FASEB bioAdvances最新文献

{"title":"Combinatorial islet protective therapeutic approaches in β-cell transplantation: Rationally designed solutions using a target product profile","authors":"Katie Lu,&nbsp;Timothy Brauns,&nbsp;Ann E. Sluder,&nbsp;Mark C. Poznansky,&nbsp;Fatma Dogan","doi":"10.1096/fba.2023-00029","DOIUrl":"10.1096/fba.2023-00029","url":null,"abstract":"<p>While progress has been made in the development of islet cell transplantation (ICT) as a viable alternative to the use of exogenous insulin therapy in the treatment of type 1 diabetes, it has not yet achieved its full potential in clinical studies. Ideally, ICT would enable lifelong maintenance of euglycemia without the need for exogenous insulin, blood glucose monitoring or systemic immune suppression. To achieve such an optimal result, therapeutic approaches should simultaneously promote long-term islet viability, functionality, and localized immune protection. In practice, however, these factors are typically tackled individually. Furthermore, while the requirements of optimal ICT are implicitly acknowledged across numerous publications, the literature contains few comprehensive articulations of the target product profile (TPP) for an optimal ICT product, including key characteristics of safety and efficacy. This review aims to provide a novel TPP for ICT and presents promising tried and untried combinatorial approaches that could be used to achieve the target product profile. We also highlight regulatory barriers to the development and adoption of ICT, particularly in the United States, where ICT is only approved for use in academic clinical trials and is not reimbursed by insurance carriers. Overall, this review argues that the clear definition of a TPP in addition to the use of combinatorial approaches could help to overcome the clinical barriers to the widespread adoption of ICT for the treatment of type 1 diabetes.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"5 7","pages":"287-304"},"PeriodicalIF":2.7,"publicationDate":"2023-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/33/f4/FBA2-5-287.PMC10320848.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10664881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive analysis of circRNAs for N7-methylguanosine methylation modification in human oral squamous cell carcinoma","authors":"Dongyuan Sun,&nbsp;Ning Song,&nbsp;Minmin Li,&nbsp;Xi Chen,&nbsp;Xinyue Zhang,&nbsp;Yang Yu,&nbsp;Jicheng Ying,&nbsp;Mengqi Xu,&nbsp;Wentian Zheng,&nbsp;Chengbing Han,&nbsp;Honghai Ji,&nbsp;Yingying Jiang","doi":"10.1096/fba.2023-00036","DOIUrl":"10.1096/fba.2023-00036","url":null,"abstract":"<p>N7-methylguanosine (m7G) modification is closely related to the occurrence of tumors. However, the m7G modification of circRNAs in oral squamous cell carcinoma (OSCC) remains to be investigated. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) was used to measure the methylation levels of m7G and identify m7G sites in circRNAs in human OSCC and normal tissues. The host genes of differentially methylated and differentially expressed circRNAs were analyzed by Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, and circRNA–miRNA–mRNA networks were predicted using the miRanda and miRDB databases. The analysis identified 2348 m7G peaks in 624 circRNAs in OSCC tissues. In addition, the source of m7G-methylated circRNAs in OSCC was mainly the sense overlap region compared with normal tissues. The most conserved m7G motif in OSCC tissues was CCUGU, whereas the most conserved motif in normal tissues was RCCUG (R = G/A). Importantly, GO enrichment and KEGG pathway analysis showed that the host genes of differentially methylated and differentially expressed circRNAs were involved in many cellular biological functions. Furthermore, the significantly differentially expressed circRNAs were analyzed to predict the circRNA–miRNA–mRNA networks. This study revealed the whole profile of circRNAs of differential m7G methylation in OSCC and suggests that m7G-modified circRNAs may impact the development of OSCC.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"5 8","pages":"305-320"},"PeriodicalIF":2.7,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/65/3b/FBA2-5-305.PMC10405248.