, may offer a therapeutic approach to renal IRI, warranting further research.</div></div><div><h3>Methods</h3><div>A mouse model was established for early-stage renal IRI, confirmed by injury markers and histological assessments. The involvement of NETs in renal I/R was demonstrated using immunofluorescence and Western blot. Renal function and pathology were further evaluated through a comprehensive set of methods, including Periodic Acid-Schiff staining (PAS) and Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling (TUNEL) staining, enzyme-linked immunosorbent assay (ELISA), Real time Glomerular Filtration Rate (RT-GFR) monitoring, Polymerase Chain Reaction (PCR), biochemical analysis, and additional Western blot and immunofluorescence assays.</div></div><div><h3>Results</h3><div>We firstly quantified NET expression in renal IRI mice, noting a peak at 24 h. Subsequently, sivelestat sodium treatment was administered, resulting in decreased MPO, CitH3, and attenuated tubular damage. Moreover, it resulted in a decrease in serum levels of creatinine, blood urea nitrogen (BUN), as well as neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1). Additionally, it lowered the abundance of renal tissue inflammatory markers interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and mitigated the levels of oxidative stress indicators malondialdehyde (MDA) and 4 Hydroxynonenal (4HNE), accompanied by a decline in renal cell apoptosis and an enhancement of GFR in renal I/R mice.</div></div><div><h3>Conclusion</h3><div>Sivelestat sodium ameliorates renal IRI by downregulating neutrophil NETs, reducing inflammation, oxidative stress, and apoptosis, thereby enhancing renal function.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"765 ","pages":"Article 110318"},"PeriodicalIF":3.8,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143036196","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}
Pub Date : 2025-01-21DOI: 10.1016/j.abb.2025.110316
Mengying Jin , Xiao Chen , Lanzhuoying Zheng , Yuanyuan Peng , Mingying Lin , Ke Liang , Xinran Liu , Zihan Xu , Yiming Yang , Baozhu Wei , Jing Wan
Background
Astaxanthin (ASX), a fat-soluble carotenoid mainly sourced from Haematococcus pluvialis, shows promise for clinical applications in chronic inflammatory diseases. This study investigates whether ASX can mitigate atherosclerosis (AS) by modulating macrophage ferroptosis and provides astaxanthin-loaded polylactic acid-glycolic acid nanoparticles (ASX-PLGA NPs) as comparison.
Method
ApoE−/− mice were fed a high-fat diet with ASX or statin intervention. Plaque area, lipid aggregation, collagen content, and ferroptosis-related indicators were assessed. Moreover, ASX-PLGA NPs were synthesized and characterized and were used to pretreat macrophages induced with oxidized low-density lipoprotein (ox-LDL). Indicators linked to ferroptosis and oxidative stress were detected. Finally, the expression of nuclear factor erythroid -related factor 2 (NRF2) was evaluated.
Results
ASX intervention significantly delayed the progression of AS plaques, characterized by reductions in plaque area and increased collagen fibers. The observed improvements in AS were consistent with statins. ASX-PLGA NPs demonstrate good safety and stability and have better therapeutic effects than ASX alone. Indicators linked to ferroptosis and oxidative stress were significantly improved in groups containing ASX in vivo and vitro. Additionally, ASX facilitated the nuclear translocation of NRF2, which could be attenuated with ML385, a specific inhibitor of NRF2.
Conclusion
ASX-PLGA NPs have better therapeutic effects than ASX alone. The regulation of NRF2/SLC7A11/GPX4 represents a novel mechanism by which ASX can counteract ferroptosis and impede AS progression.
