Top read articles in the last 30 days
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Abstract
Small molecules that modulate myofibril ATPase activity via the myosin regulatory light chain (RLC) display a broad spectrum of activity in their ability to enhance relaxation and slow contraction. EDG-7500 exhibits features consistent with a ‘diastolic-selective’ cardiac sarcomere modulator (d-CSM), and its ability to treat HCM was explored in engineered human tissue (EHT), human HCM cardiac strips, and an R403Q mutation swine model. In fibers, EDG-7500 preferentially inhibited myofibril ATPase activity and force at diastolic calcium levels, retained length-dependent force activation, accelerated relaxation, and exhibited a shallow, self-limiting inhibitory-exposure response to LV fractional shortening. Compared to CMIs, EDG-7500 moved myosin heads towards the thin filament and accelerated relaxation without decreasing force in mutated EHTs (R403Q). In human HCM cardiac strips, EDG-7500 did not alter myosin SRX state, but decreased Ca2+-sensitivity of force independent of mutation. In R403Q swine, chronic EDG-7500 normalized LV filling pressure and prevented pathological cardiac remodeling while preserving normal systolic function and cardiac reserve. EDG-7500 differentiates itself from CMIs by uniquely targeting both phases of the cardiac cycle, improving ventricular relaxation while preserving systolic function. This suggests optimal diastolic efficacy can be reached without balancing systolic impairment.
Authors
Craig A. Emter, Marcus Henze, Mike DuVall, Sarah Lehman, Lindsey Lee, Ben Barthel, Natalie A. Hawryluk, Molly Madden, Yangsong Wu, Amy Perry, Martin Beyer, Eric Wei, Cassady Rupert, Steve Roof, Angela Peter, Emily DiNatale, Sara Cantrell, Jessica Tolley, Stephen Schlachter, Jolanda van der Velden, Michelle Michels, Christine Seidman, Weikang Ma, Leslie Leinwand, Stuart Campbell, Julien Ochala, David Bluemke, Darla Tharp, Jonathan Seidman, Carlos L. del Rio, Marc Semigran, Marc Evanchik, Kevin Koch, Alan Russell
Total views: 5446
Abstract
DNA damage and the cGAS/STING innate immunity pathway have been associated with fibrosis in systemic sclerosis (SSc), but a cause-and-effect role has not been established. Here we report the effects of TY1, a noncoding RNA drug of the exomer class that suppresses DNA damage and thereby inhibits cGAS/STING, in human SSc cells and in 2 preclinical models of SSc. Macrophages from patients with SSc exhibited high levels of phosphorylated DNA damage, cGAS, 2’3’-cGAMP, STING, and IFNs, all of which decreased after exposure to TY1. In mice that had been injected s.c. with bleomycin to model SSc, exercise tolerance, cardiac function, lung hydroxyproline, and skin thickness reverted to normal levels after oral administration of TY1. Similar therapeutic benefits were evident in the genetic tsk-1 mouse model of SSc. TY1 attenuated fibrosis and/or fibrotic gene expression in both mouse models of SSc and in human SSc skin fibroblasts. Our findings support the hypothesis that cGAS/STING, activated by DNA damage, is a key driver of fibrosis in SSc.
Authors
Xaviar M. Jones, Salwa Soussi, Alessandra Ciullo, Kara Tsi, Weixin Liu, Liang Li, Mario Fournier, Thassio Mesquita, Alberto M. Marchevsky, Nunzio Bottini, Francesco Boin, Ahmed G.E. Ibrahim, Eduardo Marbán
Total views: 5099
Abstract
The mechanisms by which e-cigarette vaping (EV) affects lung health remain unclear. Clusters of EV-associated lung injury indicate that EV damages distal lung parenchyma and increases vulnerability to second-hit injury, including respiratory viral infections. Using human lung endothelial and epithelial cells and precision-cut lung slices, we investigated the mechanisms underlying distal lung cell injury and repair triggered by brief (24-hour) EV exposure. RNA-seq of lung tissue from golden Syrian hamsters evaluated the persistence of lung stress responses (10 days after 5 days of EV exposure) and the effect of EV on host defense against influenza A virus and SARS-CoV-2. EV disrupted the barrier function of human distal lung cells through JNK stress response signaling, triggered autophagy with impaired flux, suppressed mTOR signaling and cell proliferation, and culminated in apoptosis. Transcriptional responses in EV-exposed hamster lungs revealed persistent activation of JNK signaling, autophagy, barrier dysfunction, tissue remodeling, and impaired Th1 immunity. EV increased SARS-CoV-2 viral burden, downregulated antiviral genes (Ifit1, Isg15, Nfkbia), and amplified oxidative stress and IL-12 signaling. Short-term EV exposure triggered stress-induced distal lung cell injury with persistent changes in antiviral immunity and molecular pathways associated with tissue remodeling. That may increase susceptibility to viral infections and contribute to lung disease.