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10019444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Post-inflammatory administration of N-acetylcysteine reduces inflammation and alters receptor levels in a cellular model of Parkinson's disease","authors":"Zeynep Bengisu Kaya,&nbsp;Elif Karakoc,&nbsp;Pamela J. McLean,&nbsp;Esen Saka,&nbsp;Pergin Atilla","doi":"10.1096/fba.2022-00145","DOIUrl":"https://doi.org/10.1096/fba.2022-00145","url":null,"abstract":"<p>Parkinson's disease (PD) is a complex, multifactorial neurodegenerative disease with a prevalence of 1% over the age of 55. Neuropathological hallmarks of PD include the loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of Lewy bodies that contain a variety of proteins and lipids including alpha-synuclein (α-syn). Although the formation of α-syn occurs intracellularly, it can also be found in the extracellular space where it can be taken up by neighboring cells. Toll-like receptor 2 (TLR2) is an immune system receptor that has been shown to recognize extracellular α-syn and modulate its uptake by other cells. Lymphocyte-activation gene 3 (LAG3), an immune checkpoint receptor, has also been proposed to play a role in extracellular α-syn internalization; however, a recent study has disputed this role. Internalized α-syn can trigger expression and secretion of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, IL-2, and IL-6 and induce neuroinflammation, apoptosis, and mitophagy that results in cellular death. In this study, we tested if <i>N</i>-acetylcysteine (NAC), an anti-inflammatory and anti-carcinogenic drug, can circumvent the detrimental effects of neuroinflammation and induce an anti-inflammatory response by modulating transcription and expression of TLR2 and LAG3 receptors. Cells overexpressing wild-type α-syn were treated with TNF-α to induce inflammation followed by NAC to inhibit the deleterious effects of TNF-α-induced inflammation and apoptosis. <i>SNCA</i> gene transcription and α-syn protein expression were validated by q-PCR and Western blot (WB), respectively. Cell viability was measured, and apoptosis was evaluated by WB and terminal deoxynucleotidyl transferase nick end labeling methods. Alterations in LAG3 and TLR2 receptor levels were evaluated by immunofluorescent labeling, WB, and q-PCR. TNF-α not only increased inflammation but also increased endogenous and overexpressed α-syn levels. NAC treatment decreased expression of TLR2 and increased transcription of LAG3 receptor and diminished inflammation-mediated toxicity and cell death. Here, we demonstrate that NAC can reduce neuroinflammation that occurs as a result of alpha-synuclein overexpression, via a TLR2-associated pathway, making it a promising candidate for therapeutic intervention. Further studies are needed to elucidate molecular mechanisms and pathways related to neuroinflammation in PD and to develop possible new therapeutic approaches to slow the clinical progression of PD.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"5 7","pages":"263-276"},"PeriodicalIF":2.7,"publicationDate":"2023-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2022-00145","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50135130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bilateral transcranial direct-current stimulation promotes migration of subventricular zone-derived neuroblasts toward ischemic brain","authors":"Ruixue Lei,&nbsp;Shu Wang,&nbsp;Anchun Liu,&nbsp;Jing Cheng,&nbsp;Zhifeng Zhang,&nbsp;Jinyang Ren,&nbsp;Xujin Yao,&nbsp;Xiangyi Kong,&nbsp;Wenlong Ma,&nbsp;Fengyuan Che,&nbsp;Juan Chen,&nbsp;Qi Wan","doi":"10.1096/fba.2023-00017","DOIUrl":"10.1096/fba.2023-00017","url":null,"abstract":"<p>Ischemic insult stimulates proliferation of neural stem cells (NSCs) in the subventricular zone (SVZ) after stroke. However, only a fraction of NSC-derived neuroblasts from SVZ migrate toward poststroke brain region. We have previously reported that direct-current stimulation guides NSC migration toward the cathode in vitro. Accordingly, we set up a new method of transcranial direct-current stimulation (tDCS), in which the cathodal electrode is placed on the ischemic hemisphere and anodal electrode on the contralateral hemisphere of rats subjected to ischemia–reperfusion injury. We show that the application of this bilateral tDCS (BtDCS) promotes the migration of NSC-derived neuroblasts from SVZ toward the cathode direction into poststroke striatum. Reversing the position of the electrodes blocks the effect of BtDCS on the migration of neuroblasts from SVZ. BtDCS protects against neuronal death and improves the functional recovery of stroke animals. Thus, the migration of NSC-derived neuroblasts from SVZ toward poststroke brain region contributes to the effect of BtDCS against ischemia-induced neuronal death, supporting a potential development of noninvasive BtDCS as an endogenous neurogenesis-based stroke therapy.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"5 7","pages":"277-286"},"PeriodicalIF":2.7,"publicationDate":"2023-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e3/0a/FBA2-5-277.PMC10320846.