Pub Date : 2025-04-11DOI: 10.1016/j.bbagen.2025.130805
Rahul Sahoo , Sriya Pattnaik , Biswajit Mohanty , Showkat Ahmad Mir , Birendra Behera
Aryl Hydrocarbon Receptor (AHR) reported to be associated with major carcinogenic signalling cascades which cause cell proliferations, metastasis and invasion as well as immune imbalance. AHR Participates in cellular processes not only through genomic pathways to cause genomic alterations but also via nongenomic pathways to alter various cytoplasmic proteins. In addition, AHR senses a wide range of ligands that modulate its downstream mechanisms that are intricated in cancer induction and prevention. Thus, AHR functions as a two-sided sword where some AHR ligands contribute to enhance cancer whereas few are useful for cancer treatment. Therefore, AHR represent as a regulatory point in cancer progression and treatment. There is a need to reinvestigate the regulatory role of AHR in major intracellular pathways and to explore the potential of AHR ligand for the design of cancer therapeutics. This review emphasizes the interaction of AHR with pro-carcinogenic signalling pathways that modulate cancer induction and progression. Furthermore, it also discusses about the current discovery of AHR ligands for cancer initiation or inhibition. This information could be useful for development of therapeutic strategies for the management of cancer by targeting AHR.
{"title":"Aryl hydrocarbon receptor (AHR) signalling: A double-edged sword guiding both cancer progression and cancer therapy","authors":"Rahul Sahoo , Sriya Pattnaik , Biswajit Mohanty , Showkat Ahmad Mir , Birendra Behera","doi":"10.1016/j.bbagen.2025.130805","DOIUrl":"10.1016/j.bbagen.2025.130805","url":null,"abstract":"<div><div>Aryl Hydrocarbon Receptor (AHR) reported to be associated with major carcinogenic signalling cascades which cause cell proliferations, metastasis and invasion as well as immune imbalance. AHR Participates in cellular processes not only through genomic pathways to cause genomic alterations but also via nongenomic pathways to alter various cytoplasmic proteins. In addition, AHR senses a wide range of ligands that modulate its downstream mechanisms that are intricated in cancer induction and prevention. Thus, AHR functions as a two-sided sword where some AHR ligands contribute to enhance cancer whereas few are useful for cancer treatment. Therefore, AHR represent as a regulatory point in cancer progression and treatment. There is a need to reinvestigate the regulatory role of AHR in major intracellular pathways and to explore the potential of AHR ligand for the design of cancer therapeutics. This review emphasizes the interaction of AHR with pro-carcinogenic signalling pathways that modulate cancer induction and progression. Furthermore, it also discusses about the current discovery of AHR ligands for cancer initiation or inhibition. This information could be useful for development of therapeutic strategies for the management of cancer by targeting AHR.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 6","pages":"Article 130805"},"PeriodicalIF":2.8,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143830019","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}
Circadian rhythm (CR) is a self-sustaining biological oscillation that synchronizes physiological processes with the Earth's 24-h light-dark cycle. In plants, it regulates crucial physiological functions. Autophagy, a conserved degradation mechanism, maintains cellular homeostasis by recycling damaged organelles and proteins. Emerging evidence suggests an interplay between CRs and autophagy, optimizing plant survival and productivity.
Scope
This review explores the molecular mechanisms underlying CR and autophagy, highlighting their roles in growth and stress adaptation. It further examines how circadian clock components regulate autophagy-related genes (ATGs) in response to external cues.
Major conclusions
CR fine-tune autophagy by temporally regulating ATG gene expression. Key transcription factors, including TOC1 and LUX, modulate autophagic activity, ensuring energy conservation. Autophagy reciprocally influences circadian signaling, adjusting metabolic balance under stress.
General significance
Despite extensive research on circadian regulation, a comprehensive understanding of how core clock components orchestrate ATG gene expression remains lacking. Understanding the crosstalk between CR and autophagy provides insights into plant resilience and productivity, potentially informing crop improvement strategies that enhance stress tolerance and resource efficiency. This review aims to bridge this gap by summarizing recent insights and proposing future research directions.