{"title":"Astaxanthin-loaded polylactic acid-glycolic acid nanoparticles alleviates atherosclerosis by suppressing macrophage ferroptosis via the NRF2/SLC7A11/GPX4 pathway","authors":"Mengying Jin , Xiao Chen , Lanzhuoying Zheng , Yuanyuan Peng , Mingying Lin , Ke Liang , Xinran Liu , Zihan Xu , Yiming Yang , Baozhu Wei , Jing Wan","doi":"10.1016/j.abb.2025.110316","DOIUrl":"10.1016/j.abb.2025.110316","url":null,"abstract":"<div><h3>Background</h3><div>Astaxanthin (ASX), a fat-soluble carotenoid mainly sourced from Haematococcus pluvialis, shows promise for clinical applications in chronic inflammatory diseases. This study investigates whether ASX can mitigate atherosclerosis (AS) by modulating macrophage ferroptosis and provides astaxanthin-loaded polylactic acid-glycolic acid nanoparticles (ASX-PLGA NPs) as comparison.</div></div><div><h3>Method</h3><div>ApoE−/− mice were fed a high-fat diet with ASX or statin intervention. Plaque area, lipid aggregation, collagen content, and ferroptosis-related indicators were assessed. Moreover, ASX-PLGA NPs were synthesized and characterized and were used to pretreat macrophages induced with oxidized low-density lipoprotein (ox-LDL). Indicators linked to ferroptosis and oxidative stress were detected. Finally, the expression of nuclear factor erythroid -related factor 2 (NRF2) was evaluated.</div></div><div><h3>Results</h3><div>ASX intervention significantly delayed the progression of AS plaques, characterized by reductions in plaque area and increased collagen fibers. The observed improvements in AS were consistent with statins. ASX-PLGA NPs demonstrate good safety and stability and have better therapeutic effects than ASX alone. Indicators linked to ferroptosis and oxidative stress were significantly improved in groups containing ASX in vivo and vitro. Additionally, ASX facilitated the nuclear translocation of NRF2, which could be attenuated with ML385, a specific inhibitor of NRF<strong>2.</strong></div></div><div><h3>Conclusion</h3><div>ASX-PLGA NPs have better therapeutic effects than ASX alone. The regulation of NRF2/SLC7A11/GPX4 represents a novel mechanism by which ASX can counteract ferroptosis and impede AS progression.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"765 ","pages":"Article 110316"},"PeriodicalIF":3.8,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027799","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}
Pub Date : 2025-01-20DOI: 10.1016/j.abb.2025.110315
Feryal Akay , Nesrin İnceören , Cemal Nas , Beran Yokuş , Göksel Kızıl , Murat Kızıl
Diabetes Mellitus (DM), one of the oldest known metabolic disorders, dates back to 3000 BC and continues to have a profound impact on health and the economy. Nutrition plays a critical role in managing diabetes and enhancing overall quality of life. It is also vital for immune system function, as well as in the prevention and treatment of aging-related diseases. A key factor contributing to the global rise in obesity is the excessive consumption of fructose/glucose (corn) syrup, which leads to various metabolic complications. Uncontrolled intake of carbohydrates, particularly sugars like fructose, triggers the Maillard Reaction, a chemical process that occurs between sugars and proteins, resulting in advanced glycation end-products (AGEs). This process is accelerated in diabetic patients due to hyperglycemia, leading to increased glycation of plasma proteins such as immunoglobulins, which play an essential role in the immune system.
Studies show that individuals with Diabetes Mellitus experience a higher susceptibility to infections due to increased viral entry, impaired immune responses, reduced viral clearance, and dysregulated inflammatory cytokine production. In this study, human IgG proteins were glycated in vitro using fructose, simulating the damaging effects seen in diabetic conditions. A mixture containing antioxidants like glutathione, oleuropein, and selenium was prepared and incubated with the glycated IgG to assess its protective properties. Lymphocyte cells from healthy volunteers were also treated with fructose and subjected to similar experiments. Results demonstrated that fructose significantly compromises immune function by damaging key proteins, but the antioxidant mixture effectively mitigates this damage, offering a protective mechanism against glycation in the immune system.
