Integrative biology : quantitative biosciences from nano to macro最新文献

{"title":"BMI1 facilitates Wnt signaling by epigenetic silencing of Axin2 to promote cell proliferation and migration in Hirschsprung's disease.","authors":"Zhanhu Li, Dong Chen","doi":"10.1093/intbio/zyaf011","DOIUrl":"10.1093/intbio/zyaf011","url":null,"abstract":"<p><p>Hirschsprung's disease (HSCR) is a congenital intestinal disease characterized by the loss of enteric neural crest cells. BMI1 is demonstrated to be downregulated in HSCR tissues compared to normal intestinal tissues, but it is still unclear whether BMI1 is involved in the pathogenesis of HSCR. Here, we found that BMI1 expression was downregulated in HSCR-stenosed segments (HSCR-S) cases compared with HSCR-dilated segments (HSCR-D) or control cases. Pharmacological inhibition of BMI1 using PTC-209 significantly attenuated cell proliferation, migration, and cell cycle progression in both SH-SY5Y neuroblastoma cells and primary enteric neural crest cells (ENCCs), whereas BMI1 overexpression produced the opposite effects. BMI1 binds to the promoter region of the Wnt signaling pathway inhibitor Axin2 and suppressed its transcription by increasing H2AK119ub and reducing H3K4me3 at the Axin2 promoter, thereby hindering Wnt signaling. Moreover, overexpression of Axin2 decreased cell proliferation, migration and cell cycle progression. Treatment with HY-122816 (a Wnt signaling pathway agonist) reversed the inhibitory effects of PTC-209 on cell proliferation, migration, and cell cycle progression. Additionally, BMI1 upregulation promoted ganglion cell proliferation in Ednrb-/- mice. In conclusion: BMI1 facilitated Wnt signaling by mediating epigenetic silencing of Axin2, thereby promoting cell proliferation and migration in HSCR. Clinically, BMI1 expression was downregulated in HSCR-S cases compared with HSCR-D or control cases. Moreover, BMI1 was shown for the first time to promote cell proliferation, migration, and cell cycle progression in ENCCs. Molecular level probing revealed that BMI1 binds to the promoter region of Axin2, an inhibitor of the Wnt signaling pathway, and inhibited Axin2 transcription by increasing H2AK119ub and decreasing H3K4me3 in the Axin2 promoter, thereby hindering Wnt signaling. This study revealed that the BMI1/Axin2/Wnt axis may play an important role in the pathogenesis of HSCR.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":"17 ","pages":""},"PeriodicalIF":1.4,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of novel zinc-binding inhibitors against key microbial metallohydrolase DapE in Klebsiella pneumoniae: an integrated ligand-based virtual screening, molecular docking, molecular dynamics, and MM/PBSA approach.","authors":"Rhitam Biswas, Anand Anbarasu","doi":"10.1093/intbio/zyaf018","DOIUrl":"https://doi.org/10.1093/intbio/zyaf018","url":null,"abstract":"<p><p>Klebsiella pneumoniae (K. pneumoniae) has emerged as a prominent multidrug-resistant pathogen in healthcare settings and is ranked among the top three critical priority pathogens by the World Health Organization. Owing to the surge in antibiotic resistance and resulting treatment failures, there is an urgent need for alternative therapeutic approaches. N-succinyl-L, L-diaminopimelic acid desuccinylase (DapE), a crucial metalloenzyme in the lysine biosynthesis pathway in K. pneumoniae, is essential for protein synthesis and the cross-linking of the bacterial peptidoglycan cell wall. The remarkable conservation of DapE across diverse bacterial species makes it a promising target for combating drug resistance. In this study, 400 analogues were screened using virtual screening to evaluate their pharmacokinetic, toxicological, and bioactive properties. Fifty-two compounds meeting these criteria were selected for molecular docking analysis. Among these, five top-ranking compounds were identified based on docking scores, and two, ZINC262925003 (-7.1 kcal/mol) and ZINC237355153 (-7.0 kcal/mol), were selected due to their strong catalytic zinc-binding interactions at the active site. Extensive validation through 250 ns molecular dynamics simulation and Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) analysis revealed high structural stability and robust binding interactions for these complexes. These findings highlight their potential as therapeutic agents against DapE, necessitating further validation through in vitro and in vivo studies. Insight Box The study employs an integrated computational approach for identifying potential zinc-binding inhibitors against Klebsiella