Frontiers in Molecular Biosciences最新文献

{"title":"Genome-wide CRISPR/Cas9 screening identifies key profibrotic regulators of TGF-β1-induced epithelial-mesenchymal transformation and pulmonary fibrosis.","authors":"Chunjiang Tan, Juan Wang, Xiangrong Ye, Kaidirina Kasimu, Ye Li, Feng Luo, Hui Yi, Yifeng Luo","doi":"10.3389/fmolb.2025.1507163","DOIUrl":"10.3389/fmolb.2025.1507163","url":null,"abstract":"<p><strong>Background: </strong>The idiopathic pulmonary fibrosis (IPF) is a progressive and lethal interstitial lung disease with high morbidity and mortality. IPF is characterized by excessive extracellular matrix accumulation (ECM) and epithelial-mesenchymal transformation (EMT). To date, few anti-fibrotic therapeutics are available to reverse the progression of pulmonary fibrosis, and it is important to explore new profibrotic molecular regulators mediating EMT and pulmonary fibrosis.</p><p><strong>Methods: </strong>Based on our model of TGF-β1-induced EMT in BEAS-2B cells, we performed the genome-wide CRISPR/Cas9 knockout (GeCKO) screening technique, pathway and functional enrichment analysis, loss-of-function experiment, as well as other experimental techniques to comprehensively investigate profibrotic regulators contributing to EMT and the pathogenesis of pulmonary fibrosis.</p><p><strong>Results: </strong>Utilizing the GeCKO library screening, we identified 76 top molecular regulators. Ten candidate genes were subsequently confirmed by integrating the high-throughput data with findings from pathway and functional enrichment analysis. Among the candidate genes, knockout of <i>COL20A1</i> and <i>COL27A1</i> led to decreased mRNA expression of ECM components (Fibronectin and Collagen-I), as well as an increased rate of cell apoptosis. The mRNA expression of Collagen-I, together with the cell viability and migration, were inhibited when knocking out the <i>WNT11</i>. In addition, a decrease in the protein deposition of ECM components was observed by suppressing the expression of <i>COL20A1</i>, <i>COL27A1</i>, and <i>WNT11</i>.</p><p><strong>Conclusion: </strong>Our study demonstrates that the <i>COL20A1</i>, <i>COL27A1</i>, and <i>WNT11</i> serve as key profibrotic regulators of EMT. Gaining understanding and insights into these key profibrotic regulators of EMT paves the way for the discovery of new therapeutic targets against the onset and progression of IPF.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1507163"},"PeriodicalIF":3.9,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11872725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A CRISPR-Cas-based recombinase polymerase amplification assay for ultra-sensitive detection of active <i>Trypanosoma brucei evansi</i> infections.","authors":"Andrés Álvarez-Rodríguez, Zeng Li, Bo-Kyung Jin, Benoit Stijlemans, Peter Geldhof, Stefan Magez","doi":"10.3389/fmolb.2025.1512970","DOIUrl":"https://doi.org/10.3389/fmolb.2025.1512970","url":null,"abstract":"<p><strong>Introduction: </strong>Control of <i>Trypanosoma brucei evansi</i> (<i>T. b. evansi</i>) infections remains a significant challenge in managing Surra, a widespread veterinary disease affecting both wild and domestic animals. In the absence of an effective vaccine, accurate diagnosis followed by treatment is crucial for successful disease management. However, existing diagnostic methods often fail to detect active infections, particularly in field conditions. Recent advancements in CRISPR-Cas technology, combined with state-of-the-art isothermal amplification assays, offer a promising solution. This approach has led us to the development of a <i>Tev</i>RPA-CRISPR assay, a highly sensitive and specific <i>T. b. evansi</i> diagnostic tool suitable for both laboratory and field settings.</p><p><strong>Methods: </strong>First, the <i>Tev</i>CRISPR-Cas12b cleavage assay was developed and optimized, and its analytical sensitivity was evaluated. Next, this technology was integrated with the <i>Tev</i>RPA to create the <i>Tev</i>RPA-CRISPR test, with the reaction conditions being optimized and its analytical sensitivity and specificity assessed. Finally, the test's accuracy in detecting both active and cured <i>T. b. evansi</i> infections was evaluated.