Top read articles in the last 30 days
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Abstract
High dietary salt intake elevates blood pressure and drives multiorgan damage. However, the molecular programs underlying progressive organ injury remain poorly defined. Here, we present a longitudinal multiorgan transcriptomic atlas of salt-induced hypertensive injury. We profiled kidney cortex, kidney medulla, heart, and liver across 4 stages, spanning early hypertension to advanced pathology in Dahl salt-sensitive rats. We identified dynamic and tissue-specific molecular trajectories, including a shared early proliferative response that converges on proinflammatory and fibrotic remodeling. Notably, we uncovered compartment-specific renal responses, showing that the cortex and medulla, despite their proximity, follow distinct molecular trajectories during disease progression. We further identified 79 stage- and tissue-specific transcription factors that drive gene expression dynamics in salt-induced hypertensive injury. Integration with human genome-wide association studies revealed conserved pathways in endocrine signaling, ion transport, lipid metabolism, and detoxification, establishing cross-species relevance and highlighting mechanistic targets of clinical importance. Compound-transcriptome analysis revealed stage- and organ-specific therapeutic opportunities, prioritizing kinase and epigenetic modulators as candidates to rebalance maladaptive gene programs. Overall, this study provides a resource for understanding molecular mechanisms from early salt-induced hypertension to tissue-specific injury and underscores the need for precision interventions.
Authors
Ratnakar Tiwari, Olha Kravtsova, Lashodya V. Dissanayake, Melissa Lowe, Biyang Xu, Vladislav Levchenko, Steven Didik, Ruslan Bohovyk, Daria V. Ilatovskaya, Oleg Palygin, Alexander Staruschenko
Total views: 3082
Abstract
Inflammatory bowel disease (IBD) is frequently accompanied by intestinal fibrosis, with nonresponse to long-term anti–TNF-α therapy occurring in approximately 23%–46% of patients. Integrated analysis of single-cell and bulk RNA-seq datasets revealed an expansion of IL11+ fibroblasts in inflamed intestine and their significant enrichment in nonresponders. We further identified IL11+ fibroblasts as a central communication hub that engaged in extensive crosstalk with monocytes and may contribute to inflammatory amplification and fibrotic remodeling. Additionally, we employed machine learning approaches, including least absolute shrinkage and selection operator, support vector machines, and random forest, to derive an IL11+ fibroblast–related gene signature effectively predicting nonresponse to anti–TNF-α in validation and test cohorts. IHC further confirmed the overexpression of IL-11 in nonresponders. The signature genes we found are not only associated with immune and inflammatory responses but also with fibrosis, indicating a robust association between fibrosis and anti–TNF-α treatment failure. In summary, this study highlights the important role of IL11+ fibroblasts in orchestrating both inflammation and fibrosis and provides an applicable model for predicting nonresponse to anti–TNF-α in IBD, thereby laying the foundation for precision medicine and targeted therapeutic strategies.
Authors
Wangyue Li, Wei Huang, Jiaxin Wang, Yiwen Tu, Qidi Yang, Yao Zhou, Zile Zhang, Haiming Zhuang, Yubei Gu, Duowu Zou, Yao Zhang
Total views: 2469
Abstract
Immune checkpoint inhibitors have transformed cancer therapy, yet many patients fail to achieve durable responses due to insufficient T cell reinvigoration. Cytokines offer promise for enhancing immunotherapy, but their clinical use is limited by toxicity and a narrow therapeutic index. Immunocytokines, engineered fusion proteins combining antibody specificity with cytokine activity, aim to overcome these challenges by targeting cytokine delivery to immune cells or the tumor microenvironment. We describe SAR445877 (SAR’877), a potentially novel PD-1–targeted immunocytokine that fuses a high-affinity anti–PD-1 antibody with a detuned IL-15/IL-15Rα sushi domain complex. SAR’877 blocks PD-1/PD-L1 and PD-1/PD-L2 interactions while selectively delivering IL-15 signals to PD-1+ T cells, enhancing proliferation and activation of antigen-experienced CD8+ and CD4+ T cells and NK cells, while minimizing systemic inflammation. Mechanistically, SAR’877 activates STAT5 signaling in PD-1+ lymphocytes and restores effector function in exhausted T cells. In preclinical models, a murine surrogate of SAR’877 accelerated viral clearance and induced robust antitumor immunity by expanding cytotoxic CD8+ T cells and promoting Th1 polarization. Notably, SAR’877 outperformed anti–PD-1 plus untargeted IL-15, highlighting the therapeutic potential of targeted IL-15 delivery. These findings position SAR’877 as a promising next-generation immunotherapy with enhanced efficacy and reduced cytokine-associated toxicities.