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9796647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-science conspiracies pose new threats to US biomedicine in 2023","authors":"Peter Hotez","doi":"10.1096/fba.2023-00032","DOIUrl":"10.1096/fba.2023-00032","url":null,"abstract":"&lt;p&gt;As America enters its fourth pandemic year, the full toll of COVID-19 on the public health of the country is coming into view. Even beyond our staggering 1.1 million deaths are the many millions of hospitalizations and the ensuing prolonged rehabilitations expected for long COVID cases. Newer data indicate that long COVID is more likely to occur after a severe bout of the infection.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The University of Washington Institute for Health Metrics employs a metric known as disability-adjusted life years or DALYs&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; which roughly refers to the years of life lost either from premature death or disability. On both fronts we will soon have numbers assigned to the DALYs lost from COVID-19, and they will be eye-wateringly high.&lt;/p&gt;&lt;p&gt;Tragically, many of these COVID-19 deaths and DALYs in America could have been averted with better acceptance of vaccines, especially during the deadly delta variant wave in the last half of 2021, and omicron BA.1 wave in the first quarter of 2022. In the months just prior to the onset of delta wave the Biden Administration had announced that any American who wanted a vaccine would have access to one.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; During delta, COVID-19 vaccinations exhibited over 90% protective immunity versus death,&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; and yet an estimated 40,000 Texans died because they declined to get immunized.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Nationally, that number of unnecessary deaths was approximately four to five-fold higher.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The analyses from &lt;i&gt;The New York Times&lt;/i&gt; and healthcare data specialist, Charles Gaba, reports that those deaths overwhelmingly occurred in conservative or Republican-majority states.&lt;span&gt;&lt;sup&gt;7, 8&lt;/sup&gt;&lt;/span&gt; Moreover, the “redder” the state in terms of voters, the lower the immunization rates, and the higher deaths climbed. This observation was so striking that David Leonhardt at &lt;i&gt;The New York Times&lt;/i&gt; invoked the term, “red Covid”.&lt;span&gt;&lt;sup&gt;7, 8&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The phenomenon of red Covid was not a random occurrence but instead an expected outcome of predation linked to extremist politics.&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; Some members of the House Freedom Caucus and even US senators sought to discredit the effectiveness and safety of COVID-19 vaccinations during the delta and omicron waves. They kicked this off at the July 2021 CPAC (Conservative Political Action) conference held in Dallas, Texas, claiming they will vaccinate you and then take away your guns and bibles,&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt; while highlighting prominent antivaccine activists.&lt;span&gt;&lt;sup&gt;11&lt;/sup&gt;&lt;/span&gt; This was preceded and followed by multiple public statements by both House and Senate members discrediting vaccines.&lt;span&gt;&lt;sup&gt;12-16&lt;/sup&gt;&lt;/span&gt; In parallel, both the watchdog Media Matters and a social science group based at ETH Zurich, the Swiss Federal Institute of Technology in Europe, documented how evening Fox News broadcasts disparaged va","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"5 6","pages":"228-232"},"PeriodicalIF":2.7,"publicationDate":"2023-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/5c/18/FBA2-5-228.PMC10242190.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9599235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Healthcare is not about health","authors":"James O. Woolliscroft,&nbsp;Larry D. Gruppen,&nbsp;Jasna Markovac,&nbsp;Edward F. Meehan","doi":"10.1096/fba.2023-00007","DOIUrl":"10.1096/fba.2023-00007","url":null,"abstract":"<p>Initiatives designed to reduce the disease burden and improve the health of the US population that focus on increasing access to health care have been disappointing. Progress requires multifaceted change. We must first acknowledge that the healthcare system is focused on reversing or modifying disease, not enhancing health. Our conceptualization of the development of ill health and disease must also change. Scientific advances are clarifying the complex interactions among the development of ill health and disease and an individual's behaviors, their microbiota, and their physical, social, and emotional environments. A person's genetic makeup predisposes them to a wide array of disease conditions but is rarely