Pub Date : 2025-12-01Epub Date: 2025-09-29DOI: 10.1016/j.bbagen.2025.130863
Yaoyao Chen , Fanxiang Yin , Xiaoqian Wang , Huilin Zhang , Ping Tang , Mengjiao Xue , Nannan Sun , Jin Li , Chang Chen , Bingjie Wang , Qingxuan Xin , Juanxia Zhou , Yingmei Li , Shuya Wang , Shaohua Yan , Jiani Li , Yunling Zhu , Bo Qin , Baohong Yue , Yong Jiang , Rongqun Guo
Myelofibrosis (MF), a myeloproliferative neoplasm, remains incurable for most patients. Although some individuals are eligible for allogeneic hematopoietic stem cell transplantation, current therapies generally slow disease progression rather than achieve a cure. In this study, we found that type I interferon (IFN) treatment enhances midkine (MDK) expression, and MDK is involved in the differentiation and maturation of progenitor cells. Notably, MDK treatment drives tumor cells into the cell cycle, thereby increasing the therapeutic effect of busulfan. Furthermore, MDK promotes osteogenic differentiation of mesenchymal stem cells (MSC), contributing to the remodeling of the bone marrow microenvironment. In addition, type I IFN upregulates TNFSF10, leading to tumor cell death through mutual killing.
{"title":"Midkine and TNFSF10 as downstream molecules of type I interferon are involved in the treatment of myelofibrosis","authors":"Yaoyao Chen , Fanxiang Yin , Xiaoqian Wang , Huilin Zhang , Ping Tang , Mengjiao Xue , Nannan Sun , Jin Li , Chang Chen , Bingjie Wang , Qingxuan Xin , Juanxia Zhou , Yingmei Li , Shuya Wang , Shaohua Yan , Jiani Li , Yunling Zhu , Bo Qin , Baohong Yue , Yong Jiang , Rongqun Guo","doi":"10.1016/j.bbagen.2025.130863","DOIUrl":"10.1016/j.bbagen.2025.130863","url":null,"abstract":"<div><div>Myelofibrosis (MF), a myeloproliferative neoplasm, remains incurable for most patients. Although some individuals are eligible for allogeneic hematopoietic stem cell transplantation, current therapies generally slow disease progression rather than achieve a cure. In this study, we found that type I interferon (IFN) treatment enhances midkine (MDK) expression, and MDK is involved in the differentiation and maturation of progenitor cells. Notably, MDK treatment drives tumor cells into the cell cycle, thereby increasing the therapeutic effect of busulfan. Furthermore, MDK promotes osteogenic differentiation of mesenchymal stem cells (MSC), contributing to the remodeling of the bone marrow microenvironment. In addition, type I IFN upregulates TNFSF10, leading to tumor cell death through mutual killing.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 12","pages":"Article 130863"},"PeriodicalIF":2.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205518","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 : 2025-12-01Epub Date: 2025-09-11DOI: 10.1016/j.bbagen.2025.130855
Yan Hu , Shujun Xia , Yanhua Yang , Weiwei Zhan
The preoperative assessment of lymph node metastasis (LNM) is of critical importance for the selection of appropriate surgical and therapeutic strategies for papillary thyroid carcinoma (PTC). However, the mechanisms underlying LNM in PTC remain unclear, and effective diagnostic tools are currently lacking. This study aims to identify circRNAs as diagnostic molecular markers for LNM and to investigate their molecular mechanisms in the occurrence of LNM in PTC. In this study, bioinformatics analysis and qPCR verification were used and identified that circ-ATF7IP was the key molecule in PTC progression and overexpressed in PTC patients with LNM. Mechanistically, circ-ATF7IP acts as a molecular sponge for miR-488-3p in PTC cells. PTC cell-derived miR-488-3p acts on macrophage (Mɸ) through exosome transfer. In Mɸ, miR-488-3p negatively regulates IL13RA1 at post transcription stage, facilitating M2 phenotype polarization. This reshapes the tumor microenvironment, enhancing tumor invasiveness. To be brief, circ-ATF7IP is a newly identified biomarker for PTC related LNM. Targeting circ-ATF7IP/miR-488-3p/IL13RA1 axis is a promising therapeutic strategy for PTC.
