Life Science Alliance最新文献_第2页

Glycolic acid and D-lactate-putative products of DJ-1-restore neurodegeneration in FUS - and SOD1-ALS. 甘醇酸和D-乳酸--DJ-1的潜在产物--可恢复FUS-ALS和SOD1-ALS的神经退行性变。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-05-17 Print Date: 2024-08-01 DOI: 10.26508/lsa.202302535

Arun Pal, Dajana Grossmann, Hannes Glaß, Vitaly Zimyanin, René Günther, Marica Catinozzi, Tobias M Boeckers, Jared Sterneckert, Erik Storkebaum, Susanne Petri, Florian Wegner, Stephan W Grill, Francisco Pan-Montojo, Andreas Hermann

{"title":"Glycolic acid and D-lactate-putative products of DJ-1-restore neurodegeneration in FUS - and SOD1-ALS.","authors":"Arun Pal, Dajana Grossmann, Hannes Glaß, Vitaly Zimyanin, René Günther, Marica Catinozzi, Tobias M Boeckers, Jared Sterneckert, Erik Storkebaum, Susanne Petri, Florian Wegner, Stephan W Grill, Francisco Pan-Montojo, Andreas Hermann","doi":"10.26508/lsa.202302535","DOIUrl":"10.26508/lsa.202302535","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) leads to death within 2-5 yr. Currently, available drugs only slightly prolong survival. We present novel insights into the pathophysiology of Superoxide Dismutase 1 (SOD1)- and in particular Fused In Sarcoma (FUS)-ALS by revealing a supposedly central role of glycolic acid (GA) and D-lactic acid (DL)-both putative products of the Parkinson's disease associated glyoxylase DJ-1. Combined, not single, treatment with GA/DL restored axonal organelle phenotypes of mitochondria and lysosomes in FUS- and SOD1-ALS patient-derived motoneurons (MNs). This was not only accompanied by restoration of mitochondrial membrane potential but even dependent on it. Despite presenting an axonal transport deficiency as well, TDP43 patient-derived MNs did not share mitochondrial depolarization and did not respond to GA/DL treatment. GA and DL also restored cytoplasmic mislocalization of FUS and FUS recruitment to DNA damage sites, recently reported being upstream of the mitochondrial phenotypes in FUS-ALS. Whereas these data point towards the necessity of individualized (gene-) specific therapy stratification, it also suggests common therapeutic targets across different neurodegenerative diseases characterized by mitochondrial depolarization.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 8","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11101837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140958253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The F-actin bundler SWAP-70 promotes tumor metastasis. F-actin bundler SWAP-70 促进肿瘤转移。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-05-17 Print Date: 2024-08-01 DOI: 10.26508/lsa.202302307

Chao-Yuan Chang, Glen Pearce, Viktoria Betaneli, Tatsiana Kapustsenka, Kamran Hosseini, Elisabeth Fischer-Friedrich, Denis Corbeil, Jana Karbanová, Anna Taubenberger, Björn Dahncke, Martina Rauner, Giulia Furesi, Sven Perner, Fabian Rost, Rolf Jessberger

{"title":"The F-actin bundler SWAP-70 promotes tumor metastasis.","authors":"Chao-Yuan Chang, Glen Pearce, Viktoria Betaneli, Tatsiana Kapustsenka, Kamran Hosseini, Elisabeth Fischer-Friedrich, Denis Corbeil, Jana Karbanová, Anna Taubenberger, Björn Dahncke, Martina Rauner, Giulia Furesi, Sven Perner, Fabian Rost, Rolf Jessberger","doi":"10.26508/lsa.202302307","DOIUrl":"10.26508/lsa.202302307","url":null,"abstract":"Dynamic rearrangements of the F-actin cytoskeleton are a hallmark of tumor metastasis. Thus, proteins that govern F-actin rearrangements are of major interest for understanding metastasis and potential therapies. We hypothesized that the unique F-actin binding and bundling protein SWAP-70 contributes importantly to metastasis. Orthotopic, ectopic, and short-term tail vein injection mouse breast and lung cancer models revealed a strong positive dependence of lung and bone metastasis on SWAP-70. Breast cancer cell growth, migration, adhesion, and invasion assays revealed SWAP-70's key role in these metastasis-related cell features and the requirement for SWAP-70 to bind F-actin. Biophysical experiments showed that tumor cell stiffness and deformability are negatively modulated by SWAP-70. Together, we present a hitherto undescribed, unique F-actin modulator as an important contributor to tumor metastasis.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 8","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11101836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140958256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Reversal of high-glucose-induced transcriptional and epigenetic memories through NRF2 pathway activation. 通过激活 NRF2 通路逆转高葡萄糖诱导的转录和表观遗传记忆。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-05-16 Print Date: 2024-08-01 DOI: 10.26508/lsa.202302382

