Experimental and Molecular Medicine最新文献

{"title":"TIGAR coordinates senescence-associated secretory phenotype via lysosome repositioning and α-tubulin deacetylation","authors":"Hae Yun Nam, Seung-Ho Park, Geun-Hee Lee, Eun-Young Kim, SangEun Lee, Hyo Won Chang, Eun-Ju Chang, Kyung-Chul Choi, Seong Who Kim","doi":"10.1038/s12276-024-01362-4","DOIUrl":"10.1038/s12276-024-01362-4","url":null,"abstract":"TP53-induced glycolysis and apoptosis regulator (TIGAR) regulates redox homeostasis and provides the intermediates necessary for cell growth by reducing the glycolytic rate. During cellular senescence, cells undergo metabolic rewiring towards the glycolytic pathway, along with the development of the senescence-associated secretory phenotype (SASP), also known as the secretome. We observed that TIGAR expression increased during replicative senescence following the in vitro expansion of human mesenchymal stromal cells (MSCs) and that TIGAR knockout (KO) decreased SASP factors and triggered premature senescence with decelerated progression. Additionally, TIGAR KO impaired flexible lysosomal movement to the perinuclear region and decreased the autophagic flux of MSCs. Research on the mechanism of lysosomal movement revealed that, while native senescent MSCs presented low levels of Ac-α-tubulin (lysine 40) and increased sirtuin 2 (SIRT2) activity compared with those in growing cells, TIGAR KO-MSCs maintained Ac-α-tubulin levels and exhibited decreased SIRT2 activity despite being in a senescent state. The overexpression of SIRT2 reduced Ac-α-tubulin as a protein target of SIRT2 and induced the positioning of lysosomes at the perinuclear region, restoring the cytokine secretion of TIGAR KO-MSCs. Furthermore, TIGAR expression was positively correlated with SIRT2 activity, indicating that TIGAR affects SIRT2 activity partly by modulating the NAD+ level. Thus, our study demonstrated that TIGAR provides a foundation that translates the regulation of energy metabolism into lysosome positioning, affecting the secretome for senescence development. Considering the functional value of the cell-secretome in aging-related diseases, these findings suggest the feasibility of TIGAR for the regulation of secretory phenotypes. Cellular senescence is a process where cells stop dividing due to stress. Researchers found that the protein TIGAR plays a role in this process, but its exact function was unclear. In this study, researchers explored how TIGAR affects cellular senescence. They used mesenchymal stromal cells from human umbilical cord blood and conducted experiments to knock out TIGAR using CRISPR-Cas9 technology. They found that knocking out TIGAR led to early onset but slower progression of senescence. TIGAR knockout cells showed changes in lysosome positioning, reduced autophagic flux, and altered secretion of cytokines. These changes were linked to the acetylation of α-tubulin, a protein that helps in cell structure and transport. The results suggest that TIGAR regulates cellular senescence by affecting lysosome positioning and autophagy through SIRT2, an enzyme that deacetylates α-tubulin. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 12","pages":"2726-2738"},"PeriodicalIF":9.5,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01362-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142781746","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":"Author Correction: Renal fibroblasts are involved in fibrogenic changes in kidney fibrosis associated with dysfunctional telomeres","authors":"Sarita Saraswati, Paula Martínez, Rosa Serrano, Diego Mejías, Osvaldo Graña-Castro, Ruth Álvarez Díaz, Maria A. Blasco","doi":"10.1038/s12276-024-01370-4","DOIUrl":"10.1038/s12276-024-01370-4","url":null,"abstract":"","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 12","pages":"2763-2763"},"PeriodicalIF":9.5,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01370-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142781745","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":"The anticancer effect of metformin targets VDAC1 via ER-mitochondria interactions-mediated autophagy in HCC","authors":"Minjeong Ko, Jiho Kim, Raudah Lazim, Ju Yeon Lee, Jin Young Kim, Vijayakumar Gosu, Yoonji Lee, Sun Choi, Ho Jeong Kwon","doi":"10.1038/s12276-024-01357-1","DOIUrl":"10.1038/s12276-024-01357-1","url":null,"abstract":"Metformin (MetF) is used worldwide as a first-line therapy for type 2 diabetes. Recently, interest in the pleiotropic effects of MetF, such as its anticancer and antiaging properties, has increased. However, the molecular target of MetF and the detailed mechanism underlying its