{"title":"Harmonizing time with survival: Circadian rhythm and autophagy in plants","authors":"Laha Supriya , Deepika Dake , Mehanathan Muthamilarasan","doi":"10.1016/j.bbagen.2025.130807","DOIUrl":"10.1016/j.bbagen.2025.130807","url":null,"abstract":"<div><h3>Background</h3><div>Circadian rhythm (CR) is a self-sustaining biological oscillation that synchronizes physiological processes with the Earth's 24-h light-dark cycle. In plants, it regulates crucial physiological functions. Autophagy, a conserved degradation mechanism, maintains cellular homeostasis by recycling damaged organelles and proteins. Emerging evidence suggests an interplay between CRs and autophagy, optimizing plant survival and productivity.</div></div><div><h3>Scope</h3><div>This review explores the molecular mechanisms underlying CR and autophagy, highlighting their roles in growth and stress adaptation. It further examines how circadian clock components regulate autophagy-related genes (ATGs) in response to external cues.</div></div><div><h3>Major conclusions</h3><div>CR fine-tune autophagy by temporally regulating ATG gene expression. Key transcription factors, including TOC1 and LUX, modulate autophagic activity, ensuring energy conservation. Autophagy reciprocally influences circadian signaling, adjusting metabolic balance under stress.</div></div><div><h3>General significance</h3><div>Despite extensive research on circadian regulation, a comprehensive understanding of how core clock components orchestrate ATG gene expression remains lacking. Understanding the crosstalk between CR and autophagy provides insights into plant resilience and productivity, potentially informing crop improvement strategies that enhance stress tolerance and resource efficiency. This review aims to bridge this gap by summarizing recent insights and proposing future research directions.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 6","pages":"Article 130807"},"PeriodicalIF":2.8,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143829960","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 : 2025-04-03DOI: 10.1016/j.bbagen.2025.130803
Michela Bruschi, Sofia Masini, Federica Biancucci, Giovanni Piersanti, Barbara Canonico, Michele Menotta, Mauro Magnani, Alessandra Fraternale
The vascular endothelium is the first interface exposed to circulating compounds and oxidative as well as pro-inflammatory stimuli. Nowadays, cysteine pro-drugs are emerging as new and potential therapies in cardiovascular and inflammatory diseases due to their cytoprotective effects. In this study, the effects of redox modulation by a synthetic thiol compound, i.e., I-152, a precursor of N-acetylcysteine (NAC) and cysteamine (MEA), were evaluated after 6 h and 24 h treatment on human umbilical cord endothelial cell (HUVECs) energy metabolism. Following I-152 treatment, higher cysteine and glutathione (GSH) content were detected via HPLC, in concomitance with I-152 derivatives, i.e., NAC and MEA. Untargeted metabolomics confirmed GSH upregulation and NAC presence in addition to I-152 itself and other metabolites, such as dithiol compound (NACMEAA) and triacetylated I-152. Mass spectrometry revealed that I-152 boosted ATP production, specifically through the mitochondrial OXPHOS, as determined via Seahorse assay without inducing oxidative stress. Additionally, I-152 treatment of HUVECs before co-culture with LPS-stimulated macrophages provided GSH and cysteine sustainment and attenuated the transcription of adhesion molecules as well as iNOS expression. Identifying the impact of redox regulation in physiological conditions and the possible metabolic targets could aid the application of novel thiol-based therapeutics.