pneumoniae's DapE (KpDapE). In recent times, antimicrobial resistance has become a global challenge in treating bacterial infections. DapE, a metalloenzyme in the lysine biosynthesis pathway in K. pneumoniae, is essential for protein synthesis and the cross-linking of the bacterial peptidoglycan cell wall. DapE is a promising drug target to develop a new class of drugs. In this study, 400 L-Captopril analogues were screened, identifying two candidates as potent leads. Molecular docking and dynamics simulations revealed that ZINC262925003 and ZINC237355153 had significant binding affinity and stable interactions with KpDapE, supported by RMSD, RMSF, and binding-free energy analyses. This suggests that both these compounds could be potent inhibitors for KpDapE.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":"17 ","pages":""},"PeriodicalIF":1.4,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine learning applications in colorectal cancer: from early detection to personalized treatment.","authors":"Shaik Yasmin Tabasum, C Valli Nachiyar, Swetha Sunkar","doi":"10.1093/intbio/zyaf013","DOIUrl":"10.1093/intbio/zyaf013","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a significant health challenge in the world, with incidence being increasingly reported among the young population. Machine learning, therefore, is revolutionizing care in CRC, including providing advancements in early detection, staging, recurrence prediction, and individualized medicine. Techniques for analysis include support vector machines, random forests, and neural networks, which allow complex analyses of datasets, including genetic profiles and imaging data, with an improvement in diagnostic accuracy and treatment outcomes. Machine learning-driven personalized treatment strategies empower clinicians to tailor therapies to individual patients, optimizing efficacy while reducing side effects. However, integration of Machine learning (ML) in CRC management faces challenges like data quality, validation, and smooth adaptation into clinical workflow. Overcoming these barriers through multi-institutional collaboration and strong validation frameworks will be essential to unlock the full potential of ML. Advancement in research will enable the transformation of CRC care to provide more accurate diagnoses and targeted treatments, ultimately changing patient outcomes. Insight box This review examines the transformative impact of machine learning (ML) in colorectal cancer (CRC) research and care. By integrating multi-omics, radiomics, and clinical data, ML models outperform traditional diagnostic and prognostic methods, enabling precise risk prediction, personalized treatment, and early recurrence detection. The amalgamation of supervised learning, neural networks, and deep learning yields actionable insights that improve patient outcomes and address unmet needs in CRC management. The review also discusses solutions to challenges such as data standardization, ethics, and clinical workflow integration, offering a roadmap for real-world ML adoption. This work highlights the synergy between computational advances and oncology, providing a forward-thinking framework for CRC care.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":"17 ","pages":""},"PeriodicalIF":1.4,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-proteomics investigation of the early response to X-rays and carbon ion irradiations of HeLa cells.","authors":"Ousseynou Ben Diouf, Antoine Gilbert, Benoit Bernay, Mamadou Soumboundou, Cheikh Sall, François Chevalier","doi":"10.1093/intbio/zyaf008","DOIUrl":"10.1093/intbio/zyaf008","url":null,"abstract":"<p><p>Despite the considerable decline of cervical cancer incidence in developed countries, the disease remains a public health problem in low-income and middle-income countries due to the low popularity of human papillomavirus vaccination and cervical cancer screening. Mainly treated with radiotherapy, the number of recurrences linked to radioresistance increases in women suffering from this disease and constitutes major obstacle. Here, we perform a combined proteomic and phosphoproteomic profiling of HeLa cervical cancer cells after in vitro treatment with X-rays and carbon ions. We observed differential and extensive alterations at the proteins and phosphoproteins levels. In total, we observed 96 and 102 differentially expressed proteins (DEPs) after X-rays and C-ions irradiation, respectively. For phosphoproteins, our results revealed 21 and 41 DEPs in response to C-ions and X-rays ionizing radiation respectively. Furthermore, our