Authors
Isaraphorn Pratumchai, Marie Bernardo, Julien Tessier, Jaroslav Zak, Kristi L. Marquardt, Joon Sang Lee, Maheeka Bimal, AHyun Choi, Anthony M. Byers, Mikielia G. Devonish, Roberto Carrio, Dan Lu, Stella Martomo, Jeegar Patel, Yu-an Zhang, Ingeborg M. Langohr, Virna Cortez-Retamozo, Dinesh S. Bangari, Angela Hadjipanayis, Xiangming Li, Valeria R. Fantin, Donald R. Shaffer, John R. Teijaro
Total views: 2250
Abstract
Synthetic prostaglandin analogs, such as latanoprost, are first-line treatments to reduce intraocular pressure (IOP) in the management of glaucoma, treating millions of patients daily. Glaucoma is a leading cause of blindness, characterized by progressive optic neuropathy, with elevated IOP being the sole modifiable risk factor. Despite this importance, the underlying latanoprost mechanism of action is still not well defined, being associated with both acute and long-term activities, and a growing list of ocular side effects. Prostaglandins are eicosanoid lipid mediators. Yet, there has not been a comprehensive assessment of small lipid mediators in glaucomatous eyes. Here, we performed a lipidomic screen of aqueous humor sampled from patients with glaucoma and healthy control eyes. The resulting signature was surprisingly focused on significantly elevated levels of arachidonic acid (AA) and its derivative, the antiinflammatory and cytoprotective mediator, lipoxin A4 (LXA4), in glaucomatous eyes. Subsequent experiments revealed that this response was drug induced, due to latanoprost actions on trabecular meshwork cells, rather than a consequence of elevated IOP. We demonstrate that increased LXA4 inhibited proinflammatory cues and promoted TGF-β production in the anterior chamber. In concert, an autocrine prostaglandin circuit mediated canonical rapid IOP lowering. This work reveals parallel mechanisms underlying acute and long-term latanoprost activities during glaucoma treatment.
Authors
David J. Mathew, Shubham Maurya, Julian Ho, Izhar Livne-Bar, Darren Chan, Jenny Wanyu Zhang, Yvonne M. Buys, Marisa Sit, Graham Trope, Donna M. Peters, John G. Flanagan, Karsten Gronert, Jeremy M. Sivak
Total views: 2205
Abstract
Chronic kidney disease (CKD) is associated with renal metabolic disturbances, including impaired fatty acid oxidation (FAO). Nicotinamide adenine dinucleotide (NAD+) is a small molecule that participates in hundreds of metabolism-related reactions. NAD+ levels are decreased in CKD, and NAD+ supplementation is protective. However, both the mechanism of how NAD+ supplementation protects from CKD, as well as the cell types involved, are poorly understood. Using a mouse model of Alport syndrome, we show that nicotinamide riboside (NR), an NAD+ precursor, stimulated renal PPARα signaling and restored FAO in the proximal tubules, thereby protecting from CKD in both sexes. Bulk RNA-sequencing showed that renal metabolic pathways were impaired in Alport mice and activated by NR in both sexes. These transcriptional changes were confirmed by orthogonal imaging techniques and biochemical assays. Single-nuclei RNA sequencing and spatial transcriptomics, both the first of their kind to our knowledge from Alport mice, showed that NAD+ supplementation restored FAO in proximal tubule cells. Finally, we also report, for the first time to our knowledge, sex differences at the transcriptional level in this Alport model. In summary, the data herein identify a nephroprotective mechanism of NAD+ supplementation in CKD, and they demonstrate that this benefit localizes to the proximal tubule cells.
