Pub Date : 2026-02-01Epub Date: 2025-12-16DOI: 10.1016/j.bbagen.2025.130898
Krzysztof W. Fornalski
Cancer is a complex dissipative system operating far from equilibrium, characterized by increased entropy production compared to normal tissues. Traditional thermodynamic approaches often fail to capture its full dynamics. In this study, we apply non-equilibrium stochastic thermodynamics to analyze different stages of carcinogenesis: neoplastic transformation (using the Avrami–Dobrzyński approach), tumor growth (described by the Gompertz model), and metastasis, in relation to tumor entropy and self-organization. Our results reveal a relationship between entropy production and tumor expansion rate, indicating that cellular reproduction enhances entropy generation. We also examine the information entropy of hepatocellular carcinoma cells. Furthermore, we demonstrate that restricting external energy intake does not halt tumor progression, underscoring the resilience of cancer as an autonomous physical system. These findings highlight the thermodynamic nature of cancer and suggest that metastasis is an inevitable consequence of entropy-driven evolution.
{"title":"Non-equilibrium thermodynamics of cancer: Entropy dynamics and metastatic growth","authors":"Krzysztof W. Fornalski","doi":"10.1016/j.bbagen.2025.130898","DOIUrl":"10.1016/j.bbagen.2025.130898","url":null,"abstract":"<div><div>Cancer is a complex dissipative system operating far from equilibrium, characterized by increased entropy production compared to normal tissues. Traditional thermodynamic approaches often fail to capture its full dynamics. In this study, we apply non-equilibrium stochastic thermodynamics to analyze different stages of carcinogenesis: neoplastic transformation (using the Avrami–Dobrzyński approach), tumor growth (described by the Gompertz model), and metastasis, in relation to tumor entropy and self-organization. Our results reveal a relationship between entropy production and tumor expansion rate, indicating that cellular reproduction enhances entropy generation. We also examine the information entropy of <em>hepatocellular carcinoma</em> cells. Furthermore, we demonstrate that restricting external energy intake does not halt tumor progression, underscoring the resilience of cancer as an autonomous physical system. These findings highlight the thermodynamic nature of cancer and suggest that metastasis is an inevitable consequence of entropy-driven evolution.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1870 2","pages":"Article 130898"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145780065","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 : 2026-01-01Epub Date: 2025-11-01DOI: 10.1016/j.bbagen.2025.130878
Weichen Zhan , Xiaowei Ding , Zhongrui Cui , Yizhuo Wu , Yiwen Gu , Hanxiao Cheng , Xinxin Ge , Yun Wang , Jiangyun Luo , Bing Xiao
Despite significant advancements in liposome-mediated transfection technology over the past decades, achieving optimal transfection efficiency with lipoplex remains challenging in certain primary cells, such as vascular smooth muscle cells, endothelial cells, and suspension cells. Here, we present an innovative approach to significantly enhance Lipofectamine-based transient transfection efficiency in hard-to-transfect cells by applying elevated cyclic hydrostatic pressure (CHP). The plasmids encoding the enhanced green fluorescent protein (EGFP) were transfected using Lipofectamine 3000 reagent, and the transfection efficiency was evaluated by Western blot or flow cytometry. Our results demonstrate that CHP (0.0083 Hz, 0–100 mmHg) significantly enhanced the transfection efficiency of lipoplex in primary human aortic smooth muscle cells (HASMCs) and other difficult-to-transfect cell types. Mechanistic studies revealed that the enhancement of liposome-mediated transfection by CHP was dependent on the activation of clathrin-dependent endocytic pathways. Importantly, this mechanical stimulation did not affect the proliferative or migratory capacities of HASMCs, despite the identification of significantly modulated proteins (5.8 % of the total proteome) by proteomic analysis. This study establishes a novel, safe strategy to enhance lipoplex-mediated nucleic acid delivery in challenging-to-transfect cell types.