Authors
Tanner C. Rivera, Kelly S. Schweitzer, Christina Cornell, Jordan Nall, Nicholas Egersdorf, Courtney Moeder, Riley A. Cooney, Eszter K. Vladar, Steve D. Groshong, Gregory P. Downey, James P. Bridges, Richard Bowen, Hong Wei Chu, Irina Petrache
Total views: 4947
Abstract
Lineage plasticity, or transdifferentiation, is increasingly recognized as a resistance mechanism to androgen receptor (AR) inhibition in prostate cancer. Lineage plasticity is characterized by loss of AR signaling and epithelial differentiation, along with activation of stemness-associated pathways, epithelial-mesenchymal transition, or alternative differentiation programs such as neuroendocrine prostate cancer (NEPC). Loss of the tumor suppressors TP53 and RB1 is common in tumors exhibiting lineage plasticity; however, the mechanisms by which TP53/RB1 loss promotes this phenotype remain poorly understood, and effective treatments are limited. Using multiomic profiling of TP53/RB1-loss prostate cancer models, we identified alterations in chromatin accessibility, DNA methylation, and gene expression associated with lineage plasticity. Importantly, many pathways activated upon TP53/RB1 loss could be blocked through BET bromodomain inhibition. TP53/RB1-deficient cells also harbored widespread DNA methylation changes that silenced pathways linked with restraining lineage plasticity. Combined BET bromodomain and DNA methyltransferase (DNMT) inhibition was more effective than single-agent treatment in suppressing growth of TP53/RB1-loss models exhibiting a stem-like or NEPC program. This was partly explained by abrogation of discrete lineage plasticity pathways modulated by each agent. Altogether, our work suggests combined BET bromodomain and DNMT inhibition is a promising therapeutic approach for prostate tumors exhibiting lineage plasticity.
Authors
William K. Storck, Diana Flores, Anbarasu Kumaraswamy, Zhi Duan, Shrabastee Chakraborty, Chao Zhang, Eva Rodansky, Dhruv Khokhani, Olivia A. Swaim, Karan Bedi, Raymond G. Cavalcante, Canping Chen, Faming Zhao, Ya-Mei Hu, Zheng Xia, Ryan J. Rebernick, Marcin Cieslik, Rahul Mannan, Somnath Mahapatra, Arul M. Chinnaiyan, Aaron M. Udager, Joshua A. Kuleape, Catherine R. Alumkal, Hannah N. Beck, Peter S. Nelson, Colm Morrissey, Michael C. Haffner, Leigh Ellis, Yuzhuo Wang, Joel A. Yates, Joshi J. Alumkal
Total views: 4842
Mitochonic acid 5 alleviates amyotrophic lateral sclerosis phenotypes via mitochondrial augmentation
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that urgently requires effective treatment. Mitochondrial dysfunction underlies ALS pathology and represents a potential therapeutic target. Here, we demonstrated the therapeutic potential of mitochonic acid 5 (MA-5), a novel mitochondria-targeted compound that ameliorated ALS phenotypes by enhancing mitochondrial function. In a Drosophila ALS model expressing a mutant human SOD1 (G85R), MA-5 significantly improved locomotor activity, with a trend toward restoration of mitochondrial integrity. In skin fibroblasts derived from ALS patients and motor neurons derived from induced pluripotent stem cells, MA-5 restored ATP production and increased mitochondrial motility. Multiomics analyses suggested that MA-5 modulated mitochondria-linked gene expression and downregulated the glycerophosphate shuttle, contributing to mitochondrial reactive oxygen species production. Transcriptomic analysis identified C7orf31 as a potential marker for monitoring the therapeutic effects of MA-5 and diagnosing ALS subtypes. These findings support MA-5 as a promising therapeutic candidate for ALS and propose C7orf31 as a potential biomarker for treatment monitoring and for disease subtyping.