Martí Wilson-Verdugo, Brandon Bustos-García, Olga Adame-Guerrero, Jaqueline Hersch-González, Nallely Cano-Domínguez, Maribel Soto-Nava, Carlos A Acosta, Teresa Tusie-Luna, Santiago Avila-Rios, Lilia G Noriega, Victor J Valdes

{"title":"Reversal of high-glucose-induced transcriptional and epigenetic memories through NRF2 pathway activation.","authors":"Martí Wilson-Verdugo, Brandon Bustos-García, Olga Adame-Guerrero, Jaqueline Hersch-González, Nallely Cano-Domínguez, Maribel Soto-Nava, Carlos A Acosta, Teresa Tusie-Luna, Santiago Avila-Rios, Lilia G Noriega, Victor J Valdes","doi":"10.26508/lsa.202302382","DOIUrl":"10.26508/lsa.202302382","url":null,"abstract":"Diabetes complications such as nephropathy, retinopathy, or cardiovascular disease arise from vascular dysfunction. In this context, it has been observed that past hyperglycemic events can induce long-lasting alterations, a phenomenon termed \"metabolic memory.\" In this study, we evaluated the genome-wide gene expression and chromatin accessibility alterations caused by transient high-glucose exposure in human endothelial cells (ECs) in vitro. We found that cells exposed to high glucose exhibited substantial gene expression changes in pathways known to be impaired in diabetes, many of which persist after glucose normalization. Chromatin accessibility analysis also revealed that transient hyperglycemia induces persistent alterations, mainly in non-promoter regions identified as enhancers with neighboring genes showing lasting alterations. Notably, activation of the NRF2 pathway through NRF2 overexpression or supplementation with the plant-derived compound sulforaphane, effectively reverses the glucose-induced transcriptional and chromatin accessibility memories in ECs. These findings underscore the enduring impact of transient hyperglycemia on ECs' transcriptomic and chromatin accessibility profiles, emphasizing the potential utility of pharmacological NRF2 pathway activation in mitigating and reversing the high-glucose-induced transcriptional and epigenetic alterations.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 8","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11099870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140958254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Defects in integrin complex formation promote CHKB-mediated muscular dystrophy. 整合素复合物形成缺陷会促进 CHKB 介导的肌肉萎缩症。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-05-15 Print Date: 2024-08-01 DOI: 10.26508/lsa.202301956

Mahtab Tavasoli, Christopher R McMaster

{"title":"Defects in integrin complex formation promote CHKB-mediated muscular dystrophy.","authors":"Mahtab Tavasoli, Christopher R McMaster","doi":"10.26508/lsa.202301956","DOIUrl":"10.26508/lsa.202301956","url":null,"abstract":"Phosphatidylcholine (PC) is the major membrane phospholipid in most eukaryotic cells. Bi-allelic loss of function variants in CHKB, encoding the first step in the synthesis of PC, is the cause of a rostrocaudal muscular dystrophy in both humans and mice. Loss of sarcolemma integrity is a hallmark of muscular dystrophies; however, how this occurs in the absence of choline kinase function is not known. We determine that in Chkb -/- mice there is a failure of the α7β1 integrin complex that is specific to affected muscle. We observed that in Chkb -/- hindlimb muscles there is a decrease in sarcolemma association/abundance of the PI(4,5)P2 binding integrin complex proteins vinculin, and α-actinin, and a decrease in actin association with the sarcolemma. In cells, pharmacological inhibition of choline kinase activity results in internalization of a fluorescent PI(4,5)P2 reporter from discrete plasma membrane clusters at the cell surface membrane to cytosol, this corresponds with a decreased vinculin localization at plasma membrane focal adhesions that was rescued by overexpression of CHKB.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 8","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11096732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140945277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Modulating mycobacterial envelope integrity for antibiotic synergy with benzothiazoles. 调节分枝杆菌包膜的完整性，实现苯并噻唑类抗生素的协同作用。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-05-14 Print Date: 2024-07-01 DOI: 10.26508/lsa.202302509