{"title":"Elevated cyclic hydrostatic pressure enhances the transfection activity of lipoplexes by activating clathrin-mediated endocytosis","authors":"Weichen Zhan , Xiaowei Ding , Zhongrui Cui , Yizhuo Wu , Yiwen Gu , Hanxiao Cheng , Xinxin Ge , Yun Wang , Jiangyun Luo , Bing Xiao","doi":"10.1016/j.bbagen.2025.130878","DOIUrl":"10.1016/j.bbagen.2025.130878","url":null,"abstract":"<div><div>Despite significant advancements in liposome-mediated transfection technology over the past decades, achieving optimal transfection efficiency with lipoplex remains challenging in certain primary cells, such as vascular smooth muscle cells, endothelial cells, and suspension cells. Here, we present an innovative approach to significantly enhance Lipofectamine-based transient transfection efficiency in hard-to-transfect cells by applying elevated cyclic hydrostatic pressure (CHP). The plasmids encoding the enhanced green fluorescent protein (EGFP) were transfected using Lipofectamine 3000 reagent, and the transfection efficiency was evaluated by Western blot or flow cytometry. Our results demonstrate that CHP (0.0083 Hz, 0–100 mmHg) significantly enhanced the transfection efficiency of lipoplex in primary human aortic smooth muscle cells (HASMCs) and other difficult-to-transfect cell types. Mechanistic studies revealed that the enhancement of liposome-mediated transfection by CHP was dependent on the activation of clathrin-dependent endocytic pathways. Importantly, this mechanical stimulation did not affect the proliferative or migratory capacities of HASMCs, despite the identification of significantly modulated proteins (5.8 % of the total proteome) by proteomic analysis. This study establishes a novel, safe strategy to enhance lipoplex-mediated nucleic acid delivery in challenging-to-transfect cell types.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1870 1","pages":"Article 130878"},"PeriodicalIF":2.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145437017","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 : 2026-01-01Epub Date: 2025-11-04DOI: 10.1016/j.bbagen.2025.130881
Yan-Yan Guo, Xia-Nan Chu, Pei-Hua Wang, Ya-Qian Li, Li Xing
DNA damage response (DDR) signaling not only maintains genomic integrity but also plays a role in the activation of immune cells, including macrophages. In response to the stimuli, macrophages can be polarized into a proinflammatory phenotype, M1. In the monocytoid THP-1 cell-derived macrophage model, sodium butyrate was found to inhibit the expression of M1 biomarkers TNF-α, IL-6, IL-1β, and CXCL10, and downregulate DDR-associated proteins, including the apical Ataxia-Telangiectasia mutated protein kinase (ATM). However, siRNA-mediated knockdown of ATM did not reduce the expression of M1 biomarkers, but still downregulated the expression of DDR-associated proteins such as RAD50, p53, CHK1, NBS1, and γH2AX. Moreover, ATM knockdown modulated the expression of innate immunity regulatory genes, including sialic acid binding immunoglobulin type lectins 14 (Siglec14), Siglec15, signaling lymphocyte activation molecule family 1 (Siamf1), Siamf7, and guanylate binding protein 2 in response to the infection of Mycobacterium tuberculosis H37Ra. The results suggest that ATM may serve as a regulator to couple the DDR and innate immune response of macrophages, but barely contributes to the sodium butyrate-mediated inhibition of certain M1 biomarkers.
