Molecular Medicine最新文献

{"title":"TIMP1 regulates ferroptosis in osteoblasts by inhibiting TFRC ubiquitination: an in vitro and in vivo study.","authors":"Bo Peng, Zhiwei Feng, Ao Yang, Jinmin Liu, Jinwen He, Lihu Xu, Cong Tian, Xiaoyun Sheng, Yaobin Wang, Rongjin Chen, Xingwen Wang, Xiaojun Ren, Bin Geng, Yayi Xia","doi":"10.1186/s10020-024-01000-9","DOIUrl":"https://doi.org/10.1186/s10020-024-01000-9","url":null,"abstract":"<p><strong>Background: </strong>In clinical practice, alterations in the internal environment of type 2 diabetes can significantly affect bone quality. While the increased risk of fractures among diabetic patients is well-established, the precise mechanisms by which hyperglycemia influences bone quality remain largely unclear.</p><p><strong>Methods: </strong>Western blotting, immunohistochemistry (IHC), and micro-CT were used to examine ferroptosis-related protein expression and bone morphology changes in the bone tissues of type 2 diabetic mice. The CCK8 assay determined the optimal conditions for inducing ferroptosis in osteoblasts by high glucose and high fat (HGHF). Ferroptosis phenotypes in osteoblasts were analyzed using flow cytometry, Western blotting, and two-photon laser confocal microscopy. Transcriptomic sequencing of the control and HGHF groups, followed by bioinformatic analysis, identified and validated key genes. TIMP1 was knocked down in osteoblasts to assess its impact on ferroptosis, while TFRC expression was inhibited and activated to verify the role of TIMP1 in regulating ferroptosis through TFRC. The therapeutic effect of TIMP1 inhibition on osteoporosis was evaluated in a type 2 diabetic mouse model.</p><p><strong>Results: </strong>The expression of TIMP1 is increased in type 2 diabetic osteoporosis. In vitro, TIMP1 knockout inhibited ferroptosis in osteoblasts induced by high glucose and high fat (HGHF). However, overexpression of TFRC reversed the ferroptosis inhibition caused by TIMP1 knockout. Suppression of TIMP1 expression alleviated the progression of osteoporosis in type 2 diabetic mice. Mechanistic studies suggest that TIMP1 regulates HGHF-induced ferroptosis in osteoblasts through TFRC.</p><p><strong>Conclusion: </strong>This study demonstrates that TIMP1 expression is increased during type 2 diabetic osteoporosis and that TIMP1 promotes ferroptosis in osteoblasts by regulating TFRC. These findings suggest that TIMP1 is a promising novel therapeutic target for type 2 diabetic osteoporosis.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"30 1","pages":"226"},"PeriodicalIF":6.0,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Co-culture of human AT2 cells with fibroblasts reveals a MUC5B phenotype: insights from an organoid model.","authors":"Yiwen Yao, Felix Ritzmann, Sarah Miethe, Kathrin Kattler-Lackes, Betül Colakoglu, Christian Herr, Andreas Kamyschnikow, Michelle Brand, Holger Garn, Daniela Yildiz, Frank Langer, Robert Bals, Christoph Beisswenger","doi":"10.1186/s10020-024-00990-w","DOIUrl":"https://doi.org/10.1186/s10020-024-00990-w","url":null,"abstract":"<p><p>Impaired interaction of fibroblasts with pneumocytes contributes to the progression of chronic lung disease such as idiopathic pulmonary fibrosis (IPF). Mucin 5B (MUC5B) is associated with IPF. Here we analyzed the interaction of primary fibroblasts and alveolar type 2 (AT2) pneumocytes in the organoid model. Single-cell analysis, histology, and qRT-PCR revealed that fibroblasts expressing high levels of fibrosis markers regulate STAT3 signaling in AT2 cells, which is accompanied by cystic organoid growth and MUC5B expression. Cystic growth and MUC5B expression were also caused by the cytokine IL-6. The PI3K-Akt signaling pathway was activated in fibroblasts. The drug dasatinib prevented the formation of MUC5B-expressing cystic organoids. MUC5B associated with AT2 cells in samples obtained from IPF patients. Our model shows that fibrotic primary fibroblasts induce impaired differentiation of AT2 cells via STAT3 signaling pathways, as observed in IPF patients. It can be used for mechanistic studies and drug development.