Life Science AlliancePub Date : 2024-08-16Print Date: 2024-10-01DOI: 10.26508/lsa.202402656
Eldar Zehorai, Tamar Gross Lev, Elee Shimshoni, Ron Hadas, Idan Adir, Ofra Golani, Guillaume Molodij, Ram Eitan, Karl E Kadler, Orit Kollet, Michal Neeman, Nava Dekel, Inna Solomonov, Irit Sagi
{"title":"Enhancing uterine receptivity for embryo implantation through controlled collagenase intervention.","authors":"Eldar Zehorai, Tamar Gross Lev, Elee Shimshoni, Ron Hadas, Idan Adir, Ofra Golani, Guillaume Molodij, Ram Eitan, Karl E Kadler, Orit Kollet, Michal Neeman, Nava Dekel, Inna Solomonov, Irit Sagi","doi":"10.26508/lsa.202402656","DOIUrl":"10.26508/lsa.202402656","url":null,"abstract":"<p><p>Ineffective endometrial matrix remodeling, a key factor in infertility, impedes embryo implantation in the uterine wall. Our study reveals the cellular and molecular impact of human collagenase-1 administration in mouse uteri, demonstrating enhanced embryo implantation rates. Collagenase-1 promotes remodeling of the endometrial ECM, degrading collagen fibers and proteoglycans. This process releases matrix-bound bioactive factors (e.g., VEGF, decorin), facilitating vascular permeability and angiogenesis. Collagenase-1 elevates embryo implantation regulators, including NK cell infiltration and the key cytokine LIF. Remarkably, uterine tissue maintains structural integrity despite reduced endometrial collagen fiber tension. In-utero collagenase-1 application rescues implantation in heat stress and embryo transfer models, known for low implantation rates. Importantly, ex vivo exposure of human uterine tissue to collagenase-1 induces collagen de-tensioning and VEGF release, mirroring remodeling observed in mice. Our research highlights the potential of collagenases to induce and orchestrate cellular and molecular processes enhancing uterine receptivity for effective embryo implantation. This innovative approach underscores ECM remodeling mechanisms critical for embryo implantation.</p>","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11329778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996097","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}
Life Science AlliancePub Date : 2024-08-12Print Date: 2024-11-01DOI: 10.26508/lsa.202402618
Kathryn M Rubey, Alexandra Freeman, Alexander R Mukhitov, Andrew J Paris, Susan M Lin, Ryan Rue, Hossein Fazelinia, Lynn A Spruce, Jennifer Roof, Jacob S Brenner, Jennifer Heimall, Vera P Krymskaya
{"title":"Neutrophil-avid nanocarrier uptake by STAT3 dominant-negative hyper-IgE syndrome patient neutrophils.","authors":"Kathryn M Rubey, Alexandra Freeman, Alexander R Mukhitov, Andrew J Paris, Susan M Lin, Ryan Rue, Hossein Fazelinia, Lynn A Spruce, Jennifer Roof, Jacob S Brenner, Jennifer Heimall, Vera P Krymskaya","doi":"10.26508/lsa.202402618","DOIUrl":"10.26508/lsa.202402618","url":null,"abstract":"<p><p>Recurrent infections are a hallmark of STAT3 dominant-negative hyper-IgE syndrome (STAT3 HIES), a rare immunodeficiency syndrome previously known as Jobs syndrome, along with elevated IgE levels and impaired neutrophil function. We have been developing nanoparticles with neutrophil trophism that home to the sites of infection via these first-responder leukocytes, named neutrophil-avid nanocarriers (NANs). Here, we demonstrate that human neutrophils can phagocytose nanogels (NGs), a type of NAN, with enhanced uptake after particle serum opsonization, comparing neutrophils from healthy individuals to those with STAT3 HIES, where both groups exhibit NG uptake; however, the patient group showed reduced phagocytosis efficiency with serum-opsonized NANs. Proteomic analysis of NG protein corona revealed complement components, particularly C3, as predominant in both groups. Difference between groups includes STAT3 HIES samples with higher neutrophil protein and lower acute-phase protein expression. The study suggests that despite neutrophil dysfunction in STAT3 HIES, NANs have potential for directed delivery of cargo therapeutics to improve neutrophil infection clearance.</p>","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 11","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11321353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971414","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}
