IUBMB Life最新文献

{"title":"Hermansky-Pudlak Syndrome: From Molecular Pathogenesis to Targeted Therapies","authors":"Francesca Tondi,&nbsp;Roberta Annamaria Cirsmaru,&nbsp;Chiara Conti,&nbsp;Antonia Follenzi,&nbsp;Paolo Gresele,&nbsp;Cristina Olgasi,&nbsp;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,&nbsp;Shujun Guo,&nbsp;Qilin Meng,&nbsp;Junye Xie,&nbsp;Yujie Xiao,&nbsp;Yuanmeng Sun,&nbsp;Jinchi Yao,&nbsp;Xinyi Jiang,&nbsp;An Hong,&nbsp;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,&nbsp;Chen Xu,&nbsp;Yajun Liu,&nbsp;Keyou Duan,&nbsp;Zhonglian Zhu,&nbsp;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&amp;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}

{"title":"Correction to “Upstream Transcription Factor 1 Suppresses Laryngeal Squamous Cell Carcinoma Progression Through Transcriptional Activation of Junctional Adhesion Molecule 3”","authors":"","doi":"10.1002/iub.70021","DOIUrl":"https://doi.org/10.1002/iub.70021","url":null,"abstract":"<p> <span>J. Yue</span>, <span>J. Liu</span>, <span>Y. Lou</span>, <span>X. Wang</span> <span>C. Zhang</span>, <span>Y. Guo</span>, <span>Y. Jia</span>, and <span>H. Huangfu</span>, “ <span>Upstream Transcription Factor 1 Suppresses Laryngeal Squamous Cell Carcinoma Progression Through Transcriptional Activation of Junctional Adhesion Molecule 3</span>,” <i>IUBMB Life</i> <span>77</span>, no. <span>3</span> (<span>2025</span>): e70013, https://doi.org/10.1002/iub.70013.</p><p>We apologize for this error.</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.70021","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143897049","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":"Therapeutic Potential of Translational Readthrough at Disease-Associated Premature Termination Codons From Tumor Suppressor Genes","authors":"Leire Torices,&nbsp;Caroline E. Nunes-Xavier,&nbsp;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,&nbsp;Shilpi Sarkar,&nbsp;Azar Zochedh,&nbsp;Thandavarayan Kathiresan,&nbsp;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 IC₅₀ 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}

{"title":"Ischemic preconditioning attenuates ischemia/reperfusion-induced acute kidney injury dependent on mitochondrial protease CLPP","authors":"Wenjia Xie,&nbsp;Lingqi Gao,&nbsp;Xinyan Gu,&nbsp;Liu Li,&nbsp;Hui Zheng,&nbsp;Lulu Wang,&nbsp;Ping Wen,&nbsp;Yang Zhou,&nbsp;Lei Jiang,&nbsp;Chunsun Dai,&nbsp;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^mt), 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}

{"title":"Yeast models for Charcot-Marie-Tooth disease-causing aminoacyl-tRNA synthetase alleles reveal the cellular basis of disease","authors":"Maria Mahmood,&nbsp;Emma Little,&nbsp;Nicole Girard,&nbsp;Fanqi Wu,&nbsp;Tristan Samuels,&nbsp;Ilka U. Heinemann,&nbsp;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}

{"title":"Downregulation of KLF9 alleviates tubulointerstitial fibrosis by modulating FABP4-mediated lipid accumulation","authors":"Lin Zhang,&nbsp;Xin-yu Wang,&nbsp;Ting Tian,&nbsp;Yu-ping Huang,&nbsp;Lu-lu Wu,&nbsp;Li-Li Zhuang,&nbsp;Guo-ping Zhou","doi":"10.1002/iub.70016","DOIUrl":"https://doi.org/10.1002/iub.70016","url":null,"abstract":"<p>Tubulointerstitial fibrosis (TIF) is a significant determinant in the pathogenesis of chronic kidney disease (CKD) and is commonly concurrent with lipid infiltration in the renal tubules. Nonetheless, the precise regulatory mechanism of this phenomenon remains incompletely understood. This research sought to uncover the involvement and underlying mechanism of KLF9 in the accumulation of lipids linked to TIF. As renal fibrosis models, TGF-β1 treated HK-2 cells and a unilateral ureteral obstruction (UUO) mouse model were utilized. Histopathological analysis of kidney tissues were evaluated by hematoxylin eosin (HE), periodic acid schiff (PAS), and Masson's trichrome staining. The levels of KLF9 protein and mRNA were quantified through western blot and real-time quantitative PCR, respectively, while triglyceride (TG) levels and lipid accumulation were evaluated using a TG assay kit and Oil Red O staining, respectively. The Pearson correlation coefficient was employed to assess the relationship between KLF9 levels and lipid accumulation. To elucidate the mechanisms underlying KLF9's regulation of lipid accumulation in TIF, luciferase reporter assays, chromatin immunoprecipitation (ChIP), and rescue experiments were performed. This research identified a significant increase in KLF9 expression in TIF, correlating with lipid accumulation. The inhibition of KLF9 in HK-2 cells significantly mitigated TGF-β1 triggered fibrosis and lipid accumulation. Subsequent animal studies corroborated these findings, showing that downregulating KLF9 mitigated fibrosis and lipid accumulation. The expression level of FABP4 was considerably higher in TIF models both in vitro and in vivo. Mechanistically, KLF9 bound to the FABP4 promoter region and positively regulated the expression of FABP4. The KLF9-FABP4 pathway regulated lipid synthesis and promoted lipid accumulation, which in turn promotes the progression of TIF. Our study has unveiled the involvement of KLF9 in driving FABP4 expression at the transcriptional level, culminating in lipid accumulation and subsequent fibrosis in TIF. These findings propose that targeting lipid deposition as a therapeutic strategy may hold promise for addressing TIF.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 3","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143698761","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":"OTUB1 facilitates lipid accumulation in oxLDL-induced THP-1 macrophages by stabilizing scavenger receptor-A","authors":"Xianwei Huang,&nbsp;Yixuan Liu,&nbsp;Xiong Liu,&nbsp;Ping Liu,&nbsp;Jiyan Lin","doi":"10.1002/iub.70012","DOIUrl":"10.1002/iub.70012","url":null,"abstract":"<p>The formation of foam cells triggered by excessive lipid accumulation within macrophages is a hallmark of atherosclerosis development. Scavenger receptor-A (SR-A) is a key regulator of lipid uptake by macrophages during oxidized low-density lipoprotein (oxLDL)-induced foam cell formation. Ubiquitination is a crucial post-translational modification that regulates the stability and function of targeted proteins, but whether SR-A is ubiquitinated and how ubiquitination affects SR-A function is unknown. We found that ovarian tumor domain protease 1 (OTUB1), a deubiquitinase (DUBs) that removes ubiquitination of targeted proteins, can stabilize SR-A in 293 T cells and THP-1 macrophages. Knockdown of OTUB1 in THP-1 macrophages reduced the SR-A protein level and impaired lipid accumulation in oxLDL-treated THP-1 macrophages, which can be rescued by excessive SR-A. These data suggested that OTUB1-mediated stabilization of SR-A may be critical for lipid accumulation in macrophages during foam cell formation.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"77 3","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669873","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}