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"30 1","pages":"227"},"PeriodicalIF":6.0,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring Smad5: a review to pave the way for a deeper understanding of the pathobiology of common respiratory diseases.","authors":"Zeqiang Lin, Jiayu Zhuang, Lixia He, Siyuan Zhu, Weiguo Kong, Wenju Lu, Zili Zhang","doi":"10.1186/s10020-024-00961-1","DOIUrl":"https://doi.org/10.1186/s10020-024-00961-1","url":null,"abstract":"<p><p>Smad5 (small mothers against decapentaplegic 5) protein is a receptor-regulated member of the Smad family proteins, mainly participating in the bone morphogenetic protein (BMP) signaling pathway in its phosphorylated form. This article will provide a detailed review of Smad5, focusing on its gene characteristics, protein structure, and subcellular localization properties. We will also explore the related signaling pathways and the mechanisms of Smad5 in respiratory diseases, including chronic obstructive pulmonary disease (COPD), bronchial asthma, pulmonary arterial hypertension(PAH), lung cancer, and idiopathic pulmonary fibrosis (IPF). Additionally, the review will cover aspects such as proliferation, differentiation, apoptosis, anti-fibrosis, and mitochondrial function metabolism. In addition, the review will cover aspects of proliferation, differentiation, apoptosis, anti-fibrosis and functional mitochondrial metabolism related to the above topics. Numerous studies suggest that Smad5 may play a unique and important role in the pathogenesis of respiratory system diseases. However, in previous research, Smad5 was mainly used to broadly determine the activation of the BMP signaling pathway, and its own function has not been given much attention. It is worth noting that Smad5 has distinct nuclear-cytoplasmic distribution characteristics different from Smad1 and Smad8. It can undergo significant nuclear-cytoplasmic shuttling when intracellular pH (pHi) changes, playing important roles in both the classical BMP signaling pathway and non-BMP signaling pathways. Given that Smad5 can move intracellularly in response to changes in physicochemical properties, its cellular localization may play a crucial role in the development of respiratory diseases. This article will explore the possibility that its distribution characteristics may be an important factor that is easily overlooked and not adequately considered in disease research.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"30 1","pages":"225"},"PeriodicalIF":6.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyperoside induces ferroptosis in chronic myeloid leukemia cells by targeting NRF2.","authors":"Junyi Wei, Quanyou Chai, Yuqiao Qin, Long Li, Chunling Guo, Zhaoyang Lu, Huimin Liu","doi":"10.1186/s10020-024-01002-7","DOIUrl":"10.1186/s10020-024-01002-7","url":null,"abstract":"<p><strong>Background: </strong>Hyperoside (quercetin-3-O-β-D-galactopyranoside) is a flavonol glycoside compound derived from plants in the Hypericum and Crataegus genera that reportedly exhibits an array of anti-inflammatory, antioxidant, and antitumor properties such that it has been used to treat various diseases. Whether it can serve as an effective treatment for chronic myeloid leukemia (CML) cells, however, has yet to be established. The present study was thus devised to assess the therapeutic effects of hyperoside on CML cells and to clarify the underlying mechanism of action.</p><p><strong>Methods: </strong>Cellular viability, proliferative activity, migration, and apoptotic death were respectively analyzed through CCK-8, EDU, transwell, and flow cytometry assays. RNA-seq and bioinformatics approaches were further employed to evaluate the mechanisms through which hyperoside influences CML cells, while analyses of reactive oxygen species (ROS) and free iron were detected with commercial kits. Transmission electron microscopy was used to assess mitochondrial morphology. Molecular docking, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) approaches were also used to explore the ability of hyperoside to target NRF2.