Life Science AlliancePub Date : 2024-08-09Print Date: 2024-11-01DOI: 10.26508/lsa.202402885
Joseph B Shrager, Ryan Randle, Myung Lee, Syed Saadan Ahmed, Winston Trope, Natalie Lui, George Poultsides, Doug Liou, Brendan Visser, Jeffrey A Norton, Shannon M Nesbit, Hao He, Ntemena Kapula, Bailey Wallen, Emmanuel Fatodu, Cheyenne A Sadeghi, Harrison B Konsker, Irmina Elliott, Brandon Guenthart, Leah Backhus, Roger Cooke, Mark Berry, Huibin Tang
{"title":"JAK inhibition with tofacitinib rapidly increases contractile force in human skeletal muscle.","authors":"Joseph B Shrager, Ryan Randle, Myung Lee, Syed Saadan Ahmed, Winston Trope, Natalie Lui, George Poultsides, Doug Liou, Brendan Visser, Jeffrey A Norton, Shannon M Nesbit, Hao He, Ntemena Kapula, Bailey Wallen, Emmanuel Fatodu, Cheyenne A Sadeghi, Harrison B Konsker, Irmina Elliott, Brandon Guenthart, Leah Backhus, Roger Cooke, Mark Berry, Huibin Tang","doi":"10.26508/lsa.202402885","DOIUrl":"10.26508/lsa.202402885","url":null,"abstract":"<p><p>Reduction in muscle contractile force associated with many clinical conditions incurs serious morbidity and increased mortality. Here, we report the first evidence that JAK inhibition impacts contractile force in normal human muscle. Muscle biopsies were taken from patients who were randomized to receive tofacitinib (n = 16) or placebo (n = 17) for 48 h. Single-fiber contractile force and molecular studies were carried out. The contractile force of individual diaphragm myofibers pooled from the tofacitinib group (n = 248 fibers) was significantly higher than those from the placebo group (n = 238 fibers), with a 15.7% greater mean maximum specific force (<i>P</i> = 0.0016). Tofacitinib treatment similarly increased fiber force in the serratus anterior muscle. The increased force was associated with reduced muscle protein oxidation and FoxO-ubiquitination-proteasome signaling, and increased levels of smooth muscle MYLK. Inhibition of MYLK attenuated the tofacitinib-dependent increase in fiber force. These data demonstrate that tofacitinib increases the contractile force of skeletal muscle and offers several underlying mechanisms. Inhibition of the JAK-STAT pathway is thus a potential new therapy for the muscle dysfunction that occurs in many clinical conditions.</p>","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 11","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11316201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141913164","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}
Life Science AlliancePub Date : 2024-08-08Print Date: 2024-10-01DOI: 10.26508/lsa.202302239
Gezime Seferi, Harald S Mjønes, Mona Havik, Herman Reiersen, Knut Tomas Dalen, Kaja Nordengen, Cecilie Morland
{"title":"Distribution of lipid droplets in hippocampal neurons and microglia: impact of diabetes and exercise.","authors":"Gezime Seferi, Harald S Mjønes, Mona Havik, Herman Reiersen, Knut Tomas Dalen, Kaja Nordengen, Cecilie Morland","doi":"10.26508/lsa.202302239","DOIUrl":"10.26508/lsa.202302239","url":null,"abstract":"<p><p>Neuroinflammation, aging, and neurodegenerative disorders are associated with excessive accumulation of neutral lipids in lipid droplets (LDs) in microglia. Type 2 diabetes mellitus (T2DM) may cause neuroinflammation and is a risk factor for neurodegenerative disorders. Here, we show that hippocampal pyramidal neurons contain smaller, more abundant LDs than their neighboring microglia. The density of LDs varied between pyramidal cells in adjacent subregions, with CA3 neurons containing more LDs than CA1 neurons. Within the CA3 region, a gradual increase in the LD content along the pyramidal layer from the hilus toward CA2 was observed. Interestingly, the high neuronal LD content correlated with less ramified microglial morphotypes. Using the <i>db/db</i> model of T2DM, we demonstrated that diabetes increased the number of LDs per microglial cell without affecting the neuronal LD density. High-intensity interval exercise induced smaller changes in the number of LDs in microglia but was not sufficient to counteract the diabetes-induced changes in LD accumulation. The changes observed in response to T2DM may contribute to the cerebral effects of T2DM and provide a mechanistic link between T2DM and neurodegenerative disorders.