Biochimica et biophysica acta. Molecular basis of disease最新文献

{"title":"Therapeutic potential of GNRHR analogs and SRC/FAK inhibitors to counteract tumor growth and metastasis in breast cancer","authors":"Joselina Magali Mondaca ,&nbsp;Juan Manuel Fernandez Muñoz ,&nbsp;Gustavo Adolfo Barraza ,&nbsp;Fiorella Vanderhoeven ,&nbsp;Analía Lourdes Redondo ,&nbsp;Marina Inés Flamini ,&nbsp;Angel Matias Sanchez","doi":"10.1016/j.bbadis.2025.167826","DOIUrl":"10.1016/j.bbadis.2025.167826","url":null,"abstract":"<div><div>Breast cancer (BC) is the leading cause of cancer death in women, with hormone-dependent BC accounting for about 80 % of cases, primarily affecting postmenopausal women with gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) elevated. Treatments targeting the gonadotropin-releasing hormone receptor (GnRHR), such as the agonist leuprorelin (LEU) and antagonist degarelix (DEGA), are used for hormone-dependent tumors. While the functional role of gonadotropin receptors in extragonadal tissues remains uncertain, recent studies suggest LH contributes to tumor development and progression. Tumor progression involves reorganization in the actin cytoskeleton, induction of adhesion, and cell migration, driven by proteins such as Src and the focal adhesion kinase (FAK), which are related to invasive behaviors. The overexpression of both protein kinases generates an invasive and metastatic phenotype, then inhibitors targeting Src (PP2) and FAK (FAKi) have been developed to counteract this effect. This study combined GnRH analogs with Src and FAK inhibitors to target BC progression. We found that LH treatment influenced gene expression linked to tumor development. Examining the GnRHR-LEU and GnRHR-DEGA complexes revealed structural differences affecting ligand binding. In an orthotopic tumor model, DEGA reduced tumor growth, while LEU had the opposite effect. Combining DEGA with PP2 or FAKi enhanced tumor inhibition, improving mice survival. These findings provide valuable insights into the essential regulatory role of gonadotropins in genes involved in tumorigenic processes, highlighting the potential of GnRHR antagonists combined with Src or FAK inhibitors as a promising strategy to develop new drugs that interfere with the ability of breast tumor progression.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167826"},"PeriodicalIF":4.2,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143785205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aminolevulinate/iron exposure elicited Nrf-2-mediated cytoprotection in DARS2 deficient fibroblasts with impaired energy and antioxidant metabolisms","authors":"Wei-Lin Huang ,&nbsp;Tuany Eichwald ,&nbsp;Alexander Stover ,&nbsp;Milad Gazanfari ,&nbsp;Philip H. Schwartz ,&nbsp;Alexandra Latini ,&nbsp;Jose E. Abdenur","doi":"10.1016/j.bbadis.2025.167824","DOIUrl":"10.1016/j.bbadis.2025.167824","url":null,"abstract":"<div><div>Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is a disorder caused by mutations in the mitochondrial aspartyl-tRNA synthetase gene <em>DARS2</em>, which compromises mitochondrial protein translation. The typical presentation is juvenile in onset with gradually progressive spasticity and ataxia. Only palliative treatment is available for LBSL individuals. Here we showed that the use of the Food and Drug Administration-approved heme precursors, aminolevulinate plus ferrous iron (ALA/Fe), can result in a novel pharmacological treatment that increases energy status in DARS2 deficient cells. The marked mitochondrial and antioxidant deficiencies observed in fibroblasts from two LBSL-affected brothers, harboring intron-2 (c.228-17C &gt; G) and intron-5 (c.492 + 2 T &gt; C) DARS2 mutations, were rescued by ALA/Fe exposure, and the use of dexamethasone, a known Nrf-2 inhibitor, blocked the positive effects of ALA/Fe. Altogether, this study showed that fibroblasts can be used as a biological system to identify potential new treatments for LBSL that can reduce morbidity and mortality, and that the activation of Nrf-2-mediated cytoprotection can be targeted for the treatment of LBSL and other mitochondrial diseases.