Authors
Yoshitsugu Oikawa, Yuhan Luo, Naoki Suzuki, Tomoko Kasahara, Yoshiyasu Tongu, Yuki Yoshida, Tsukasa Tominari, Shogo Tanabe, Yoshiko Suto, Hitomi Kashiwagi, Saki Saito, Kensuke Ikeda, Chitose Suzuki, Arata Kuranaga, Tetsuya Akiyama, Satoru Morimoto, Yoshitsugu Aoki, Rieko Muramatsu, Tomoyoshi Soga, Masashi Aoki, Hideyuki Okano, Tetsuhiro Tanaka, Takaaki Abe, Erina Kuranaga, Takafumi Toyohara
Total views: 4693
Abstract
ACE2 is a membrane-bound monocarboxypeptidase strongly expressed in the renal proximal tubule (PT) with high affinity to degrade the vasopressor angiotensin II (AngII). We employed a mouse model of PT-specific ACE2 deletion (PT ACE2–KO) to demonstrate that the renal PT is a critical site for ACE2 regulation of blood pressure (BP) via modulation of the intrarenal renin-angiotensin system (RAS). While deletion of ACE2 from the PT had a minimal effect on baseline physiology, PT ACE2–KO mice were more susceptible to AngII hypertension than control mice. At day 5 of AngII infusion, the enhanced BP response was associated with cardiac hypertrophy, increased renal AngII levels, failure to suppress epithelial sodium channel (ENaC) γ cleavage, and increased sodium pump activity in PT ACE2–KO mice. Control mice instead increased renal ACE2 expression to reduce renal AngII accumulation and suppress intrarenal RAS activation, which offered protection from hypertension and complications. Transcriptional analysis corroborated changes in intrarenal RAS components and revealed alterations in distinct physiological pathways during AngII hypertension in PT ACE2–KO mice. Our studies provide evidence for alterations in ENaC regulation to contribute to the development of AngII hypertension and support PT-derived ACE2 as an integral member of the intrarenal RAS.
Authors
Jacqueline M. Emathinger, Zhidan Xiang, Jonathan W. Nelson, Matthew W. Hagen, Nakyung Kim, David I. Ortiz-Melo, Natalie Mattocks, Jorge F. Giani, Dexter L. Lee, Hannah Hartman-Houstman, Donna L. Ralph, Alicia A. McDonough, Brianna Chen, Stan G. Louie, Thomas M. Coffman, Susan B. Gurley
Total views: 4408
Abstract
BACKGROUND Dichloroacetate (DCA) is an orally administered structural analog of pyruvate, an endogenous pyruvate dehydrogenase kinase inhibitor.METHODS We conducted a phase III multicenter trial in 34 children with pyruvate dehydrogenase complex deficiency (PDCD). Participants were randomly allocated to 4 months of treatment with DCA or a placebo, followed by a 1-month washout period and crossover to the alternate arm, and could continue into an open-label extension period. DCA dosing was predetermined by pharmacogenomic analysis of GSTZ1, which modulates DCA metabolism. The primary endpoint was the observer-reported outcomes motor domain (ObsROmotor) score. Additional assessments evaluated motor function, plasma lactate levels, and survival.RESULTS Chronic DCA was well tolerated and safe. The primary endpoint, ObsROmotor, was not statistically significantly different between the treatment and placebo groups (P = 0.512). However, longer-term treatment, including the open-label extension, showed a statistically significant treatment effect (P = 0.002), especially in participants with higher baseline motor impairment (ObsROmotor ≥ 8; P = 0.001). DCA decreased plasma lactate –0.48 (0.82) mmol/L (–20%; P = 0.006). Survival of participants was significantly greater than that of a natural history cohort (log-rank P = 0.027).CONCLUSION Longer-term treatment with DCA, dosed based on GSTZ1 haplotype, is safe and was associated with a statistically significant improvement in patient motor function, plasma lactate, and survival.FUNDING NIH (R01FD005407; R42HD089804), University of Florida Department of Medicine, Saol Therapeutics.
Authors
Peter W. Stacpoole, Jose E. Abdenur, Jirair K. Bedoyan, Lorenzo Botto, Gregory M. Enns, Marni J. Falk, Rebecca Ganetzky, Cheryl Garganta, Kevin Glinton, Andrea Gropman, Sharon Hamm, Eugenia Henry, Nicola Longo, Richard Neiberger, Russell P. Saneto, Fernando Scaglia, Sub H. Subramony, Jerry Vockley, Richard E. Wagner
Total views: 4188
Abstract
Prader-Willi syndrome (PWS) is a complex genetic disorder resulting from the deficiency of several maternally imprinted genes, including SNORD116, in the 15q11-q13 region. Loss of Snord116 in mice recapitulates some of the most salient clinical features of PWS, including growth hormone (GH) deficiency and hypogonadism. This study explored the impact of Snord116 deficiency on early postnatal pituitary development and growth in Snord116-KO mice. Snord116 was found to be expressed in both the anterior and posterior pituitary. Pituitary transcriptomes of Snord116-KO and WT mice at 2 developmental stages, P0 and 4 weeks of age, were interrogated and related to ex vivo analyses of GH secretion in the pituitaries of 5-week-old mice. Significant differences in pituitary transcriptomes were detected between Snord116-KO and WT mice at 4 weeks of age but not at P0. The differentially expressed genes and affected molecular pathways play important roles in regulating embryonic and postnatal pituitary development. Our results suggested that PWS GH deficiency was mainly due to pituitary hypoplasia and decreased GH production but not to reduced GH secretory function per se, implicating Snord116 in the specific molecular/cellular pathways that account for impaired postnatal pituitary development and GH deficiency in PWS.
