IUBMB LifePub Date : 2025-05-21DOI: 10.1002/iub.70019
Xin Jin, Qingqing Zhao, Xiaowen Hao, Peicong Shi, Yan Wang, Pei Wang
{"title":"Proline- and Serine-Rich Coiled-Coil 1 Predicts an Unfavorable Prognosis and Exhibits Oncogenic Activities in Breast Cancer","authors":"Xin Jin, Qingqing Zhao, Xiaowen Hao, Peicong Shi, Yan Wang, Pei Wang","doi":"10.1002/iub.70019","DOIUrl":"https://doi.org/10.1002/iub.70019","url":null,"abstract":"<div>\u0000 \u0000 <p>Proline- and serine-rich coiled-coil 1 (PSRC1) has been implicated in various cancers, yet its role in breast cancer (BRCA) remains incompletely understood. Here, we employed the UALCAN database to explore PSRC1 expression in BRCA and obtained survival prognosis data from the Kaplan–Meier Plotter database. Additionally, PSRC1 expression was analyzed in 81 pairs of BRCA tissues and their corresponding adjacent noncancerous tissues through quantitative real-time PCR, western blotting, and immunohistochemistry. We observed PSRC1 was overexpressed in BRCA tissues, especially in triple negative breast cancer (TNBC). Higher PSRC1 levels correlated with poorer outcomes for BRCA patients. In 81 BRCA tumor tissues, PSRC1 protein levels were significantly associated with positive vessel tumor embolus. Subsequently, the clinical relevance of PSRC1 in BRCA was assessed using the chi-square test, the Kaplan–Meier model with a Log-rank test, as well as univariate and multivariate analyses. Patients with high PSRC1 had worse prognoses. Elevated PSRC1 expression served as an independent predictor of prognosis. Moreover, we investigated the effects of PSRC1 on BRCA cell phenotypes in MCF-7 and BT549 cells and used a mouse xenograft model with BT549 cells to determine its in vivo effect. Both in vitro and in vivo experiments demonstrated that silencing PSRC1 inhibited cell proliferation, migration, and tumor development. In summary, our results indicate that high PSRC1 expression is closely linked to BRCA patient survival and could be a valuable prognostic biomarker for this disease.</p>\u0000 </div>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 5","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144100541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
IUBMB LifePub Date : 2025-05-20DOI: 10.1002/iub.70022
Shuqing Yang, Xinxin Xu, Lulu Wang, Yi Fang, Yang Zhou, Chunsun Dai, Lei Jiang, Boqing Zhang, Jing Luo
{"title":"Contrast-Induced Acute Kidney Injury is Modulated by Circadian CLOCK/NRF2 Pathway","authors":"Shuqing Yang, Xinxin Xu, Lulu Wang, Yi Fang, Yang Zhou, Chunsun Dai, Lei Jiang, Boqing Zhang, Jing Luo","doi":"10.1002/iub.70022","DOIUrl":"https://doi.org/10.1002/iub.70022","url":null,"abstract":"<div>\u0000 \u0000 <p>Numerous kidney functions exhibit substantial circadian oscillations, such as renal blood flow, glomerular filtration rate, tubular reabsorption function, and erythropoietin production. The onset and the injury of acute kidney injury caused by ischemia or drugs also have a circadian rhythmicity. Contrast media are widely used in clinical diagnosis and treatment; however, whether contrast-induced kidney injury exhibits a time-of-day dependence is unknown. We retrospectively analyzed 33 patients who underwent percutaneous coronary angiography and found that contrast induced the increase of serum neutrophil gelatinase-associated lipocalin (NGAL) was more obvious in the group who underwent operation during 6:00 ~ 13:00 than the group who underwent operation between 13:00 ~ 20:00. In addition, C57BL/6J mice were injected with iohexol at different times. The kidney injury of mice injected with iohexol at ZT12 was more severe than that at ZT0, which was manifested in the increase of urinary KIM1 and NGAL, enhanced renal tubular lipid peroxidation, and increased tubular ferroptosis. Inhibition of ferroptosis could alleviate kidney injury induced by iohexol at ZT12. Mechanistically, we found that nuclear factor erythrocyte 2-associated factor 2 (NRF2) expression has a 24-h circadian rhythm and is directly regulated by CLOCK. Administration of 4-Octyl itaconate at ZT12 to increase NRF2 expression could attenuate iohexol-induced tubular ferroptosis. These findings provide a new insight into the pathology of contrast medium-induced kidney injury, in which oscillatory NRF2 expression regulated by CLOCK contributes to the susceptibility of contrast-induced kidney injury in a time-of-day–specific fashion.</p>\u0000 </div>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 5","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144091893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