{"title":"The role of ATM in sodium butyrate-mediated inhibition of macrophage polarization","authors":"Yan-Yan Guo, Xia-Nan Chu, Pei-Hua Wang, Ya-Qian Li, Li Xing","doi":"10.1016/j.bbagen.2025.130881","DOIUrl":"10.1016/j.bbagen.2025.130881","url":null,"abstract":"<div><div>DNA damage response (DDR) signaling not only maintains genomic integrity but also plays a role in the activation of immune cells, including macrophages. In response to the stimuli, macrophages can be polarized into a proinflammatory phenotype, M1. In the monocytoid THP-1 cell-derived macrophage model, sodium butyrate was found to inhibit the expression of M1 biomarkers TNF-α, IL-6, IL-1β, and CXCL10, and downregulate DDR-associated proteins, including the apical Ataxia-Telangiectasia mutated protein kinase (ATM). However, siRNA-mediated knockdown of ATM did not reduce the expression of M1 biomarkers, but still downregulated the expression of DDR-associated proteins such as RAD50, p53, CHK1, NBS1, and γH2AX. Moreover, ATM knockdown modulated the expression of innate immunity regulatory genes, including sialic acid binding immunoglobulin type lectins 14 (Siglec14), Siglec15, signaling lymphocyte activation molecule family 1 (Siamf1), Siamf7, and guanylate binding protein 2 in response to the infection of <em>Mycobacterium tuberculosis</em> H37Ra. The results suggest that ATM may serve as a regulator to couple the DDR and innate immune response of macrophages, but barely contributes to the sodium butyrate-mediated inhibition of certain M1 biomarkers.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1870 1","pages":"Article 130881"},"PeriodicalIF":2.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145457084","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 : 2026-01-01Epub Date: 2025-10-25DOI: 10.1016/j.bbagen.2025.130871
Zhiyong Peng , Xiaojuan Cao , Hejun Gao , Cuiling Li , Jinhan Zhang , Youtan Liu
Sepsis, a severe inflammatory response to infection, is characterized by complex and rapidly evolving pathophysiology with high mortality. Mitochondrial DNA (mtDNA) in exosomes is a key damage-associated molecular pattern implicated in sepsis; however, its exact role and mechanisms are unclear. This study investigates how exosome-derived mtDNA induces mitochondrial dysfunction via protein kinase C delta (PKCδ), leading to endothelial barrier disruption and the progression of sepsis. Our analysis revealed significantly elevated levels of the mtDNA markers ND2 and D-loop in serum exosomes from sepsis patients compared to healthy controls. These elevated exosomal mtDNA levels correlated with disease severity and showed a positive association with lung injury markers, including SRAGE, SP-D, and CC16. In vitro experiments demonstrated that both isolated mtDNA and exosomes significantly impaired mitochondrial membrane potential, increased reactive oxygen species (ROS) levels, and reduced the oxygen consumption rate (OCR), suggesting the induction of mitochondrial dysfunction. Moreover, mtDNA promoted endothelial cell damage and increased permeability via PKCδ. Crucially, PKCδ knockdown markedly restored mtDNA-induced mitochondrial dysfunction and cellular permeability damage. In conclusion, Exosome-derived mtDNA triggers mitochondrial dysfunction and endothelial barrier disruption via PKCδ, promoting sepsis progression, suggesting potential therapeutic targets.
{"title":"Exosome-derived mtDNA disrupts endothelial barrier integrity and accelerates sepsis progression by inducing mitochondrial dysfunction through the PKCδ gene","authors":"Zhiyong Peng , Xiaojuan Cao , Hejun Gao , Cuiling Li , Jinhan Zhang , Youtan Liu","doi":"10.1016/j.bbagen.2025.130871","DOIUrl":"10.1016/j.bbagen.2025.130871","url":null,"abstract":"<div><div>Sepsis, a severe inflammatory response to infection, is characterized by complex and rapidly evolving pathophysiology with high mortality. Mitochondrial DNA (mtDNA) in exosomes is a key damage-associated molecular pattern implicated in sepsis; however, its exact role and mechanisms are unclear. This study investigates how exosome-derived mtDNA induces mitochondrial dysfunction via protein kinase C delta (PKCδ), leading to endothelial barrier disruption and the progression of sepsis. Our analysis revealed significantly elevated levels of the mtDNA markers ND2 and D-loop in serum exosomes from sepsis patients compared to healthy controls. These elevated exosomal mtDNA levels correlated with disease severity and showed a positive association with lung injury markers, including SRAGE, SP-D, and CC16. In vitro experiments demonstrated that both isolated mtDNA and exosomes significantly impaired mitochondrial membrane potential, increased reactive oxygen species (ROS) levels, and reduced the oxygen consumption rate (OCR), suggesting the induction of mitochondrial dysfunction. Moreover, mtDNA promoted endothelial cell damage and increased permeability via PKCδ. Crucially, PKCδ knockdown markedly restored mtDNA-induced mitochondrial dysfunction and cellular permeability damage. In conclusion, Exosome-derived mtDNA triggers mitochondrial dysfunction and endothelial barrier disruption via PKCδ, promoting sepsis progression, suggesting potential therapeutic targets.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1870 1","pages":"Article 130871"},"PeriodicalIF":2.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145428824","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 : 2026-01-01Epub Date: 2025-11-12DOI: 10.1016/j.bbagen.2025.130886
Yulia V. Bertsova, Marina V. Serebryakova, Alexander A. Baykov, Alexander V. Bogachev
Bacteria coping with oxygen deficiency can switch to alternative terminal electron acceptors, which can be normal metabolic intermediates or products of dedicated coupled reactions. In the latter case, the genes for the respective terminal reductase and coupling enzyme are expected to cluster in the genome. Here, we determined the roles of two uncharacterized periplasmic proteins encoded by the swoo_3912–swoo_3913 gene cluster in the facultatively anaerobic marine bacterium Shewanella woodyi. We confirmed the current database annotation of the former protein as “urocanate reductase” but identified the latter protein as a histidine betaine trimethylammonia-lyase (HBTL). HBTL converts histidine betaine into urocanate and trimethylamine and is remarkably specific for histidine betaine as substrate. HBTL requires Mg2+ for activity and undergoes slow reversible inactivation at low Mg2+ concentrations. HBTL activity was not evident in S. woodyi cells grown aerobically but was induced in cells grown anaerobically. Both histidine betaine and urocanate supported anaerobic S. woodyi growth and, hence, respiration. Similar gene clusters are found in many anaerobic bacteria, suggesting a wide occurrence of the anaerobic respiration pathway discovered in this work in the bacterial world.