study revealed several mechanisms significantly activated by cells in response to ionizing radiation, potentially related to cancer radioresistance, including sister chromatid segregation, rRNA processing, ribosomal large subunit biogenesis, positive regulation of phagocytosis, engulfment, peptidase regulatory activity and negative regulation of ERK1/2 cascade. We also identified three proteins IPM3, DUSP3 and COQ7, oppositely expressed across the C-ions and X-rays groups while MX2 phosphorylation was downregulated in both radiation qualities. Finally, our study revealed a specific kinase signature, associated with Hela cells radioresistance: CDK5, MTOR and CDK2 kinases were predicted in the group of X-rays irradiation while CDK1, PLK1 SRC and MAPK1 kinases were predicted in the group of C-ions irradiation. Taken together, these findings could help to define new potential pathways and biomarkers to be targeted in the treatment of cervical cancer. Insight Box Statement of Integration, Innovation and Insight In this study, a robust proteomic and phospho-proteomic strategy was developed in order to display HELA cells responses to radiations. Two time points were selected to highlight the early responses of cells, following irradiation with low and high LET. CDK1, SRC, MAPK1 kinases were predicted to be activated in response to carbon ions irradiation, while CDK5, MTOR, ATM kinases were predicted in response to X-rays. Several accessions, playing pivotal role in cell proliferation and resistance, were upregulated in X-rays irradiated cells and down regulated in carbon ions irradiated cells. This study gives an accurate picture of molecular events linked with HELA cells radioresistance and offer potential drug targets for optimization of cervical cancer radiotherapy.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":"17 ","pages":""},"PeriodicalIF":1.4,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144328408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The diagnosis and prognostic value and biological function of annexin A2 in hepatocellular carcinoma: a bioinformatic and experimental study.","authors":"Ya Li, Huhu Zhang, Fulin Sun, Chunjuan Yu, Shuyao Jiang, Lina Yang","doi":"10.1093/intbio/zyaf017","DOIUrl":"https://doi.org/10.1093/intbio/zyaf017","url":null,"abstract":"<p><p>Annexin A2 (ANXA2) is a Annexin family proteins member that plays a role in regulating cell growth and signal transduction pathways. However, its role in hepatocellular carcinoma (HCC) remains incompletely elucidated. We used bioinformatics methods to analyze the expression, diagnosis and prognostic value of ANXA2 in HCC using data from the TCGA, GTEx, GEO, HCCDB, HPA databases. Next, we predicted ANXA2-associated proteins and constructed a protein-protein interaction network via the STRING database. Furthermore, we obtained the biological processes associated with ANXA2 in HCC through GO, KEGG and GSEA enrichment analysis. Finally, CCK8, wound healing, and transwell were used to verify these biological processes in HCCLM3 cell lines. Insight box ANXA2 is highly expressed in a variety of tumors, with significantly higher levels in HCC than in normal tissues. ANXA2 expression is positively correlated with T stage, histologic grade, residual tumor, pathologic stage, tumor status and fibrosis ishak score in HCC, and high ANXA2 expression suggests a poorer prognosis. Additionally, ANXA2 has diagnostic value in HCC. Its expression is closely associated with S100A family proteins and immune infiltration. Enrichment analysis showed that high ANXA2 expression activates biological processes such as epithelial-mesenchymal transition (EMT), NF-κB and Wnt signaling pathways. The results of cell experiment were consistent with bioinformatics analysis. Our study explored the role of ANXA2 in the occurrence and development of HCC, which may provide reference for the treatment of HCC.