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

{"title":"The role of the tumor microenvironment and inflammatory pathways in driving drug resistance in gastric cancer: A systematic review and meta-analysis","authors":"Francesco Albano ,&nbsp;Francesca Lospinoso Severini ,&nbsp;Giovanni Calice ,&nbsp;Pietro Zoppoli ,&nbsp;Geppino Falco ,&nbsp;Tiziana Notarangelo","doi":"10.1016/j.bbadis.2025.167821","DOIUrl":"10.1016/j.bbadis.2025.167821","url":null,"abstract":"<div><div>Tumor microenvironment (TME) plays a pivotal role in progression and low responsiveness to chemotherapy of gastric cancer (GC). The cascade of events that culminate with a sustained and chronic activation of inflammatory pathways underlies gastric tumorigenesis. Infiltrating immune cells enrolling in crosstalk with cancer cells that regulate inflammatory and immune status, generating an immunosuppressive TME that influences the response to therapy. Here we discuss the role of TME and the activation of inflammatory pathways to comprehend strategies to improve drug response. Furthermore, we provides systematic insight the role of TME cytotypes and related signatures reinforcing the critical roles of TAMs and Tregs, in promoting GC chemoresistance and tumor progression.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167821"},"PeriodicalIF":4.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143817275","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":"Differential roles of the ADAM9/NF-κB and the ADAM9/STAT3 feedback loops in HIV-1 Tat-induced microglial inflammatory response and subsequent neuronal apoptosis","authors":"Xiaoting Qiao ,&nbsp;Hongke Wei ,&nbsp;Weixi Sun ,&nbsp;Cailian Ruan ,&nbsp;Duo Cao","doi":"10.1016/j.bbadis.2025.167831","DOIUrl":"10.1016/j.bbadis.2025.167831","url":null,"abstract":"<div><div>ADAM has been implicated in causing several neurodegenerative diseases to progress. However, the precise function they play in HIV-associated neurocognitive disorders (HAND) remains incompletely elucidated. The HIV-1 transcriptional activator (Tat) has the capacity to evoke an inflammatory reaction within the microglia of the central nervous system. This, subsequently, initiates the apoptosis of neuronal cells. In the present research, our attention was centered on the part that ADAM9 plays in the microglia's response to Tat. We discovered that the stimulation with soluble Tat remarkably enhanced the manifestation of ADAM9 by means of the NF-κB and STAT3 pathway. In contrast, inhibition of ADAM9 significantly reduced Tat-triggered NF-κB and STAT3 signaling. Moreover, both ADAM9/NF-κB and ADAM9/STAT3 feedback loops exacerbated Tat-induced microglia inflammatory responses. However, further studies showed that the ADAM9/NF-κB feedback loop more significantly promoted neuronal apoptosis mediated by conditioned medium secreted by microglia after Tat stimulation. This study offers a novel perspective on the function of diverse feedback circuits in the etiopathogenesis of HAND. It can be posited that, when considered as a collective entity, ADAM9 may represent a viable candidate for therapeutic intervention in the context of preventing neuronal injury associated with HAND by modulating the inflammatory response of microglia and influencing neuronal injury.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167831"},"PeriodicalIF":4.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826219","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":"The phosphomimetic Rab10 T73D mutation in mice leads to postnatal lethality and aberrations in neuronal development","authors":"DaoBin Han ,&nbsp;Jing Zhang ,&nbsp;Yuan Zheng ,&nbsp;LuWen Wang ,&nbsp;Hui Yu ,&nbsp;Bo Su","doi":"10.1016/j.bbadis.2025.167830","DOIUrl":"10.1016/j.bbadis.2025.167830","url":null,"abstract":"<div><div>The phosphorylation of the evolutionarily conserved Thr73 residue of Rab10 has been implicated in various neurodegenerative diseases. However, its impact on neuronal physiological function remains poorly understood. In this study, we generated a novel mouse model constitutively expressing the phosphomimetic Rab10 T73D to investigate its effects. Our findings revealed that homozygous Rab10 T73D mutant mice were postnatally lethal and exhibited brain developmental defects characterized by cortical thinning and shortened neuronal processes. Further investigation demonstrated that cultured hippocampal neurons with homozygous T73D mutation displayed decreased axon development, with reduced accumulation of Rab10 at the tips of neuronal processes and increased Rab10 localization at lysosomes. Mechanistically, the T73D mutation induces a constitutively GTP-bound state and while substantially weakening interaction with GDI1, GDI2 and JIP1. These molecular alterations collectively lead to altered T73D Rab10-positive vesicle trafficking dynamics, manifesting as decreased anterograde transport and increased movement velocity. Notably, comparative localization studies in RPE cells confirmed fundamental discrepancies between T73D distribution patterns and authentic phosphorylated Rab10 dynamics, validating limitations of this phosphomimetic approach. Collectively, our study elucidates the potential physiological roles of phosphorylated Rab10 in the regulation of neuronal process outgrowth and underscores its significance in the neural system. Additionally, it highlights the limitations of the T73D mutant in fully mimicking Rab10 phosphorylation.