{"title":"Redox modulation via a synthetic thiol compound reshapes energy metabolism in endothelial cells and ameliorates angiogenic expression in a co-culture study with activated macrophages","authors":"Michela Bruschi, Sofia Masini, Federica Biancucci, Giovanni Piersanti, Barbara Canonico, Michele Menotta, Mauro Magnani, Alessandra Fraternale","doi":"10.1016/j.bbagen.2025.130803","DOIUrl":"10.1016/j.bbagen.2025.130803","url":null,"abstract":"<div><div>The vascular endothelium is the first interface exposed to circulating compounds and oxidative as well as pro-inflammatory <em>stimuli</em>. Nowadays, cysteine pro-drugs are emerging as new and potential therapies in cardiovascular and inflammatory diseases due to their cytoprotective effects. In this study, the effects of redox modulation by a synthetic thiol compound, i.e., I-152, a precursor of <em>N</em>-acetylcysteine (NAC) and cysteamine (MEA), were evaluated after 6 h and 24 h treatment on human umbilical cord endothelial cell (HUVECs) energy metabolism. Following I-152 treatment, higher cysteine and glutathione (GSH) content were detected via HPLC, in concomitance with I-152 derivatives, i.e., NAC and MEA. Untargeted metabolomics confirmed GSH upregulation and NAC presence in addition to I-152 itself and other metabolites, such as dithiol compound (NACMEAA) and triacetylated I-152. Mass spectrometry revealed that I-152 boosted ATP production, specifically through the mitochondrial OXPHOS, as determined via Seahorse assay without inducing oxidative stress. Additionally, I-152 treatment of HUVECs before co-culture with LPS-stimulated macrophages provided GSH and cysteine sustainment and attenuated the transcription of adhesion molecules as well as <em>iNOS</em> expression. Identifying the impact of redox regulation in physiological conditions and the possible metabolic targets could aid the application of novel thiol-based therapeutics.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 6","pages":"Article 130803"},"PeriodicalIF":2.8,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143786054","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 : 2025-04-03DOI: 10.1016/j.bbagen.2025.130804
Fuko Horie, Ryoko Ando, Koharu Sekimoto, Vo Thi Anh Nguyet, Shingo Izawa
Severe ethanol stress (10 % v/v) causes the denaturation and aggregation of certain mitochondrial proteins, such as aconitase (Aco1), forming the deposits of unfolded mitochondrial proteins (DUMPs) in the budding yeast Saccharomyces cerevisiae. Pre-exposing yeast cells to mild stress often induces adaptation to subsequent severe stress. However, whether pre-exposing yeast cells to mild ethanol stress mitigates mitochondrial protein aggregation remains unclear. Therefore, in this study, we examined the effects of pre-exposing yeast cells to mild ethanol stress on the yeast mitochondrial protein quality control (mtPQC) system under severe ethanol stress. Pretreatment with 6 % (v/v) ethanol significantly mitigated the formation of DUMPs and Aco1 aggregates under subsequent 10 % ethanol stress in wild-type cells but not in hsp78∆ and mdj1∆ cells. Pretreatment with 6 % ethanol increased the protein levels of mtPQC-related factors, Hsp78, Mdj1, and Hsp10; however, hsp78∆ cells showed significantly lower levels of Ssc1 (mtHsp70) and its co-chaperone Mdj1 than wild-type cells. Moreover, intracellular reactive oxygen species levels and the frequency of respiration-deficient mutants under 10 % ethanol stress were reduced after pretreatment with 6 % ethanol in wild-type cells but not in hsp78∆ cells. Overall, this study demonstrated that pre-exposing yeast cells to mild ethanol stress mitigated ethanol-induced mitochondrial damage by activating the mtPQC system, including HSP78 expression, providing novel insights into the effects of ethanol stress on mitochondria and the corresponding responses in yeast.