</p><p><strong>Results: </strong>The optimized <i>Tev</i>CRISPR-Cas12b cleavage assay demonstrated the ability to detect <i>T. b. evansi</i> target DNA at picomolar concentrations. Integrating <i>Tev</i>CRISPR-Cas12b with RPA in Two-Pot and One-Pot <i>Tev</i>RPA-CRISPR tests achieved up to a 100-fold increase in analytical sensitivity over RPA alone, detecting attomolar concentrations of <i>T. b. evansi</i> target DNA, while maintaining analytical specificity for <i>T. b. evansi</i>. Both assays exhibited performance comparable to the gold standard <i>Tev</i>PCR in experimental mouse infections, validating their effectiveness for detecting active infections and assessing treatment efficacy.</p><p><strong>Discussion: </strong>The <i>Tev</i>RPA-CRISPR tests prove highly effective for diagnosing active infections and assessing treatment efficacy, while being adaptable for both laboratory and field use. Thus, the <i>Tev</i>RPA-CRISPR assays emerge as a promising addition to current diagnostic tools, offering efficient and reliable detection of active <i>T. b. evansi</i> infections.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1512970"},"PeriodicalIF":3.9,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11867955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An unfolded protein response (UPR)-signature regulated by the NFKB-miR-29b/c axis fosters tumor aggressiveness and poor survival in bladder cancer.","authors":"Jian Zhang, Xiaosong Fan, Yu Chen, Yichao Han, Weixing Yu, Shaolin Zhang, Bicheng Yang, Junlong Zhang, Yanling Chen","doi":"10.3389/fmolb.2025.1542650","DOIUrl":"https://doi.org/10.3389/fmolb.2025.1542650","url":null,"abstract":"<p><strong>Background: </strong>Bladder cancer continues to pose a substantial global health challenge, marked by a high mortality rate despite advances in treatment options. Therefore, in-depth understanding of molecular mechanisms related to disease onset, progression, and patient survival is of utmost importance in bladder cancer research. Here, we aimed to investigate the underlying mechanisms using a stringent differential expression and survival analyses-based pipeline.</p><p><strong>Methods: </strong>Gene and miRNA expression data from TCGA and NCBI GEO databases were analyzed. Differentially expressed genes between normal vs tumor, among tumor aggressiveness groups and between early vs advanced stage were identified using Student's t-test and ANOVA. Kaplan-Meier survival analyses were conducted using R. Functional annotation, miRNA target and transcription factor prediction, network construction, random walk analysis and gene set enrichment analyses were performed using DAVID, miRDIP, TransmiR, Cytoscape, Java and GSEA respectively.</p><p><strong>Results: </strong>We identified elevated endoplasmic reticulum (ER) stress response as key culprit, as an eight-gene unfolded protein response (UPR)-related gene signature (UPR-GS) drives aggressive disease and poor survival in bladder cancer patients. This elevated UPR-GS is linked to the downregulation of two miRNAs from the miR-29 family (miR-29b-2-5p and miR-29c-5p), which can limit UPR-driven tumor aggressiveness and improve patient survival. At further upstream, the inflammation-related NFKB transcription factor inhibits miR-29b/c expression, driving UPR-related tumor progression and determining poor survival in bladder cancer patients.</p><p><strong>Conclusion: </strong>These findings highlight that the aberrantly activated UPR, regulated by the NFKB-miR-29b/c axis, plays a crucial role in tumor aggressiveness and disease progression in bladder cancer, highlighting potential targets for therapeutic interventions and prognostic markers in bladder cancer management.