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":"17 ","pages":""},"PeriodicalIF":1.4,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144986338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LARP4B inhibits ferroptosis and accelerates the progression of pancreatic cancer by activating WNK1-induced NRF2/GCH1/BH4 pathway.","authors":"Jiehao Tu, Lun Zhang","doi":"10.1093/intbio/zyaf019","DOIUrl":"10.1093/intbio/zyaf019","url":null,"abstract":"<p><p>Ferroptosis plays a crucial role in inhibiting tumor progression. La Ribonucleoprotein 4B (LARP4B) is known to function as a pro-oncogenic factor in digestive tumors, but its specific role and potential mechanisms remain unclear in pancreatic cancer (PC). In this study, we found that LARP4B was upregulated in PC tissues and cells. Overexpression of LARP4B promoted PC cell proliferation and invasion, while knockdown of LARP4B inhibited PC cell proliferation and invasion. Furthermore, knockdown of LARP4B was associated with intracellular iron overload, increased levels of reactive oxygen species (ROS) and malondialdehyde (MDA), and decreased glutathione (GSH) content and superoxide dismutase (SOD) activity in PC cells. Mechanistically, LARP4B binds to mRNA of with-no-lysine kinase 1 (WNK1) and promotes its stability, and WNK1 competitively binds to the partial Kelch domain of Kelch-like ECH-associated protein 1 (Keap1) to promote the nuclear translocation of nuclear factor erythroid-2-related factor 2 (NRF2), thereby activating the NRF2/GCH1/BH4 pathway and inhibiting ferroptosis in PC cells. ML385, a NRF2 nuclear translocation inhibitor, partially rescued the inhibitory effect of WNK1 on ferroptosis in PC cells. Finally, in vivo experiments showed that knockdown of LARP4B suppressed tumor growth in PC xenograft mice. In conclusion, our study demonstrated that LARP4B inhibited ferroptosis by activating the WNK1-mediated NRF2/GCH1/BH4 pathway, thereby promoting PC progression. Insight Box This work provides evidence for LARP4B as a pro-oncogenic factor in pancreatic cancer, while also offers new insights into the further understanding of the biological functions of LARP4B and the oncological mechanisms of pancreatic cancer. We found that LARP4B is upregulated in PC tissues and cells, and its overexpression promotes the proliferation and invasion of PC cells. Additionally, we discovered that LARP4B binds to WNK1 mRNA and enhances its stability. WNK1 competitively binds to Keap1 to facilitate NRF2 nuclear translocation, thereby activating the NRF2/GCH1/BH4 pathway and inhibiting ferroptosis in PC cells. These findings provide significant insights for further research on PC and the development of therapeutic strategies.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":"17 ","pages":""},"PeriodicalIF":1.4,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145180949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prediction of protein-protein interaction sites between Russell's viper PLA2 and the γ-phospholipase inhibitor PIP from the amino acid frequency distribution of a bio-panned peptide set.","authors":"Karthika Rajan, Margaret Reick, Aswathy Alangode, Martin Reick","doi":"10.1093/intbio/zyaf012","DOIUrl":"10.1093/intbio/zyaf012","url":null,"abstract":"<p><p>We screened a random peptide phage display library using Russell's viper venom phospholipase A2 (RV-PLA2) as bait. Sequence information from the resulting set of bio-panned heptapeptides was analyzed and mined to determine likely sites of interaction between two subunits of RV-PLA2 homo dimers and between RV-PLA2 and the γPLA2 inhibitor PIP from Malayopython reticulatus. This was accomplished in part by sequence alignment of the affinity-selected peptides with the sequences of RV-PLA2 and PIP. Because similarity scores calculated from sequence alignments proved inadequate to determine interaction interfaces accurately for RV-PLA2 dimers, we explored the use of amino acid frequency-based interactions scores (SFI/SFIN) for a more accurate prediction of protein-protein interaction sites. Heptamers with elevated SFI(N) scores were compared to interfaces of interaction observed in crystal structures of RV-PLA2 homodimers and to sites of interaction predicted by protein-protein docking between structures of RV-PLA2 and model of PIP. Segments with a high density of protein-protein contacts coincided with heptamer sequences exhibiting SFI and/or SFIN scores significantly above average, in both RV-PLA2 homodimers and in RV-PLA2 γPLI heteromeric structures. Elevated SFI and SFIN scores were associated with peptide function since the heptamers with some of the highest SFI and SFI(N) scores, LPGLPLS, GLPLSLQ and SLQNGLY constitute the known PLA2 inhibitor P-PB.I (LPGLPLSLQNGLY) while KLGRVDI, and WDGVYIR, constitute PIP-17 (LGRVDIHVWDGVYIRGR), IC50 for hsPLA2: 5.3 μM. A graph showing the alignment of maxima between SFI scores and average solvent accessibility (per heptamer) suggests that solvent accessibility is a major driver of both protein-protein interaction and phage selection. Insights We show by computational methods that in sets of small phage-displayed peptides of the same length selected for binding to the same target protein, amino acids contributing to binding at a particular position occur at higher frequencies than in random peptides. This position-specific selection of particular amino acids can be detected in the position-specific amino acid frequency distribution of that set of selected peptides. Therefore, when this position-specific amino acid frequency is mapped back onto a particular amino acid sequence of the same length, the sum of these frequencies can function as a measure of enrichment of selected amino acids.