Eva Habjan, Alexander Lepioshkin, Vicky Charitou, Anna Egorova, Elena Kazakova, Vien Qt Ho, Wilbert Bitter, Vadim Makarov, Alexander Speer

{"title":"Modulating mycobacterial envelope integrity for antibiotic synergy with benzothiazoles.","authors":"Eva Habjan, Alexander Lepioshkin, Vicky Charitou, Anna Egorova, Elena Kazakova, Vien Qt Ho, Wilbert Bitter, Vadim Makarov, Alexander Speer","doi":"10.26508/lsa.202302509","DOIUrl":"10.26508/lsa.202302509","url":null,"abstract":"Developing effective tuberculosis drugs is hindered by mycobacteria's intrinsic antibiotic resistance because of their impermeable cell envelope. Using benzothiazole compounds, we aimed to increase mycobacterial cell envelope permeability and weaken the defenses of Mycobacterium marinum, serving as a model for Mycobacterium tuberculosis Initial hit, BT-08, significantly boosted ethidium bromide uptake, indicating enhanced membrane permeability. It also demonstrated efficacy in the M. marinum-zebrafish embryo infection model and M. tuberculosis-infected macrophages. Notably, BT-08 synergized with established antibiotics, including vancomycin and rifampicin. Subsequent medicinal chemistry optimization led to BT-37, a non-toxic and more potent derivative, also enhancing ethidium bromide uptake and maintaining synergy with rifampicin in infected zebrafish embryos. Mutants of M. marinum resistant to BT-37 revealed that MMAR_0407 (Rv0164) is the molecular target and that this target plays a role in the observed synergy and permeability. This study introduces novel compounds targeting a new mycobacterial vulnerability and highlights their cooperative and synergistic interactions with existing antibiotics.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11094368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140922656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inflammatory risk contributes to post-COVID endothelial dysfunction through anti-ACKR1 autoantibody. 炎症风险通过抗ACKR1自身抗体导致COVID后内皮功能障碍。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-05-13 Print Date: 2024-07-01 DOI: 10.26508/lsa.202402598

Ee-Soo Lee, Nhi Nguyen, Barnaby E Young, Hannah Wee, Vanessa Wazny, Khang Leng Lee, Kai Yi Tay, Liuh Ling Goh, Florence Wj Chioh, Michelle Cy Law, I Russel Lee, Lay Teng Ang, Kyle M Loh, Mark Y Chan, Bingwen E Fan, Rinkoo Dalan, David C Lye, Laurent Renia, Christine Cheung

{"title":"Inflammatory risk contributes to post-COVID endothelial dysfunction through anti-ACKR1 autoantibody.","authors":"Ee-Soo Lee, Nhi Nguyen, Barnaby E Young, Hannah Wee, Vanessa Wazny, Khang Leng Lee, Kai Yi Tay, Liuh Ling Goh, Florence Wj Chioh, Michelle Cy Law, I Russel Lee, Lay Teng Ang, Kyle M Loh, Mark Y Chan, Bingwen E Fan, Rinkoo Dalan, David C Lye, Laurent Renia, Christine Cheung","doi":"10.26508/lsa.202402598","DOIUrl":"10.26508/lsa.202402598","url":null,"abstract":"Subclinical vascular impairment can be exacerbated in individuals who experience sustained inflammation after COVID-19 infection. Our study explores the prevalence and impact of autoantibodies on vascular dysfunction in healthy COVID-19 survivors, an area that remains inadequately investigated. Focusing on autoantibodies against the atypical chemokine receptor 1 (ACKR1), COVID-19 survivors demonstrated significantly elevated anti-ACKR1 autoantibodies, correlating with systemic cytokines, circulating damaged endothelial cells, and endothelial dysfunction. An independent cohort linked these autoantibodies to increased vascular disease outcomes during a median 6.7-yr follow-up. We analyzed a single-cell transcriptome atlas of endothelial cells from diverse mouse tissues, identifying enriched Ackr1 expressions in venous regions of the brain and soleus muscle vasculatures, which holds intriguing implications for tissue-specific venous thromboembolism manifestations reported in COVID-19. Functionally, purified immunoglobulin G (IgG) extracted from patient plasma did not trigger cell apoptosis or increase barrier permeability in human vein endothelial cells. Instead, plasma IgG enhanced antibody-dependent cellular cytotoxicity mediated by patient PBMCs, a phenomenon alleviated by blocking peptide or liposome ACKR1 recombinant protein. The blocking peptide uncovered that purified IgG from COVID-19 survivors possessed potential epitopes in the N-terminal extracellular domain of ACKR1, which effectively averted antibody-dependent cellular cytotoxicity. Our findings offer insights into therapeutic development to mitigate autoantibody reactivity in blood vessels in chronic inflammation.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11091471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140916672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Timing of TORC1 inhibition dictates Pol III involvement in Caenorhabditis elegans longevity. TORC1抑制的时间决定了Pol III在秀丽隐杆线虫长寿过程中的参与程度。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-05-13 Print Date: 2024-07-01 DOI: 10.26508/lsa.202402735