</p><p><strong>Results: </strong>From a mechanistic perspective, hyperoside was able to inhibit SLC7A11/GPX4 signaling in a manner that was abrogated by the ferroptosis inhibitor ferrostatin-1. NRF2 was also closely associated with the inactivation of the SLC7A11/GPX4 axis mediated by hyperoside such that overexpressing NRF2 ablated the benefits associated with hyperoside treatment.</p><p><strong>Conclusions: </strong>The present analyses indicate that hyperoside can target the NRF2/SLC7A11/GPX4 axis to induce ferroptotic CML cell death.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"30 1","pages":"224"},"PeriodicalIF":6.0,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elabela alleviates cuproptosis and vascular calcification in vitaminD3- overloaded mice via regulation of the PPAR-γ /FDX1 signaling.","authors":"Rui-Qiang Qi, Yu-Fei Chen, Jing Cheng, Jia-Wei Song, Yi-Hang Chen, Si-Yuan Wang, Ying Liu, Kai-Xin Yan, Xiao-Yan Liu, Jing Li, Jiu-Chang Zhong","doi":"10.1186/s10020-024-00997-3","DOIUrl":"10.1186/s10020-024-00997-3","url":null,"abstract":"<p><strong>Background: </strong>Vascular calcification is a crucial pathophysiological process associated with age-related cardiovascular diseases. Elabela, a recently identified peptide, has emerged as a significant player in the regulation of cardiovascular function and homeostasis. However, the effects and underlying mechanisms of Elabela on age-related vascular calcification remain largely unexplored.</p><p><strong>Methods: </strong>In-vivo vascular calcifications of C57BL/6J mice (8-week-old) and young (8-week-old) or aged (72-week-old) SD rats were injected with vitamin D3 (VitD3) or saline, respectively. Furthermore, the VitD3-overloaded mice received Elabela (1 mg/kg/d), peroxisome proliferators-activated receptor-γ (PPAR-γ) activator Rosiglitazone (5 mg/kg/d) or copper-ionophore Elesclomol (20 mg/kg/d), respectively. As for in-vitro studies, primary rat vascular smooth muscle cells (VSMCs) were isolated from aortas and cultured for explore the role and underlying mechanism of Elabela in vascular calcification.</p><p><strong>Results: </strong>There were marked increases in FDX1 and Slc31a1 levels in both aortas and VSMCs during vascular calcification, coinciding with a rise in copper levels and a decrease in Elabela levels. Alizarin red and von-Kossa staining indicated that the administration of Elabela effectively hindered the progression of vascular cuproptosis and arterial calcification in VitD3-overloaded mice and rat arterial rings models. Moreover, Elabela significantly suppressed osteogenic differentiation and calcium deposition in VSMCs and strikingly reversed high phosphate-induced augmentation of FDX1 expression, DLAT aggregation as well as intracellular copper ion levels. More importantly, Elabela exhibited remarkable abilities to prevent mitochondrial dysfunctions in primary rat VSMCs by maintaining mitochondrial membrane potential, inhibiting mitochondrial division, reducing mitochondrial ROS production and increasing ATP levels. Interestingly, Elabela mitigated cellular senescence and production of pro-inflammatory cytokines including IL-1α, IL-1β, IL-6, IL-18 and TNF-α, respectively. Furthermore, Elabela upregulated the protein levels of PPAR-γ in VitD3-overloaded mice. Administrating PPAR-γ inhibitor GW9662 or blocking the efflux of intracellular copper abolished the protective effect of Elabela on vascular calcification by enhancing levels of FDX1, Slc31a1, Runx2, and BMP2.</p><p><strong>Conclusion: </strong>Elabela plays a crucial role in protecting against vascular cuproptosis and arterial calcification by activating the PPAR-γ /FDX1 signaling. Elabela supplementation and cuproptosis suppression serve as effective therapeutic approaches for managing vascular calcification and related cardiovascular disorders.