ability to inhibit cell growth through autophagy induction remain incompletely understood. In this study, using an innovative label-free drug affinity responsive target stability (DARTS)-LC-MS/MS method, we discovered that mitochondrial voltage-dependent anion channel 1 (VDAC1) is a novel binding protein involved in the induction of autophagy-related cell death by high-dose MetF in hepatocellular carcinoma (HCC). Computational alanine scanning mutagenesis revealed that MetF and VDAC1 (D9, E203) interact electrostatically. MetF disrupts the IP3R-GRP75-VDAC1 complex, which plays a key role in stabilizing mitochondria-associated ER membranes (MAMs), by binding to VDAC1. This disruption leads to increased cytosolic calcium levels, thereby contributing to autophagy induction. MetF also decreased the AMP/ATP ratio and activated the AMPK pathway. Cells with genetic knockdown of VDAC1 mimicked the activity of MetF. In conclusion, this study provides new insights into the involvement of MetF in ionic interactions with VDAC1, contributing to its anticancer effects in HCC. These findings help elucidate the diverse biological and pharmacological effects of MetF, particularly its influence on autophagy, as well as the potential of MetF as a therapeutic agent for diseases characterized by VDAC1 overexpression. Metformin, a common type 2 diabetes drug, is known for its glucose-lowering effects. The study used several cell lines and advanced techniques to investigate how Metformin induces cancer cell death. This experimental research included cell cultures and molecular analysis. They found that Metformin targets a mitochondrial protein called VDAC1. This interaction disrupts energy production and increases autophagy, leading to cancer cell death. The results showed that Metformin binds to VDAC1, reducing mitochondrial calcium and ATP levels, which activates autophagy and kills cancer cells. The researchers concluded that the ionic interaction of Metformin with VDAC1 is critical for its anticancer effects. Future studies could explore Metformin as a treatment for cancers with high VDAC1 expression. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 12","pages":"2714-2725"},"PeriodicalIF":9.5,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01357-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774494","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":"Neddylation steers the fate of cellular receptors","authors":"Jun Bum Park, Min Young Lee, Jooseung Lee, Geon Ho Moon, Sung Joon Kim, Yang-Sook Chun","doi":"10.1038/s12276-024-01358-0","DOIUrl":"10.1038/s12276-024-01358-0","url":null,"abstract":"Cellular receptors regulate physiological responses by interacting with ligands, thus playing a crucial role in intercellular communication. Receptors are categorized on the basis of their location and engage in diverse biochemical mechanisms, which include posttranslational modifications (PTMs). Considering the broad impact and diversity of PTMs on cellular functions, we focus narrowly on neddylation, a modification closely resembling ubiquitination. We systematically organize its canonical and noncanonical roles in modulating proteins associated with cellular receptors with the goal of providing a more detailed perspective on the intricacies of both intracellular and cell-surface receptors. Proteins undergo posttranslational modifications (PTMs) to maintain physiological balance. Neddylation, a type of PTM, involves attaching a small ubiquitin-like molecule, NEDD8, to target proteins. In this study, J.B.P. and colleagues explore the role of neddylation role in cellular receptors. The researchers conducted a review to understand how neddylation affects different types of receptors, including membrane and intracellular receptors. They examined both canonical (cullin-dependent) and noncanonical pathways regulated by neddylation. The study systematically analyzes the impact of neddylation on receptor stability, signaling, and function. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 12","pages":"2569-2577"},"PeriodicalIF":9.