Loss of ferroptosis contributes to the development of human cancer, and restoration of ferroptosis has been demonstrated as a potential therapeutic strategy in cancer treatment. However, the mechanisms of how ferroptosis escape contributes to ovarian cancer (OV) development are not well elucidated. Here we show that ferroptosis negative regulation (FNR) signatures correlated with the tumorigenesis of OV and were associated with poor prognosis, suggesting that restoration of ferroptosis represents a potential therapeutic strategy in OV. High throughput drug screening with a kinase inhibitor library identified MEK inhibitors as ferroptosis inducers in OV cells. We further demonstrated that MEK inhibitor resistant OV cells were less vulnerable to trametinib-induced ferroptosis. Mechanistically, mTOR/4EBP1 signaling promoted SLC7A11 protein synthesis, leading to ferroptosis inhibition in MEK inhibitor resistant cells. Dual inhibition of MEK and mTOR/4EBP1 signaling restrained the protein synthesis of SLC7A11 via suppression of the mTOR-4EBP1 activity to reactivate ferroptosis in resistant cells. Together, these findings provide a promising therapeutic option for OV treatment through ferroptosis restoration by the combined inhibition of MEK and mTOR/4EBP1 pathways.
Jiaxin Yin, Jianfeng Chen, Jing Han Hong, Yulin Huang, Rong Xiao, Shini Liu, Peng Deng, Yichen Sun, Kelila Xin Ye Chai, Xian Zeng, Jason Yongsheng Chan, Peiyong Guan, Yali Wang, Peili Wang, Chongjie Tong, Qiang Yu, Xiaojun Xia, Choon Kiat Ong, Bin Tean Teh, Ying Xiong, Jing Tan
Sleep disturbance usually accompanies anxiety disorders and exacerbates their incidence rates. The precise circuit mechanisms remain poorly understood. Here, we found that glutamatergic neurons in the posteroventral medial amygdala (MePVGlu) are involved in arousal and anxiety-like behaviors. Excitation of MePVGlu neurons not only promoted wakefulness but also increased anxiety-like behaviors. Different projections of MePVGlu neurons played various roles in regulating anxiety-like behaviors and sleep-wakefulness. MePVGlu neurons promoted wakefulness through the MePVGlu-posteromedial cortical amygdaloid area (PMCo) pathway and the MePVGlu-bed nucleus of the stria terminals (BNST) pathway. In contrast, MePVGlu neurons increased anxiety-like behaviors through the MePVGlu-ventromedial hypothalamus (VMH) pathway. Chronic sleep disturbance increased anxiety levels and reduced reparative sleep, accompanied by the enhanced excitability of MePVGlu-PMCo and MePVGlu-VMH circuits but suppressed responses of glutamatergic neurons in the BNST. Inhibition of the MePVGlu neurons could rescue chronic sleep deprivation-induced phenotypes. Our findings provide important circuit mechanisms for chronic sleep disturbance-induced hyperarousal response and obsessive anxiety-like behavior, and are expected to provide a promising strategy for treating sleep-related psychiatric disorders and insomnia.
Ying Li, Yuchen Deng, Yifei Zhang, Dan Xu, Xuefen Zhang, Yue Li, Yidan Li, Ming Chen, Yuxin Wang, Jiyan Zhang, Like Wang, Yufeng Cang, Peng Cao, Linlin Bi, Haibo Xu
Patients with autoimmune diseases are at higher risk for severe infection due to their underlying disease and immunosuppressive treatments. In this real-world observational study of 463 autoimmune subjects, we examined risk factors for poor B and T cell responses to SARS-CoV-2 vaccination. We show a high frequency of inadequate anti-spike IgG responses to vaccination and boosting in the autoimmune population but minimal suppression of T cell responses. Low IgG responses in B cell–depleted multiple sclerosis (MS) subjects were associated with higher CD8 T cell responses. By contrast, subjects taking mycophenolate mofetil exhibited concordant suppression of B and T cell responses. Treatments with highest risk for low IgG anti-spike response included B cell depletion within the last year, fingolimod, and combination treatment with mycophenolate mofetil (MMF) and belimumab. Our data show that the mRNA-1273 (Moderna) vaccine, is the most effective vaccine in the autoimmune population. There was minimal induction of either disease flares or autoantibodies by vaccination and no significant effect of pre-existing anti-type I interferon antibodies on either vaccine response or breakthrough infections. The low frequency of breakthrough infections and lack of SARS-CoV-2–related deaths suggest that T cell immunity contributes to protection in autoimmune disease.