{"title":"Circ-ATF7IP promotes IL13RA1 dependent M2 polarization of macrophage via sponging MiR-488-3p in papillary thyroid carcinoma","authors":"Yan Hu , Shujun Xia , Yanhua Yang , Weiwei Zhan","doi":"10.1016/j.bbagen.2025.130855","DOIUrl":"10.1016/j.bbagen.2025.130855","url":null,"abstract":"<div><div>The preoperative assessment of lymph node metastasis (LNM) is of critical importance for the selection of appropriate surgical and therapeutic strategies for papillary thyroid carcinoma (PTC). However, the mechanisms underlying LNM in PTC remain unclear, and effective diagnostic tools are currently lacking. This study aims to identify circRNAs as diagnostic molecular markers for LNM and to investigate their molecular mechanisms in the occurrence of LNM in PTC. In this study, bioinformatics analysis and qPCR verification were used and identified that circ-ATF7IP was the key molecule in PTC progression and overexpressed in PTC patients with LNM. Mechanistically, circ-ATF7IP acts as a molecular sponge for miR-488-3p in PTC cells. PTC cell-derived miR-488-3p acts on macrophage (Mɸ) through exosome transfer. In Mɸ, miR-488-3p negatively regulates IL13RA1 at post transcription stage, facilitating M2 phenotype polarization. This reshapes the tumor microenvironment, enhancing tumor invasiveness. To be brief, circ-ATF7IP is a newly identified biomarker for PTC related LNM. Targeting circ-ATF7IP/miR-488-3p/IL13RA1 axis is a promising therapeutic strategy for PTC.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 12","pages":"Article 130855"},"PeriodicalIF":2.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145057444","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 : 2025-12-01Epub Date: 2025-10-10DOI: 10.1016/j.bbagen.2025.130866
Jessica D. Carder , Barbara Barile , Alessia Memeo , Eric P. Jacobo , Grazia Paola Nicchia , James A. Brozik
Human aquaporin-4 (AQP4) is a water-channel protein crucial for water-ion homeostasis in the central nervous system. Dysregulation of AQP4 function is linked to neurological conditions like brain edema, neuromyelitis optica, and epilepsy. AQP4 has two isoforms, M1 and M23. The M23 isoform forms large structures known as Orthogonal Arrays of Particles (OAPs), while M1 coats the outer surface of OAPs. The dynamics of OAP aggregation may modulate water permeability and ion homeostasis in the brain. This study shows that the palmitoylation state of M1 influences OAP self-assembly, with depalmitoylated M1 producing OAPs 20 % larger than those formed by palmitoylated M1 at the same concentration. This, along with prior research on M1 aggregation, suggests palmitoylated M1 forms a single outer layer arounf OPAs, whereas depalmitoylated M1 creates a double layer. Single-particle tracking was used to study M23 OAP formation in lipid bilayers under equilibrium conditions. Our data support the idea that M1 regulates M23 OAP size, showing that average OAP size decreases as M1 concentration increases. This study explores the inhibitory effects of M1 on AQP4 M23 assembly and how M1's palmitoylation state affects OAP size regulation. These insights could lead to new therapeutic approaches for managing AQP4 assembly and function in related conditions.
{"title":"Size of aquaporin-4 orthogonal arrays of particles are affected by the palmitoylation state of the M1 isoform","authors":"Jessica D. Carder , Barbara Barile , Alessia Memeo , Eric P. Jacobo , Grazia Paola Nicchia , James A. Brozik","doi":"10.1016/j.bbagen.2025.130866","DOIUrl":"10.1016/j.bbagen.2025.130866","url":null,"abstract":"<div><div>Human aquaporin-4 (AQP4) is a water-channel protein crucial for water-ion homeostasis in the central nervous system. Dysregulation of AQP4 function is linked to neurological conditions like brain edema, neuromyelitis optica, and epilepsy. AQP4 has two isoforms, M1 and M23. The M23 isoform forms large structures known as Orthogonal Arrays of Particles (OAPs), while M1 coats the outer surface of OAPs. The dynamics of OAP aggregation may modulate water permeability and ion homeostasis in the brain. This study shows that the palmitoylation state of M1 influences OAP self-assembly, with depalmitoylated M1 producing OAPs 20 % larger than those formed by palmitoylated M1 at the same concentration. This, along with prior research on M1 aggregation, suggests palmitoylated M1 forms a single outer layer arounf OPAs, whereas depalmitoylated M1 creates a double layer. Single-particle tracking was used to study M23 OAP formation in lipid bilayers under equilibrium conditions. Our data support the idea that M1 regulates M23 OAP size, showing that average OAP size decreases as M1 concentration increases. This study explores the inhibitory effects of M1 on AQP4 M23 assembly and how M1's palmitoylation state affects OAP size regulation. These insights could lead to new therapeutic approaches for managing AQP4 assembly and function in related conditions.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 12","pages":"Article 130866"},"PeriodicalIF":2.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145278893","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 : 2025-12-01Epub Date: 2025-10-08DOI: 10.1016/j.bbagen.2025.130859
Sharanbasappa D. Madival , Dwijesh Chandra Mishra , Krishna Kumar Chaturvedi , Neeraj Budhlakoti , Mohammad Samir Farooqi , Sudhir Srivastava , Anu Sharma , Shivadarshan S. Jirli , Alka Arora , Girish K. Jha , Shesh N. Rai
Biosynthetic gene clusters (BGCs) encode enzymatic pathways that produce diverse natural products with applications in pharmaceuticals, agriculture, and biotechnology. Broad-spectrum tools such as antiSMASH and DeepBGC cover many BGC classes but may face challenges in detecting atypical or hybrid architectures. Here we present RFBGCPred, an open-source machine learning classifier focused on five clinically and agriculturally important classes—PKS, NRPS, RiPPs, terpenes, and PKS–NRPS hybrids. Rather than replacing existing pipelines, RFBGCPred complements them by improving class-level discrimination within this subset.