{"title":"Histidine betaine trimethylammonia-lyase, enzyme coupled with terminal urocanate reductase in Shewanella woodyi grown anaerobically","authors":"Yulia V. Bertsova, Marina V. Serebryakova, Alexander A. Baykov, Alexander V. Bogachev","doi":"10.1016/j.bbagen.2025.130886","DOIUrl":"10.1016/j.bbagen.2025.130886","url":null,"abstract":"<div><div>Bacteria coping with oxygen deficiency can switch to alternative terminal electron acceptors, which can be normal metabolic intermediates or products of dedicated coupled reactions. In the latter case, the genes for the respective terminal reductase and coupling enzyme are expected to cluster in the genome. Here, we determined the roles of two uncharacterized periplasmic proteins encoded by the <em>swoo_3912</em>–<em>swoo_3913</em> gene cluster in the facultatively anaerobic marine bacterium <em>Shewanella woodyi</em>. We confirmed the current database annotation of the former protein as “urocanate reductase” but identified the latter protein as a histidine betaine trimethylammonia-lyase (HBTL). HBTL converts histidine betaine into urocanate and trimethylamine and is remarkably specific for histidine betaine as substrate. HBTL requires Mg<sup>2+</sup> for activity and undergoes slow reversible inactivation at low Mg<sup>2+</sup> concentrations. HBTL activity was not evident in <em>S. woodyi</em> cells grown aerobically but was induced in cells grown anaerobically. Both histidine betaine and urocanate supported anaerobic <em>S. woodyi</em> growth and, hence, respiration. Similar gene clusters are found in many anaerobic bacteria, suggesting a wide occurrence of the anaerobic respiration pathway discovered in this work in the bacterial world.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1870 1","pages":"Article 130886"},"PeriodicalIF":2.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145522421","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}
In this study we expressed, purified and demonstrated the protein liquid-liquid phase separation (LLPS) formation by the receptor binding domain (RBD) of coronavirus spike protein in vitro.
Our molecular dynamics simulations revealed multiple structurally disordered regions lacking secondary structural elements within RBD that exhibited high structural flexibility with deviations as high as 6 Å over 500 ns in support of our in vitro findings.
Additionally these disordered regions overlap with epitopes potentially altering their architecture.
Based on these results we conclude that the structural disorderedness of RBD causes LLPS formation in vitro and may potentially challenge the COVID-19 vaccine efficacy.