Authors
Bryce A. Jones, Debora L. Gisch, Komuraiah Myakala, Amber Sadiq, Ying-Hua Cheng, Elizaveta Taranenko, Julia Panov, Kyle Korolowicz, Ricardo Melo Ferreira, Xiaoping Yang, Briana A. Santo, Katherine C. Allen, Teruhiko Yoshida, Xiaoxin X. Wang, Avi Z. Rosenberg, Sanjay Jain, Michael T. Eadon, Moshe Levi
Total views: 1964
Abstract
BACKGROUND There are no known serum biomarkers that provide mechanistic insight or prognostic enrichment for post–COVID-19 pulmonary fibrosis.METHODS We tested associations of serum biomarkers with radiographic fibrosis-like abnormalities (reticulation, traction bronchiectasis, or honeycombing) on thoracic computed tomography (CT) scans 4 months, 15 months, and 3 years after hospitalization in an American discovery cohort of severe-to-critical COVID-19 survivors, and externally validated findings in 2 Canadian cohorts of moderate-to-critical COVID-19 survivors. In the discovery cohort, we investigated the dose-response relationship of the biomarker with CT-derived airway-to-lung ratio. We performed single-cell RNA sequencing (scRNA-seq) of transbronchial lung biopsies from COVID-19 survivors obtained 3 years after COVID-19 hospitalization and conducted immunofluorescence analysis of COVID-19 lung explants.RESULTS Among 150 discovery cohort participants, only higher levels of circulating club cell secretory protein-16 (CC16, encoded by the SCGB1A1 gene) at hospital discharge, 4 months, 15 months, and 3 years were associated with thoracic CT fibrosis-like abnormalities in cross-sectional and longitudinal analyses. Higher CC16 levels were associated with thoracic CT fibrosis-like abnormalities in 2 validation cohorts (n = 56 and n = 37). CC16 levels were linearly associated with increased airway-to-lung ratio. scRNA-seq revealed increased proportions of epithelial cells expressing SCGB1A1 and SCGB1A1/MUC5B in COVID-19 survivors with fibrosis. Immunofluorescence analysis of COVID-19 lung explants demonstrated increased numbers of SCGB1A1-expressing epithelial cells only in small (<100 μm) airways, with 3-fold more CC16/MUC5B-coexpressing cells in respiratory bronchioles..CONCLUSION. Higher CC16 levels are associated with CT fibrosis-like abnormalities for up to 3 years following moderate-to-critical COVID-19. Increased CC16 reflects dysregulated small airway epithelial progenitor cell remodeling and increased expansion of CC16+MUC5B+ epithelial cells in respiratory bronchioles after COVID-19.TRIAL REGISTRATION Not applicable.FUNDING Department of Defense, NIH, and Japan Society for the Promotion of Science for Young Scientists.
Authors
Matthew R. Baldwin, Ansley E. Jones, David Zhang, Chandan Gurung, Zain Khan, Anjali Saqi, Xuehan Yang, Ying Wei, Renu Nandakumar, Scarlett O. Murphy, Claire F. McGroder, Faisal Shaikh, Selim Arcasoy, Luke Benvenuto, Harpreet Grewal, Benjamin M. Smith, Eric A. Hoffman, Agnes C.Y. Yuen, Parteek Johal, Christopher Carlsten, Christopher J. Ryerson, J. Brent Richards, Alyson W. Wong, Tomoko Nakanishi, Aditi S. Shah, Christine Kim Garcia
Total views: 1903
Abstract
Impaired adhesion and differentiation of keratinocytes is a hallmark of several skin diseases, but only some of the factors that regulate these processes have been identified. Here, we studied the role of isoform-rich dermokine — a wound- and tumor-regulated protein — in keratinocytes using a combination of multiomics and functional approaches. CRISPR/Cas9-induced knockout of dermokine isoforms in human keratinocytes inhibited differentiation of these cells in 3-dimensional organotypic skin cultures, which was confirmed by quantitative proteomics. In 2-dimensional monocultures, dermokine deficiency affected the proteome and phosphoproteome as revealed by mass spectrometry. We found reduced abundance of differentiation-specific proteins and increased phosphorylation of the cell adhesion protein p120 (catenin δ-1). The adhesive strength of dermokine-knockout keratinocytes was impaired, which was rescued by p120 knockdown or ROCK inhibition. Finally, we verified the correlation between decreased dermokine expression and increased p120 phosphorylation in human non-healing wounds. These results identify dermokine as a regulator of keratinocyte adhesion and differentiation, involving at least in part its effect on p120 phosphorylation and ROCK. Our data point to a function of dermokine in the pathogenesis of chronic wounds.
Authors
Vahap Canbay, Till Wüstemann, Weihua Tian, Tobias A. Beyer, Camilla Reiter Elbæk, Michael Stumpe, Gaetana Restivo, Chatpakorn Christiansen, Anabel Migenda Herranz, Susanne Mailand, Jürg Hafner, Rune Busk Damgaard, Steffen Goletz, Jörn Dengjel, Ulrich auf dem Keller, Chiara Francavilla
Total views: 1871
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a multifactorial disease that develops in several clinical settings. Despite its complex pathogenesis, evidence indicates a central role for fibrosis in the progression of left ventricular diastolic dysfunction (LVDD). Through exploratory research into adipokines derived from brown adipose tissue (BAT), we identified a secreted-type profibrotic protein, procollagen C-endopeptidase enhancer-1 (PCPE-1), whose expression increased in BAT with aging. PCPE-1 promotes the cleavage of procollagens and is a critical initiator of fibrillogenesis. This molecule was increased in the plasma of aged mice. In addition to aging, obesity led to an increase in PCPE-1 expression in the LV of mice. Both systemic and BAT-specific PCPE-1 depletion ameliorated LV fibrosis and LVDD in the obese HFpEF model. Our data also showed that age-associated LVDD was ameliorated in the systemic PCPE-1–KO mouse fed with a normal chow diet. Conversely, the overexpression of PCPE-1 expression in BAT was shown to lead to aggravation of LV fibrosis and LVDD. Mechanistically, we found ROS/DNA damage/c-Fos/c-Jun signaling resulted in an increased production of PCPE-1 in brown adipocytes. These results indicate PCPE-1 may represent a druggable target for aging- and obesity-related HFpEF.