</p>","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11310565/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141907010","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}
Life Science AlliancePub Date : 2024-08-07Print Date: 2024-10-01DOI: 10.26508/lsa.202402755
Peng Wang, Zixian Li, Sung-Hoon Kim, Haijin Xu, Hao Huang, Chutong Yang, Abby Snape, Jung-Hyun Choi, Sara Bermudez, Marie-Noelle Boivin, Nicolas Ferry, Jason Karamchandani, Bhushan Nagar, Nahum Sonenberg
{"title":"PPM1G dephosphorylates eIF4E in control of mRNA translation and cell proliferation.","authors":"Peng Wang, Zixian Li, Sung-Hoon Kim, Haijin Xu, Hao Huang, Chutong Yang, Abby Snape, Jung-Hyun Choi, Sara Bermudez, Marie-Noelle Boivin, Nicolas Ferry, Jason Karamchandani, Bhushan Nagar, Nahum Sonenberg","doi":"10.26508/lsa.202402755","DOIUrl":"10.26508/lsa.202402755","url":null,"abstract":"<p><p>The mRNA 5'cap-binding eukaryotic translation initiation factor 4E (eIF4E) plays a critical role in the control of mRNA translation in health and disease. One mechanism of regulation of eIF4E activity is via phosphorylation of eIF4E by MNK kinases, which promotes the translation of a subset of mRNAs encoding pro-tumorigenic proteins. Work on eIF4E phosphatases has been paltry. Here, we show that PPM1G is the phosphatase that dephosphorylates eIF4E. We describe the eIF4E-binding motif in PPM1G that is similar to 4E-binding proteins (4E-BPs). We demonstrate that PPM1G inhibits cell proliferation by targeting phospho-eIF4E-dependent mRNA translation.</p>","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11306785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902133","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}
Life Science AlliancePub Date : 2024-08-06Print Date: 2024-10-01DOI: 10.26508/lsa.202402713
Sishir Subedi, Tomokazu S Sumida, Yongjin P Park
{"title":"A scalable approach to topic modelling in single-cell data by approximate pseudobulk projection.","authors":"Sishir Subedi, Tomokazu S Sumida, Yongjin P Park","doi":"10.26508/lsa.202402713","DOIUrl":"10.26508/lsa.202402713","url":null,"abstract":"<p><p>Probabilistic topic modelling has become essential in many types of single-cell data analysis. Based on probabilistic topic assignments in each cell, we identify the latent representation of cellular states. A dictionary matrix, consisting of topic-specific gene frequency vectors, provides interpretable bases to be compared with known cell type-specific marker genes and other pathway annotations. However, fitting a topic model on a large number of cells would require heavy computational resources-specialized computing units, computing time and memory. Here, we present a scalable approximation method customized for single-cell RNA-seq data analysis, termed ASAP, short for Annotating a Single-cell data matrix by Approximate Pseudobulk estimation. Our approach is more accurate than existing methods but requires orders of magnitude less computing time, leaving much lower memory consumption. We also show that our approach is widely applicable for atlas-scale data analysis; our method seamlessly integrates single-cell and bulk data in joint analysis, not requiring additional preprocessing or feature selection steps.</p>","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897728","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}
Life Science AlliancePub Date : 2024-08-06Print Date: 2024-10-01DOI: 10.26508/lsa.202402754
Robert A Chesters, Jiajie Zhu, Bethany M Coull, David Baidoe-Ansah, Lea Baumer, Lydia Palm, Niklas Klinghammer, Seve Chen, Anneke Hahm, Selma Yagoub, Lídia Cantacorps, Daniel Bernardi, Katrin Ritter, Rachel N Lippert