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"30 1","pages":"223"},"PeriodicalIF":6.0,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11577739/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FUT8 upregulates CD36 and its core fucosylation to accelerate pericyte-myofibroblast transition through the mitochondrial-dependent apoptosis pathway during AKI-CKD.","authors":"Yaxi Shang, Ziran Wang, Fan Yang, Weidong Wang, Qingzhu Tang, Xianan Guo, Xiangning Du, Xu Zhang, Jiaojiao Hao, Hongli Lin","doi":"10.1186/s10020-024-00994-6","DOIUrl":"10.1186/s10020-024-00994-6","url":null,"abstract":"<p><strong>Background: </strong>Activation of pericytes leads to renal interstitial fibrosis, but the regulatory mechanism of pericytes in the progression from AKI to CKD remains poorly understood. CD36 activation plays a role in the progression of CKD. However, the significance of CD36 during AKI-CKD, especially in pericyte, remains to be fully defined.</p><p><strong>Methods: </strong>GEO and DISCO database were used to analyze the expression of CD36 in pericyte during AKI-CKD; IRI to conduct AKI-CKD mouse model; Hypoxia/Reoxygenation (H/R) to induce the cell model; RT-qPCR and Western blotting to detect gene expression; IP and confocal-IF to determine the core fucosylation (CF) level of CD36. Flow cytometry (AV/PI staining) to detect the cell apoptosis and JC-1 staining to react to the change of mitochondrial membrane potential.</p><p><strong>Results: </strong>During AKI to CKD progression, CD36 expression in pericytes is higher and may be influenced by CF. Moreover, we confirmed the positive association of CD36 expression with pericyte-myofibroblast transition and the progression of AKI-CKD in an IRI mouse model and hypoxia/reoxygenation (H/R) pericytes. Notably, we discovered that FUT8 upregulates both CD36 expression and its CF level, contributing to the activation of the mitochondrial-dependent apoptosis signaling pathway in pericytes, ultimately leading to the progression of AKI-CKD.</p><p><strong>Conclusion: </strong>These results further identify FUT8 and CD36 as potential targets for the treatment in the progression of AKI-CKD.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"30 1","pages":"222"},"PeriodicalIF":6.0,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11577590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Post-sepsis chronic muscle weakness can be prevented by pharmacological protection of mitochondria.","authors":"Meagan S Kingren, Alexander R Keeble, Alyson M Galvan-Lara, Jodi M Ogle, Zoltán Ungvári, Daret K St Clair, Timothy A Butterfield, Allison M Owen, Christopher S Fry, Samir P Patel, Hiroshi Saito","doi":"10.1186/s10020-024-00982-w","DOIUrl":"10.1186/s10020-024-00982-w","url":null,"abstract":"<p><strong>Background: </strong>Sepsis, mainly caused by bacterial infections, is the leading cause of in-patient hospitalizations. After discharge, most sepsis survivors suffer from long-term medical complications, particularly chronic skeletal muscle weakness. To investigate this medical condition in detail, we previously developed a murine severe sepsis-survival model that exhibits long-term post-sepsis skeletal muscle weakness. While mitochondrial abnormalities were present in the skeletal muscle of the sepsis surviving mice, the relationship between abnormal mitochondria and muscle weakness remained unclear. Herein, we aimed to investigate whether mitochondrial abnormalities have a causal role in chronic post-sepsis muscle weakness and could thereby serve as a therapeutic target.