IUBMB LifePub Date : 2025-05-19DOI: 10.1002/iub.70025
Francesca Tondi, Roberta Annamaria Cirsmaru, Chiara Conti, Antonia Follenzi, Paolo Gresele, Cristina Olgasi, Loredana Bury
{"title":"Hermansky-Pudlak Syndrome: From Molecular Pathogenesis to Targeted Therapies","authors":"Francesca Tondi, Roberta Annamaria Cirsmaru, Chiara Conti, Antonia Follenzi, Paolo Gresele, Cristina Olgasi, Loredana Bury","doi":"10.1002/iub.70025","DOIUrl":"https://doi.org/10.1002/iub.70025","url":null,"abstract":"<p>Hermansky-Pudlak syndrome (HPS) is a rare inherited disorder caused by defects in lysosome-related organelles (LROs) in various tissues, including platelets, melanocytes, and endothelial cells. Key features of HPS include oculocutaneous albinism, bleeding tendency, and, in some cases, pulmonary fibrosis, granulomatous colitis, and immunodeficiency. The condition is linked to mutations in 11 genes involved in the formation of LROs. Currently, treatment options for HPS are limited and often ineffective. Though cell and gene therapies have been explored for melanosomes and epithelial cells, there is limited knowledge about their application to platelets and endothelial cells. Understanding the detailed mechanisms of HPS pathogenesis is crucial, and using induced pluripotent stem cell (iPSC) models may provide valuable insights into the disease's molecular processes, aiding the development of new treatments. In this review, we will focus on the genetics and molecular mechanisms of HPS, on its clinical manifestations and current therapeutic approaches, highlighting the need for further research into the disease mechanisms and potential innovative therapies.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 5","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/iub.70025","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085415","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":"The combination of midkine inhibitor with Lenvatinib amplifies the suppression of hepatocellular carcinoma","authors":"Xue Chen, Shujun Guo, Qilin Meng, Junye Xie, Yujie Xiao, Yuanmeng Sun, Jinchi Yao, Xinyi Jiang, An Hong, Xiaojia Chen","doi":"10.1002/iub.70014","DOIUrl":"https://doi.org/10.1002/iub.70014","url":null,"abstract":"<p>Hepatocellular carcinoma (HCC) accounts for 75%–85% of primary liver cancer cases globally. HCC patients have a poor prognosis because of tumor metastasis and medication resistance; thus, novel therapy targets and techniques are needed. By using the Kaplan–Meier plotter database, we identified a strong association between midkine (MDK) and HCC mortality and validated its high expression in numerous HCC cell lines. In vitro, MDK down-regulation decreased HCC cell growth and macrophage M2-type polarization, whereas the presence of the MDK factor led to an increase in these processes. Combined with the first-line chemotherapeutic agent for HCC, Lenvatinib, zebrafish experiments showed that the inhibitor iMDK inhibited the growth of intersegmental vessels and subintestinal vessels, while also mitigating the pericardial edema side effect. In a subcutaneous mouse model, the combination of iMDK with Lenvatinib inhibited HCC growth, angiogenesis, and M2-type macrophage infiltration. These results indicate that MDK represents a promising therapeutic target for HCC. Furthermore, the combination of iMDK with Lenvatinib enhances HCC inhibition, thereby presenting a novel therapy option.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 5","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143905094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Modulation of Osteogenic Differentiation by CYBB in Osteoporotic Models","authors":"Zhaodong Wang, Chen Xu, Yajun Liu, Keyou Duan, Zhonglian Zhu, Jianzhong Guan","doi":"10.1002/iub.70023","DOIUrl":"https://doi.org/10.1002/iub.70023","url":null,"abstract":"<div>\u0000 \u0000 <p>Osteoporosis (OP) is a prevalent systemic skeletal disease characterized by increased bone fragility and fracture risk. Identifying factors that influence osteogenic differentiation in OP is crucial. We screened genes associated with OP from the Gene Expression Omnibus (GEO) database and constructed a weighted correlation network analysis (WGCNA) to identify hub genes, validating our findings in external and clinical cohorts. Various experiments assessed the proliferation, apoptosis, and osteogenic differentiation abilities of bone marrow mesenchymal stem cells (BMSCs) following CYBB knockdown. We established a postmenopausal OP model in rats through bilateral ovariectomy (OVX) and evaluated OP severity using