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01358-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774491","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":"Diet-induced obesity and aging-induced upregulation of Trib3 interfere with energy homeostasis by downregulating the thermogenic capacity of BAT","authors":"Hyejin Yeo, Ji-Hye Lim, Ji Eom, MinJeong Kim, Hyeji Kwon, Sang-Wook Kang, Youngsup Song","doi":"10.1038/s12276-024-01361-5","DOIUrl":"10.1038/s12276-024-01361-5","url":null,"abstract":"Characterized by UCP1 expression and abundant mitochondria, brown adipose tissue (BAT) plays a crucial role in energy balance by converting chemical energy into heat through the cost of ATP production. In this study, it was demonstrated that Trib3 is a critical determinant of BAT-mediated energy expenditure and whole-body energy homeostasis. Under 60% high-fat diet conditions, Trib3 expression in BAT was elevated. Mice deficient in Trib3 are resistant to diet-induced obesity and exhibit improved glucose homeostasis due to enhanced BAT activity. Furthermore, brown adipocyte progenitor cells (APCs) lacking Trib3 exhibited increased proliferation and promoted brown adipocyte differentiation and mitochondrial biogenesis, contributing to the increase in the maximal thermogenic capacity of BAT in Trib3-deficient mice. Mechanistically, it was discovered that Trib3 expression is upregulated by free fatty acids at the transcriptional level and synergistically upregulated by DAG-PKC at the posttranslational level. This occurs through the modulation of COP1-mediated Trib3 protein turnover. Interestingly, the level of Trib3 expression in BAT increased with age. Trib3 knockout mice were protected from aging-related weight gain and impaired glucose homeostasis. These results suggest that Trib3 acts as an obesity- and aging-associated factor that negatively regulates BAT activity and that the loss of Trib3 may provide a beneficial approach to prevent obesity and aging-associated metabolic syndrome by increasing the thermogenic capacity of BAT. The study investigates how the Trib3 gene influences energy balance and obesity. Researchers discovered that Trib3 knockout mice, which lack the Trib3 gene, are resistant to diet and aging-induced obesity. This study fills a gap in understanding Trib3’s role in brown adipose tissue, a type of fat that generates heat. Researchers conducted experiments on Trib3 KO mice to examine their resistance to obesity using methods like glucose tolerance tests, indirect calorimetry, and PET imaging to analyze the mice. Results showed that Trib3 KO mice had lower body weight and better glucose metabolism compared to control mice. They concluded that Trib3 KO mice have increased energy expenditure due to enhanced BAT activity. This suggests that targeting Trib3 could help treat obesity and related metabolic disorders. Future research could explore Trib3’s role in other tissues and its potential as a therapeutic target. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 12","pages":"2690-2702"},"PeriodicalIF":9.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01361-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774109","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":"EPRS1-mediated fibroblast activation and mitochondrial dysfunction promote kidney fibrosis","authors":"Seung Seob Son, Hee Seul Jeong, Seong-Woo Lee, Eun Soo Lee, Jeong Geon Lee, Ji-Hye Lee, Jawoon Yi, Mi Ju Park, Min Sun Choi, Donghyeong Lee, Sin Young Choi, Jiheon Ha, Jeong Suk Kang, Nam-Jun Cho, Samel Park, Hyo-Wook Gil, Choon Hee Chung, Joon Seok Park, Myung Hee Kim, Jihwan Park, Eun Young Lee","doi":"10.1038/s12276-024-01360-6","DOIUrl":"10.1038/s12276-024-01360-6","url":null,"abstract":"Kidney fibrosis causes irreversible structural damage in chronic kidney disease and is characterized by aberrant extracellular matrix (ECM) accumulation. Although glutamyl-prolyl-tRNA synthetase 1 (EPRS1) is a crucial enzyme involved in proline-rich protein synthesis, its role in kidney fibrosis remains unclear. The present study revealed that EPRS1 expression levels were increased in the fibrotic kidneys of patients and mice, especially in fibroblasts and proximal tubular epithelial cells, on the basis of single-cell analysis and immunostaining of fibrotic kidneys. Moreover, C57BL/6 EPRS1tm1b heterozygous knockout (Eprs1+/−) and pharmacological EPRS1 inhibition with the first-in-class EPRS1 inhibitor DWN12088 protected against kidney fibrosis and dysfunction by preventing fibroblast activation and proximal tubular injury. Interestingly, in vitro assays demonstrated that EPRS1-mediated nontranslational pathways in addition to translational pathways under transforming growth factor β-treated conditions by phosphorylating SMAD family member 3 in fibroblasts and signal transducers and activators of transcription 3 in injured proximal tubules. EPRS1 knockdown and catalytic inhibition suppressed these pathways, preventing fibroblast activation, proliferation, and subsequent collagen production. Additionally, we revealed that EPRS1 caused mitochondrial damage in proximal tubules but that this damage was attenuated by EPRS1 inhibition. Our findings suggest that