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167824"},"PeriodicalIF":4.2,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptional profile and quantitative proteomics revealed NGF-p75NTR-associated synaptic plasticity and heterogeneity for diabetic encephalopathy and the potential role of CoQ10 for diabetic induced cognitive deficits in mice","authors":"Qiong Xiang ,&nbsp;Hu Lin ,&nbsp;Li-Ni Liu ,&nbsp;Jing Deng ,&nbsp;Jia-Sheng Tao ,&nbsp;Xian-Hui Li","doi":"10.1016/j.bbadis.2025.167823","DOIUrl":"10.1016/j.bbadis.2025.167823","url":null,"abstract":"<div><h3>Background</h3><div>Diabetic encephalopathy (DE) is one of the diabetes complications, which showing heterogeneous at different stage in course of disease. CoQ10 is well-known for its neuroprotection effects in cardiovascular system. However, whether CoQ10 could modulate synaptic plasticity in DE remains unknown. This study aims to explore the cellular and molecular characteristics of CoQ10 and its potential role in diabetic induced cognitive deficits (DICD).</div></div><div><h3>Methods</h3><div>TMT-based quantitative proteomics was applied for investigating differentially expressed proteins (DEPs) among CoQ10 treated DICD, DICD and control (health) groups mice. Analysis of GO and KEGG pathway enrichment of DEPs among different groups. ScRNA-sequencing was applied for identifying heterogeneity among different groups; differentially expressed genes (DEGs), KEGG pathway enrichment were analyzed as well as Protein-protein interaction (PPI) networks were constructed. Western blotting was performed to validate the expressions of p75, BDNF in neurotrophin pathway and p-Akt in PI3K-Akt pathway, p-ERK as well as p-p38 in MAPK pathways among those groups.</div></div><div><h3>Results</h3><div>29 upregulated and 13 downregulated DEPs (db vs control, <em>p</em> &lt; 0.05); 46 upregulated and 11 downregulated DEPs (db + CoQ10 vs control, <em>p</em> &lt; 0.05) and 8 upregulated and 7 downregulated DEPs (db vs db + CoQ10,p &lt; 0.05) were identified totally. 35 KEGG pathways were enriched by DEPs between DICD and CoQ10 treated DICD, including neurotrophing signaling pathway that had a crucial role in development, plasticity, and repair of the nervous system; Zfp369 that could interact with p75 and was upregulated after CoQ10 treatment among the down regulated DEPs in DICD; Further, scRNA-seq was applied, and the integrated analysis showed type IC spiral ganglion neuron with marker gene expression in cluster2,3,5 and 9, which were involved in synaptic plasticity regulation such as axon guidance, positive regulation of neuron projection development, negative regulation of BDNF binding and negative regulation basement membrane and dendritic microtuble formation as well as axoneme assembly.</div></div><div><h3>Conclusions</h3><div>CoQ10 treatment was very important in neural plasticity of DICD mice. It was the pioneering study to investigate DICD- related and CoQ10 treated proteomic changes and the correlated heterogeneity alterations between DICD and control. And also, NGF-p75NTR signaling pathways were significantly involved in synaptic plasticity regulation. The findings supplied the cellular and molecular evidence to clarify the potential role of CoQ10 in DICD, and combined drugs for diabetic patients in clinic.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167823"},"PeriodicalIF":4.2,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143789391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Triiodothyronine promotes the proliferation and chemoresistance of cholangiocarcinoma cells via HIF-1α/Glut1-stimulated glycolysis","authors":"Dihua Huang ,&nbsp;Feng Xu ,&nbsp;Luohang Xu ,&nbsp;Zekai Tang ,&nbsp;Yanxin Hu ,&nbsp;Jiandong Li ,&nbsp;Jianhua Yu","doi":"10.1016/j.bbadis.2025.167814","DOIUrl":"10.1016/j.bbadis.2025.167814","url":null,"abstract":"<div><div>Thyroid hormones not only are crucial for normal growth, development, and metabolism but also influence the development and progression of various malignancies. The effects of thyroid hormones on cholangiocarcinoma remain unclear. Here, we examined the effects of triiodothyronine (T3), a major thyroid hormone, on the behavior of cultured human cholangiocarcinoma cells after short-term (1 week) or long-term (6 months) T3 treatment. Whereas short-term T3 treatment did not influence the growth or behavior of cholangiocarcinoma cells, long-term T3 treatment had several significant effects. Cell proliferation, colony-forming and spheroid formation assays indicated the long-term T3 treatment increased cholangiocarcinoma cell growth <em>in vitro</em> and in mouse xenografts, and increased resistance to gemcitabine and cisplatin. Cells exposed to T3 long-term also exhibited increased glycolysis in a manner dependent on the glucose transporter 1 (Glut1). Expression of both Glut1 and hypoxia-inducible transcription factor 1α (HIF-1α) was upregulated in long-term T3-treated cholangiocarcinoma cells. Either pharmacological inhibition of Glut1 activity or siRNA-mediated knockdown of HIF-1α expression suppressed the increase in proliferation and chemoresistance induced by long-term T3 treatment. Notably, HIF-1α knockdown also reversed the effects of T3 exposure on Glut1 expression and glycolytic rate. Moreover, inhibition of lactate dehydrogenase suppressed upregulated expression of HIF-1α in long-term T3-treated cells. Finally, we found that elevated T3 levels activated the HIF-1α/Glut1 axis in ICC tissues and was associated with a worse prognosis of ICC patients. These results demonstrate that chronic exposure to T3 can promote the proliferation and chemoresistance of cholangiocarcinoma cells through a pathway involving HIF-1α, Glut1, and glycolysis.