three-dimensional computed tomography (3D-CT) and H&E staining. Differential gene expression analysis revealed that CYBB was significantly upregulated in OP, with the highest area under the curve (AUC) among differentially expressed genes (DEGs). Notably, CYBB expression in BMSCs decreased over time. Knockdown of CYBB promoted BMSC proliferation and reduced apoptosis, as demonstrated by Alizarin red and ALP staining, which indicated enhanced osteogenic differentiation. Markers such as RUNX1, RUNX2, ALP, secreted phosphoprotein 1 (SPP1), and bone sialoprotein (BSP) were upregulated post-knockdown. In vivo, CYBB knockdown improved bone mineral density (BMD), relative bone volume fraction (BV/TV), and trabecular number (Tb.N). In conclusion, CYBB influences OP progression by modulating bone formation.</p>\u0000 </div>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 5","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143897048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
IUBMB LifePub Date : 2025-05-02DOI: 10.1002/iub.70018
Leire Torices, Caroline E. Nunes-Xavier, Rafael Pulido
{"title":"Therapeutic Potential of Translational Readthrough at Disease-Associated Premature Termination Codons From Tumor Suppressor Genes","authors":"Leire Torices, Caroline E. Nunes-Xavier, Rafael Pulido","doi":"10.1002/iub.70018","DOIUrl":"https://doi.org/10.1002/iub.70018","url":null,"abstract":"<p>Tumor suppressor genes are frequently targeted by mutations introducing premature termination codons (PTC) in the protein coding sequence, both in sporadic cancers and in the germline of patients with cancer predisposition syndromes. These mutations have a high pathogenic impact since they generate C-terminal truncated proteins with altered stability and function. In addition, PTC mutations trigger transcript degradation by nonsense-mediated mRNA decay. Suppression of PTC by translational readthrough restores protein biosynthesis and stabilizes the PTC-targeted mRNA, making a suitable therapeutic approach the reconstitution of active full-length tumor suppressor proteins by pharmacologically-induced translational readthrough. Here, we review the recent advances in small molecule pharmacological induction of translational readthrough of disease-associated PTC from tumor suppressor genes, and discuss the therapeutic potential of translational readthrough in specific groups of patients with hereditary syndromic cancers.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 5","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/iub.70018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143896967","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":"Synergistic Effects of Epirubicin-Vorinostat-Pimozide Drug Cocktail on Proliferation, Stemness, Invasiveness, and Fatty Acid Metabolism in Breast Cancer Cells","authors":"Thirukumaran Kandasamy, Shilpi Sarkar, Azar Zochedh, Thandavarayan Kathiresan, Siddhartha Sankar Ghosh","doi":"10.1002/iub.70020","DOIUrl":"https://doi.org/10.1002/iub.70020","url":null,"abstract":"<div>\u0000 \u0000 <p>Chemotherapeutic treatments for breast cancer are often associated with severe toxicity due to the requirement of high concentrations of the drugs for efficacy. The combination of chemotherapy drugs along with repurposed drugs offers a promising strategy to enhance efficacy while reducing toxicity. However, the effectiveness of such combinations is likely to be hindered by improper metabolism of the drugs due to the sharing of the same metabolizing enzymes. In this study, we explored a novel approach to enhance the efficacy of Pimozide (repurposed drug) by combining it with chemotherapeutic drugs that utilize different metabolizing enzymes than Pimozide, thereby reducing metabolic load and toxicity. The Epirubicin-SAHA(Vorinostat)-Pimozide (ESP) combination emerged as highly synergistic, reducing the IC<sub>50</sub> of Pimozide from 16.54 to 0.57 μM in MCF-7 cells and from 17.5 to 3.35 μM in MDA-MB-231 cells, representing a significant enhancement in efficacy. Mechanistic studies revealed increased intracellular reactive oxygen species (ROS) generation and activation of the intrinsic apoptosis pathway, as indicated by a 10-fold increase in the cleaved PARP levels. In MDA-MB-231 cells, there was also a 2-fold increase in p53 and a 10-fold increase in p21 expression, with a concomitant reduction in AKT signaling. Furthermore, the ESP combination reduced cancer stemness, invasiveness, fatty acid uptake, and lipid droplet accumulation, pointing to its broad impact on cancer cell survival and metabolism. These findings suggest that the ESP combination holds promise as an effective therapeutic strategy for breast cancer, with reduced toxicity and enhanced efficacy.</p>\u0000 </div>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 5","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