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":"17 ","pages":""},"PeriodicalIF":1.4,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144577585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identify new pseudogene RPL7P1-oriented network as a drug target against infections pre-existing diabetes.","authors":"Jiajun Chen, Chenxi Li, Ying Wang, Shiwei Chen, Xiangqi Li","doi":"10.1093/intbio/zyaf015","DOIUrl":"10.1093/intbio/zyaf015","url":null,"abstract":"<p><strong>Background: </strong>Diabetes coexisting with infections (DCI) significantly increases the risk of severe outcomes and mortality in patients. This study proposes that RPL7P1, an uncharacterized pseudogene, plays a role in the pathogenesis of DCI.</p><p><strong>Methods: </strong>Using a multifaceted approach, we employed experimental datasets from ENCODE to identify key genes. Drug repositioning was performed using gene network analysis with z-scores and the ROCR package. Network expansion was facilitated by NetworkAnalyst's core algorithms, with disease validation through the NHGRI GWAS Catalog. Cytoscape was utilized for network visualization.</p><p><strong>Results: </strong>Our findings reveal RPL7P1's potential involvement in DCI through modulation of CBL and STXBP3 by sequestering hsa-miR-144-3p, interaction with IGF2BP2 protein, and crosstalk with ATP6V1E1 RNA. Single-cell profiling pinpointed endothelial cells as a potential signaling nexus. Therapeutic agents targeting the RPL7P1-centric network showed promise in managing infections in diabetic patients. Additionally, we identified key molecular players, the m6A modification of RPL7P1, and its role in cuproptosis-a novel form of cell death.</p><p><strong>Conclusion: </strong>This research elucidates the potential role of the novel pseudogene RPL7P1 in DCI, highlighting the importance of pseudogenes in complex diseases and providing novel insights into the epigenetic modulation of diabetes complicated by infections. Insight Box Diabetes and infections often coexist, complicating our understanding of their shared mechanisms. To address this, we employed a comprehensive suite of bioinformatics methods, including pathway mapping, ceRNA analysis, PPI evaluation, single-cell dissection, network modeling, and drug repositioning strategies. Our research revealed that RPL7P1 modulates signaling pathways by sponging miR-144-3p, interacting with IGF2BP2 and ATP6V1E1 RNA, and influencing cuproptosis-a novel form of cell death-through m6A modification, a key RNA modification. We identified endothelial cells as key mediators of the RPL7P1 network in the liver. Additionally, our integrative approach uncovered five potential therapeutic drugs targeting the RPL7P1 network. These findings provide novel insights into coexisting diabetes and infections, underscoring the value of multidisciplinary strategies in uncovering coexisting disease mechanisms and treatment opportunities.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":"17 ","pages":""},"PeriodicalIF":1.4,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144763067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USP46 sensitizes BeWo trophoblasts to ferroptosis by stabilizing CIRBP.","authors":"Linlin Hu, Caihong Chen","doi":"10.1093/intbio/zyaf010","DOIUrl":"10.1093/intbio/zyaf010","url":null,"abstract":"<p><p>Preeclampsia is a type of pregnancy complication that manifests as hypertension and albuminuria, associated with improper development of blood vessels in the placenta. However, the precise cause of preeclampsia is not well defined. Ferroptosis is a type of cell death involving abnormal accumulation of iron and lipid reactive oxygen species (ROS) in cells. Accumulating evidence indicates that ferroptosis may contribute to preeclampsia development, but the underlying mechanism remains unclear. Several ubiquitin-specific proteases (USPs) have been reported to repress ferroptosis, but whether other USPs regulate ferroptosis and preeclampsia development remains elusive. Here we identified USP46 as a potent regulator of erastin-induced