IUBMB Life [JOURNAL]
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200 papers
Advancing Therapeutic Strategies for Nonsense-Related Diseases: From Small Molecules to Nucleic Acid-Based Innovations.
Ricci D, Cruciata I, Fiduccia I … +6 more , Vitale E, Corrao F, Branchini A, Carollo PS, Pibiri I, Lentini L
IUBMB Life · 2025 May · PMID 40420818 · Full text
Nonsense mutations in gene coding regions introduce an in-frame premature termination codon (PTC) in the mRNA transcript, resulting in the early termination of translation and the production of a truncated, nonfunctional...
Nonsense mutations in gene coding regions introduce an in-frame premature termination codon (PTC) in the mRNA transcript, resulting in the early termination of translation and the production of a truncated, nonfunctional protein. The absence of protein expression and the consequent loss of essential cellular functions are responsible for the severe phenotypes in the so-called genetic nonsense-related diseases (NRDs), such as cystic fibrosis, hemophilia, Duchenne muscular dystrophy, Fabry disease, Choroideremia, Usher syndrome, Shwachman-Diamond syndrome, and even certain types of cancer. Nonsense mutations pose a significant challenge in the treatment of NRDs, as a specific approach directly addressing this genetic defect is currently unavailable. Developing new therapeutic strategies for nonsense suppression is a crucial goal of precision medicine. This review describes some of the most promising therapeutic approaches and emerging strategies for treating NRDs. It considered both the use of small molecules to interfere with molecular mechanisms related to nonsense mutations, such as translational readthrough-inducing drugs (TRIDs) or inhibitors of the nonsense-mediated decay (NMD) pathway, and also innovative approaches involving nucleic acids, such as gene editing, anticodon engineered-tRNA (ACE-tRNA), or mRNA-based therapy. Future research should focus on refining these approaches and exploring integrated and personalized treatments to enhance therapeutic outcomes and ensure continuous improvement in the quality of care.
Blood Coagulation Factor IX: Structure, Function, and Regulation.
Ivanciu L, Camire RM
IUBMB Life · 2025 May · PMID 40402203 · Full text
Blood coagulation factor IX plays a crucial role in the intrinsic pathway of coagulation by generating factor Xa, ultimately leading to thrombin formation. Over the past 50 years, extensive research has deepened our unde...
Blood coagulation factor IX plays a crucial role in the intrinsic pathway of coagulation by generating factor Xa, ultimately leading to thrombin formation. Over the past 50 years, extensive research has deepened our understanding of the biology, physiology, pathology, biochemistry, and molecular genetics of factor IX. This wealth of knowledge has revealed how the factor IX gene and protein evolved, how factor IX is regulated, how it functions within the coagulation cascade, and how structural changes affect its function. In this review, we will summarize current knowledge on the biology of factor IX, with a focus on its structure-function relationships, gene structure, and regulation.
Discovery and Validation of a New Biomarker Integrating Ferroptosis and Glycolysis-Related Genes in Bladder Cancer.
Wang C, Shu Y, Shan J … +6 more , Li K, Wan S, Chen S, Li X, Niu J, Yang L
IUBMB Life · 2025 May · PMID 40401561 · Publisher ↗
Bladder cancer (BCa) is a highly invasive tumor with few successful therapies, and its unfavorable prognosis mainly stems from late diagnosis and resistance to treatment. Ferroptosis is a type of non-apoptotic cell death...
Bladder cancer (BCa) is a highly invasive tumor with few successful therapies, and its unfavorable prognosis mainly stems from late diagnosis and resistance to treatment. Ferroptosis is a type of non-apoptotic cell death characterized by iron-dependent regulated necrosis due to extensive lipid peroxidation. Glycolysis is fundamental to cancer cell metabolism, with cancer cells developing various strategies to enhance this process. In this study, we combined ferroptosis and glycolysis gene sets, two biological processes closely related to tumorigenesis and development, and obtained ferroptosis and glycolysis-related gene sets (FGRGs). By leveraging both single-cell and bulk transcriptome data from BCa, we have investigated the presence and role of FGRGs in the onset and progression of BCa through various approaches. Using machine learning algorithms, we identified a feature gene set consisting of 13 genes in the TCGA data set to predict the prognosis of BCa and verified it in the GEO data set. After that, we explored FGRGs in depth using a variety of bioinformatics analyses, such as mutational landscape analysis, functional enrichment analysis, immune infiltration analysis, FGRGs-associated risk and clinical characterization, and drug susceptibility analysis. Finally, we validated the function of the core gene chondroitin polymerizing factor 2 (CHPF2) using CCK-8, clone formation, transwell, and wound healing assays. Our research innovatively combines ferroptosis with glycolytic genes and applies it as an independent prognostic factor in the study of BCa. It reveals new characteristic genes and therapeutic targets that can predict the prognosis of BCa patients and lays a foundation for the study of the occurrence and development mechanism of BCa and targeted data strategies.