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1542650"},"PeriodicalIF":3.9,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11867963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolite profiling, antimalarial potentials of <i>Schleichera oleosa</i> using LC-MS and GC-MS: <i>in vitro</i>, molecular docking and molecular dynamics.","authors":"Peetha Vanaja, N S Hari Narayana Moorthy, Vivek Singh Rajpoot, Harshawardhan Rao, Rohit Kumar Goswami, Paranthaman Subash, Sulekha Khute, Kareti Srinivasa Rao","doi":"10.3389/fmolb.2025.1543939","DOIUrl":"https://doi.org/10.3389/fmolb.2025.1543939","url":null,"abstract":"<p><strong>Purpose: </strong>To explore the phytochemical composition of <i>Schleichera oleosa</i> bark and evaluate its potential antimalarial activity through <i>in vitro</i> and <i>in silico</i> analyses.</p><p><strong>Methods: </strong>The bark of <i>S. oleosa</i> was subjected to Soxhlet extraction using petroleum ether, chloroform, and methanol. The quantitative analysis of the extracts was performed to determine total phenolic, flavonoid, and tannin contents. Advanced analytical techniques such as Gas Chromatography-Mass Spectrometry (GC-MS) and Liquid Chromatography-Mass Spectrometry (LC-MS) were employed to identify 175 phytoconstituents from the methanolic extract In-vitro antimalarial activity was assessed against Plasmodium falciparum using the candle jar method, measuring parasite growth inhibition. The inhibitory concentration (IC50) values were calculated and compared with standard antimalarial drugs, chloroquine and quinine. Furthermore, computational analyses, including molecular docking and molecular dynamics simulations, were conducted to evaluate the interactions of identified phytochemicals with key malarial targets (1CEQ and 4ZL4). The efficacy of these compounds was compared with standard drugs like artesunate and chloroquine. Additionally, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiling and drug-likeness assessments were performed.</p><p><strong>Results: </strong>The methanolic extract of <i>S. oleosa</i> exhibited promising <i>in-vitro</i> antimalarial activity with an average IC50 value of 0.780 μg/mL, which, while higher than chloroquine (0.020 μg/mL) and quinine (0.268 μg/mL), still demonstrated significant efficacy. GC-MS and LC-MS analyses identified 175 phytoconstituents, among which two novel lead compounds, scillarenin and 4-[(Z)-(6-hydroxy-3-oxo-1-benzofuran-2(3H)-ylidene) methyl] phenyl beta-Dglucopyranoside, exhibited the highest docking scores and favorable ADMET profiles. Molecular docking and dynamics simulations confirmed strong binding affinities to malarial targets, surpassing some standard drugs in efficacy.</p><p><strong>Conclusion: </strong>This study reports, for the first time, the antimalarial potential of bioactive constituents derived from the bark of <i>S. oleosa</i>. The identified compounds, scillarenin and 4-[(Z)-(6-hydroxy-3-oxo-1-benzofuran-2(3H)-ylidene) methyl] phenyl beta-D-glucopyranoside, demonstrated promising antiplasmodial activity, validating traditional medicinal claims. The findings highlight the potential of <i>S. oleosa</i> as a source of novel antimalarial agents with fewer side effects compared to existing therapies. Further <i>in vivo</i> studies are warranted to confirm these results and support the development of new antimalarial drugs. This groundbreaking discovery contributes to the growing evidence supporting the role of medicinal plants in drug discovery.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1543939"},"PeriodicalIF":3.9,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11867967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term iron supplementation in four patients with X-linked erythropoietic protoporphyria: associations with serum proteins and erythrocyte protoporphyrin levels-a single-centre retrospective study.","authors":"Anna-Elisabeth Minder, Francesca Granata, Franziska van Breemen, Xiaoye Schneider-Yin, Elisabeth I Minder, Lanja Saleh, Jasmin Barman-Aksözen","doi":"10.3389/fmolb.2025.1509803","DOIUrl":"10.3389/fmolb.2025.1509803","url":null,"abstract":"<p><strong>Introduction: </strong>X-linked erythropoietic protoporphyria (XLEPP) is an ultra-rare inborn error of the heme biosynthesis characterised by the accumulation of large amounts of protoporphyrin IX (PPIX) and zinc-protoporphyrin in the erythrocytes. PPIX absorbs the energy of the visible