{"title":"Fructose-derived glycation and immune function: Effects on antigen binding in human IgG and lymphocytes","authors":"Feryal Akay , Nesrin İnceören , Cemal Nas , Beran Yokuş , Göksel Kızıl , Murat Kızıl","doi":"10.1016/j.abb.2025.110315","DOIUrl":"10.1016/j.abb.2025.110315","url":null,"abstract":"<div><div>Diabetes Mellitus (DM), one of the oldest known metabolic disorders, dates back to 3000 BC and continues to have a profound impact on health and the economy. Nutrition plays a critical role in managing diabetes and enhancing overall quality of life. It is also vital for immune system function, as well as in the prevention and treatment of aging-related diseases. A key factor contributing to the global rise in obesity is the excessive consumption of fructose/glucose (corn) syrup, which leads to various metabolic complications. Uncontrolled intake of carbohydrates, particularly sugars like fructose, triggers the Maillard Reaction, a chemical process that occurs between sugars and proteins, resulting in advanced glycation end-products (AGEs). This process is accelerated in diabetic patients due to hyperglycemia, leading to increased glycation of plasma proteins such as immunoglobulins, which play an essential role in the immune system.</div><div>Studies show that individuals with Diabetes Mellitus experience a higher susceptibility to infections due to increased viral entry, impaired immune responses, reduced viral clearance, and dysregulated inflammatory cytokine production. In this study, human IgG proteins were glycated in vitro using fructose, simulating the damaging effects seen in diabetic conditions. A mixture containing antioxidants like glutathione, oleuropein, and selenium was prepared and incubated with the glycated IgG to assess its protective properties. Lymphocyte cells from healthy volunteers were also treated with fructose and subjected to similar experiments. Results demonstrated that fructose significantly compromises immune function by damaging key proteins, but the antioxidant mixture effectively mitigates this damage, offering a protective mechanism against glycation in the immune system.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"765 ","pages":"Article 110315"},"PeriodicalIF":3.8,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021757","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}
Breast cancer is one of the most common cancers found in women worldwide. Besides the availability of clinical drugs, drug resistance and considerable side effects are concerning issues driven the needs for the discovery of novel anticancer agents. Aromatase inhibition is one of the effective strategies for management of hormone-dependent breast cancer. Triazole, coumarin, and isatin are heterocyclic scaffolds holding great attention in the field of drug design. Molecular hybridization is a well-known strategy to achieve new molecules with improved potency and properties. Herein, a set of 27 triazole-based hybrids (i.e., coumarin-triazoles series 5–6 and isatin-triazoles series 7) were synthesized and investigated for their anti-proliferation, apoptosis induction, and aromatase inhibitory potentials. Anti-proliferative study against the hormone-dependent breast cancer (T47D) cell line indicated that coumarin-triazoles 5h (R=NO2) and 6i (R=SO2NH2) were the two most potent antiproliferative agents. Particularly, compound 5h showed comparable potency and superior selectivity index than that of the reference drug, doxorubicin. Moreover, the coumarin-triazole 5h induced cellular apoptosis of the estrogen-dependent breast cancer (MCF-7) cells. Additionally, findings from the aromatase inhibitory assay suggested four compounds as potential aromatase inhibitors (i.e., 5i, 6f, 6g and 6i, IC50 = 1.4–2.4 μM). Two QSAR models with preferable predictive performances were constructed to reveal key properties influencing antiproliferative and aromatase inhibitory effects. Molecular docking was conducted to elucidate the possible binding modalities against the target aromatase enzyme. Key structural features essential for the binding were highlighted. Moreover, the drug-like properties of top-ranking compounds were assessed to ensure their possibilities for successful development.