Authors
Yung-Ting Hsiao, Yohko Yoshida, Hirotsugu Tsuchimochi, Jingyuan Tang, Tin May Aung, Chun-Han Chang, Agian Jeffilano Barinda, Zhihong Li, Nur Syakirah Binti Othman, Tom Yoshizaki, Yiwei Ling, Shujiro Okuda, Manabu Abe, Seiya Mizuno, Satoru Takahashi, Takayuki Inomata, Hidetaka Kioka, Yasushi Sakata, Daichi Maeda, Yuya Matsue, Takaaki Furihata, Hiroshi Iwata, James T. Pearson, Kinya Otsu, Kenneth Walsh, Akihito Ishigami, Tohru Minamino, Ippei Shimizu
Total views: 1867
Abstract
BACKGROUND Enhancing NAD+ levels with nicotinamide riboside (NR) confers antiinflammatory effects in human disease, although immunoregulatory mechanisms remain poorly characterized. We previously showed that ex vivo NR supplementation of primary CD4+ T cells from psoriatic individuals dampened immune responsiveness.METHODS To validate this in vivo, we performed a randomized, placebo-controlled NR supplementation study in individuals with mild-to-moderate psoriasis. Participants received oral NR (500 mg twice daily) or matching placebo for 4 weeks, with blood samples collected at baseline and after supplementation. NR reduced Th17 immune responsiveness.RESULTS Bulk CD4+ T cell RNA-seq identified induction of the SLIT-ROBO signaling pathway. NR supplementation increased circulating SLIT2 levels and enhanced SLIT2 production in dermal fibroblasts. Pharmacologic and genetic interrogation in CD4+ T cells and fibroblasts demonstrated that SLIT2, acting through the ROBO1 receptor, inhibited Rho GTPase signaling, thereby attenuating canonical Th17 polarization and fibroblast inflammatory activation.CONCLUSION These findings indicate that NAD+ augmentation exerts anti-inflammatory effects in psoriasis through SLIT2-ROBO1-mediated crosstalk between dermal fibroblasts and circulating CD4+ T cells, leading to suppression of Th17-driven inflammation.TRIAL REGISTRATION ClinicalTrials.gov NCT04271735 (registration date – 2020-08026), NCT01143454 (registration date - 2010-07-21), NCT01778569 (registration date – 2013-01-22), and NCT00001846 (registration date – 2001-01-11).FUNDING The NHLBI Division of Intramural Research (HL005102 – MNS).
Authors
Kim Han, Rachael J. Klein, Thomas C. Recupero, Anna Chiara Russo, Rahul Sharma, Anand K. Gupta, Shahin Hassanzadeh, Rebecca D. Huffstutler, Pradeep K. Dagur, Bryan Fisk, Neelam R. Redekar, Michael N. Sack
Total views: 1843
Abstract
Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI) leading to renal fibrosis. Here, we investigate the kinetics of autophagy, apoptosis, and necroptosis activation in tubular epithelial cells (TECs) and peritubular capillaries (PTCs) after renal IRI, and their relative contributions to renal fibrogenesis. IRI with renal artery clamping in GFP-LC3 transgenic mice induced a predominant and sustained necroptotic response in TECs, while apoptosis and autophagy played minor roles. PTCs showed early and persistent activation of apoptosis, brief necroptosis induction, and increased autophagy at a distance from IRI. Disruption of the autophagic process with chloroquine (CHQ) injections in association with renal IRI did not modulate tubular death but enhanced PTC apoptosis and increased microvascular rarefaction and fibrosis. Apoptosis-deficient GFP-LC3/Caspase-3–/– mice exposed to renal IRI showed enhanced PTC autophagy, reduced PTC rarefaction, and inhibition of renal fibrosis, in spite of increased necroptosis in TECs. Inhibition of both autophagy with CHQ and apoptosis in GFP-LC3/Caspase-3–/– mice led to a marked switch toward necroptosis in PTCs. This was associated with aggravated microvascular rarefaction, increased leukocyte infiltration, and enhanced renal fibrosis. These findings establish a predominant role for PTC autophagy and caspase-3–dependent apoptosis in the development of renal fibrosis after IRI.
Authors
Hyunyun Kim, Francis Migneault, Shanshan Lan, Imane Kaci, Julie Turgeon, Annie Karakeussian Rimbaud, Martin Dupont, Shijie Qi, Mélanie Dieudé, Marie-Josée Hébert
Total views: 1828