light range and upon exposure causes painful phototoxic reactions and tissue damage. In addition, PPIX is excreted via the liver and bile, and can induce liver failure that requires life-saving liver transplantation. Case reports and data from a limited number of patients enrolled in a prospective study indicate that supplementation with iron, a co-substrate of the heme biosynthesis, can decrease blood PPIX concentrations and improve liver damage and photosensitivity in patients with XLEPP. However, long-term data on safety and effectiveness of iron supplementation in XLEPP to support this treatment strategy is limited.</p><p><strong>Methode: </strong>Here, we report the experience and long-term effects over up to 8 years of iron supplementation of the four patients with XLEPP in the Swiss cohort.</p><p><strong>Results: </strong>Our study shows that iron supplementation was safe and effective in lowering blood PPIX concentrations in our patients in the long term.</p><p><strong>Discussion: </strong>However, monitoring for adequate dosing and long-term effects is advisable and a standardisation of treatment protocols and international best practice guidelines are needed.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1509803"},"PeriodicalIF":3.9,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11864907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blood pressure improvement after resection of non-functioning adrenal adenomas: influencing factors and serum metabolic features.","authors":"Jianlei Zhang, Peiqiang Wu, Yule Chen, Min Wang, Wenbin Song","doi":"10.3389/fmolb.2025.1524121","DOIUrl":"10.3389/fmolb.2025.1524121","url":null,"abstract":"<p><strong>Introduction: </strong>Non-functioning adrenal adenomas (NFAs) are typically regarded as benign tumors that lack hormonal secretion. However, emerging evidence has shown that some patients with NFAs and hypertension experience improvements in blood pressure after adrenalectomy, indicating a potential correlation between NFAs and hypertension. Nevertheless, the precise mechanisms that underpin this phenomenon remain elusive.</p><p><strong>Methods: </strong>We collected data from all patients with adrenal adenomas who underwent unilateral laparoscopic partial or total adrenalectomy at the First Affiliated Hospital of Xi'an Jiaotong University in 2023. A statistical analysis was conducted on factors such as tumor diameter, duration of hypertension, BMI, and age. Additionally, we gathered serum samples from six patients who experienced postoperative blood pressure improvement and six patients who did not. These samples were subjected to targeted and untargeted metabolomic analyses to identify significant serum metabolites.</p><p><strong>Results: </strong>Our findings revealed that 50.9% of patients with NFAs and hypertension experienced blood pressure improvement after surgery. Additionally, patients in the improvement group (IG) exhibited larger tumor diameters alongside shorter durations of hypertension compared to their counterparts in the nonimprovement group (NIG). Untargeted metabolomic analysis identified 89 differentially abundant metabolites in the serum between the IG and NIG. In particular, we found that guanidinoacetic acid (GAA), a precursor of creatine synthesis that possibly participates in the occurrence of hypertension, was enriched in patients in the IG and reduced after surgery.</p><p><strong>Discussion: </strong>The findings of our study indicated that duration of hypertension and tumor diameter may exert an influence on the extent of postoperative blood pressure improvement, and NFAs might promote hypertension through GAA-related creatine metabolism.