Using curated data from the MiBIG database, we applied Word2Vec for feature extraction, supervised UMAP for dimensionality reduction, and SMOTE to address class imbalance. Multiple classifiers were benchmarked, with Random Forest identified as the top performer using the TOPSIS decision-making criterion. The final model achieved an accuracy of 98.0 % (MCC: 0.9752, AUC: 0.9928) on a balanced test set, and maintained strong generalization on an unbalanced validation set (accuracy: 94.8 %, MCC: 0.89, AUC: 0.96). Compared with antiSMASH and DeepBGC, RFBGCPred showed improved recall for hybrid PKS–NRPS clusters while sustaining competitive precision, thereby reducing misclassification of atypical arrangements.
RFBGCPred supports FASTA, GenBank, and CSV inputs, with full source code, curated datasets, and documentation available at: https://github.com/SHARANBASAPPA/RFBGCPred.git.
{"title":"RFBGCpred: A Random forest based tool for prediction of biosynthetic gene clusters","authors":"Sharanbasappa D. Madival , Dwijesh Chandra Mishra , Krishna Kumar Chaturvedi , Neeraj Budhlakoti , Mohammad Samir Farooqi , Sudhir Srivastava , Anu Sharma , Shivadarshan S. Jirli , Alka Arora , Girish K. Jha , Shesh N. Rai","doi":"10.1016/j.bbagen.2025.130859","DOIUrl":"10.1016/j.bbagen.2025.130859","url":null,"abstract":"<div><div>Biosynthetic gene clusters (BGCs) encode enzymatic pathways that produce diverse natural products with applications in pharmaceuticals, agriculture, and biotechnology. Broad-spectrum tools such as antiSMASH and DeepBGC cover many BGC classes but may face challenges in detecting atypical or hybrid architectures. Here we present RFBGCPred, an open-source machine learning classifier focused on five clinically and agriculturally important classes—PKS, NRPS, RiPPs, terpenes, and PKS–NRPS hybrids. Rather than replacing existing pipelines, RFBGCPred complements them by improving class-level discrimination within this subset.</div><div>Using curated data from the MiBIG database, we applied Word2Vec for feature extraction, supervised UMAP for dimensionality reduction, and SMOTE to address class imbalance. Multiple classifiers were benchmarked, with Random Forest identified as the top performer using the TOPSIS decision-making criterion. The final model achieved an accuracy of 98.0 % (MCC: 0.9752, AUC: 0.9928) on a balanced test set, and maintained strong generalization on an unbalanced validation set (accuracy: 94.8 %, MCC: 0.89, AUC: 0.96). Compared with antiSMASH and DeepBGC, RFBGCPred showed improved recall for hybrid PKS–NRPS clusters while sustaining competitive precision, thereby reducing misclassification of atypical arrangements.</div><div>RFBGCPred supports FASTA, GenBank, and CSV inputs, with full source code, curated datasets, and documentation available at: <span><span>https://github.com/SHARANBASAPPA/RFBGCPred.git</span><svg><path></path></svg></span>.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 12","pages":"Article 130859"},"PeriodicalIF":2.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273544","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 : 2025-10-01Epub Date: 2025-08-21DOI: 10.1016/j.bbagen.2025.130849
Suman Gusain , Rakesh Kumar , Rohit Joshi
Drought is a major abiotic factor leading to decreased productivity. The current study investigates the effects of prolonged drought stress and subsequent recovery in Crocus sativus L. through the exogenous application of abscisic acid (ABA) under field conditions in the Dhauladhar range of the Himalayan region. To evaluate the influence of drought stress, saffron corms (both large and medium) were subjected to three treatments: irrigation, water deficit (withheld irrigation), and ABA application (via foliar spray). The results indicated that morphological and physiological traits, including fresh weight and dry weight (leaf, root, mother corm and daughter corm), sprouting percentage, total biomass, flower number, stomatal aperture, relative water content, photosynthetic activity and Fv/Fm were negatively affected by drought stress. Further, histological analysis revealed a reduction in starch granule accumulation, while root metaxylem cells were found to be enlarged under water deficit conditions. Additionally, RT-PCR analysis indicated higher transcript abundance of DREB1, DREB2 and SnRK2 under drought conditions compared to the control, while the expression levels of MYB37, WRKY1, DHN1, DHN1 and AREB1 remained unchanged under similar conditions. Nevertheless, exogenous abscisic acid improved the drought tolerance of C. sativus. A decrease in lipid peroxidation and an increase in proline, chlorophyll content, and antioxidant activity were observed when ABA was applied under drought conditions. Overall, our study demonstrates ABA-mediated regulation of several key transcription factors under drought stress. These findings provide new insights into the mechanisms of drought tolerance in saffron, which will facilitate future breeding programmes for this highly valuable crop.