{"title":"Receptor binding domain of SARS CoV2 spike protein exhibits in vitro liquid-liquid phase separation due to structural disorderedness that may challenge the vaccine-generated antibody binding","authors":"Manikanta Sodasani , Abhinav V.K.S. Grandhi , Niharikha Mukala , Jahnavi Chintalapati , Madhuri Vissapragada , Madhumita Aggunna , Ravikiran S. Yedidi","doi":"10.1016/j.bbagen.2025.130889","DOIUrl":"10.1016/j.bbagen.2025.130889","url":null,"abstract":"<div><div>In this study we expressed, purified and demonstrated the protein liquid-liquid phase separation (LLPS) formation by the receptor binding domain (RBD) of coronavirus spike protein <em>in vitro</em>.</div><div>Our molecular dynamics simulations revealed multiple structurally disordered regions lacking secondary structural elements within RBD that exhibited high structural flexibility with deviations as high as 6 Å over 500 ns in support of our <em>in vitro</em> findings.</div><div>Additionally these disordered regions overlap with epitopes potentially altering their architecture.</div><div>Based on these results we conclude that the structural disorderedness of RBD causes LLPS formation <em>in vitro</em> and may potentially challenge the COVID-19 vaccine efficacy.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1870 1","pages":"Article 130889"},"PeriodicalIF":2.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145572886","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 : 2026-01-01Epub Date: 2025-11-08DOI: 10.1016/j.bbagen.2025.130880
Patricia Andrea Garavaglia , Sebastián Aduviri , Pablo Trujillo , Laura Mónica Tasso , Joaquín Juan Bautista Cannata , Monica Pickholz , Gabriela Andrea García
Chagas disease, caused by the protozoan Trypanosoma cruzi, has become a global health concern due to increased globalization. Several studies suggest that the aldo-keto reductase from T. cruzi (TcAKR) is involved in resistance to benznidazole, the drug commonly used to treat this infection.
To further support the role of TcAKR in drug resistance, we evaluated its interaction with four compounds —quercetin, flufenamic acid, phenolphthalein, and menadione—previously reported as inhibitors of other AKRs. Molecular docking was performed to assess affinity and molecular specific interactions, and the inhibitory effects of these compounds on both TcAKR activities —aldo-keto reductase and quinone-oxidoreductase— were experimentally determined.
Binding affinities, in decreasing order, were: quercetin > flufenamic acid > phenolphthalein > menadione. Both quercetin and flufenamic acid interacted with amino acid residues located outside the enzyme's active site. Quercetin completely inhibited both TcAKR activities, while flufenamic acid inhibited approximately 50 %. Phenolphthalein and menadione showed low levels of inhibition. The inhibition profiles of quercetin and flufenamic acid were consistent with a noncompetitive mechanism.
The effect of quercetin on benznidazole resistance was evaluated in transfected parasites overexpressing TcAKR, which are 1.8-fold more resistant to this drug. Quercetin treatment restored benznidazole sensitivity in these parasites, reducing the IC₅₀ to levels comparable to those of control parasites. These results provide further evidence of TcAKR's involvement in benznidazole resistance and suggest that its inhibition can enhance treatment efficacy.
{"title":"Pharmacological inhibition of Trypanosoma cruzi aldo-keto reductase (TcAKR) and its effect on benznidazole resistance","authors":"Patricia Andrea Garavaglia , Sebastián Aduviri , Pablo Trujillo , Laura Mónica Tasso , Joaquín Juan Bautista Cannata , Monica Pickholz , Gabriela Andrea García","doi":"10.1016/j.bbagen.2025.130880","DOIUrl":"10.1016/j.bbagen.2025.130880","url":null,"abstract":"<div><div>Chagas disease, caused by the protozoan <em>Trypanosoma cruzi</em>, has become a global health concern due to increased globalization. Several studies suggest that the aldo-keto reductase from <em>T. cruzi</em> (<em>T</em>cAKR) is involved in resistance to benznidazole, the drug commonly used to treat this infection.</div><div>To further support the role of <em>Tc</em>AKR in drug resistance, we evaluated its interaction with four compounds —quercetin, flufenamic acid, phenolphthalein, and menadione—previously reported as inhibitors of other AKRs. Molecular docking was performed to assess affinity and molecular specific interactions, and the inhibitory effects of these compounds on both <em>Tc</em>AKR activities —aldo-keto reductase and quinone-oxidoreductase— were experimentally determined.</div><div>Binding affinities, in decreasing order, were: quercetin > flufenamic acid > phenolphthalein > menadione. Both quercetin and flufenamic acid interacted with amino acid residues located outside the enzyme's active site. Quercetin completely inhibited both <em>Tc</em>AKR activities, while flufenamic acid inhibited approximately 50 %. Phenolphthalein and menadione showed low levels of inhibition. The inhibition profiles of quercetin and flufenamic acid were consistent with a noncompetitive mechanism.</div><div>The effect of quercetin on benznidazole resistance was evaluated in transfected parasites overexpressing <em>Tc</em>AKR, which are 1.8-fold more resistant to this drug. Quercetin treatment restored benznidazole sensitivity in these parasites, reducing the IC₅₀ to levels comparable to those of control parasites. These results provide further evidence of <em>Tc</em>AKR's involvement in benznidazole resistance and suggest that its inhibition can enhance treatment efficacy.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1870 1","pages":"Article 130880"},"PeriodicalIF":2.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145464715","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 : 2026-01-01Epub Date: 2025-11-11DOI: 10.1016/j.bbagen.2025.130885
Neha Attal , Trenton A. Pritt , Melissa Stair , Tony E. Reeves , Iain H. McKillop
Background
Early alcohol-dependent liver disease (ALD) is characterized by increased hepatic fat storage (hepatosteatosis). Fatty acid binding protein 4 (FABP4), a protein not normally expressed in liver, becomes highly expressed in ALD. This study developed a hepatocyte-specific FABP4 mouse knockout (HS-Fabp4−/−) to study liver responses to alcohol.