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1524121"},"PeriodicalIF":3.9,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11864923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Omics in endocrinology: from biomarker discovery to targeting therapeutic strategies.","authors":"Michele Costanzo, Shereen M Aleidi, Anas Abdel Rahman","doi":"10.3389/fmolb.2025.1567250","DOIUrl":"10.3389/fmolb.2025.1567250","url":null,"abstract":"","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1567250"},"PeriodicalIF":3.9,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11865747/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calcium-dependent adhesion protein CDH18, a potential biomarker for prognosis in uterine corpus endometrial carcinoma.","authors":"Xiaoxuan Tang, Shanxing Dang, Jie Qiu, Ruilan Zhou, Jing Ling, Limei Zhang, Xiaopeng Peng, Qingyun Li, Jin Liu, Wei Liao, Qingxiu Mei, Miao Xie, Yehong Sun, Jianmei Huang, Xuelian Du, Wencong Song","doi":"10.3389/fmolb.2025.1530253","DOIUrl":"10.3389/fmolb.2025.1530253","url":null,"abstract":"<p><strong>Background: </strong>Uterine corpus endometrial carcinoma (UCEC) is one of the most common cancers in women, yet lacks specific and sensitive tumor markers for diagnosis, as traditional markers like CA125 show limited specificity. This study investigates the clinical significance and prognostic value of CDH18, a calcium-dependent adhesion protein linked to tumor progression, in UCEC.</p><p><strong>Methods: </strong>Clinical data from UCEC patients were sourced from The Cancer Genome Atlas (TCGA) database. Pan-cancer analysis, differential expression examination, and survival analysis were conducted to investigate the differential expression of the calcium associated protein-CDH18 and its prognostic relevance. CDH18 mutations in UCEC were examined using the cBioPortal database. Additional analyses included functional enrichment, tumor mutational burden, tumor microenvironment (TME) estimates via ESTIMATE, and immune infiltration assessment to clarify CDH18's potential mechanisms in UCEC. Drug sensitivity testing was utilized to identify more suitable therapeutic options for patients. Immunofluorescence staining (IF) and Real-Time Polymerase Chain Reaction techniques (RT-PCR) confirmed CDH18 expression in UCEC tumor.</p><p><strong>Results: </strong>CDH18 expression was markedly increased in UCEC and showed a significant association with poorer prognosis, which was confirmed by our IF and RT-PCR results. Thirteen mutation sites were identified, and survival analysis showed that patients with higher CDH18 expression had shorter overall survival. The expression of CDH18 was confirmed to be an independent predictor of overall survival by multivariate COX regression analysis. Additionally, a predictive nomogram model was developed to accurately forecast outcomes for individuals with UCEC. Correlation analysis revealed that CDH18 expression exhibited a negative correlation with CD8 T cell levels and a positive correlation with resting NK cell and macrophage M2 levels. In the group with high CDH18 expression, the IC50 values for (5Z)-7-Oxozeaenol, AG-014699, CEP-701, Mitomycin C, PD-0325901, PD-0332991, PHA-665752, SL 0101-1, and SN-38 were notably elevated.</p><p><strong>Conclusion: </strong>CDH18 is a novel promising biomarker in UCEC, uniquely associating tumor progression, immune modulation, and chemotherapy resistance, offering enhanced prognostic accuracy and guiding individualized therapeutic strategies for improved patient outcomes.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1530253"},"PeriodicalIF":3.9,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11864935/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simulations of pH and thermal effects on SARS-CoV-2 spike glycoprotein.","authors":"Ziyuan Niu, Georgios Kementzidis, Miriam Rafailovich, Marcia Simon, Evangelos Papadopoulos, Bertal H Aktas, Yuefan Deng","doi":"10.3389/fmolb.2025.1545041","DOIUrl":"10.3389/fmolb.2025.1545041","url":null,"abstract":"<p><p>We performed triplicate and long-time all-atom molecular dynamics simulations to investigate the structures and dynamics of the SARS-CoV-2 spike glycoprotein (S-protein) for a broad range of pH = 1 through 11 and temperatures of 3°C through 75°C. This study elucidates the complex interplay between pH and thermal effects on S-protein structures, with implications for its behavior under diverse conditions, and identifies the RBD as a primary region of the structural deviations. We found: 1) Structural deviations in the S-protein backbone at pH = 1 are 210% greater than those at pH = 7 at 75°C, with most of the deviations appearing in the receptor-binding domain (RBD). Smaller structural changes are observed at pH = 3 and 11. 