{"title":"Yeast Hsp78 plays an essential role in adapting to severe ethanol stress via mild ethanol stress pretreatment in mitochondrial protein quality control","authors":"Fuko Horie, Ryoko Ando, Koharu Sekimoto, Vo Thi Anh Nguyet, Shingo Izawa","doi":"10.1016/j.bbagen.2025.130804","DOIUrl":"10.1016/j.bbagen.2025.130804","url":null,"abstract":"<div><div>Severe ethanol stress (10 % v/v) causes the denaturation and aggregation of certain mitochondrial proteins, such as aconitase (Aco1), forming the deposits of unfolded mitochondrial proteins (DUMPs) in the budding yeast <em>Saccharomyces cerevisiae</em>. Pre-exposing yeast cells to mild stress often induces adaptation to subsequent severe stress. However, whether pre-exposing yeast cells to mild ethanol stress mitigates mitochondrial protein aggregation remains unclear. Therefore, in this study, we examined the effects of pre-exposing yeast cells to mild ethanol stress on the yeast mitochondrial protein quality control (mtPQC) system under severe ethanol stress. Pretreatment with 6 % (v/v) ethanol significantly mitigated the formation of DUMPs and Aco1 aggregates under subsequent 10 % ethanol stress in wild-type cells but not in <em>hsp78</em>∆ and <em>mdj1</em>∆ cells. Pretreatment with 6 % ethanol increased the protein levels of mtPQC-related factors, Hsp78, Mdj1, and Hsp10; however, <em>hsp78</em>∆ cells showed significantly lower levels of Ssc1 (mtHsp70) and its co-chaperone Mdj1 than wild-type cells. Moreover, intracellular reactive oxygen species levels and the frequency of respiration-deficient mutants under 10 % ethanol stress were reduced after pretreatment with 6 % ethanol in wild-type cells but not in <em>hsp78</em>∆ cells. Overall, this study demonstrated that pre-exposing yeast cells to mild ethanol stress mitigated ethanol-induced mitochondrial damage by activating the mtPQC system, including <em>HSP78</em> expression, providing novel insights into the effects of ethanol stress on mitochondria and the corresponding responses in yeast.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 6","pages":"Article 130804"},"PeriodicalIF":2.8,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787636","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 : 2025-04-01DOI: 10.1016/j.bbagen.2025.130802
Seung-Min Lee , Ju Yeon Kwak , Dongryeol Ryu , Yeo Jin Shin , Younglang Lee , Yong Ryoul Yang , Kwang-Pyo Lee , Jae Myoung Suh , Ki-Sun Kwon
High glucose induces an atypical lipid composition in skeletal muscle, leading to loss of muscle mass and strength. However, the mechanisms underlying this glucose toxicity are not fully understood. Analysis of genes associated with a phenotype using the BXD phenome resource revealed that increased Fabp3 expression in skeletal muscle correlated with hyperglycemia. FABP3 expression was also increased in hyperglycemic mouse models such as leptin-deficient ob/ob, Ins2Akita, and high-fat fed mice, as well as in aged mice. In cultured myotubes, high glucose elevated the mRNA and protein levels of FABP3, which contributes to decreased membrane fluidity, along with other mechanisms. FABP3 expression was dependent on the NAD+/NADH ratio and SIRT1 activity, suggesting a mechanism by which FABP3 is upregulated in hyperglycemic conditions. Our findings propose that FABP3 links hyperglycemia to atypical membrane physicochemical properties, which may weaken contractile and metabolic function, particularly in skeletal muscle.
{"title":"High glucose induces FABP3-mediated membrane rigidity via downregulation of SIRT1","authors":"Seung-Min Lee , Ju Yeon Kwak , Dongryeol Ryu , Yeo Jin Shin , Younglang Lee , Yong Ryoul Yang , Kwang-Pyo Lee , Jae Myoung Suh , Ki-Sun Kwon","doi":"10.1016/j.bbagen.2025.130802","DOIUrl":"10.1016/j.bbagen.2025.130802","url":null,"abstract":"<div><div>High glucose induces an atypical lipid composition in skeletal muscle, leading to loss of muscle mass and strength. However, the mechanisms underlying this glucose toxicity are not fully understood. Analysis of genes associated with a phenotype using the BXD phenome resource revealed that increased <em>Fabp3</em> expression in skeletal muscle correlated with hyperglycemia. FABP3 expression was also increased in hyperglycemic mouse models such as leptin-deficient <em>ob/ob</em>, <em>Ins2</em>Akita, and high-fat fed mice, as well as in aged mice. In cultured myotubes, high glucose elevated the mRNA and protein levels of FABP3, which contributes to decreased membrane fluidity, along with other mechanisms. FABP3 expression was dependent on the NAD<sup>+</sup>/NADH ratio and SIRT1 activity, suggesting a mechanism by which FABP3 is upregulated in hyperglycemic conditions. Our findings propose that FABP3 links hyperglycemia to atypical membrane physicochemical properties, which may weaken contractile and metabolic function, particularly in skeletal muscle.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 6","pages":"Article 130802"},"PeriodicalIF":2.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143759688","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}