Methods
An HS-Fabp4−/− mouse was created using a Cre/loxP embryonic stem cell approach. Male and female HS-Fabp4−/− and wildtype (WT; C57Bl/6) mice were maintained on ethanol-drinking water (EtOH-DW) for 4-weeks. Liver damage, triglyceride content and pathology were assessed. Hepatic FABP1–9 mRNA and FABP4 and FABP5 protein were measured. Human hepatoma cell proliferation in response to exogenous FABP4 or FABP5 was analyzed.
Results
Hepatocyte-specific FABP4 deletion was confirmed in HS-Fabp4−/− mice. No gross phenotypic differences were observed between HS-Fabp4−/− and WT. Maintenance on EtOH-DW resulted in microsteatosis, increased hepatic triglycerides, and elevated aspartate and alanine transaminases, with no differences detected between pair-matched HS-Fabp4−/− and WT mice. Hepatic FABP1–9 mRNA analysis revealed increased FABP4 and FABP5 mRNA expression in WT mice, and elevated FABP5 mRNA in HS-Fabp4−/− mice in response to EtOH-DW, effects that were mirrored in serum FABP4/5 protein. Exposure of hepatoma cells to FABP4 or FABP5 revealed FABP4, but not FABP5, stimulated cell proliferation.
Conclusions
Hepatocyte-specific FABP4 deletion does not alter hepatic fat accumulation in response to EtOH feeding. Hepatic FABP4 protein produced in response to EtOH is released from hepatocytes and exogenous FABP4 promotes hepatoma cell proliferation in vitro, an effect not observed for FABP5.
{"title":"Hepatic response to ethanol feeding in a hepatocyte-specific fatty acid binding protein-4 knock out mouse model","authors":"Neha Attal , Trenton A. Pritt , Melissa Stair , Tony E. Reeves , Iain H. McKillop","doi":"10.1016/j.bbagen.2025.130885","DOIUrl":"10.1016/j.bbagen.2025.130885","url":null,"abstract":"<div><h3>Background</h3><div>Early alcohol-dependent liver disease (ALD) is characterized by increased hepatic fat storage (hepatosteatosis). Fatty acid binding protein 4 (FABP4), a protein not normally expressed in liver, becomes highly expressed in ALD. This study developed a hepatocyte-specific FABP4 mouse knockout (HS-<em>Fabp4</em><sup>−/−</sup>) to study liver responses to alcohol.</div></div><div><h3>Methods</h3><div>An HS-<em>Fabp4</em><sup>−/−</sup> mouse was created using a Cre/loxP embryonic stem cell approach. Male and female HS-<em>Fabp4</em><sup>−/−</sup> and wildtype (WT; C57Bl/6) mice were maintained on ethanol-drinking water (EtOH-DW) for 4-weeks. Liver damage, triglyceride content and pathology were assessed. Hepatic FABP1–9 mRNA and FABP4 and FABP5 protein were measured. Human hepatoma cell proliferation in response to exogenous FABP4 or FABP5 was analyzed.</div></div><div><h3>Results</h3><div>Hepatocyte-specific FABP4 deletion was confirmed in HS-<em>Fabp4</em><sup>−/−</sup> mice. No gross phenotypic differences were observed between HS-<em>Fabp4</em><sup>−/−</sup> and WT. Maintenance on EtOH-DW resulted in microsteatosis, increased hepatic triglycerides, and elevated aspartate and alanine transaminases, with no differences detected between pair-matched HS-<em>Fabp4</em><sup>−/−</sup> and WT mice. Hepatic FABP1–9 mRNA analysis revealed increased FABP4 and FABP5 mRNA expression in WT mice, and elevated FABP5 mRNA in HS-<em>Fabp4</em><sup>−/−</sup> mice in response to EtOH-DW, effects that were mirrored in serum FABP4/5 protein. Exposure of hepatoma cells to FABP4 or FABP5 revealed FABP4, but not FABP5, stimulated cell proliferation.</div></div><div><h3>Conclusions</h3><div>Hepatocyte-specific FABP4 deletion does not alter hepatic fat accumulation in response to EtOH feeding. Hepatic FABP4 protein produced in response to EtOH is released from hepatocytes and exogenous FABP4 promotes hepatoma cell proliferation <em>in vitro</em>, an effect not observed for FABP5.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1870 1","pages":"Article 130885"},"PeriodicalIF":2.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145511575","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}