{"title":"Abscisic acid-mediated modulation of morpho-physiological traits and transcript accumulation improves drought resilience in Crocus sativus L.","authors":"Suman Gusain , Rakesh Kumar , Rohit Joshi","doi":"10.1016/j.bbagen.2025.130849","DOIUrl":"10.1016/j.bbagen.2025.130849","url":null,"abstract":"<div><div>Drought is a major abiotic factor leading to decreased productivity. The current study investigates the effects of prolonged drought stress and subsequent recovery in <em>Crocus sativus</em> L. through the exogenous application of abscisic acid (ABA) under field conditions in the Dhauladhar range of the Himalayan region. To evaluate the influence of drought stress, saffron corms (both large and medium) were subjected to three treatments: irrigation, water deficit (withheld irrigation), and ABA application (via foliar spray). The results indicated that morphological and physiological traits, including fresh weight and dry weight (leaf, root, mother corm and daughter corm), sprouting percentage, total biomass, flower number, stomatal aperture, relative water content, photosynthetic activity and Fv/Fm were negatively affected by drought stress. Further, histological analysis revealed a reduction in starch granule accumulation, while root metaxylem cells were found to be enlarged under water deficit conditions. Additionally, RT-PCR analysis indicated higher transcript abundance of <em>DREB1, DREB2</em> and <em>SnRK2</em> under drought conditions compared to the control, while the expression levels of <em>MYB37, WRKY1, DHN1, DHN1</em> and <em>AREB1</em> remained unchanged under similar conditions. Nevertheless, exogenous abscisic acid improved the drought tolerance of <em>C. sativus</em>. A decrease in lipid peroxidation and an increase in proline, chlorophyll content, and antioxidant activity were observed when ABA was applied under drought conditions. Overall, our study demonstrates ABA-mediated regulation of several key transcription factors under drought stress. These findings provide new insights into the mechanisms of drought tolerance in saffron, which will facilitate future breeding programmes for this highly valuable crop.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 11","pages":"Article 130849"},"PeriodicalIF":2.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144879352","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 : 2025-10-01Epub Date: 2025-08-25DOI: 10.1016/j.bbagen.2025.130852
Sirintra Udomkitkosol , Pondthip Thaiorn , Phisit Sintusen , Kulthida Vaeteewoottacharn , James R. Ketudat-Cairns , Sumalee Obchoei , Siriporn Proungvitaya , Tin May Aung , Atsushi Kuno , Sayaka Fuseya , Atit Silsirivanit , Sopit Wongkham , Sukanya Luang
Native Butea monosperma agglutinin (nBMA), is a lectin isolated from the seeds of the Butea monosperma plant, which binds specifically to galactose, N-acetylgalactosamine, and lactose. This study developed a recombinant β-chain of BMA (rBMA) expressed in Escherichia coli. The rBMA exists in a monomeric form, retains native structure and sugar-binding capacity without exhibiting hemagglutination activity. The binding activity of rBMA was evaluated through lectin-cytofluorescent staining of CCA cell lines. Similar to nBMA, rBMA exhibited a positive signal to CCA cell lines but displayed a strong signal in different cell lines. Sodium periodate treatment abolished rBMA binding in CCA tissues and serum dot blots, confirming carbohydrate-dependent interactions. The neutralizing activity for sugar binding specificity indicated that rBMA binds to the complex glycosylated glycans rather than mono- and di-saccharides. Elevated levels of rBMA binding glycans in serum dot blots were found to differentiate CCA patients from healthy individuals, achieving a diagnostic sensitivity of 92.9%, specificity of 36%, and overall accuracy of 74%. High levels of serum rBMA-binding glycans were associated with poorer survival in CCA patients, and directly correlated with serum alkaline phosphatase levels. No correlation was found with carcinoembryonic antigen and CA19–9 levels. These findings position serum rBMA-binding glycans as potential biomarkers reflecting CCA progression. The monomeric nature and retained glycan specificity of rBMA, coupled with its absence of hemagglutination activity, make it a superior candidate to nBMA for diagnostic applications and a promising platform for targeted therapeutic development for CCA.