Proline- and Serine-Rich Coiled-Coil 1 Predicts an Unfavorable Prognosis and Exhibits Oncogenic Activities in Breast Cancer.
Jin X, Zhao Q, Hao X … +3 more , Shi P, Wang Y, Wang P
IUBMB Life · 2025 May · PMID 40396877 · Publisher ↗
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 expressi...
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.
Contrast-Induced Acute Kidney Injury is Modulated by Circadian CLOCK/NRF2 Pathway.
Yang S, Xu X, Wang L … +6 more , Fang Y, Zhou Y, Dai C, Jiang L, Zhang B, Luo J
IUBMB Life · 2025 May · PMID 40391788 · Publisher ↗
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...
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.
Hermansky-Pudlak Syndrome: From Molecular Pathogenesis to Targeted Therapies.
Tondi F, Cirsmaru RA, Conti C … +4 more , Follenzi A, Gresele P, Olgasi C, Bury L
IUBMB Life · 2025 May · PMID 40387003 · Full text
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 includ...
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.
The combination of midkine inhibitor with Lenvatinib amplifies the suppression of hepatocellular carcinoma.
Chen X, Guo S, Meng Q … +7 more , Xie J, Xiao Y, Sun Y, Yao J, Jiang X, Hong A, Chen X
IUBMB Life · 2025 May · PMID 40321061 · Publisher ↗
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 techni...
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.
Modulation of Osteogenic Differentiation by CYBB in Osteoporotic Models.
Wang Z, Xu C, Liu Y … +3 more , Duan K, Zhu Z, Guan J
IUBMB Life · 2025 May · PMID 40317963 · Publisher ↗
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 as...
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.
Correction to "Upstream Transcription Factor 1 Suppresses Laryngeal Squamous Cell Carcinoma Progression Through Transcriptional Activation of Junctional Adhesion Molecule 3".
IUBMB Life · 2025 May · PMID 40317864 · Publisher ↗
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Therapeutic Potential of Translational Readthrough at Disease-Associated Premature Termination Codons From Tumor Suppressor Genes.
Torices L, Nunes-Xavier CE, Pulido R
IUBMB Life · 2025 May · PMID 40317855 · Full text
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 predispositi...
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.
Synergistic Effects of Epirubicin-Vorinostat-Pimozide Drug Cocktail on Proliferation, Stemness, Invasiveness, and Fatty Acid Metabolism in Breast Cancer Cells.
Kandasamy T, Sarkar S, Zochedh A … +2 more , Kathiresan T, Ghosh SS
IUBMB Life · 2025 May · PMID 40305333 · Publisher ↗
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...
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 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.
Ischemic preconditioning attenuates ischemia/reperfusion-induced acute kidney injury dependent on mitochondrial protease CLPP.
Xie W, Gao L, Gu X … +8 more , Li L, Zheng H, Wang L, Wen P, Zhou Y, Jiang L, Dai C, Cao H
IUBMB Life · 2025 Apr · PMID 40172021 · Publisher ↗
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 remai...
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 misfolded/unfolded 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 misfolded/unfolded proteins and signs of AKI. The increase in CLPP levels suggests potential activation of the mitochondrial unfolded protein response (UPR), 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 Clpp 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. Clpp 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.
Yeast models for Charcot-Marie-Tooth disease-causing aminoacyl-tRNA synthetase alleles reveal the cellular basis of disease.
Mahmood M, Little E, Girard N … +4 more , Wu F, Samuels T, Heinemann IU, Reynolds NM
IUBMB Life · 2025 Apr · PMID 40156251 · Full text
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 r...
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.
Downregulation of KLF9 alleviates tubulointerstitial fibrosis by modulating FABP4-mediated lipid accumulation.
Zhang L, Wang XY, Tian T … +4 more , Huang YP, Wu LL, Zhuang LL, Zhou GP
IUBMB Life · 2025 Mar · PMID 40134141 · Publisher ↗
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 regulat...
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.
OTUB1 facilitates lipid accumulation in oxLDL-induced THP-1 macrophages by stabilizing scavenger receptor-A.