Authors
Gabriel F. Batzli, Kaiying Guo, Fahrünisa Meryem Betül Erol, Charles A. LeDuc, Lisa C. Burnett, Rudolph L. Leibel, Yiying Zhang
Total views: 4177
Abstract
Pulmonary arterial hypertension (PAH) is a progressive vascular syndrome characterized by aberrant signaling, severe pulmonary artery remodeling, and right ventricular (RV) failure, a major driver of morbidity and mortality. Dysregulation of the apelinergic pathway has been implicated in pulmonary vascular remodeling in PAH. Using a sugen-hypoxia rat model of PAH, we assessed the ability of a potentially novel apelin analog, resistant to native peptidase degradation, to reverse the pathological hallmarks of PAH and RV dysfunction. Apelin analog therapy corrected the vascular lesions in the lungs and nearly normalized pulmonary arterial pressures. Early cardiorenal syndrome, RV dilation, and dysfunction, as well as RV cardiomyocyte and fibroblast activation induced by pressure overload, were also reversed by apelin analog treatment. Single-nucleus RNA-seq of the lungs and RV revealed apelin-analog treatment activated several protective pathways, including rebalancing protective bone morphogenetic protein receptor type 2 (BMPR2) signaling to counteract excessive pathogenic TGF-β receptor 2 (TGFBR2) activity in PAH. These findings highlight the therapeutic potential of exogenous apelin in reversing pulmonary vascular and cardiac pathologies in PAH and support further investigation to evaluate the clinical benefits of apelin analog treatment in patients with PAH and RV failure.
Authors
Jennie Vu, Pavel Zhabyeyev, Kemar J. Brown, Joshua Gorham, Daniel M. DeLaughter, Huachen Chen, Thilina U. Jayawardena, Ander Vergara, Maria Alexiou, Anjalee Wijewardane, Conrad Fischer, Charlotte Avet, Abby Ewasiuk, Faqi Wang, Mark C. Chappell, Yuri Kim, Michel Bouvier, John C. Vederas, Christine E. Seidman, Jonathan G. Seidman, Gavin Y. Oudit
Total views: 3951
Abstract
Surgical stress, such as liver ischemia/reperfusion (I/R) injury characterized by robust neutrophil infiltration and immune activation, induces sterile inflammation that reshapes tissue immunity and contributes to organ dysfunction, yet the intercellular circuits that spatially orchestrate these responses within the hepatic immune microenvironment remain incompletely defined. Here, we integrate single-cell RNA sequencing, spatial transcriptomics, high-dimensional spectral flow cytometry, and metabolomics to resolve the hepatic immune landscape following I/R at cellular and spatial resolution. While confirming extensive immune remodeling, we identify a dominant neutrophil–Kupffer cell communication axis mediated by neutrophil-derived thrombospondin-1 (TSP-1), which selectively engages CD36 on Kupffer cells. This interaction drives coordinated immune-metabolic reprogramming in Kupffer cells, characterized by suppression of oxidative phosphorylation, enhanced glycolysis, and remodeling of sphingolipid metabolism, including accumulation of hexosylceramides. Spatial analyses reveal preferential neutrophil–Kupffer cell colocalization within necrotic niches, and cross-species integration with human liver transplant datasets demonstrates conserved upregulation of the TSP-1/CD36 axis following reperfusion. Pharmacologic inhibition of TSP-1 attenuates liver injury and inflammatory responses in vivo. Together, these findings define a spatially organized, neutrophil-driven immune-metabolic circuit that governs functional reprogramming of Kupffer cells during surgical stress and identify the TSP-1/CD36 pathway as a conserved and targetable mediator of sterile liver injury.
Authors
Hongji Zhang, Xingping Huang, Preethi Jayakumar, Yunwei Zhang, Ti Yang, Xiaorong Guo, Grace Wu, Amrendra Kumar, Vijaya Bharti, Amblessed Onuma, Chengli Shen, Dequan Lou, Patricia S. Latham, James M. Crawford, Kong Chen, Anna E. Vilgelm, Lopa Mishra, Allan Tsung, Meihong Deng, Hai Huang
Total views: 3865