Chromatin structure and its plasticity are central to gene regulation and DNA-associated processes, yet their nanoscale architecture and dynamic assembly remain elusive. Here, we propose a novel in situ approach—combining hypotonic treatment with high-drop spreading—to obtain native, naked chromosomes and visualize chromatin fine structure using atomic force microscopy (AFM). This strategy enables minimally invasive observation of chromatin under near-physiological conditions. We reveal that chromatin is composed of ∼10 nm DNA–histone particles as its fundamental units. Strikingly, these particles exhibit remarkable structural plasticity, dynamically assembling into heterogeneous nucleosome-beaded chains through stacking and partial melting. This challenges the classical “beads-on-a-string” model by demonstrating that chromatin is neither uniform nor static, but structurally versatile at the nanoscale. In addition, we investigated how histone acetylation and ATP modulate chromatin plasticity. Our findings highlight the coexistence of core particle stability and spatial-temporal variability, providing a revised molecular framework for chromatin's functional adaptability. These insights offer a fresh perspective on how chromatin structural diversity underpins its complex regulatory capacity.
{"title":"Decoding chromatin nanoscale plasticity in situ: Insights from native AFM imaging","authors":"Hongfeng Cui, Yu Zhang, Tianyu Chen, Mengzhu Guo, Qi Wen, Jiawei Peng, Yifei Yang, Xian Hao","doi":"10.1016/j.bbagen.2025.130887","DOIUrl":"10.1016/j.bbagen.2025.130887","url":null,"abstract":"<div><div>Chromatin structure and its plasticity are central to gene regulation and DNA-associated processes, yet their nanoscale architecture and dynamic assembly remain elusive. Here, we propose a novel <em>in situ</em> approach—combining hypotonic treatment with high-drop spreading—to obtain native, naked chromosomes and visualize chromatin fine structure using atomic force microscopy (AFM). This strategy enables minimally invasive observation of chromatin under near-physiological conditions. We reveal that chromatin is composed of ∼10 nm DNA–histone particles as its fundamental units. Strikingly, these particles exhibit remarkable structural plasticity, dynamically assembling into heterogeneous nucleosome-beaded chains through stacking and partial melting. This challenges the classical “beads-on-a-string” model by demonstrating that chromatin is neither uniform nor static, but structurally versatile at the nanoscale. In addition, we investigated how histone acetylation and ATP modulate chromatin plasticity. Our findings highlight the coexistence of core particle stability and spatial-temporal variability, providing a revised molecular framework for chromatin's functional adaptability. These insights offer a fresh perspective on how chromatin structural diversity underpins its complex regulatory capacity.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1870 1","pages":"Article 130887"},"PeriodicalIF":2.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145562483","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 : 2026-01-01Epub Date: 2025-10-29DOI: 10.1016/j.bbagen.2025.130874
Marcela Andrade-Soares , Mayra Alves , Clara Rodrigues-Ferreira , Jarlene A. Lopes , Thuany Crisóstomo , Gloria Costa-Sarmento , Christina M. Takiya , Amaury Pereira-Acácio , Adalberto Vieyra