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167830"},"PeriodicalIF":4.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143807352","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":"HSPA8 and HSPA9: Two prognostic and therapeutic targets in breast, colon, and kidney cancers?","authors":"Alessia Ruzza ,&nbsp;Elisabetta Zaltron ,&nbsp;Federica Vianello,&nbsp;Ilaria Celotti,&nbsp;Matteo Scavezzon,&nbsp;Filippo Severin ,&nbsp;Luigi Leanza","doi":"10.1016/j.bbadis.2025.167827","DOIUrl":"10.1016/j.bbadis.2025.167827","url":null,"abstract":"<div><div>The process of protein folding is important to ensure the efficient functioning of cells. The capacity of a protein to attain the three-dimensional native conformation can impact its structure and function. Errors in this process result in the accumulation of misfolded proteins, which can contribute to the development of various diseases, including cancer. To prevent the pileup of misfolded proteins, a number of control systems have been developed over the course of evolution. In this scenario, a pivotal function has been attributed to molecular chaperones and the ubiquitin-proteasome degradation system. In this paper, we concentrate on molecular chaperones, with a particular focus on a family of heat shock proteins (HSPs), to highlight any potential correlation between their expression and function and the development of cancer. Hence, we have collected data from various public databases regarding the HSP70 protein family. By employing mRNA expression signatures, prognostic value analysis, and differentially expressed gene ontology analysis, we have elucidated the tumor-specific role of two members of the HSP70 family, namely HSPA8 and HSPA9, in kidney renal clear cell carcinoma (KIRC), colon adenocarcinoma (COAD), and breast invasive carcinoma (BRCA). Our research shed light on the controversial and tumor-specific role of HSP70s. More in detail, we have identified HSPA8 and HSPA9 as potential prognostic and therapeutic targets involved in several biological processes leading to tumorigenesis, including nucleic acid maturation, cell signaling, vesicle trafficking, mitochondrial structure and function, and protein maturation.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 6","pages":"Article 167827"},"PeriodicalIF":4.2,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143797254","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":"Dipeptidyl peptidase 9 (DPP9) depletion from hepatocytes in experimental primary liver cancer","authors":"JiaLi Carrie Huang ,&nbsp;Xinlin Linda Tong ,&nbsp;Michelle Sui Wen Xiang ,&nbsp;Badwi B. Boumelhem ,&nbsp;Diarmid P. Foulis ,&nbsp;MingChang Zhang ,&nbsp;Catriona A. McKenzie ,&nbsp;Geoffrey W. McCaughan ,&nbsp;Thomas Reinheckel ,&nbsp;Hui E. Zhang ,&nbsp;Mark D. Gorrell","doi":"10.1016/j.bbadis.2025.167819","DOIUrl":"10.1016/j.bbadis.2025.167819","url":null,"abstract":"<div><div>Dipeptidyl peptidase 9 (DPP9) is an indispensable intracellular protease. Among its many molecular functions is suppression of the NLRP1 inflammasome. Inhibitors targeting all four proteases of the DPP4 family, including DPP9, can reduce tumour burden, including in mouse liver. To explore hepatocyte DPP9 in experimental hepatocellular carcinoma (HCC), we generated hepatocyte-specific DPP9-KO mice by crossing albumin-Cre mice with DPP9 floxed mice and treated sequentially with diethylnitrosamine, then with thioacetamide combined with an atherogenic high-fat diet until 28 weeks of age. DPP9-KO mice had less body, liver and subcutaneous adipose tissue mass, lower fasting plasma glucose and fewer small macroscopic liver nodules compared to DPP9-WT control mice. However, there were no differences in the total number of macroscopic liver nodules, or of microscopic tumour burden, inflammation, fibrosis or steatosis. Consistent with the known function of DPP9 to suppress NLRP1 activation, activated caspase-1 protein and inflammation markers <em>Nfkbib, Cxcl10</em> and <em>Ccl5</em> were elevated in DPP9-KO liver. The tumour suppressor protein p53 was increased and the autophagy proteins beclin1, LC3B and p62 were altered. In conclusion, hepatocyte-specific DPP9 gene deletion in experimental primary liver cancer improved energy metabolism and may reduce liver cancer initiation, <em>via</em> mechanisms that may include increased autophagy and tumour suppression.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167819"},"PeriodicalIF":4.2,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143768754","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":"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}