</p><p><strong>Methods: </strong>Experimental polymicrobial abdominal sepsis was induced in 16-18 months old male and female mice using cecal slurry injection with subsequent antibiotic and fluid resuscitation. To evaluate the pathological roles of mitochondrial abnormalities in post-sepsis skeletal muscle weakness, we utilized a transgenic mouse strain overexpressing the mitochondria-specific antioxidant enzyme manganese superoxide dismutase (MnSOD). Following sepsis development in C57BL/6 mice, we evaluated the effect of the mitochondria-targeting synthetic tetrapeptide SS-31 in protecting mitochondria from sepsis-induced damage and preventing skeletal muscle weakness development. In vivo and in vitro techniques were leveraged to assess muscle function at multiple timepoints throughout sepsis development and resolution. Histological and biochemical analyses including bulk mRNA sequencing were used to detect molecular changes in the muscle during and after sepsis RESULTS: Our time course study revealed that post sepsis skeletal muscle weakness develops progressively after the resolution of acute sepsis and in parallel with the accumulation of mitochondrial abnormalities and changes in the mitochondria-related gene expression profile. Transgenic mice overexpressing MnSOD were protected from mitochondrial abnormalities and muscle weakness following sepsis. Further, pharmacological protection of mitochondria utilizing SS-31 during sepsis effectively prevented the later development of muscle weakness.</p><p><strong>Conclusions: </strong>Our study revealed that the accumulation of mitochondrial abnormalities is the major cause of post-sepsis skeletal muscle weakness. Pharmacological protection of mitochondria during acute sepsis is a potential clinical treatment strategy to prevent post-sepsis muscle weakness.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"30 1","pages":"221"},"PeriodicalIF":6.0,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11577827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BMSC-derived exosomes promote osteoporosis alleviation via M2 macrophage polarization.","authors":"Yanbin Zhang, Jing Bai, Bin Xiao, Chunyan Li","doi":"10.1186/s10020-024-00904-w","DOIUrl":"10.1186/s10020-024-00904-w","url":null,"abstract":"<p><p>Osteoporosis is characterized by reduced bone mass due to imbalanced bone metabolism. Exosomes derived from bone mesenchymal stem cells (BMSCs) have been shown to play roles in various diseases. This study aimed to clarify the regulatory function and molecular mechanism of BMSCs-derived exosomes in osteogenic differentiation and their potential therapeutic effects on osteoporosis. Exosomes were extracted from BMSCs. Bone marrow-derived macrophages (BMDMs) were cultured and internalized with BMSCs-derived exosomes. Real-time quantitative PCR was used to detect the expression of macrophage surface markers and tripartite motif (TRIM) family genes. BMDMs were co-cultured with human osteoblasts to assess osteogenic differentiation. Western blot was performed to analyze the ubiquitination of triggering receptor expressed on myeloid cell 1 (TREM1) mediated by TRIM25. An ovariectomized mice model was established to evaluate the role of TRIM25 and exosomes in osteoporosis. Exosomes were successfully isolated from BMSCs. BMSCs-derived exosomes upregulated TRIM25 expression, promoting M2 macrophage polarization and osteogenic differentiation. TRIM25 facilitated the ubiquitination and degradation of TREM1. Overexpression of TREM1 reversed the enhanced M2 macrophage polarization and osteogenic differentiation caused by TRIM25 overexpression. TRIM25 enhanced the protective effect of BMSCs-derived exosomes against bone loss in mice. These findings suggested that BMSCs-derived exosomes promoted osteogenic differentiation by regulating M2 macrophage polarization through TRIM25-mediated ubiquitination and degradation of TREM1. This mechanism might provide a novel approach for treating osteoporosis.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"30 1","pages":"220"},"PeriodicalIF":6.0,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11577737/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CKS2 induces autophagy-mediated glutathione metabolic reprogramming to facilitate ferroptosis resistance in colon cancer.","authors":"Leilei Yang, Chengfeng Fang, Jiaju Han, Yufeng Ren, Zaiping Yang, Lingyan Shen, Dinghai Luo, Ruili Zhang, Yan Chen, Shenkang Zhou","doi":"10.1186/s10020-024-00979-5","DOIUrl":"10.1186/s10020-024-00979-5","url":null,"abstract":"<p><strong>Background: </strong>Ferroptosis, a form of cell death characterized by lipid peroxidation, plays a crucial role in tumor suppression, offering novel avenues for cancer therapy. Previous studies have indicated that high levels of cyclin-dependent kinase subunit 2 (CKS2) promote the progression of various cancers. However, the potential interplay between CKS2 and ferroptosis in colon cancer (CC) remains unclear.