{"title":"Development of a monomeric recombinant Butea monosperma agglutinin as a diagnostic and prognostic biomarker for cholangiocarcinoma","authors":"Sirintra Udomkitkosol , Pondthip Thaiorn , Phisit Sintusen , Kulthida Vaeteewoottacharn , James R. Ketudat-Cairns , Sumalee Obchoei , Siriporn Proungvitaya , Tin May Aung , Atsushi Kuno , Sayaka Fuseya , Atit Silsirivanit , Sopit Wongkham , Sukanya Luang","doi":"10.1016/j.bbagen.2025.130852","DOIUrl":"10.1016/j.bbagen.2025.130852","url":null,"abstract":"<div><div>Native <em>Butea monosperma</em> agglutinin (nBMA), is a lectin isolated from the seeds of the <em>Butea monosperma</em> plant, which binds specifically to galactose, <em>N</em>-acetylgalactosamine, and lactose. This study developed a recombinant β-chain of BMA (rBMA) expressed in <em>Escherichia coli</em>. The rBMA exists in a monomeric form, retains native structure and sugar-binding capacity without exhibiting hemagglutination activity. The binding activity of rBMA was evaluated through lectin-cytofluorescent staining of CCA cell lines. Similar to nBMA, rBMA exhibited a positive signal to CCA cell lines but displayed a strong signal in different cell lines. Sodium periodate treatment abolished rBMA binding in CCA tissues and serum dot blots, confirming carbohydrate-dependent interactions. The neutralizing activity for sugar binding specificity indicated that rBMA binds to the complex glycosylated glycans rather than mono- and di-saccharides. Elevated levels of rBMA binding glycans in serum dot blots were found to differentiate CCA patients from healthy individuals, achieving a diagnostic sensitivity of 92.9%, specificity of 36%, and overall accuracy of 74%. High levels of serum rBMA-binding glycans were associated with poorer survival in CCA patients, and directly correlated with serum alkaline phosphatase levels. No correlation was found with carcinoembryonic antigen and CA19–9 levels. These findings position serum rBMA-binding glycans as potential biomarkers reflecting CCA progression. The monomeric nature and retained glycan specificity of rBMA, coupled with its absence of hemagglutination activity, make it a superior candidate to nBMA for diagnostic applications and a promising platform for targeted therapeutic development for CCA.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 11","pages":"Article 130852"},"PeriodicalIF":2.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144917164","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 : 2025-10-01Epub Date: 2025-08-13DOI: 10.1016/j.bbagen.2025.130851
Lei Pan, Feixia Ma, Hongchen Zhang, Yin Duan
Background
In breast cancer (BRCA), mitophagy is essential for the survival and metastasis of cancer cells. However, the interaction between translocase of the outer mitochondrial membrane 40 (TOMM40) and prohibitin 1 (PHB1) in regulating mitophagy in BRCA remains poorly understood.
Methods
Based on bioinformatics analysis, the interaction between PHB1 and key mitophagy regulators in BRCA was explored. The effects of mitochondrial division inhibitor-1 (Mdivi-1) and Fluorizoline on mitophagy, cell viability, and sphere formation ability in MDA-MB-231 cells were assessed. In the cell model activated by carbonyl cyanide m-chlorophenylhydrazone (CCCP) to induce mitophagy, the effects of TOMM40 on cell viability, sphere formation ability, mitochondrial membrane potential, reactive oxygen species (ROS) levels, mitochondrial DNA (mtDNA) release, and PHB1 regulation were analyzed. In vivo, the impact of TOMM40 knockdown on tumor progression and mitophagy was also evaluated.
Results
PHB1 interacted with TOMM40. Mdivi-1 or Fluorizoline treatment inhibited mitophagy, and significantly reduced BRCA cell viability and sphere formation. CCCP treatment induced mitophagy, increased mtDNA release and PHB1 levels, decreased mitochondrial membrane potential and ROS, and promoted cell viability and sphere formation ability, which were all reversed by TOMM40 knockdown. Additionally, TOMM40 knockdown led to decreased PHB1 levels and increased ROS accumulation in tumor tissue, thus repressing tumor progression.
Conclusion
This study identifies TOMM40 as a key regulator that enhances PHB1-mediated mtDNA release and induces mitophagy in BRCA cells, thus promoting breast cancer progression.