Yasir Malik, Isabel Goncalves Silva, Rene Rivera Diazgranados, Colin Selman, Nazif Alic, Jennifer Ma Tullet

{"title":"Timing of TORC1 inhibition dictates Pol III involvement in Caenorhabditis elegans longevity.","authors":"Yasir Malik, Isabel Goncalves Silva, Rene Rivera Diazgranados, Colin Selman, Nazif Alic, Jennifer Ma Tullet","doi":"10.26508/lsa.202402735","DOIUrl":"10.26508/lsa.202402735","url":null,"abstract":"Organismal growth and lifespan are inextricably linked. Target of Rapamycin (TOR) signalling regulates protein production for growth and development, but if reduced, extends lifespan across species. Reduction in the enzyme RNA polymerase III, which transcribes tRNAs and 5S rRNA, also extends longevity. Here, we identify a temporal genetic relationship between TOR and Pol III in Caenorhabditis elegans, showing that they collaborate to regulate progeny production and lifespan. Interestingly, the lifespan interaction between Pol III and TOR is only revealed when TOR signaling is reduced, specifically in adulthood, demonstrating the importance of timing to control TOR regulated developmental versus adult programs. In addition, we show that Pol III acts in C. elegans muscle to promote both longevity and healthspan and that reducing Pol III even in late adulthood is sufficient to extend lifespan. This demonstrates the importance of Pol III for lifespan and age-related health in adult C. elegans.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11091362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140916674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Human T-cell activation with Toxoplasma gondii antigens loaded in maltodextrin nanoparticles. 麦芽糊精纳米颗粒中的弓形虫抗原对人类 T 细胞的激活作用

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-05-09 Print Date: 2024-07-01 DOI: 10.26508/lsa.202302486

Laura García-López, Alejandro Zamora-Vélez, Mónica Vargas-Montes, Juan Camilo Sanchez-Arcila, François Fasquelle, Didier Betbeder, Jorge Enrique Gómez-Marín

{"title":"Human T-cell activation with Toxoplasma gondii antigens loaded in maltodextrin nanoparticles.","authors":"Laura García-López, Alejandro Zamora-Vélez, Mónica Vargas-Montes, Juan Camilo Sanchez-Arcila, François Fasquelle, Didier Betbeder, Jorge Enrique Gómez-Marín","doi":"10.26508/lsa.202302486","DOIUrl":"10.26508/lsa.202302486","url":null,"abstract":"Toxoplasmosis is the most prevalent parasitic zoonosis worldwide, causing ocular and neurological diseases. No vaccine has been approved for human use. We evaluated the response of peripheral blood mononuclear cells (PBMCs) to a novel construct of Toxoplasma gondii total antigen in maltodextrin nanoparticles (NP/TE) in individuals with varying infectious statuses (uninfected, chronic asymptomatic, or ocular toxoplasmosis). We analyzed the concentration of IFN-γ after NP/TE ex vivo stimulation using ELISA and the immunophenotypes of CD4+ and CD8+ cell populations using flow cytometry. In addition, serotyping of individuals with toxoplasmosis was performed by ELISA using GRA6-derived polypeptides. Low doses of NP/TE stimulation (0.9 μg NP/0.3 μg TE) achieved IFN-γ-specific production in previously exposed human PBMCs without significant differences in the infecting serotype. Increased IFN-γ expression in CD4+ effector memory cell subsets was found in patients with ocular toxoplasmosis with NP/TE but not with TE alone. This is the first study to show how T-cell subsets respond to ex vivo stimulation with a vaccine candidate for human toxoplasmosis, providing crucial insights for future clinical trials.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11082450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140898590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Brd4::Nutm1 fusion gene initiates NUT carcinoma in vivo. Brd4::Nutm1 融合基因在体内引发 NUT 癌。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-05-09 Print Date: 2024-07-01 DOI: 10.26508/lsa.202402602