Huang X, Liu Y, Liu X … +2 more , Liu P, Lin J
IUBMB Life · 2025 Mar · PMID 40114404 · Publisher ↗
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...
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.
Conventional and innovative approaches to black fungi control for stone heritage preservation.
Celi D, Marvasi M, Perito B
IUBMB Life · 2025 Mar · PMID 40111005 · Full text
Black Meristematic Fungi (BMF) are characterized by a thick melanized cell wall and an isodiametric cellular expansion. BMF represent one of the most damaging groups of microorganisms causing the deterioration of outdoor...
Black Meristematic Fungi (BMF) are characterized by a thick melanized cell wall and an isodiametric cellular expansion. BMF represent one of the most damaging groups of microorganisms causing the deterioration of outdoor exposed stone monuments mainly due to the formation of dark spots and patches leading to the darkening of their surface, cracking, and bio-pitting. BMF are among the most stress-resistant organisms on Earth, known for their remarkable ability to withstand solar radiation, desiccation, and extreme temperature fluctuations, which has led to their widespread distribution across the globe. These features make BMF very difficult to remove and restrict, representing a challenge for restorers. Despite the number of scientific works about BMF isolation and ecology, little is known about their response to antimicrobial treatments. Conventional biocides remain the most used treatment for the control of biodeterioration on stone artworks. In recent years, interest in alternative and safer antimicrobial treatments has risen in conservation strategies. The number of scientific works in which their efficacy against BMF is evaluated is, however, still low. The aim of this review is to assess existing studies regarding the response of BMF to both conventional and innovative treatments. This will encompass an in-depth examination of methodologies for the application and evaluation of treatments. Furthermore, we aim to highlight future research directions that will contribute to a more informed selection of effective anti-BMF interventions for stone preservation. We underscore the significance of pioneering, environmentally low-impact solutions.
Upstream transcription factor 1 suppresses laryngeal squamous cell carcinoma progression through transcriptional activation of junctional adhesion molecule 3.
Jia Y, Liu J, Lou Y … +4 more , Wang X, Zhang C, Guo Y, Huangfu H
IUBMB Life · 2025 Mar · PMID 40071730 · Publisher ↗
Laryngeal squamous cell carcinoma (LSCC) exhibits aggressive growth, frequent recurrence, and a notable resistance to existing treatments. Building upon prior discoveries that identified junctional adhesion molecule 3 (J...
Laryngeal squamous cell carcinoma (LSCC) exhibits aggressive growth, frequent recurrence, and a notable resistance to existing treatments. Building upon prior discoveries that identified junctional adhesion molecule 3 (JAM3) as a critical tumor suppressor in LSCC, this study delves into the transcriptional regulation by upstream stimulatory factor 1 (USF1) and its implications for LSCC pathogenesis. Employing dual-luciferase assays and chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR), we confirmed USF1's direct binding to the E-box within the JAM3 promoter, thereby enhancing JAM3 expression in AMC-HN-8 and FD-LSC-1 cells. Complementary in vitro assays and in vivo experiments corroborated that USF1 overexpression markedly reduces tumor aggressiveness, linked to heightened JAM3 activity. Further analysis, including Western blot and immunohistochemistry of xenograft tumor tissues, revealed that increased JAM3, stimulated by USF1, activates the Hippo signaling pathway, underscoring its role in tumor suppression. These findings position USF1 and JAM3 as pivotal elements in the molecular framework of LSCC, suggesting their potential as targets for therapeutic intervention.
The cGAS-STING-related signature affects the prognosis of colorectal cancer through its regulation of multiple immune cells.
Li Y, Jiang X, Cao H … +7 more , Wu X, Zhang H, Ma H, Wang L, Kang B, Xie M, Li S
IUBMB Life · 2025 Mar · PMID 40035384 · Full text
The cGAS-STING signaling pathway has emerged as a critical player in the immune response against cancer, including colorectal adenocarcinoma (COAD). Understanding the impact of this pathway on COAD at multiple omics leve...