{"title":"Unraveling the power of TOMM40: Driving PHB1-mediated mtDNA release and mitophagy to fuel breast cancer progression","authors":"Lei Pan, Feixia Ma, Hongchen Zhang, Yin Duan","doi":"10.1016/j.bbagen.2025.130851","DOIUrl":"10.1016/j.bbagen.2025.130851","url":null,"abstract":"<div><h3>Background</h3><div>In breast cancer (BRCA), mitophagy is essential for the survival and metastasis of cancer cells. However, the interaction between translocase of the outer mitochondrial membrane 40 (TOMM40) and prohibitin 1 (PHB1) in regulating mitophagy in BRCA remains poorly understood.</div></div><div><h3>Methods</h3><div>Based on bioinformatics analysis, the interaction between PHB1 and key mitophagy regulators in BRCA was explored. The effects of mitochondrial division inhibitor-1 (Mdivi-1) and Fluorizoline on mitophagy, cell viability, and sphere formation ability in MDA-MB-231 cells were assessed. In the cell model activated by carbonyl cyanide <em>m</em>-chlorophenylhydrazone (CCCP) to induce mitophagy, the effects of TOMM40 on cell viability, sphere formation ability, mitochondrial membrane potential, reactive oxygen species (ROS) levels, mitochondrial DNA (mtDNA) release, and PHB1 regulation were analyzed. In vivo, the impact of TOMM40 knockdown on tumor progression and mitophagy was also evaluated.</div></div><div><h3>Results</h3><div>PHB1 interacted with TOMM40. Mdivi-1 or Fluorizoline treatment inhibited mitophagy, and significantly reduced BRCA cell viability and sphere formation. CCCP treatment induced mitophagy, increased mtDNA release and PHB1 levels, decreased mitochondrial membrane potential and ROS, and promoted cell viability and sphere formation ability, which were all reversed by TOMM40 knockdown. Additionally, TOMM40 knockdown led to decreased PHB1 levels and increased ROS accumulation in tumor tissue, thus repressing tumor progression.</div></div><div><h3>Conclusion</h3><div>This study identifies TOMM40 as a key regulator that enhances PHB1-mediated mtDNA release and induces mitophagy in BRCA cells, thus promoting breast cancer progression.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 11","pages":"Article 130851"},"PeriodicalIF":2.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858810","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 : 2025-10-01Epub Date: 2025-08-13DOI: 10.1016/j.bbagen.2025.130850
Carla Mayora Justel , Tamara Valladares , Lucía Gargiulo , Verónica González-Pardo , Maximiliano De Sousa , María del Carmen Esandi , Carlos Davio , Isabel Lüthy , Ariana Bruzzone
Purpose
cAMP regulates key processes in mammary cell biology. Previous studies suggested reduced cAMP production in more malignant cells. This study investigates the role of cAMP in mammary biology using non-tumor (MCF-10A and HBL-100) and tumor (MCF-7 and MDA-MB-231) human breast cell lines.
Methods
cAMP levels were quantified using a competitive radio-binding assay. Cell proliferation and viability were assessed by cell counting and MTT assay. Gene expression was analyzed by real-time PCR and immunofluorescence. Additional assays included migration, colony formation, annexin V/IP staining, comet assay, and caspase-3 activity. Public datasets were consulted. Phosphodiesterase (PDE) inhibitors were tested: the broad-spectrum PDE inhibitor IBMX (3-Isobutyl-1-methylxanthine), the PDE4-selective inhibitor roflumilast, and the PDE7-selective inhibitor BRL-50481.
Results
Non-tumor cells produced more cAMP than tumor cells, with or without IBMX. IBMX decreases cell proliferation and viability in all cell lines. Gene expression data revealed higher ADCY2, 3, 4, 5, 6, and 8 expression in normal tissues. Roflumilast reduced cell viability in all tested cells, while the PDE7-specific inhibitor BRL-50481 only affected MCF-7 cells. All PDE inhibitors exhibited an additive effect with tamoxifen, reducing MCF-7 cell viability. In tumor cells roflumilast decreased cell migration. In MDA-MB-231 cells, although IBMX and roflumilast showed a trend toward further decreasing viability compared to doxorubicin or paclitaxel alone, the differences were not statistically significant.
Conclusion
The selective PDE4 inhibitor roflumilast demonstrated potential as a therapeutic agent when combined with specific breast cancer treatments, offering a novel approach in breast cancer therapy.