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167814"},"PeriodicalIF":4.2,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improving the safety of N,N-dimethylacetamide (DMA) as a potential treatment for preterm birth in a pregnant mouse model using a vaginal nanoformulation","authors":"Asad Mir ,&nbsp;Teeshavi Acosta ,&nbsp;Marta Concheiro-Guisan ,&nbsp;Steven M. Yellon ,&nbsp;Ketan Patel ,&nbsp;Sandra E. Reznik","doi":"10.1016/j.bbadis.2025.167822","DOIUrl":"10.1016/j.bbadis.2025.167822","url":null,"abstract":"<div><div>Vaginal administration and the uterine first pass effect allow for preferential delivery of drugs to the reproductive tract. Dimethylacetamide has previously been shown to delay preterm birth in a pregnant mouse model when given intraperitoneally but the effectiveness of a vaginal nanoformulation of dimethylacetamide has yet to be tested. The purpose of this study was to compare the two formulations of dimethylacetamide for efficacy in rescuing pups from preterm birth in an inflammation-induced mouse model, effects on the maternal fetal interface, and pharmacokinetic profiles in maternal plasma. Timed pregnant CD1 mice were given a 1.56 mg/kg intraperitoneal dose of lipopolysaccharide followed by 3 doses of either vaginal dimethylacetamide or intraperitoneal dimethylacetamide. Mice were monitored for 48 h and times of deliveries were recorded. Additionally, CD1 mice in late gestation were given a single dose of either vaginal or intraperitoneal dimethylacetamide and blood was drawn at 3 different time points following administration. Vaginal administration of dimethylacetamide had similar efficacy in delaying inflammation induced preterm birth as intraperitoneal administration but resulted in lower concentrations in the systemic circulation and decreased effects on the maternal fetal interface. Vaginal nanoformulations should be explored for their potential therapeutic value for the delay of preterm birth.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167822"},"PeriodicalIF":4.2,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the connection between dementia and cardiovascular risk with a focus on ADAM10","authors":"Ana Beatriz Aparecida Targas ,&nbsp;Pedro Henrique Moreira Victoriano ,&nbsp;Mateus Balleiro Bertoldo Garcia ,&nbsp;Vanessa Alexandre-Silva ,&nbsp;Marcia Regina Cominetti","doi":"10.1016/j.bbadis.2025.167825","DOIUrl":"10.1016/j.bbadis.2025.167825","url":null,"abstract":"<div><div>Alzheimer's disease (AD) represents a leading cause of dementia, characterized by progressive cognitive and functional decline. Although extensive research has unraveled critical aspects of AD pathology, its etiology remains incompletely understood, urging further exploration into potential risk factors. Growing evidence underscores a significant link between cardiovascular disease (CVD) risk factors and AD, with modifiable lifestyle elements - such as physical inactivity, high low-density lipoprotein (LDL) levels, obesity, hypertension, atherosclerosis, and diabetes - emerging as contributors to cerebrovascular damage and neurodegeneration. ADAM10, a disintegrin and metalloproteinase involved in the non-amyloidogenic processing of amyloid precursor protein (APP), has garnered interest for its dual role in cardiovascular and neurodegenerative processes. ADAM10's regulation of neuroinflammation, endothelial function, and proteolytic cleavage of APP potentially moderates amyloid-β (Aβ) peptide formation, thus influencing both cardiovascular and brain health. Given these interconnected roles, this narrative review investigates whether ADAM10-driven vascular dysfunction accelerates neurodegeneration, how lipid metabolism influences ADAM10 activity in CVD and AD, and whether targeting ADAM10 could offer a dual-benefit therapeutic strategy to mitigate disease burden. By exploring epidemiological data, clinical studies, and molecular pathways, we aim to clarify ADAM10's bridging function between AD and cardiovascular risk, offering a new perspective into therapeutic opportunities to alleviate the dual burden of these interrelated conditions.