Inflammasomes are complex protein assemblies responsible for regulating the development and release of proinflammatory cytokines like interleukin-1beta (IL-1β) and interleukin-18 (IL-18) against the intracellular triggers. Among these, the Nod-like receptor protein 3 (NLRP3) inflammasome stands out as the most extensively studied and well-characterized member, implicated in numerous pathological conditions. A systematic literature search was conducted on the PubMed such as PubMed, Scopus, Google Scholar database to identify peer-reviewed publications pertaining to the role of NLRP3 in oral cancer pathogenesis and its inhibitors for targeted therapy. Recent research highlights the emerging significance of the NLRP3 inflammasome in tumorigenesis, garnering attention as a potential target for anticancer therapies. This review delves into the involvement of NLRP3 in cancer development and progression, providing an in-depth overview of its activation (and inhibition) and its impact on oral cancer pathogenesis. The manuscript provides a detailed review of the natural and synthetic compounds inhibiting the NLRP3 signaling pathway, which might act as therapeutic lead molecules in oral cancer. This holds promise to overcome targeted and effective treatment options the development of novel drugs targeting the NLRP3 inflammasome-mediated mechanisms in oral cancer.
{"title":"Inhibitors of inflammasome (NLRP3) signaling pathway as promising therapeutic candidates for oral cancer","authors":"Shreya Agrawal , Shatakshi Narang , Yadvendra Shahi , Sayali Mukherjee","doi":"10.1016/j.bbagen.2025.130800","DOIUrl":"10.1016/j.bbagen.2025.130800","url":null,"abstract":"<div><div>Inflammasomes are complex protein assemblies responsible for regulating the development and release of proinflammatory cytokines like interleukin-1beta (IL-1β) and interleukin-18 (IL-18) against the intracellular triggers. Among these, the Nod-like receptor protein 3 (NLRP3) inflammasome stands out as the most extensively studied and well-characterized member, implicated in numerous pathological conditions. A systematic literature search was conducted on the PubMed such as PubMed, Scopus, Google Scholar database to identify peer-reviewed publications pertaining to the role of NLRP3 in oral cancer pathogenesis and its inhibitors for targeted therapy. Recent research highlights the emerging significance of the NLRP3 inflammasome in tumorigenesis, garnering attention as a potential target for anticancer therapies. This review delves into the involvement of NLRP3 in cancer development and progression, providing an in-depth overview of its activation (and inhibition) and its impact on oral cancer pathogenesis. The manuscript provides a detailed review of the natural and synthetic compounds inhibiting the NLRP3 signaling pathway, which might act as therapeutic lead molecules in oral cancer. This holds promise to overcome targeted and effective treatment options the development of novel drugs targeting the NLRP3 inflammasome-mediated mechanisms in oral cancer.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 6","pages":"Article 130800"},"PeriodicalIF":2.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143769156","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 : 2025-03-29DOI: 10.1016/j.bbagen.2025.130801
Zhiliang Xiao , Yuan Wang , Dehua Pan , Xin Liu , Jin Gan , Liang Huang , Yan Feng
Clear cell renal cell carcinoma (ccRCC) is the most prevalent type of renal malignancy, and the deubiquitinase USP3 has been implicated as a critical factor in tumor biology. However, the precise mechanisms by which USP3 contributes to ccRCC progression remain unclear. This study investigates the role of USP3 in ccRCC and elucidates its underlying molecular mechanisms. Data from TCGA and GTEx databases showed elevated USP3 expression in ccRCC tissues and cell lines compared to normal renal tissues. Further analysis using qPCR and Western blot confirmed this upregulation in ccRCC cell lines. Functional assays revealed that silencing USP3 significantly impaired cell proliferation, migration, and invasion, while promoting apoptosis. Additionally, co-immunoprecipitation assays demonstrated an interaction between USP3 and MYC, with subsequent ubiquitination assays showing that USP3 regulates MYC stability. USP3 depletion also led to alterations in glycolysis-related gene expression, which could be partially reversed by MYC overexpression. These findings suggest that USP3 modulates ccRCC progression by stabilizing MYC, highlighting its potential as a therapeutic target in ccRCC treatment.