ferroptosis in BeWo trophoblasts, which serve as an in vitro model to study preeclampsia. We found that overexpression of USP46 promoted erastin-induced ferroptosis in BeWo cells, while knockdown of USP46 led to resistance to erastin-induced ferroptosis. This resistance could be reversed by excessive cold-inducible RNA-binding protein (CIRBP). Immunoprecipitation experiments showed that USP46 interacts with CIRBP to inhibit its ubiquitination. These findings suggest that USP46 sensitizes BeWo cells to ferroptosis by stabilizing CIRBP. Insight Box Preeclampsia is a severe pregnancy complication with an unknown pathogenesis. Studies have shown that several ubiquitin-specific proteases (USPs) can inhibit ferroptosis and affect the occurrence of preeclampsia. However, given the numerous genes in the USP family, it remains unclear whether other USPs regulate ferroptosis and the development of preeclampsia. In this study, we identified USP46 as a strong regulator of ferroptosis in BeWo cells. USP46 interacts with CIRBP to reduce its ubiquitination and stabilize its expression, thereby promoting ferroptosis. This study reveals the key role of USP46 in regulating ferroptosis and provides a new target for etiological research and treatment of preeclampsia.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":"17 ","pages":""},"PeriodicalIF":1.4,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144562616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative bioinformatics and drug repurposing for metastatic prostate cancer: identifying novel therapeutic targets by transcriptional profiling and molecular Modeling.","authors":"Haseeb Nisar, Jignesh Prajapati, Asma Muhammad Mumtaz, Atiqa Iftikhar, Faria Faran, Rimsha Hamid Mehmood, Samiah Shahid, Dweipayan Goswami","doi":"10.1093/intbio/zyaf016","DOIUrl":"https://doi.org/10.1093/intbio/zyaf016","url":null,"abstract":"<p><p>Metastasis is one of the leading factors of cancer-related deaths worldwide. New potential targets and treatment strategies are needed to extend survival and enhance the quality of life for these patients. We performed an in-depth bioinformatics analysis to identify potential genes and associated potential therapeutic compounds for metastasis of prostate adenocarcinoma. The differentially expressed genes (DEGs) were first identified using four datasets (GSE8511), (GSE3325), (GSE27616) and (GSE6919) present in the Gene Expression Omnibus (GEO) database and analyzed using the GEO2R. WGCNA was performed to find a significant gene cluster. Network analysis was performed using MCODE and Cytohubba plugins of Cytoscape to select hub genes. Moreover, expression validation of key genes was carried out using the TCGA dataset. Functional annotation and pathway enrichment analyses were conducted for validation, while survival analysis was applied to assess potential therapeutic effects. DEGs retrieved from the GEO were submitted to the Connectivity Map database to identify potentially related compounds. Molecular docking, ADMET analysis and drug-likeness properties, MD simulations and MM-GBSA analysis were performed to screen for the best potential drugs. We identified three compounds-Prunetin, Ofloxacin, and ALW-II-49-7 that may help extend disease-free survival in patients with tumor metastasis. Additionally, ACTA2, MYLK, and CNN1 were recognized as potential therapeutic targets for these compounds. These drugs' potential effectiveness and binding efficiency were screened using induced fit molecular docking followed by 100 ns MD-based Simulations and MM-GBSA analysis. However, further in vitro and in vivo studies are needed to confirm these findings. Insight box This study integrates microarray gene expression profiling with bioinformatics tools to identify differentially expressed genes (DEGs) and co-expression networks using WGCNA. Network analysis in Cytoscape was used to screen hub genes, and the Connectivity Map (cMAP) database was searched for potential candidate drugs. Binding efficiency of repurposed drugs was evaluated using molecular docking, molecular dynamics (MD) simulations, and MM-GBSA analysis. Our findings provide the potential therapeutic drugs and targets of prostate adenocarcinoma metastasis with possibilities for follow-up in vitro and in vivo validation.</p>","PeriodicalId":520649,"journal":{"name":"Integrative biology : quantitative biosciences from nano to macro","volume":"17 ","pages":""},"PeriodicalIF":1.4,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144986405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}