{"title":"Inhibition of phosphodiesterase 4 and 7 regulates breast cancer cell proliferation","authors":"Carla Mayora Justel , Tamara Valladares , Lucía Gargiulo , Verónica González-Pardo , Maximiliano De Sousa , María del Carmen Esandi , Carlos Davio , Isabel Lüthy , Ariana Bruzzone","doi":"10.1016/j.bbagen.2025.130850","DOIUrl":"10.1016/j.bbagen.2025.130850","url":null,"abstract":"<div><h3>Purpose</h3><div>cAMP regulates key processes in mammary cell biology. Previous studies suggested reduced cAMP production in more malignant cells. This study investigates the role of cAMP in mammary biology using non-tumor (MCF-10A and HBL-100) and tumor (MCF-7 and MDA-MB-231) human breast cell lines.</div></div><div><h3>Methods</h3><div>cAMP levels were quantified using a competitive radio-binding assay. Cell proliferation and viability were assessed by cell counting and MTT assay. Gene expression was analyzed by real-time PCR and immunofluorescence. Additional assays included migration, colony formation, annexin V/IP staining, comet assay, and caspase-3 activity. Public datasets were consulted. Phosphodiesterase (PDE) inhibitors were tested: the broad-spectrum PDE inhibitor IBMX (3-Isobutyl-1-methylxanthine), the PDE4-selective inhibitor roflumilast, and the PDE7-selective inhibitor BRL-50481.</div></div><div><h3>Results</h3><div>Non-tumor cells produced more cAMP than tumor cells, with or without IBMX. IBMX decreases cell proliferation and viability in all cell lines. Gene expression data revealed higher ADCY2, 3, 4, 5, 6, and 8 expression in normal tissues. Roflumilast reduced cell viability in all tested cells, while the PDE7-specific inhibitor BRL-50481 only affected MCF-7 cells. All PDE inhibitors exhibited an additive effect with tamoxifen, reducing MCF-7 cell viability. In tumor cells roflumilast decreased cell migration. In MDA-MB-231 cells, although IBMX and roflumilast showed a trend toward further decreasing viability compared to doxorubicin or paclitaxel alone, the differences were not statistically significant.</div></div><div><h3>Conclusion</h3><div>The selective PDE4 inhibitor roflumilast demonstrated potential as a therapeutic agent when combined with specific breast cancer treatments, offering a novel approach in breast cancer therapy.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 11","pages":"Article 130850"},"PeriodicalIF":2.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858809","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 : 2025-10-01Epub Date: 2025-08-29DOI: 10.1016/j.bbagen.2025.130853
Priyanka Pathak , Manisha Banerjee
Photosynthetic organisms often rely on two-component regulatory system to adapt to environmental changes. This system is crucial for connecting external signals with the response mechanism by controlling gene expression, eventually allowing the organism to acclimatize to various stresses. Cyanobacteria, in particular, possess a large number of these two-component systems. Chloroplast Sensor Kinase (CSK) is a conserved histidine kinase present in all photosynthetic organisms.
In the present study, Hik2, a CSK homolog found in the filamentous cyanobacterium Anabaena PCC 7120, was investigated to understand its role in the signaling mechanism of this organism. Recombinant Hik2 was found to undergo autophosphorylation on a conserved histidine residue, which remains unaffected by low salt concentrations but is slightly inhibited at elevated concentrations. Rre1 was identified as a potential partner for Hik2 through in silico analysis. Further experiments, including pull-down and surface plasmon resonance analysis, confirmed a physical interaction between Hik2 and Rre1. Interestingly, rapid dephosphorylation of Hik2 in the presence of Rre1 suggested a phosphotransfer from Phospho-Hik2 to its cognate partner Rre1. In silico analysis further identified probable heat-responsive regulons of Anabaena Rre1, suggesting the possible role of the Hik2-Rre1 interaction in the signaling mechanism of Anabaena PCC 7120.
Overall, this study sheds light on the importance of the Hik2-Rre1 interaction in facilitating signaling processes in filamentous cyanobacteria, providing valuable insights into the acclimatization mechanisms of these photosynthetic organisms.
{"title":"The Hik2-Rre1 interaction acts as a two-component signaling system in filamentous cyanobacterium Anabaena PCC 7120","authors":"Priyanka Pathak , Manisha Banerjee","doi":"10.1016/j.bbagen.2025.130853","DOIUrl":"10.1016/j.bbagen.2025.130853","url":null,"abstract":"<div><div>Photosynthetic organisms often rely on two-component regulatory system to adapt to environmental changes. This system is crucial for connecting external signals with the response mechanism by controlling gene expression, eventually allowing the organism to acclimatize to various stresses. Cyanobacteria, in particular, possess a large number of these two-component systems. Chloroplast Sensor Kinase (CSK) is a conserved histidine kinase present in all photosynthetic organisms.</div><div>In the present study, Hik2, a CSK homolog found in the filamentous cyanobacterium <em>Anabaena</em> PCC 7120, was investigated to understand its role in the signaling mechanism of this organism. Recombinant Hik2 was found to undergo autophosphorylation on a conserved histidine residue, which remains unaffected by low salt concentrations but is slightly inhibited at elevated concentrations. Rre1 was identified as a potential partner for Hik2 through <em>in silico</em> analysis. Further experiments, including pull-down and surface plasmon resonance analysis, confirmed a physical interaction between Hik2 and Rre1. Interestingly, rapid dephosphorylation of Hik2 in the presence of Rre1 suggested a phosphotransfer from Phospho-Hik2 to its cognate partner Rre1. <em>In silico</em> analysis further identified probable heat-responsive regulons of <em>Anabaena</em> Rre1, suggesting the possible role of the Hik2-Rre1 interaction in the signaling mechanism of <em>Anabaena</em> PCC 7120.