deterministic in and of itself. Factors extrinsic to the individual, including the social determinants of health, play a major role in disease development, often decades later. The complexity of health and disease requires a “team” accountable for the health of our populations, and these teams must be expanded beyond the medical professions. Governmental officials, architects, business leaders, civic organizations, social and neighborhood groups are among the key stakeholders on the health side of the equation. If and when disease does become manifest, then the care part of the healthcare system assumes the larger role. This has major implications for the education of our clinically focused health science students, but also of professional disciplines previously deemed peripheral to health. Simply redoubling our efforts and focusing on our current healthcare system is insufficient to make progress in the health of the populace. One example of a multipronged approach in Allentown, PA is explored in depth.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"5 6","pages":"221-227"},"PeriodicalIF":2.7,"publicationDate":"2023-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1b/6a/FBA2-5-221.PMC10242194.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9599237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Local fat content determines global and local stiffness in livers with simple steatosis","authors":"David Li,&nbsp;Paul A. Janmey,&nbsp;Rebecca G. Wells","doi":"10.1096/fba.2022-00134","DOIUrl":"10.1096/fba.2022-00134","url":null,"abstract":"<p>Fat accumulation during liver steatosis precedes inflammation and fibrosis in fatty liver diseases, and is associated with disease progression. Despite a large body of evidence that liver mechanics play a major role in liver disease progression, the effect of fat accumulation by itself on liver mechanics remains unclear. Thus, we conducted ex vivo studies of liver mechanics in rodent models of simple steatosis to isolate and examine the mechanical effects of intrahepatic fat accumulation, and found that fat accumulation softens the liver. Using a novel adaptation of microindentation to permit association of local mechanics with microarchitectural features, we found evidence that the softening of fatty liver results from local softening of fatty regions rather than uniform softening of the liver. These results suggest that fat accumulation itself exerts a softening effect on liver tissue. This, along with the localized heterogeneity of softening within the liver, has implications in what mechanical mechanisms are involved in the progression of liver steatosis to more severe pathologies and disease. Finally, the ability to examine and associate local mechanics with microarchitectural features is potentially applicable to the study of the role of heterogeneous mechanical microenvironments in both other liver pathologies and other organ systems.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"5 6","pages":"251-261"},"PeriodicalIF":2.7,"publicationDate":"2023-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ef/23/FBA2-5-251.PMC10242205.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10093838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPX2 promotes EMT and metastasis in non-small cell lung cancer by activating PI3K/AKT/mTOR/Snail signaling axis","authors":"Fang Peng,&nbsp;Qiushi Xu,&nbsp;Xiaomeng Jing,&nbsp;Xinming Chi,&nbsp;Zheming Zhang,&nbsp;Xiangpeng Meng,&nbsp;Xinyuan Liu,&nbsp;Jiao Yan,&nbsp;Xuefeng Liu,&nbsp;Shujuan Shao","doi":"10.1096/fba.2022-00045","DOIUrl":"10.1096/fba.2022-00045","url":null,"abstract":"<p>Lung cancer, with non-small cell lung cancer (NSCLC) being the main subtype, is the leading cause of cancer death worldwide, which is mainly due to the cancer metastasis. Glutathione peroxidase 2 (GPX2), an antioxidant enzyme, is involved in tumor progression and metastasis. Nevertheless, the role of GPX2 in NSCLC metastasis has not been clarified. In this study, we found that GPX2 expression was elevated in NSCLC tissues and high GPX2 expression was correlated with poor prognosis in patients with NSCLC. In addtion, GPX2 expression was related to the patient's clinicopathological features, including lymph node metastasis, tumor size, and TNM stage. Overexpression of GPX2 promoted epithelial–mesenchymal transition (EMT), migration, and invasion of NSCLC cells in vitro. Knockdown of GPX2 showed the opposite effects in vitro and inhibited the metastasis of NSCLC cells in nude mice. Furthermore, GPX2 reduced reactive oxygen species (ROS) accumulation and activated the PI3K/AKT/mTOR/Snail signaling axis. Therefore, our results indicate that GPX2 promotes EMT and metastasis of NSCLC cells by activating the PI3K/AKT/mTOR/Snail signaling axis via the removal of ROS. GPX2 may be an effective diagnostic and prognostic biomarker for NSCLC.