the EPRS1-mediated ECM accumulation induces kidney fibrosis via fibroblast activation and mitochondrial dysfunction. Therefore, targeting EPRS1 could be a potential therapeutic target for alleviating fibrotic injury in chronic kidney disease. Kidney fibrosis, a common result of chronic kidney disease, leads to irreversible kidney dysfunction. Researchers found that the enzyme EPRS1 plays a key role in this process. Researchers discovered elevated EPRS1 levels in fibrotic kidneys of both patients and mice. The study involved patients, mice, and in vitro cells such as NRK-49F, NIH3T3, and HK-2 cells. The researchers used multiple techniques, including immunohistochemistry, western blot, electron microscopy and single-cell RNA sequencing, to identify EPRS1’s role. They found that EPRS1 promotes fibrosis by activating fibroblasts and causing mitochondrial dysfunction. Single-cell RNA sequencing and western blotting identified the pathophysiological molecular pathways. Inhibiting EPRS1 by genetic and pharmacological methods reduced kidney fibrosis and improved function, suggesting it could be a new treatment for kidney fibrosis. Future research may explore EPRS1 inhibitors as potential therapies for chronic kidney disease. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 12","pages":"2673-2689"},"PeriodicalIF":9.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01360-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774448","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":"ErbB4 precludes the occurrence of PTSD-like fear responses by supporting the bimodal activity of the central amygdala","authors":"Kibong Sung, Min-Jae Jeong, Taesik Yoo, Jung Hoon Jung, Sumin Kang, Jong-Yeon Yoo, Hyun Jin Kim, Kyunghyun Park, Jung Hyun Pyo, Hyun-Yong Lee, Noah Koo, Soo-Hee Choi, Joung-Hun Kim","doi":"10.1038/s12276-024-01365-1","DOIUrl":"10.1038/s12276-024-01365-1","url":null,"abstract":"Post-traumatic stress disorder (PTSD) often arises after exposure to traumatic events and is characterized by dysregulated fear responses. Although the associations of erb-b2 receptor tyrosine kinase 4 (ErbB4) with various neuropsychiatric diseases, including schizophrenia and bipolar disorder, have been widely examined, the physiological roles of ErbB4 in PTSD and fear responses remain unclear. Using Cre-dependent ErbB4 knockout (KO) mice, we observed that PTSD-like fear behaviors emerged in ErbB4-deficient mice, particularly in inhibitory neurons. Specifically, the loss of ErbB4 in somatostatin-expressing (SST+) neurons was sufficient to induce PTSD-like fear responses. We also adopted the CRISPR/Cas9 system for region-specific KO of ErbB4, which revealed that ErbB4 deletion in SST+ neurons of the lateral division of the amygdala (CeL) caused elevated anxiety and PTSD-like fear generalization. Consistent with its physiological role, ErbB4 expression was diminished in CeLSST neurons from mice that exhibited PTSD-like phenotypes. While fear On and Off cells identified in the CeL displayed distinct responses to conditioned and novel cues, as previously shown, the selectivity of those On and Off cells was compromised in SSTErbB4-/- and stressed mice, which displayed strong fear generalization. Therefore, the bimodal activity that CeL On/Off cells display is likely required for proper discrimination of fearful stimuli from ambient stimuli, which should be sustained by the presence of ErbB4. Taken together, our data substantiate the correlation between PTSD-like fear responses and ErbB4 expression in CeLSST neurons and further underscore the functional effects of ErbB4 in CeLSST neurons, supporting the bimodal responses of CeL neurons. Post-traumatic stress disorder is a mental health condition that can develop after experiencing traumatic events. Researchers tried to understand the biological basis of PTSD using animal models. The researchers investigated the role of a protein called ErbB4 in fear responses related to PTSD. They used mice to study how deleting ErbB4 in specific brain cells affects fear behavior. They focused on somatostatin(SST)-expressing neurons in a brain region called the central amygdala, which is involved in processing fear. The study involved genetic modification, behavioral tests, and in vivo recording to observe changes in fear responses. The findings showed that removing ErbB4 from SST+ neurons led to increased anxiety and generalized fear, like PTSD symptoms, with specific alteration of neuronal activity. This suggests that ErbB4 helps regulate fear responses, and its absence may contribute to PTSD-like behaviors. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 12","pages":"2703-2713"},"PeriodicalIF":9.