{"title":"USP3 promotes clear cell renal cell carcinoma progression by stabilizing MYC and enhancing glycolysis","authors":"Zhiliang Xiao , Yuan Wang , Dehua Pan , Xin Liu , Jin Gan , Liang Huang , Yan Feng","doi":"10.1016/j.bbagen.2025.130801","DOIUrl":"10.1016/j.bbagen.2025.130801","url":null,"abstract":"<div><div>Clear cell renal cell carcinoma (ccRCC) is the most prevalent type of renal malignancy, and the deubiquitinase USP3 has been implicated as a critical factor in tumor biology. However, the precise mechanisms by which USP3 contributes to ccRCC progression remain unclear. This study investigates the role of USP3 in ccRCC and elucidates its underlying molecular mechanisms. Data from TCGA and GTEx databases showed elevated USP3 expression in ccRCC tissues and cell lines compared to normal renal tissues. Further analysis using qPCR and Western blot confirmed this upregulation in ccRCC cell lines. Functional assays revealed that silencing USP3 significantly impaired cell proliferation, migration, and invasion, while promoting apoptosis. Additionally, co-immunoprecipitation assays demonstrated an interaction between USP3 and MYC, with subsequent ubiquitination assays showing that USP3 regulates MYC stability. USP3 depletion also led to alterations in glycolysis-related gene expression, which could be partially reversed by MYC overexpression. These findings suggest that USP3 modulates ccRCC progression by stabilizing MYC, highlighting its potential as a therapeutic target in ccRCC treatment.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 6","pages":"Article 130801"},"PeriodicalIF":2.8,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747224","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 : 2025-03-27DOI: 10.1016/j.bbagen.2025.130797
Jaehong Park , Dong-Hyun Lee
Protein phosphatase 4 inhibitory protein (PP4IP) has recently emerged as a key player in cellular processes, particularly in DNA double-strand break repair and telomere maintenance, although research on its functions remains limited. To further investigate the cellular pathways involving PP4IP, we conducted transcriptomic analysis via RNA sequencing in PP4IP-knockout cells and observed an upregulation of p21 expression. This upregulation was linked to an increased population of p21-positive G1-phase cells in the absence of PP4IP. Prior studies have suggested that unresolved under-replicated DNA in mother cells, transmitted to daughter cells, can trigger a quiescent G1 phase characterized by p21 expression and the formation of p53-binding protein 1 (53BP1) nuclear bodies. Consistent with this, we found a higher proportion of 53BP1 nuclear bodies-positive G1 cells in PP4IP-knockout cells compared to controls. Additionally, PP4IP-deficient cells displayed an increased occurrence of anaphase bridges—indicative of incomplete DNA replication—without a corresponding increase in lagging chromosomes. Furthermore, PP4IP-knockout cells exhibited a heightened susceptibility to replication stress, as evidenced by an elevated frequency of replication stress-induced chromatid breaks and increased sensitivity to such stress. Collectively, these results suggest that PP4IP plays a critical role in safeguarding cells from replication stress and ensuring genomic stability.