{"title":"Fasting-induced activity changes in MC3R neurons of the paraventricular nucleus of the thalamus.","authors":"Robert A Chesters, Jiajie Zhu, Bethany M Coull, David Baidoe-Ansah, Lea Baumer, Lydia Palm, Niklas Klinghammer, Seve Chen, Anneke Hahm, Selma Yagoub, Lídia Cantacorps, Daniel Bernardi, Katrin Ritter, Rachel N Lippert","doi":"10.26508/lsa.202402754","DOIUrl":"10.26508/lsa.202402754","url":null,"abstract":"<p><p>The brain controls energy homeostasis by regulating food intake through signaling within the melanocortin system. Whilst we understand the role of the hypothalamus within this system, how extra-hypothalamic brain regions are involved in controlling energy balance remains unclear. Here we show that the melanocortin 3 receptor (MC3R) is expressed in the paraventricular nucleus of the thalamus (PVT). We tested whether fasting would change the activity of MC3R neurons in this region by assessing the levels of c-Fos and pCREB as neuronal activity markers. We determined that overnight fasting causes a significant reduction in pCREB levels within PVT-MC3R neurons. We then questioned whether perturbation of MC3R signaling, during fasting, would result in altered refeeding. Using chemogenetic approaches, we show that modulation of MC3R activity, during the fasting period, does not impact body weight regain or total food intake in the refeeding period. However, we did observe significant differences in the pattern of feeding-related behavior. These findings suggest that the PVT is a region where MC3R neurons respond to energy deprivation and modulate refeeding behavior.</p>","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303869/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897729","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}
Life Science AlliancePub Date : 2024-08-05Print Date: 2024-10-01DOI: 10.26508/lsa.202402702
Sam Dawes, Nicholas Hurst, Gabriel Grey, Lukasz Wieteska, Nathan V Wright, Iain W Manfield, Mohammed H Hussain, Arnout P Kalverda, Jozef R Lewandowski, Beining Chen, Anastasia Zhuravleva
{"title":"Chaperone BiP controls ER stress sensor Ire1 through interactions with its oligomers.","authors":"Sam Dawes, Nicholas Hurst, Gabriel Grey, Lukasz Wieteska, Nathan V Wright, Iain W Manfield, Mohammed H Hussain, Arnout P Kalverda, Jozef R Lewandowski, Beining Chen, Anastasia Zhuravleva","doi":"10.26508/lsa.202402702","DOIUrl":"10.26508/lsa.202402702","url":null,"abstract":"<p><p>The complex multistep activation cascade of Ire1 involves changes in the Ire1 conformation and oligomeric state. Ire1 activation enhances ER folding capacity, in part by overexpressing the ER Hsp70 molecular chaperone BiP; in turn, BiP provides tight negative control of Ire1 activation. This study demonstrates that BiP regulates Ire1 activation through a direct interaction with Ire1 oligomers. Particularly, we demonstrated that the binding of Ire1 luminal domain (LD) to unfolded protein substrates not only trigger conformational changes in Ire1-LD that favour the formation of Ire1-LD oligomers but also exposes BiP binding motifs, enabling the molecular chaperone BiP to directly bind to Ire1-LD in an ATP-dependent manner. These transient interactions between BiP and two short motifs in the disordered region of Ire1-LD are reminiscent of interactions between clathrin and another Hsp70, cytoplasmic Hsc70. BiP binding to substrate-bound Ire1-LD oligomers enables unfolded protein substrates and BiP to synergistically and dynamically control Ire1-LD oligomerisation, helping to return Ire1 to its deactivated state when an ER stress response is no longer required.</p>","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11300964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893775","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}
Life Science AlliancePub Date : 2024-08-01Print Date: 2024-10-01DOI: 10.26508/lsa.202402621
Narasaem Lee, Subin Kim, Na Young Lee, Heeji Jo, Pyeonghwa Jeong, Haushabhau S Pagire, Suvarna H Pagire, Jin Hee Ahn, Mi Sun Jin, Chul-Seung Park