Dejin Zheng, Ahmed A Elnegiry, Chenxiang Luo, Mohammed Amine Bendahou, Liangqi Xie, Diana Bell, Yoko Takahashi, Ehab Hanna, George I Mias, Mayra F Tsoi, Bin Gu

{"title":"Brd4::Nutm1 fusion gene initiates NUT carcinoma in vivo.","authors":"Dejin Zheng, Ahmed A Elnegiry, Chenxiang Luo, Mohammed Amine Bendahou, Liangqi Xie, Diana Bell, Yoko Takahashi, Ehab Hanna, George I Mias, Mayra F Tsoi, Bin Gu","doi":"10.26508/lsa.202402602","DOIUrl":"10.26508/lsa.202402602","url":null,"abstract":"NUT carcinoma (NC) is an aggressive cancer with no effective treatment. About 70% of NUT carcinoma is associated with chromosome translocation events that lead to the formation of a BRD4::NUTM1 fusion gene. Because the BRD4::NUTM1 gene is unequivocally cytotoxic when ectopically expressed in cell lines, questions remain on whether the fusion gene can initiate NC. Here, we report the first genetically engineered mouse model for NUT carcinoma that recapitulates the human t(15;19) chromosome translocation in mice. We demonstrated that the mouse t(2;17) syntenic chromosome translocation, forming the Brd4::Nutm1 fusion gene, could induce aggressive carcinomas in mice. The tumors present histopathological and molecular features similar to human NC, with enrichment of undifferentiated cells. Similar to the reports of human NC incidence, Brd4::Nutm1 can induce NC from a broad range of tissues with a strong phenotypical variability. The consistent induction of poorly differentiated carcinoma demonstrated a strong reprogramming activity of BRD4::NUTM1. The new mouse model provided a critical preclinical model for NC that will lead to better understanding and therapy development for NC.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11082452/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140898588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mitochondrial translation failure represses cholesterol gene expression via Pyk2-Gsk3β-Srebp2 axis. 线粒体翻译失败通过 Pyk2-Gsk3β-Srebp2 轴抑制胆固醇基因的表达。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-05-08 Print Date: 2024-07-01 DOI: 10.26508/lsa.202302423

Takahiro Toshima, Mikako Yagi, Yura Do, Haruka Hirai, Yuya Kunisaki, Dongchon Kang, Takeshi Uchiumi

{"title":"Mitochondrial translation failure represses cholesterol gene expression via Pyk2-Gsk3β-Srebp2 axis.","authors":"Takahiro Toshima, Mikako Yagi, Yura Do, Haruka Hirai, Yuya Kunisaki, Dongchon Kang, Takeshi Uchiumi","doi":"10.26508/lsa.202302423","DOIUrl":"10.26508/lsa.202302423","url":null,"abstract":"Neurodegenerative diseases and other age-related disorders are closely associated with mitochondrial dysfunction. We previously showed that mice with neuron-specific deficiency of mitochondrial translation exhibit leukoencephalopathy because of demyelination. Reduced cholesterol metabolism has been associated with demyelinating diseases of the brain such as Alzheimer's disease. However, the molecular mechanisms involved and relevance to the pathogenesis remained unknown. In this study, we show that inhibition of mitochondrial translation significantly reduced expression of the cholesterol synthase genes and degraded their sterol-regulated transcription factor, sterol regulatory element-binding protein 2 (Srebp2). Furthermore, the phosphorylation of Pyk2 and Gsk3β was increased in the white matter of p32cKO mice. We observed that Pyk2 inhibitors reduced the phosphorylation of Gsk3β and that GSK3β inhibitors suppressed degradation of the transcription factor Srebp2. The Pyk2-Gsk3β axis is involved in the ubiquitination of Srebp2 and reduced expression of cholesterol gene. These results suggest that inhibition of mitochondrial translation may be a causative mechanism of neurodegenerative diseases of aging. Improving the mitochondrial translation or effectiveness of Gsk3β inhibitors is a potential therapeutic strategy for leukoencephalopathy.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11079605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140892300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0