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01365-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774463","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":"Distribution and impact of p16INK4A+ senescent cells in elderly tissues: a focus on senescent immune cell and epithelial dysfunction","authors":"Soon Sang Park, Young-Kyoung Lee, Young Hwa Kim, So Hyun Park, Hee Young Kang, Jin Cheol Kim, Dong Jun Kim, Su Bin Lim, Gyesoon Yoon, Jang-Hee Kim, Yong Won Choi, Tae Jun Park","doi":"10.1038/s12276-024-01354-4","DOIUrl":"10.1038/s12276-024-01354-4","url":null,"abstract":"Cellular senescence, recognized as a key hallmark of aging, leads to the accumulation of senescent cells in various tissues over time. While the detrimental effects of these cells on age-related pathological conditions are well-documented, there is still limited information about how senescent cells are distributed in normal tissues of both young and aged organs. Our research indicates that fully senescent p16INK4A+ cells are rarely identified in the parenchyma of organic tissues and in the stromal cells crucial for structural maintenance, such as fibroblasts and smooth muscle cells. Instead, p16INK4A+ cells are more commonly found in immune cells, whether they reside in the organ or are infiltrating. Notably, p16INK4A+ senescent T cells have been observed to induce apoptosis and inflammation in colonic epithelial cells through Granzyme A-PARs signaling, compromising the integrity of the epithelial lining. This study showed that the senescence of immune cells could affect the phenotypical change of the parenchymal cells in the elderly and suggests that targeting immunosenescence might be a strategy to control functional decline in this population. Cellular senescence accumulates in tissues as we age, causing dysfunction and inflammation. However, the specific cell types that become senescent and their removal are not well understood. Researchers aimed to map senescent cells in young and elderly tissues, creating a “Senescence Atlas.” This study involved analyzing human tissues and mouse tissues using immunohistochemistry and single-cell RNA-sequencing. They focused on p16INK4A and found that senescent cells were rare in both young and elderly tissues. However, immune cells, especially T cells, showed increased senescence in elderly tissues. Results showed that senescent T cells release granzyme A, which activates protease-activated receptors in epithelial cells, leading to inflammation and cell death. This suggests that targeting senescent immune cells could improve organ function in the elderly. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 12","pages":"2631-2641"},"PeriodicalIF":9.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01354-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774297","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":"Hypothermic oxygenated perfusion inhibits CLIP1-mediated TIRAP ubiquitination via TFPI2 to reduce ischemia‒reperfusion injury of the fatty liver","authors":"Pengpeng Yue, Xiaoyan Lv, Hankun Cao, Yongkang Zou, Jian You, Jun Luo, Zhongshan Lu, Hao Chen, Zhongzhong Liu, Zibiao Zhong, Yan Xiong, Xiaoli Fan, Qifa Ye","doi":"10.1038/s12276-024-01350-8","DOIUrl":"10.1038/s12276-024-01350-8","url":null,"abstract":"The use of fatty livers in liver transplantation has emerged as a crucial strategy to expand the pool of donor livers; however, fatty livers are more sensitive to ischemia‒reperfusion injury (IRI). Excessive congenital inflammatory responses are crucial in IRI. Hypothermic oxygenated perfusion (HOPE) is a novel organ preservation technique that may improve marginal donor liver quality by reducing the inflammatory response. Tissue factor pathway inhibitor-2 (TFPI2) and CAP-Gly domain-containing linker protein 1 (CLIP1) exhibit modulatory effects on the inflammatory response. However, the underlying mechanisms of HOPE in fatty liver and the effects of TFPI2 and CLIP1 in fatty liver IRI remain unclear. Here, we aimed to explore the impact of HOPE on the inflammatory response in a rat model of fatty liver IRI and the mechanisms of action of TFPI2 and CLIP1. HOPE significantly reduces liver injury, especially the inflammatory response, and alleviates damage to hepatocytes and endothelial cells. Mechanistically, HOPE exerts its effects by inhibiting TFPI2, and CLIP1 can rescue the damaging effects of TFPI2. Moreover, HOPE promoted the ubiquitination and subsequent degradation of Toll/interleukin-1 receptor domain-containing adapter protein (TIRAP) by regulating the binding of R24 of the KD1 domain of TFPI2 