</p><p><strong>Methods: </strong>Bioinformatics and RNA-seq analyses were employed to study genes associated with the ferroptosis signaling pathway. CKS2 expression was evaluated using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot (WB). The in vitro and in vivo effects of CKS2 on CC cells were assessed through the CCK-8 assay, colony formation assay, propidium iodide (PI) staining, BODIPY staining, DCFH-DA staining, and animal experiments. Additionally, the impact of CKS2 on autophagy and glutathione (GSH) metabolism was investigated using a transmission electron microscope (TEM), immunofluorescence (IF) assays, WB experiments, and relevant assay kits.</p><p><strong>Results: </strong>CKS2 expression was elevated in CC, indicating a poor clinical outcome. Knockdown of CKS2 significantly enhanced Erastin-induced ferroptosis in CC cells, leading to reduced GSH metabolism. Conversely, CKS2 overexpression produced opposite effects. Mechanistically, CKS2-induced autophagy reinforced GSH metabolism, thereby increasing resistance to ferroptosis in CC cells. Furthermore, inhibiting CKS2 promoted tumor ferroptosis by downregulating GPX4 expression. Additionally, CKS2 knockdown effectively increased sorafenib-induced ferroptosis both in vitro and in vivo.</p><p><strong>Conclusion: </strong>CKS2 suppresses ferroptosis in CC by modulating GSH metabolism in both in vitro and in vivo settings. These findings offer new insights into targeting CKS2 for CC treatment and shed light on the mechanism of ferroptosis in CC.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"30 1","pages":"219"},"PeriodicalIF":6.0,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11568617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tetrandrine induces muscle atrophy involving ROS-mediated inhibition of Akt and FoxO3.","authors":"Xin-Qi Shan, Na Zhou, Chuang-Xin Pei, Xue Lu, Cai-Ping Chen, Hua-Qun Chen","doi":"10.1186/s10020-024-00981-x","DOIUrl":"10.1186/s10020-024-00981-x","url":null,"abstract":"<p><p>Tetrandrine (Tet), a well-known drug of calcium channel blocker, has been broadly applied for anti-inflammatory and anti-fibrogenetic therapy. However, due to the functional diversity of ubiquitous calcium channels, potential side-effects may be expected. Our previous report revealed an inhibitory effect of Tet on myogenesis of skeletal muscle. Here, we found that Tet induced protein degradation resulting in the myofibril atrophy. Upon administration with a relative high dose (40 mg/kg) of Tet for 28 days, the mice displayed significantly reduced muscle mass, strength force, and myosin heavy chain (MyHC) protein levels. The MyHC reduction was further detected in C2C12 myotubes after treating with Tet. Interestingly, the expression of Atrogin-1 and Murf-1, the skeletal muscle specific E3 ligases of protein ubiquitin-proteasome system (UPS), was accordingly up-regulated, and the reduced MyHC was significantly mitigated by MG132, a 26S proteasome inhibitor, indicating a key role of UPS in the protein degradation of muscle cells. Further study showed that Tet induced autophagy also participated in the protein degradation. Mechanistically, Tet treatment caused ROS production in myotubes that in turn targeted on FoxO3/AKT signaling, resulting in the activation of UPS and autophagy processes that were involved in the protein degradation. Our study reveals a potential side-effect of Tet on skeletal muscle atrophy, particularly when the drug dose is relatively high.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"30 1","pages":"218"},"PeriodicalIF":6.0,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11566300/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}