</div><div>Overall, this study sheds light on the importance of the Hik2-Rre1 interaction in facilitating signaling processes in filamentous cyanobacteria, providing valuable insights into the acclimatization mechanisms of these photosynthetic organisms.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 11","pages":"Article 130853"},"PeriodicalIF":2.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940734","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 : 2025-10-01Epub Date: 2025-08-15DOI: 10.1016/j.bbagen.2025.130848
Xuan Lan Thi Hoang , Nguyen Nguyen Chuong , Nguyen Cao Nguyen , Nguyen Ngoc Hai , Dung Tien Le , Yasuko Watanabe , Keiichi Mochida , Tien-Dung Nguyen , Henry T Nguyen , Lam-Son Phan Tran , Nguyen Phuong Thao
Climatic change-induced osmotic stresses, especially drought and salinity, have arisen as major environmental constraints to crop productivity and sustainable agriculture. Previously, soybean GmIPT10, which encodes an adenine isopentenyl transferase enzyme working in the biosynthesis of cytokinin phytohormone, has been identified as a drought-responsive gene. In this study, the aim is to explore the drought-associated attributes of GmIPT10 in planta, by using homologous expression system. Our findings demonstrated that the transgenic plants might acquire better drought tolerance potential. Following the drought application at vegetative stage, they not only had higher drought-tolerance index by 3–4-fold but also displayed certain advantages in maintaining agronomic traits such as better plant growth, dry biomass accumulation and cellular water contents under adverse conditions than the wild-type plants. Importantly, the greater enhancement in antioxidant enzymatic activities in the transgenic plants (i.e. 2.4–3.8-fold increase) compared with the WT counterparts (1.2–2.3-fold increase) indicated the better defense ability towards drought-induced oxidative stress of the former group. Additional investigation on the drought effects at the reproductive stage further highlighted a less inhibition status of the photosynthetic activities in the transgenic lines, whereby they displayed more active gaseous exchange, higher chlorophyll contents and photochemical efficiency. Although there was no difference in average seed weights, the drought-treated transgenic plants could maintain higher average pod numbers by 10 %, which contributed to higher productivity. Taking these data altogether, our results demonstrated the beneficial role of soybean IPT10 and its mediating actions in alleviating the adverse drought effects on plants.
{"title":"Enhancing soybean tolerance to drought by homologous expression of cytokinin synthase gene GmIPT10","authors":"Xuan Lan Thi Hoang , Nguyen Nguyen Chuong , Nguyen Cao Nguyen , Nguyen Ngoc Hai , Dung Tien Le , Yasuko Watanabe , Keiichi Mochida , Tien-Dung Nguyen , Henry T Nguyen , Lam-Son Phan Tran , Nguyen Phuong Thao","doi":"10.1016/j.bbagen.2025.130848","DOIUrl":"10.1016/j.bbagen.2025.130848","url":null,"abstract":"<div><div>Climatic change-induced osmotic stresses, especially drought and salinity, have arisen as major environmental constraints to crop productivity and sustainable agriculture. Previously, soybean <em>GmIPT10</em>, which encodes an adenine isopentenyl transferase enzyme working in the biosynthesis of cytokinin phytohormone, has been identified as a drought-responsive gene. In this study, the aim is to explore the drought-associated attributes of GmIPT10 <em>in planta</em>, by using homologous expression system. Our findings demonstrated that the transgenic plants might acquire better drought tolerance potential. Following the drought application at vegetative stage, they not only had higher drought-tolerance index by 3–4-fold but also displayed certain advantages in maintaining agronomic traits such as better plant growth, dry biomass accumulation and cellular water contents under adverse conditions than the wild-type plants. Importantly, the greater enhancement in antioxidant enzymatic activities in the transgenic plants (<em>i.e.</em> 2.4–3.8-fold increase) compared with the WT counterparts (1.2–2.3-fold increase) indicated the better defense ability towards drought-induced oxidative stress of the former group. Additional investigation on the drought effects at the reproductive stage further highlighted a less inhibition status of the photosynthetic activities in the transgenic lines, whereby they displayed more active gaseous exchange, higher chlorophyll contents and photochemical efficiency. Although there was no difference in average seed weights, the drought-treated transgenic plants could maintain higher average pod numbers by 10 %, which contributed to higher productivity. Taking these data altogether, our results demonstrated the beneficial role of soybean IPT10 and its mediating actions in alleviating the adverse drought effects on plants.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 11","pages":"Article 130848"},"PeriodicalIF":2.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144841908","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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