with CLIP1, thereby negatively regulating the TLR4/NF-κB-mediated inflammatory response and reducing IRI. Furthermore, TFPI2 expression increased and CLIP1 expression decreased following cold ischemia in human fatty livers. Overall, our results suggest that targeting the inflammatory response by modulating the TFPI2/CLIP1/TIRAP signaling pathway via HOPE represents a potential therapeutic approach to ameliorate IRI during fatty liver transplantation. Liver transplantation is the only effective treatment for end-stage liver disease, but donor organ shortages limit its progress. Researchers found that fatty livers, which make up 15-30% of donations, are more prone to damage during transplantation. In this study, the researchers used a rat model to explore how hypothermic oxygenated perfusion (HOPE) affects fatty liver transplants. HOPE is a technique where the liver is preserved at low temperatures with oxygenated fluid. They divided rats into three groups: sham, cold storage (CS), and HOPE. Results showed that HOPE significantly reduces liver injury, especially the inflammatory response, and alleviates oxidative stress to improve liver function. The researchers concluded that HOPE can protect fatty livers during transplantation by inhibiting inflammation. Future studies could explore HOPE’s potential in human liver transplants. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 12","pages":"2588-2601"},"PeriodicalIF":9.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01350-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774469","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":"VIM-AS1, which is regulated by CpG methylation, cooperates with IGF2BP1 to inhibit tumor aggressiveness via EPHA3 degradation in hepatocellular carcinoma","authors":"Su-hyang Han, Je Yeong Ko, Sungju Jung, Sumin Oh, Do Yeon Kim, Eunseo Kang, Myung Sup Kim, Kyung-Hee Chun, Kyung Hyun Yoo, Jong Hoon Park","doi":"10.1038/s12276-024-01352-6","DOIUrl":"10.1038/s12276-024-01352-6","url":null,"abstract":"Early tumor recurrence in hepatocellular carcinoma (HCC) remains a challenging area, as the mechanisms involved are not fully understood. While microvascular invasion is linked to early recurrence, established biomarkers for diagnosis and prognostication are lacking. In this study, our objective was to identify DNA methylation sites that can predict the outcomes of liver cancer patients and elucidate the molecular mechanisms driving HCC aggressiveness. Using DNA methylome data from HCC patient samples from the CGRC and TCGA databases, we pinpointed hypermethylated CpG sites in HCC. Our analysis revealed that cg02746869 acts as a crucial regulatory site for VIM-AS1 (vimentin antisense RNA1), a 1.8 kb long noncoding RNA. RNA sequencing of HCC cells with manipulated VIM-AS1 expression revealed EPHA3 as a pathogenic target of VIM-AS1, which performs an oncogenic function in HCC. Hypermethylation-induced suppression of VIM-AS1 significantly impacted HCC cell dynamics, particularly impairing motility and invasiveness. Mechanistically, reduced VIM-AS1 expression stabilized EPHA3 mRNA by enhancing the binding of IGF2BP1 to EPHA3 mRNA, leading to increased expression of EPHA3 mRNA and the promotion of HCC progression. In vivo experiments further confirmed that the VIM-AS1‒EPHA3 axis controlled tumor growth and the tumor microenvironment in HCC. These findings suggest that the downregulation of VIM-AS1 due to hypermethylation at cg02746869 increased EPHA3 mRNA expression via a m6A-dependent mechanism to increase HCC aggressiveness. Despite advancements in treatment, cancer remains a life-threatening disease that can recur (come back) and metastasize. Researchers found a knowledge gap in understanding how DNA methylation affects cancer progression. Researchers conducted an experiment to identify DNA methylation markers related to liver cancer prognosis. They used human liver cancer cell lines and analyzed DNA methylation and gene expression. The researchers discovered that hypermethylation of a specific DNA region in the VIM-AS1 gene is linked to poor prognosis in liver cancer. They concluded that DNA methylation affects gene expression and cancer cell behavior. This finding could lead to new diagnostic and treatment strategies for liver cancer. Future research may explore how to target these epigenetic changes for better cancer therapies. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 12","pages":"2617-2630"},"PeriodicalIF":9.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01352-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774495","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}