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"5 6","pages":"233-250"},"PeriodicalIF":2.7,"publicationDate":"2023-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ed/d9/FBA2-5-233.PMC10242197.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9971674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting XBP1 mRNA splicing sensitizes glioblastoma to chemotherapy","authors":"Amiee Dowdell,&nbsp;Mark Marsland,&nbsp;Sam Faulkner,&nbsp;Craig Gedye,&nbsp;James Lynam,&nbsp;Cassandra P. Griffin,&nbsp;Joanne Marsland,&nbsp;Chen Chen Jiang,&nbsp;Hubert Hondermarck","doi":"10.1096/fba.2022-00141","DOIUrl":"10.1096/fba.2022-00141","url":null,"abstract":"<p>Glioblastoma (GBM) is the most frequent and deadly primary brain tumor in adults. Temozolomide (TMZ) is the standard systemic therapy in GBM but has limited and restricted efficacy. Better treatments are urgently needed. The role of endoplasmic reticulum stress (ER stress) is increasingly described in GBM pathophysiology. A key molecular mediator of ER stress, the spliced form of the transcription factor x-box binding protein 1 (XBP1s) may constitute a novel therapeutic target; here we report XBP1s expression and biological activity in GBM. Tumor samples from patients with GBM (<i>n</i> = 85) and low-grade glioma (<i>n</i> = 20) were analyzed by immunohistochemistry for XBP1s with digital quantification. XBP1s expression was significantly increased in GBM compared to low-grade gliomas. XBP1s mRNA showed upregulation by qPCR analysis in a panel of patient-derived GBM cell lines. Inhibition of XBP1 splicing using the small molecular inhibitor MKC-3946 significantly reduced GBM cell viability and potentiated the effect of TMZ in GBM cells, particularly in those with methylated O⁶-methylguanine-DNA methyl transferase gene promoter. GBM cells resistant to TMZ were also responsive to MKC-3946 and the long-term inhibitory effect of MKC-3946 was confirmed by colony formation assay. In conclusion, this data reveals that XBP1s is overexpressed in GBM and contributes to cancer cell growth. XBP1s warrants further investigation as a clinical biomarker and therapeutic target in GBM.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"5 5","pages":"211-220"},"PeriodicalIF":2.7,"publicationDate":"2023-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/37/53/FBA2-5-211.PMC10158625.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9430164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The RNA-binding protein Snd1/Tudor-SN regulates hypoxia-responsive gene expression","authors":"Juha Saarikettu,&nbsp;Saara Lehmusvaara,&nbsp;Marko Pesu,&nbsp;Ilkka Junttila,&nbsp;Juha Partanen,&nbsp;Petra Sipilä,&nbsp;Matti Poutanen,&nbsp;Jie Yang,&nbsp;Teemu Haikarainen,&nbsp;Olli Silvennoinen","doi":"10.1096/fba.2022-00115","DOIUrl":"10.1096/fba.2022-00115","url":null,"abstract":"<p>Snd1 is an evolutionarily conserved RNA-binding protein implicated in several regulatory processes in gene expression including activation of transcription, mRNA splicing, and microRNA decay. Here, we have investigated the outcome of <i>Snd1</i> gene deletion in the mouse. The knockout mice are viable showing no gross abnormalities apart from decreased fertility, organ and body size, and decreased number of myeloid cells concomitant with decreased expression of granule protein genes. Deletion of <i>Snd1</i> affected the expression of relatively small number of genes in spleen and liver. However, mRNA expression changes in the knockout mouse liver showed high similarity to expression profile in adaptation to hypoxia. MicroRNA expression in liver showed upregulation of the hypoxia-induced microRNAs miR-96 and -182. Similar to Snd1 deletion, mimics of miR-96/182 enhanced hypoxia-responsive reporter activity. To further elucidate the function of SND1, BioID biotin proximity ligation assay was performed in HEK-293T cells to identify interacting proteins. Over 50% of the identified interactors were RNA-binding proteins, including stress granule proteins. Taken together, our results show that in normal growth conditions, Snd1 is not a critical factor for mRNA transcription in the mouse, and describe a function for Snd1 in hypoxia adaptation through negatively regulating hypoxia-related miRNAs and hypoxia-induced transcription consistent with a role as stress response regulator.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"5 5","pages":"183-198"},"PeriodicalIF":2.7,"publicationDate":"2023-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2022-00115","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9423029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}