{"title":"Loss of protein phosphatase 4 inhibitory protein leads to genomic instability and heightens vulnerability to replication stress","authors":"Jaehong Park , Dong-Hyun Lee","doi":"10.1016/j.bbagen.2025.130797","DOIUrl":"10.1016/j.bbagen.2025.130797","url":null,"abstract":"<div><div>Protein phosphatase 4 inhibitory protein (PP4IP) has recently emerged as a key player in cellular processes, particularly in DNA double-strand break repair and telomere maintenance, although research on its functions remains limited. To further investigate the cellular pathways involving PP4IP, we conducted transcriptomic analysis via RNA sequencing in PP4IP-knockout cells and observed an upregulation of p21 expression. This upregulation was linked to an increased population of p21-positive G1-phase cells in the absence of PP4IP. Prior studies have suggested that unresolved under-replicated DNA in mother cells, transmitted to daughter cells, can trigger a quiescent G1 phase characterized by p21 expression and the formation of p53-binding protein 1 (53BP1) nuclear bodies. Consistent with this, we found a higher proportion of 53BP1 nuclear bodies-positive G1 cells in PP4IP-knockout cells compared to controls. Additionally, PP4IP-deficient cells displayed an increased occurrence of anaphase bridges—indicative of incomplete DNA replication—without a corresponding increase in lagging chromosomes. Furthermore, PP4IP-knockout cells exhibited a heightened susceptibility to replication stress, as evidenced by an elevated frequency of replication stress-induced chromatid breaks and increased sensitivity to such stress. Collectively, these results suggest that PP4IP plays a critical role in safeguarding cells from replication stress and ensuring genomic stability.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 6","pages":"Article 130797"},"PeriodicalIF":2.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143739770","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 : 2025-03-27DOI: 10.1016/j.bbagen.2025.130799
Xiaozhou Yao , Junru Ji , Dandan Chen , Yike Zhu , Xingjun Cai
Myocardial dysfunction is one of the most severe sepsis syndromes. EZH2 participates in regulating the inflammatory response in tissues; however, its role in septic myocarditis remains unclear. In this study, various concentrations of lipopolysaccharide (LPS) were used to treat H9C2 cells in order to mimic sepsis. Cell pyroptosis was detected by flow cytometry, and further confirmed by the expression of biomarkers and levels of cytokines. Caspase-1 activity was evaluated by flow cytometry and immunofluorescence assays. Gene expression was detected by reverse transcription-PCR (RT-PCR) and western blotting. Chromatin Immunoprecipitation – Quantitative PCR was used to detect the levels of histone methylation in the Nrf2 promoter region. Our results showed that LPS activated cell pyroptosis, promoted EZH2 expression, and inhibited Nrf2 expression in H9C2 cells. Overexpression of EZH2 enhanced LPS-induced cell pyroptosis, as shown by increased Caspase-1 activity, increased expression of N-GSDMD and NLRP3 proteins, and higher levels of IL-1β, IL-18, and LDH. Moreover, overexpression of EZH2 inhibited Nrf2 transcription. In contrast, knockdown of EZH2 suppressed pyroptosis and promoted Nrf2 expression in LPS-treated H9C2 cells. Results of chromatin immunoprecipitation – quantitative PCR verified that EZH2 regulated Nrf2 transcription via H3K27me3 modification. Furthermore, overexpression of Nrf2 inhibited cell pyroptosis and knockdown of Nrf2 promoted cell pyroptosis. Knockdown of Nrf2 reversed the cardioprotective effect of EZH2 knockdown. Collectively, our results suggest that EZH2 promotes cell pyroptosis by enhancing H3K27me3 expression and inhibiting Nrf2 transcription in cardiomyocytes under inflammatory conditions.