Acute kidney injury (AKI) induced by ischemia-reperfusion (I/R) remains a significant clinical challenge due to its rapid progression, limited therapeutic options, and high morbidity. Mitochondrial dysfunction is a critical component of AKI pathogenesis, contributing to oxidative stress, impaired bioenergetics, and tissue injury. Extracellular vesicles (EV) derived from mesenchymal stem cells (MSC) have emerged as potential candidates for organ protection through the modulation of inflammatory and oxidative pathways. This study evaluated the effects of EV secreted by hypoxia-preconditioned adipose-derived MSC on mitochondrial function in a rat model of I/R-induced AKI. Wistar rats were assigned to four groups: SHAM, I/R, SHAM + EV, and I/R + EV. Hypoxia-preconditioned EV (2 × 109) or vehicle were administered subcapsularly 1 h prior to bilateral renal artery clamping (45 min ischemia, 1 h reperfusion). Histological analyses demonstrated that EV treatment effectively prevented tubular injury, inflammatory infiltration, and preserved renal architecture. EV enhanced Nrf2 nuclear translocation, upregulated HO-1 expression, and stabilized antioxidant defenses. Furthermore, EV preserved mitochondrial membrane potential, respiratory control ratio, ATP synthesis, and the abundance of electron transport chain complexes I, III, and IV, although complex II remained vulnerable. Proton leak responses were unaffected. These results demonstrate that hypoxia-preconditioned MSC-derived EV exert rapid protective effects on renal mitochondria and redox homeostasis during early reperfusion, offering a promising therapeutic strategy for AKI prevention in clinical scenarios such as transplantation and major cardiovascular surgeries. Further studies are needed to characterize the cargo of EV and their long-term outcomes.
{"title":"Extracellular vesicles from hypoxia-preconditioned mesenchymal stem cells preserve mitochondrial functions and redox homeostasis in ischemia–reperfusion-induced acute kidney injury","authors":"Marcela Andrade-Soares , Mayra Alves , Clara Rodrigues-Ferreira , Jarlene A. Lopes , Thuany Crisóstomo , Gloria Costa-Sarmento , Christina M. Takiya , Amaury Pereira-Acácio , Adalberto Vieyra","doi":"10.1016/j.bbagen.2025.130874","DOIUrl":"10.1016/j.bbagen.2025.130874","url":null,"abstract":"<div><div>Acute kidney injury (AKI) induced by ischemia-reperfusion (I/R) remains a significant clinical challenge due to its rapid progression, limited therapeutic options, and high morbidity. Mitochondrial dysfunction is a critical component of AKI pathogenesis, contributing to oxidative stress, impaired bioenergetics, and tissue injury. Extracellular vesicles (EV) derived from mesenchymal stem cells (MSC) have emerged as potential candidates for organ protection through the modulation of inflammatory and oxidative pathways. This study evaluated the effects of EV secreted by hypoxia-preconditioned adipose-derived MSC on mitochondrial function in a rat model of I/R-induced AKI. Wistar rats were assigned to four groups: SHAM, I/R, SHAM + EV, and I/R + EV. Hypoxia-preconditioned EV (2 × 10<sup>9</sup>) or vehicle were administered subcapsularly 1 h prior to bilateral renal artery clamping (45 min ischemia, 1 h reperfusion). Histological analyses demonstrated that EV treatment effectively prevented tubular injury, inflammatory infiltration, and preserved renal architecture. EV enhanced Nrf2 nuclear translocation, upregulated HO-1 expression, and stabilized antioxidant defenses. Furthermore, EV preserved mitochondrial membrane potential, respiratory control ratio, ATP synthesis, and the abundance of electron transport chain complexes I, III, and IV, although complex II remained vulnerable. Proton leak responses were unaffected. These results demonstrate that hypoxia-preconditioned MSC-derived EV exert rapid protective effects on renal mitochondria and redox homeostasis during early reperfusion, offering a promising therapeutic strategy for AKI prevention in clinical scenarios such as transplantation and major cardiovascular surgeries. Further studies are needed to characterize the cargo of EV and their long-term outcomes.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1870 1","pages":"Article 130874"},"PeriodicalIF":2.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145420862","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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