2) The pH and thermal conditions impact on the protein structures: substantial acidic and basic conditions expand the protein's solvent exposure, while high heat contracts. This effect is primarily pH-driven at extreme acidity and thermo-driven at moderate pH. 3) The Gibbs free energy landscape reveals that pH as the main driver of structural changes. 4) The parametrized methods enable the predictions of the S-protein properties at any reasonable pH and thermal conditions without explicit MD simulations.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1545041"},"PeriodicalIF":3.9,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850259/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143499813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-6/GATA2/SERPINE1 pathway is implicated in regulating cellular senescence after acute kidney injury.","authors":"Hongshuang Su, Xiaoxi Lin, Ayinuer Paredong, Congcong Yao, Yan Zhang, Mengke Geng, Yuqian Guan, Lichao Gong, Feng Jiang, Qi Lv, Songtao Shou, Heng Jin","doi":"10.3389/fmolb.2025.1538526","DOIUrl":"10.3389/fmolb.2025.1538526","url":null,"abstract":"<p><strong>Purpose: </strong>Acute kidney injury (AKI) secondary to Rhabdomyolysis syndrome represents a life-threatening complication, characterized by notably high incidence and mortality rates. The role of cellular senescence in the progression of AKI has increasingly garnered attention in recent years. Our previous research has demonstrated that remote ischemic postconditioning (RIPC) can attenuate renal cellular senescence and elevation of serum level of interleukin-6 (IL-6) induced by ischemia-reperfusion injury following crush injury. The objective of this study is to investigate the specific role of IL-6 in Rhabdomyolysis-induced AKI (RM-AKI).</p><p><strong>Methods: </strong>We established a mouse model of RM-AKI by intramuscular injection of glycerol and simulated RM-AKI at the cellular level by treating Hk-2 cells with myoglobin. Tocilizumab (TCZ), a humanized monoclonal antibody against the interleukin-6 (IL-6) receptor, is a key substance. IL-6, a multifunctional cytokine, plays a crucial role in the occurrence and development of various kidney diseases. It can promote inflammatory responses, cell proliferation, fibrosis, and other processes. TCZ exerts a protective effect on the kidneys by specifically binding to the IL-6 receptor and blocking the signal transduction of IL-6. Additionally, the levels of IL-6 were detected by employing ELISA kits. RNA sequencing analysis was performed on cells treated with myoglobin and tocilizumab. Flow cytometry was utilized to assess cell cycle distribution and the percentage of senescent cells. The expression levels of SERPINE1, GATA2, p53, and p21 were determined by real-time quantitative PCR and Western blot. Additionally, a dual-luciferase reporter gene assay was conducted to validate the binding effect of SERPINE1 and GATA2.</p><p><strong>Results: </strong>Transcriptome Analysis revealed that genes including GATA2 and SERPINE1 were downregulated in HK-2 cells following tocilizumab treatment. Inhibition of the IL-6 receptor by tocilizumab in these cells led to a reduction in cellular senescence, accompanied by decreased of the cell cycle regulatory proteins P53 and P21 in mRNA and protein levels, while alleviating cell cycle arrest. Additionally, a dual-luciferase reporter assay confirmed that GATA2 binds to the promoter of SERPINE1 (PAI-1), thereby initiating its transcription.</p><p><strong>Conclusion: </strong>The IL-6/GATA2/SERPINE1 pathway mediates cellular senescence after acute kidney injury, and inhibiting IL-6 can alleviate AKI-induced cellular senescence, providing an important basis for exploring new therapeutic strategies.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1538526"},"PeriodicalIF":3.9,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143499340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}