{"title":"EZH2-induced histone methylation in the Nrf2 promoter region mediates pyroptosis in inflammatory cardiomyocyte injury","authors":"Xiaozhou Yao , Junru Ji , Dandan Chen , Yike Zhu , Xingjun Cai","doi":"10.1016/j.bbagen.2025.130799","DOIUrl":"10.1016/j.bbagen.2025.130799","url":null,"abstract":"<div><div>Myocardial dysfunction is one of the most severe sepsis syndromes. EZH2 participates in regulating the inflammatory response in tissues; however, its role in septic myocarditis remains unclear. In this study, various concentrations of lipopolysaccharide (LPS) were used to treat H9C2 cells in order to mimic sepsis. Cell pyroptosis was detected by flow cytometry, and further confirmed by the expression of biomarkers and levels of cytokines. Caspase-1 activity was evaluated by flow cytometry and immunofluorescence assays. Gene expression was detected by reverse transcription-PCR (RT-PCR) and western blotting. Chromatin Immunoprecipitation – Quantitative PCR was used to detect the levels of histone methylation in the Nrf2 promoter region. Our results showed that LPS activated cell pyroptosis, promoted EZH2 expression, and inhibited Nrf2 expression in H9C2 cells. Overexpression of EZH2 enhanced LPS-induced cell pyroptosis, as shown by increased Caspase-1 activity, increased expression of N-GSDMD and NLRP3 proteins, and higher levels of IL-1β, IL-18, and LDH. Moreover, overexpression of EZH2 inhibited <em>Nrf2</em> transcription. In contrast, knockdown of EZH2 suppressed pyroptosis and promoted Nrf2 expression in LPS-treated H9C2 cells. Results of chromatin immunoprecipitation – quantitative PCR verified that EZH2 regulated <em>Nrf2</em> transcription via H3K27me3 modification. Furthermore, overexpression of Nrf2 inhibited cell pyroptosis and knockdown of Nrf2 promoted cell pyroptosis. Knockdown of Nrf2 reversed the cardioprotective effect of EZH2 knockdown. Collectively, our results suggest that EZH2 promotes cell pyroptosis by enhancing H3K27me3 expression and inhibiting <em>Nrf2</em> transcription in cardiomyocytes under inflammatory conditions.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 6","pages":"Article 130799"},"PeriodicalIF":2.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742093","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 : 2025-03-26DOI: 10.1016/j.bbagen.2025.130798
Vijay Phanindra Srikanth Kompella , Maria Carmen Romano , Ian Stansfield , Ricardo L. Mancera
The mechanism by which aminoacyl-tRNAs are supplied to translating ribosomes for protein synthesis is likely to involve a process of diffusion within the cellular environment, which is inevitably impacted by macromolecular crowding. Osmotic stress leading to cell shrinkage increases the concentration of macromolecules in the cytoplasm, reducing protein diffusion. The impact of macromolecular crowding on the translation machinery in eukaryotes remains uncharacterised. In this study Brownian dynamics simulation were used for the first time to study the effect of macromolecular crowding on the microsecond-time scale diffusion properties of tRNAs and their ternary complexes within a model yeast cytoplasmic environment. Under normal cell-like conditions, the diffusion of tRNAs and ternary complexes was predicted to be reduced by up to 8-fold (compared with dilute conditions), whilst diffusion under severe osmotic stress conditions decreased by up to a remarkable 80-fold. All molecules exhibited sub-diffusive behaviour, which was stronger under osmotic stress. These findings may be readily used to predict protein translation dynamics, including the crucial process of tRNA delivery to the ribosome, under a variety of conditions.
{"title":"Diffusion properties of transfer RNAs in the yeast cytoplasm under normal and osmotic stress conditions","authors":"Vijay Phanindra Srikanth Kompella , Maria Carmen Romano , Ian Stansfield , Ricardo L. Mancera","doi":"10.1016/j.bbagen.2025.130798","DOIUrl":"10.1016/j.bbagen.2025.130798","url":null,"abstract":"<div><div>The mechanism by which aminoacyl-tRNAs are supplied to translating ribosomes for protein synthesis is likely to involve a process of diffusion within the cellular environment, which is inevitably impacted by macromolecular crowding. Osmotic stress leading to cell shrinkage increases the concentration of macromolecules in the cytoplasm, reducing protein diffusion. The impact of macromolecular crowding on the translation machinery in eukaryotes remains uncharacterised. In this study Brownian dynamics simulation were used for the first time to study the effect of macromolecular crowding on the microsecond-time scale diffusion properties of tRNAs and their ternary complexes within a model yeast cytoplasmic environment. Under normal cell-like conditions, the diffusion of tRNAs and ternary complexes was predicted to be reduced by up to 8-fold (compared with dilute conditions), whilst diffusion under severe osmotic stress conditions decreased by up to a remarkable 80-fold. All molecules exhibited sub-diffusive behaviour, which was stronger under osmotic stress. These findings may be readily used to predict protein translation dynamics, including the crucial process of tRNA delivery to the ribosome, under a variety of conditions.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 6","pages":"Article 130798"},"PeriodicalIF":2.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143734779","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}
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