The cGAS-STING signaling pathway has emerged as a critical player in the immune response against cancer, including colorectal adenocarcinoma (COAD). Understanding the impact of this pathway on COAD at multiple omics levels is crucial for advancing cancer immunotherapy and precision medicine. This study aimed to investigate the relationship between cGAS-STING-related genes and COAD, analyzing gene mutations, copy number variations, DNA methylation, and gene expression to uncover the pathway's influence on COAD prognosis. Utilizing multi-omics sequencing data from TCGA and GEO databases, key core genes in the cGAS-STING pathway were identified and further validated through PCR and Western blot analysis. Mutations and copy number variations in the CASP8 and RIPK1 genes, differential DNA methylation patterns, and mRNA expression levels of specific genes were assessed to determine their impact on COAD prognosis. Validation through tissue samples highlighted NLRC3, CASP1, AIM2, and CXCL10 as core genes in the cGAS-STING pathway. Our findings demonstrate that mutations and copy number variations in CASP8 and RIPK1, differential DNA methylation patterns, and altered gene expression levels significantly influence the prognosis of COAD. The identification of core genes in the cGAS-STING pathway, particularly NLRC3, CASP1, AIM2, and CXCL10, has led to the development of a prognostic model predicting poor tumor outcomes through immune cell infiltration. This study provides valuable insights into the mechanisms of the cGAS-STING pathway in COAD and offers potential directions for future research in cancer immunotherapy and precision medicine.
Histone demethylase LSD1 promotes castration-resistant prostate cancer by causing widespread gene expression derangements.
Li H, Fan X, Fang X … +1 more , Wang Y
IUBMB Life · 2025 Mar · PMID 40033561 · Publisher ↗
Lysine-specific demethylase 1 (LSD1), a histone demethylase crucial for embryonic development and tissue differentiation, has an undefined role in prostate cancer (PCa), especially castration-resistant PCa. The present s...
Lysine-specific demethylase 1 (LSD1), a histone demethylase crucial for embryonic development and tissue differentiation, has an undefined role in prostate cancer (PCa), especially castration-resistant PCa. The present study represents a pioneering endeavor to comprehensively dissect the function of LSD1 within the PCa landscape. Our investigations revealed that attenuation of LSD1 expression exerts multiple inhibitory effects on PCa cells. Specifically, it curtails the proliferation and colony-forming ability of PC-3 cells, concomitantly promotes apoptosis, and impedes cell invasion. Notably, knockdown of LSD1 triggers significant perturbations in the expression profiles of pivotal proteins, such as prostate-specific antigen (PSA), forkhead box A1 (FOXA1), and NKX3.1, thereby shedding new light on the underlying molecular mechanisms governing PCa progression. Leveraging bioinformatics analysis and transcriptome sequencing, we unearthed that LSD1 knockdown precipitates widespread gene expression dysregulation, with 3166 genes exhibiting differential expression patterns, which in turn impact a broad spectrum of cellular processes. Importantly, we identified that LSD1 modulates the methylation modification of histone H3 lysine 4 monomethylation (H3K4me1) in the promoter region of matrix metallopeptidase 13 (MMP13), thereby orchestrating its expression. In both orthotopic and metastatic tumor models, as well as in vitro cell cultures, the LSD1 inhibitor GSK2879552 demonstrated potent efficacy in suppressing PCa progression. To sum up, this study not only uncovers the oncogenic role of LSD1 in PCa but also validates the therapeutic promise of GSK2879552, furnishing novel perspectives and prospective targets for the clinical management of PCa.
Purification and validation of asparaginyl-tRNA synthetase heterodimer with indistinguishable subunits.
Vallee I, Shapiro R, Yang XL
IUBMB Life · 2025 Feb · PMID 39994779 · Full text
Oligomerization can influence the stability and activity of a protein. The majority of enzymes, including aminoacyl-tRNA synthetases, become catalytically active upon forming homodimers. Residues located at the dimerizat...
Oligomerization can influence the stability and activity of a protein. The majority of enzymes, including aminoacyl-tRNA synthetases, become catalytically active upon forming homodimers. Residues located at the dimerization interface are highly conserved and mutations arising within can cause severe disease phenotypes. Beyond homozygous mutations, other disease-causing mutations, such as compound heterozygous and mono-allelic mutations, can lead to the formation of heterodimers between two distinct subunits. Purifying a recombinant heterodimer is required for its thorough characterization in vitro, yet there is a lack of established biochemical methods for the preparation. Here we describe a heterodimer purification and validation method with the example of a disease-causing mono-allelic, nonsense mutation R534* in cytoplasmic asparaginyl-tRNA synthetase (NARS1 or AsnRS). Our method involves co-expression of two separately tagged constructs to allow for purification of the wild-type and the R534* mutant heterodimers. While the two subunits can hardly be distinguished by size, their separate detection is achieved by western blotting against the tags. Quantification analysis confirmed that the subunits within the heterodimer are present in nearly equal proportions. This simple protocol can be adapted to study other size-indistinguishable heterodimers.
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