{"title":"Synthesis, anti-proliferation, apoptosis induction in breast cancer cells, and aromatase inhibition of coumarin-triazole hybrids: In vitro and in silico studies","authors":"Amporn Saekee , Pichjira Sooknual , Sakdiphong Punpai , Veda Prachayasittikul , Sakchai Hongthong , Wanlaya Tanechpongtamb , Supaluk Prachayasittikul , Somsak Ruchirawat , Virapong Prachayasittikul , Ratchanok Pingaew","doi":"10.1016/j.abb.2025.110308","DOIUrl":"10.1016/j.abb.2025.110308","url":null,"abstract":"<div><div>Breast cancer is one of the most common cancers found in women worldwide. Besides the availability of clinical drugs, drug resistance and considerable side effects are concerning issues driven the needs for the discovery of novel anticancer agents. Aromatase inhibition is one of the effective strategies for management of hormone-dependent breast cancer. Triazole, coumarin, and isatin are heterocyclic scaffolds holding great attention in the field of drug design. Molecular hybridization is a well-known strategy to achieve new molecules with improved potency and properties. Herein, a set of 27 triazole-based hybrids (i.e., coumarin-triazoles series <strong>5</strong>–<strong>6</strong> and isatin-triazoles series <strong>7</strong>) were synthesized and investigated for their anti-proliferation, apoptosis induction, and aromatase inhibitory potentials. Anti-proliferative study against the hormone-dependent breast cancer (T47D) cell line indicated that coumarin-triazoles <strong>5h</strong> (R=NO<sub>2</sub>) and <strong>6i</strong> (R=SO<sub>2</sub>NH<sub>2</sub>) were the two most potent antiproliferative agents. Particularly, compound <strong>5h</strong> showed comparable potency and superior selectivity index than that of the reference drug, doxorubicin. Moreover, the coumarin-triazole <strong>5h</strong> induced cellular apoptosis of the estrogen-dependent breast cancer (MCF-7) cells. Additionally, findings from the aromatase inhibitory assay suggested four compounds as potential aromatase inhibitors (i.e., <strong>5i</strong>, <strong>6f</strong>, <strong>6g</strong> and <strong>6i,</strong> IC<sub>50</sub> = 1.4–2.4 μM). Two QSAR models with preferable predictive performances were constructed to reveal key properties influencing antiproliferative and aromatase inhibitory effects. Molecular docking was conducted to elucidate the possible binding modalities against the target aromatase enzyme. Key structural features essential for the binding were highlighted. Moreover, the drug-like properties of top-ranking compounds were assessed to ensure their possibilities for successful development.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"765 ","pages":"Article 110308"},"PeriodicalIF":3.8,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998872","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}
Pub Date : 2025-01-18DOI: 10.1016/j.abb.2025.110314
Jianan Wang , Aqing Jian , Depeng Sun , Mingxun Cui , Chunxiang Piao , Juan Wang , Baide Mu , Tingyu Li , Guanhao Li , Hongmei Li
Acer tegmentosum Maxim (AT) has a variety of pharmacological activities, however, the effects of AT on liver injury and gut microbiota in alcoholic liver disease (ALD) mice is still unclear. This study aimed to evaluate the preventive effect of AT extract on acute alcoholic liver disease. Six-week-old male C57BL/6J mice were randomly divided into 6 groups. Each group was intragastrically treated saline or different concentration of AT extract solution for 5 weeks continuously. After the last gavage, except for the NC group, all the other groups were gavaged twice with 56 % alcohol to establish the acute ALD model and biochemical indexes, histopathological, and gut microbiota were analyzed. Established an acute ALD mouse model and detected serum, liver oxidation levels, and alcohol metabolism-related gene expressions. Through 16S rRNA sequencing, analyzed gut microbiota, explored the relationship between gut microbiota and liver indicators. AT extract significantly decreased lipid levels, promoted ADH, ALDH, and increased the antioxidant activities. Meanwhile, AT extract significantly downregulated the expression of lipid oxidation and inflammatory factors, upregulated alcohol metabolism genes. In addition, 16S rRNA sequencing and analysis showed that AT extract effectively regulated the gut microbiota diversity of ALD mice, significantly improved the structural disturbance of intestinal microflora. AT extract regulated gut microbiota and had a strong correlation with serum, liver-related indexes, and gene expression levels. All these results showed that AT can alleviate alcohol induced liver injury by regulating oxidative stress, inflammatory response, alcohol metabolism, and gut microbiota disorder.