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167825"},"PeriodicalIF":4.2,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143768850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ACE-dependent Alzheimer's disease: Further assessment of the impact of ACE mutations on blood ACE levels","authors":"Ekaterina A. Korf ,&nbsp;Daria A. Belinskaia ,&nbsp;Andrei S. Glotov ,&nbsp;Oleg S. Glotov ,&nbsp;Yulia S. Novokovich ,&nbsp;Dmitry O. Korostin ,&nbsp;Denis V. Rebrikov ,&nbsp;Steven M. Dudek ,&nbsp;Nikolay V. Goncharov ,&nbsp;Sergei M. Danilov","doi":"10.1016/j.bbadis.2025.167817","DOIUrl":"10.1016/j.bbadis.2025.167817","url":null,"abstract":"<div><h3>Background</h3><div>Carriers of damaging mutations in the angiotensin-I-converting enzyme (ACE) that result in low ACE levels may be at increased risk for late-onset Alzheimer's disease (AD).</div></div><div><h3>Methodology/principal findings</h3><div>We measured blood ACE levels in EDTA-plasma from 74 subjects with 12 different heterozygous ACE mutations. Using a panel of monoclonal antibodies to ACE and two ACE substrates, we assessed the impact of these mutations on ACE phenotypes. We identified several mutations spanning both ACE domains, including the most frequent mutation, Y215C, that significantly reduce blood ACE levels. Therefore, these mutations may serve as potential risk factors for late-onset AD. Additionally, two mutations tested, G325R and E738K, altered ACE catalytic properties. We also found that the binding of certain mAbs to mutant ACEs could serve as markers for these and other ACE mutations. This would enable monitoring the fate of mutant ACEs in the blood during potential future therapies, particularly in the case of transport-deficient ACE mutations. The interaction between ACE and amyloid beta 1–42 (Aβ42) was studied using molecular modeling, which predicts which ACE mutations may influence Aβ42 hydrolysis, and consequently increase the risk of AD development.</div></div><div><h3>Conclusions/significance</h3><div>Systematic analysis of blood ACE levels in patients with ACE mutations holds promise for identifying individuals at increased risk of late-onset AD. Patients with ACE mutations affecting transport efficiency may potentially benefit from therapeutic strategies combining chemical and pharmacological chaperones with proteasome inhibitors, as demonstrated previously in a cellular model of the transport-deficient ACE mutation Q1069R.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167817"},"PeriodicalIF":4.2,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An unusual phenotype of hereditary AApoAI amyloidosis caused by a novel Asp20Tyr substitution is linked to pH-dependent aggregation of apolipoprotein A-I","authors":"Tatiana Prokaeva ,&nbsp;Shobini Jayaraman ,&nbsp;Elena Klimtchuk ,&nbsp;Natasha Burke ,&nbsp;Brian Spencer ,&nbsp;Dobrin Nedelkov ,&nbsp;Hui Chen ,&nbsp;Surendra Dasari ,&nbsp;Ellen D. McPhail ,&nbsp;Lucas Pereira ,&nbsp;Michael C. Payne ,&nbsp;Sherry Wong ,&nbsp;Eric J. Burks ,&nbsp;Vaishali Sanchorawala ,&nbsp;Olga Gursky","doi":"10.1016/j.bbadis.2025.167820","DOIUrl":"10.1016/j.bbadis.2025.167820","url":null,"abstract":"<div><div>Apolipoprotein A-I (apoA-I) plays beneficial roles as the major structural and functional protein on plasma high-density lipoproteins (HDL). However, <em>APOA1</em> gene mutations can cause protein misfolding and pathologic amyloid deposition in various organs in human hereditary AApoAI amyloidosis, a potentially lethal systemic disease. We report esophageal and duodenal AApoAI amyloidosis in a 56-year-old patient with Barrett's esophagus, a condition involving chronic acid reflux. Amyloid deposits contained full-length apoA-I featuring a novel D20Y mutation identified by gene sequencing and protein mass spectrometry. Genetic analysis of asymptomatic family members revealed autosomal dominant inheritance. Fibril formation by the full-length variant apoA-I rather than its fragments and the location of the mutation in a conserved amyloid-prone N-terminal segment were highly unusual for hereditary AApoA-I amyloidosis. Structural and stability studies of the recombinant D20Y and wild-type apoA-I showed small but significant mutation-induced structural perturbations in the native lipid-free protein at pH 7.4. Major destabilization and aggregation of the variant protein were observed at pH 4.0. We propose that acidic conditions in Barrett's esophagus promoted protein misfolding and amyloid formation by the D20Y variant. These findings expand our understanding of the clinical features and molecular basis of AApoAI amyloidosis and suggest clinical strategies.