{"title":"Activation mechanism and novel binding sites of the BK<sub>Ca</sub> channel activator CTIBD.","authors":"Narasaem Lee, Subin Kim, Na Young Lee, Heeji Jo, Pyeonghwa Jeong, Haushabhau S Pagire, Suvarna H Pagire, Jin Hee Ahn, Mi Sun Jin, Chul-Seung Park","doi":"10.26508/lsa.202402621","DOIUrl":"10.26508/lsa.202402621","url":null,"abstract":"<p><p>The large-conductance calcium-activated potassium (BK<sub>Ca</sub>) channel, which is crucial for urinary bladder smooth muscle relaxation, is a potential target for overactive bladder treatment. Our prior work unveiled CTIBD as a promising BK<sub>Ca</sub> channel activator, altering <i>V</i> <sub><i>1/2</i></sub> and <i>G</i> <sub><i>max</i></sub> This study investigates CTIBD's activation mechanism, revealing its independence from the Ca<sup>2+</sup> and membrane voltage sensing of the BK<sub>Ca</sub> channel. Cryo-electron microscopy disclosed that two CTIBD molecules bind to hydrophobic regions on the extracellular side of the lipid bilayer. Key residues (W22, W203, and F266) are important for CTIBD binding, and their replacement with alanine reduces CTIBD-mediated channel activation. The triple-mutant (W22A/W203A/F266A) channel showed the smallest <i>V</i> <sub><i>1/2</i></sub> shift with a minimal impact on activation and deactivation kinetics by CTIBD. At the single-channel level, CTIBD treatment was much less effective at increasing <i>P</i> <sub><i>o</i></sub> in the triple mutant, mainly because of a drastically increased dissociation rate compared with the WT. These findings highlight CTIBD's mechanism, offering crucial insights for developing small-molecule treatments for BK<sub>Ca</sub>-related pathophysiological conditions.</p>","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11294680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875271","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}
Life Science AlliancePub Date : 2024-08-01Print Date: 2024-10-01DOI: 10.26508/lsa.202402653
Luisa P Mori, Michael J Corley, Andrew T McAuley, Alina Pang, Thomas Venables, Lishomwa C Ndhlovu, Matthew E Pipkin, Susana T Valente
{"title":"Transcriptional and methylation outcomes of didehydro-cortistatin A use in HIV-1-infected CD4<sup>+</sup> T cells.","authors":"Luisa P Mori, Michael J Corley, Andrew T McAuley, Alina Pang, Thomas Venables, Lishomwa C Ndhlovu, Matthew E Pipkin, Susana T Valente","doi":"10.26508/lsa.202402653","DOIUrl":"10.26508/lsa.202402653","url":null,"abstract":"<p><p>Ongoing viral transcription from the reservoir of HIV-1 infected long-lived memory CD4<sup>+</sup> T cells presents a barrier to cure and associates with poorer health outcomes for people living with HIV, including chronic immune activation and inflammation. We previously reported that didehydro-cortistatin A (dCA), an HIV-1 Tat inhibitor, blocks HIV-1 transcription. Here, we examine the impact of dCA on host immune CD4<sup>+</sup> T-cell transcriptional and epigenetic states. We performed a comprehensive analysis of genome-wide transcriptomic and DNA methylation profiles upon long-term dCA treatment of primary human memory CD4<sup>+</sup> T cells. dCA prompted specific transcriptional and DNA methylation changes in cell cycle, histone, interferon-response, and T-cell lineage transcription factor genes, through inhibition of both HIV-1 and Mediator kinases. These alterations establish a tolerogenic Treg/Th2 phenotype, reducing viral gene expression and mitigating inflammation in primary CD4<sup>+</sup> T cells during HIV-1 infection. In addition, dCA suppresses the expression of lineage-defining transcription factors for Th17 and Th1 cells, critical HIV-1 targets, and reservoirs. dCA's benefits thus extend beyond viral transcription inhibition, modulating the immune cell landscape to limit HIV-1 acquisition and inflammatory environment linked to HIV infection.</p>","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11294679/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875272","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}
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