{"title":"Acer tegmeutosum Maxim extract alleviates acute alcohol-induced liver disease and regulates gut microbiota dysbiosis in mice","authors":"Jianan Wang , Aqing Jian , Depeng Sun , Mingxun Cui , Chunxiang Piao , Juan Wang , Baide Mu , Tingyu Li , Guanhao Li , Hongmei Li","doi":"10.1016/j.abb.2025.110314","DOIUrl":"10.1016/j.abb.2025.110314","url":null,"abstract":"<div><div><em>Acer tegmentosum</em> Maxim (AT) has a variety of pharmacological activities, however, the effects of AT on liver injury and gut microbiota in alcoholic liver disease (ALD) mice is still unclear. This study aimed to evaluate the preventive effect of AT extract on acute alcoholic liver disease. Six-week-old male C57BL/6J mice were randomly divided into 6 groups. Each group was intragastrically treated saline or different concentration of AT extract solution for 5 weeks continuously. After the last gavage, except for the NC group, all the other groups were gavaged twice with 56 % alcohol to establish the acute ALD model and biochemical indexes, histopathological, and gut microbiota were analyzed. Established an acute ALD mouse model and detected serum, liver oxidation levels, and alcohol metabolism-related gene expressions. Through 16S rRNA sequencing, analyzed gut microbiota, explored the relationship between gut microbiota and liver indicators. AT extract significantly decreased lipid levels, promoted ADH, ALDH, and increased the antioxidant activities. Meanwhile, AT extract significantly downregulated the expression of lipid oxidation and inflammatory factors, upregulated alcohol metabolism genes. In addition, 16S rRNA sequencing and analysis showed that AT extract effectively regulated the gut microbiota diversity of ALD mice, significantly improved the structural disturbance of intestinal microflora. AT extract regulated gut microbiota and had a strong correlation with serum, liver-related indexes, and gene expression levels. All these results showed that AT can alleviate alcohol induced liver injury by regulating oxidative stress, inflammatory response, alcohol metabolism, and gut microbiota disorder.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"765 ","pages":"Article 110314"},"PeriodicalIF":3.8,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997967","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}
Non-alcoholic steatohepatitis (NASH) is the progressive form of non-alcoholic fatty liver disease (NAFLD) which is the most common chronic liver disease worldwide. Hypoxia-inducible factor-1α (HIF1α) inhibitor is emerging as a promising therapeutic strategy for diseases. However, the role of HIF1α inhibitor in NASH is still unclear. A choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) -induced NASH mouse model was established to identify the impacts of HIF1α inhibitor KC7F2 on the development of NASH. We found that KC7F2 treatment substantially aggravated lipid accumulation, inflammation, and fibrosis in the liver of NASH mice presumably via increasing Tsukushi (TSKU) expression in the liver. Mechanistically, KC7F2 up-regulated expression of TSKU in hepatocyte in vitro, which led to increased hepatocellular lipid accumulation and was reversed when TSKU was knockdown in hepatocyte. Our findings indicated that HIF1α inhibitor promotes the development of NASH presumably via increasing TSKU expression in the liver, suggesting that HIF1α attenuates NASH, and that we should assess the potential liver toxicity when use HIF1α inhibitor or medicines that can decrease the expression of HIF1α to therapy other diseases.
{"title":"Hypoxia-inducible factor-1α inhibitor promotes non-alcoholic steatohepatitis development and increases hepatocellular lipid accumulation via TSKU upregulation","authors":"Renli Zeng , Yuxin Wang , Jielu Wen , Zhipeng Cen , Tengyao Wang , Meng Duan , Xiuyi Huang , Zhengde Zhao , Zhongyu Zhang , Chuan Yang , Sifan Chen","doi":"10.1016/j.abb.2025.110313","DOIUrl":"10.1016/j.abb.2025.110313","url":null,"abstract":"<div><div>Non-alcoholic steatohepatitis (NASH) is the progressive form of non-alcoholic fatty liver disease (NAFLD) which is the most common chronic liver disease worldwide. Hypoxia-inducible factor-1α (HIF1α) inhibitor is emerging as a promising therapeutic strategy for diseases. However, the role of HIF1α inhibitor in NASH is still unclear. A choline-deficient, <span>l</span>-amino acid-defined, high-fat diet (CDAHFD) -induced NASH mouse model was established to identify the impacts of HIF1α inhibitor KC7F2 on the development of NASH. We found that KC7F2 treatment substantially aggravated lipid accumulation, inflammation, and fibrosis in the liver of NASH mice presumably via increasing Tsukushi (TSKU) expression in the liver. Mechanistically, KC7F2 up-regulated expression of TSKU in hepatocyte <em>in vitro</em>, which led to increased hepatocellular lipid accumulation and was reversed when TSKU was knockdown in hepatocyte. Our findings indicated that HIF1α inhibitor promotes the development of NASH presumably via increasing TSKU expression in the liver, suggesting that HIF1α attenuates NASH, and that we should assess the potential liver toxicity when use HIF1α inhibitor or medicines that can decrease the expression of HIF1α to therapy other diseases.</div></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":"765 ","pages":"Article 110313"},"PeriodicalIF":3.8,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998851","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}
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