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167820"},"PeriodicalIF":4.2,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inosine from purine metabolism enhances fracture healing by coupling fibrinolysis and angiogenesis of type H vessels","authors":"Guan-Lin Lee ,&nbsp;Chih-Chien Hu ,&nbsp;Mei-Feng Chen ,&nbsp;Yuhan Chang ,&nbsp;Yu-Chih Lin ,&nbsp;Ying-Yu Wu ,&nbsp;Yung-Heng Hsu","doi":"10.1016/j.bbadis.2025.167818","DOIUrl":"10.1016/j.bbadis.2025.167818","url":null,"abstract":"<div><div>Fibrinolysis–angiogenesis coupling is crucial for successful fracture healing, in which type H vessels play an indispensable role. However, the metabolic control of fibrinolysis-type H angiogenesis coupling in fracture healing remains unclear. We used a metabolomics approach to gain metabolic insights from mouse fracture models (0.3 mm and 1.0 mm femur defects). Furthermore, human umbilical vein endothelial cells (HUVECs) and MC3T3-E1 cells were employed as <em>in vitro</em> models to examine the effects of identified metabolites on endothelial events and osteogenesis, respectively. CD31 and endomucin (Emcn) were used for detecting type H markers, and tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) for fibrinolysis. A femur defect of 1.5 mm in mice was included to validate the therapeutic potential of identified metabolites by bone imaging and micro-CT. Purine metabolism is the most significant pathway in fracture healing; three purinergic metabolites, adenosine, adenine, and inosine, are regulated in mouse serum. According to the <em>in vivo</em> results, CD31^HiEmcn^Hi type H vessels are upregulated near the defect site in mouse femur and are associated with tPA expression, but not PAI-1. Additionally, <em>in vitro</em> experiments examining the endothelial functions of HUVECs demonstrated that these three metabolites promote cell migration and tube formation rather than proliferation. Fibrinolytic activity and type H phenotype in HUVECs were induced only by inosine through activation of the adenosine A2A receptor. Inosine, regulated during fracture healing, has the capacity to synchronously induce fibrinolysis and type H phenotype in line with osteogenesis, indicating its role in enhancing fracture healing.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167818"},"PeriodicalIF":4.2,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GEF-H1 drives breast cancer cells to tumor progression","authors":"Lucía Fernández Chávez,&nbsp;Karen Schweitzer,&nbsp;Exequiel Gonzalo Alonso,&nbsp;María Julia Ferronato,&nbsp;María Eugenia Fermento,&nbsp;Eliana Noelia Alonso,&nbsp;María Marta Facchinetti,&nbsp;Alejandro Carlos Curino,&nbsp;Georgina Pamela Coló","doi":"10.1016/j.bbadis.2025.167816","DOIUrl":"10.1016/j.bbadis.2025.167816","url":null,"abstract":"<div><div>Rho GTPases are involved in several biological processes, including cytoskeletal remodeling, gene transcription, cell proliferation and differentiation. Dysregulation of Rho GTPases activity can lead to enhanced tumor cell proliferation and metastasis. Rho guanine nucleotide exchange factor-H1 (GEF<img>H1) is a RhoA activator that is associated with microtubules (MT) and its localization and activity are regulated, in part, by MT and fibronectin-binding integrins. Our findings showed that GEF-H1 expression is significantly higher in human breast cancer biopsies than in normal tissues. Moreover, patients with increased GEF-H1 expression had a lower survival rate and a higher incidence of metastasis. We generated a GEF-H1 knockout (KO) breast cancer cell line and observed a significant reduction in the number of focal adhesions, formation of stress fibers, and activation of downstream signaling pathways. Concordantly, cell proliferation, migration, adhesion, and invasion were reduced.</div><div>Furthermore, when GEF-H1 knockout (KO) cells were orthotopically implanted into the mammary fat pads of BALB/c mice, a significant decrease was observed in both tumor formation and lung metastasis compared to control breast cancer cells.</div><div>These results suggest that GEF-H1/RhoA activation mediates cytoskeletal remodeling and signaling pathways critical for breast cancer cell proliferation, migration, and invasion. <em>In vivo</em> assays and human biopsy studies further support GEF-H1 as a potential biomarker of breast tumor progression.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167816"},"PeriodicalIF":4.2,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}