IUBMB LifePub Date : 2025-04-02DOI: 10.1002/iub.70015
Wenjia Xie, Lingqi Gao, Xinyan Gu, Liu Li, Hui Zheng, Lulu Wang, Ping Wen, Yang Zhou, Lei Jiang, Chunsun Dai, Hongdi Cao
{"title":"Ischemic preconditioning attenuates ischemia/reperfusion-induced acute kidney injury dependent on mitochondrial protease CLPP","authors":"Wenjia Xie, Lingqi Gao, Xinyan Gu, Liu Li, Hui Zheng, Lulu Wang, Ping Wen, Yang Zhou, Lei Jiang, Chunsun Dai, Hongdi Cao","doi":"10.1002/iub.70015","DOIUrl":"https://doi.org/10.1002/iub.70015","url":null,"abstract":"<p>Ischemic preconditioning (IPC) is a phenomenon in which brief periods of ischemia trigger protective mechanisms that alleviate subsequent ischemia–reperfusion injury (IRI), although the precise protective mechanism remains unclear. This study investigated the mechanism by which IPC protects acute kidney injury (AKI) induced by renal IRI. We found that IPC for 10 min significantly ameliorated IRI-induced AKI, whereas IPC for 5 or 15 min did not have any protective effects. Renal ischemia increased the expression of caseinolytic protease P (CLPP) in tubular epithelial cells. The peak effect was reached after 10 min of renal ischemia, during which no mitochondrial deposition of <b>misfolded/unfolded</b> proteins or signs of AKI were evident. However, after 15 min of renal ischemia, there was no further increase in CLPP levels, which was accompanied by mitochondrial deposition of <b>misfolded/unfolded</b> proteins and signs of AKI. The increase in CLPP levels suggests potential activation of the mitochondrial unfolded protein response (UPR<sup>mt</sup>), which is a cellular stress response pathway that regulates the expression of mitochondrial chaperones and proteases to maintain protein homeostasis within the mitochondria. Knockdown of <i>Clpp</i> led to the aggregation of mitochondrial unfolded/misfolded proteins and phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which indicated integrated stress response (ISR) activation. <i>Clpp</i> knockdown in mice antagonized the protective effects induced by IPC for 10 min during renal IRI. Furthermore, the inhibition of ISR activation by an ISR inhibitor (ISRIB) may also impede the protective effects of IPC for 10 min. This study indicates that IPC can ameliorate renal IRI injury and that its effect is dependent on CLPP.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 4","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143749463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
IUBMB LifePub Date : 2025-03-29DOI: 10.1002/iub.70017
Maria Mahmood, Emma Little, Nicole Girard, Fanqi Wu, Tristan Samuels, Ilka U. Heinemann, Noah M. Reynolds
{"title":"Yeast models for Charcot-Marie-Tooth disease-causing aminoacyl-tRNA synthetase alleles reveal the cellular basis of disease","authors":"Maria Mahmood, Emma Little, Nicole Girard, Fanqi Wu, Tristan Samuels, Ilka U. Heinemann, Noah M. Reynolds","doi":"10.1002/iub.70017","DOIUrl":"https://doi.org/10.1002/iub.70017","url":null,"abstract":"<p>Charcot-Marie-Tooth disease (CMT) is a genetically diverse hereditary disorder that affects the motor and sensory nerves, impacting about 1 in 2500 people. It can be inherited through autosomal dominant (AD), autosomal recessive (AR), or X-linked genetic patterns. CMT2, one of the primary subtypes, is characterized by axonal degeneration and commonly presents with muscle weakness, atrophy, foot deformities, and sensory loss. Aminoacyl-tRNA synthetases (aaRSs) play an important role in the genetic underpinnings of CMT2, with more than 60 disease-causing alleles identified across eight different aaRSs, including alanyl-, asparaginyl-, histidyl-, glycyl-, methionyl-, tryptophanyl-, seryl-, and tyrosyl-tRNA synthetases. Mutations in aaRS genes can lead to destabilization of the enzyme, reduced aminoacylation, and aberrant protein complex formation. Yeast as a simple organism provides a robust model system to study the pathogenic effects of aaRS CMT mutations. In this review, we discuss the advantages and limitations of the yeast model systems for CMT2-causative mutations in aaRS.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 4","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/iub.70017","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143726859","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}