Erik Anderson, Michael Powell, Emily Yang, Ananya Kar, Tung Ming Leung, Cristina Sison, Rebecca Steinberg, Raven Mims, Ananya Choudhury, Carlo Espinosa, Joshua Zelmanovich, Nkemakonam C. Okoye, Eun Jung Choi, Galina Marder, Sonali Narain, Peter K. Gregersen, Meggan Mackay, Betty Diamond, Todd Levy, Theodoros P. Zanos, Arezou Khosroshahi, Ignacio Sanz, Eline T. Luning Prak, Amit Bar-Or, Joan Merrill, Cristina Arriens, Gabriel Pardo, Joel Guthridge, Judith James, Aimee Payne, Paul J. Utz, Jeremy M. Boss, Cynthia Aranow, Anne Davidson
The non-physiological nutrient levels found in traditional culture media have been shown to affect numerous aspects of cancer cell physiology, including how cells respond to certain therapeutic agents. Here, we comprehensively evaluated how physiological nutrient levels impact therapeutic response by performing drug screening in human plasma-like medium (HPLM). We observed dramatic nutrient-dependent changes in sensitivity to a variety of FDA-approved and clinically trialed compounds including rigosertib, an experimental cancer therapeutic that has recently failed in phase 3 clinical trials. Mechanistically, we found that the ability of rigosertib to destabilize microtubules is strongly inhibited by the purine metabolism end product uric acid, which is uniquely abundant in humans relative to traditional in vitro and in vivo cancer models. These results demonstrate the broad and dramatic effects nutrient levels can have on drug response, and how incorporation of human-specific physiological nutrient media might help to identify compounds whose efficacy could be impacted in humans.
Vipin Rawat, Patrick DeLear, Prarthana Prashanth, Mete Emir Ozgurses, Anteneh Tebeje, Philippa A. Burns, Kelly O. Conger, Christopher Solís, Yasir Hasnain, Anna Novikova, Jennifer E. Endress, Paloma González-Sánchez, Wentao Dong, Greg Stephanopoulos, Gina M. DeNicola, Isaac Harris, David Sept, Frank M. Mason, Jonathan L. Coloff
Influenza poses a persistent health burden worldwide. To design equitable vaccines effective across all demographics, it is essential to better understand how host factors such as genetic background and aging affect the single-cell immune landscape of influenza infection. Cytometry by time-of-flight (CyTOF) represents a promising technique in this pursuit, but interpreting its large, high-dimensional data remains difficult. We’ve developed a new analytical approach iGATE (in-silico gating annotating training elucidating) based on probabilistic support vector machine classification. By rapidly and accurately “gating” tens of millions of cells in silico into user-defined types, iGATE enabled us to track 25 canonical immune cell types in mouse lung over the course of influenza infection. Applying iGATE to study effects of host genetic background, we show that the lower survival of C57BL/6 mice compared to BALB/c is associated with a more rapid accumulation of inflammatory cell types and decreased IL-10 expression. Further, we demonstrate that the most prominent effect of aging is a defective T-cell response, reducing survival of aged mice. Finally, iGATE reveals that the 25 canonical immune cell types exhibit differential influenza infection susceptibility and replication permissiveness in vivo, but neither property varies with host genotype or aging. Software is available at https://github.com/UmichWenLab/iGATE.
Brett D. Hill, Andrew J. Zak, Sanjeev Raja, Luke F. Bugada, Syed M. Rizvi, Saiful B. Roslan, Hong Nhi Nguyen, Judy Chen, Hui Jiang, Akira Ono, Daniel R. Goldstein, Fei Wen
BACKGROUND. Identifying patients with acute kidney injury (AKI) who are at higher risk of chronic kidney disease (CKD) progression at time of AKI diagnosis remains a major challenge in clinical practice. METHODS. Kidney transcriptome sequencing was applied to identify the top up-regulated genes in mice with AKI. The product of the top-ranked gene was identified in the tubular cells and urine both in mouse and human AKI. Data from two cohorts of patients with a prehospitalization estimated glomerular filtration rate (eGFR) ≥ 45 ml/min/1.73m2 who survived for at least 90 days after AKI were used to derive and validate multivariable prediction models. AKI to CKD progression was defined as a persistent eGFR < 60 ml/min/1.73m2 and with a minimum 25% reduction from baseline eGFR 90 days after AKI in patients with prehospitalization eGFR ≥ 60 ml/min/1.73m2. AKI to advanced CKD was defined by a sustained reduction of eGFR < 30 ml/min/1.73m2 90 days after AKI in those with prehospitalization eGFR 45–60 ml/min/1.73m2. RESULTS. Kidney cytokeratin 20 (CK20) was up-regulated in injured proximal tubular cells and detectable in urine within 7 days after AKI. High concentrations of urinary CK20 (uCK20) were independently associated with the severity of histological AKI and the risk of AKI to CKD or advanced CKD progression. In Test set, the AUC of uCK20 for predicting AKI to CKD or advanced CKD was 0.80, outperformed currently used biomarkers for detecting kidney tubular injury. Addition of uCK20 to an established clinical model improved the ability for predicting AKI-CKD progression with an AUC of 0.90, and largely improved the risk reclassification. CONCLUSION. This finding highlighted uCK20 as a useful predictor for AKI to CKD progression, and may provide a tool to early identify patients at high risk of CKD following AKI. FUNDING. The National Natural Science Foundation of China (Key Program).
Rui Ma, Han Ouyang, Shihong Meng, Jun Liu, Jianwei Tian, Nan Jia, Youhua Liu, Xin Xu, Xiaobing Yang, Fan Fan Hou
Tumor evolution is driven by genetic variation; however, it is the tumor microenvironment (TME) that provides the selective pressure contributing to evolution in cancer. Despite high histopathological heterogeneity within glioblastoma (GBM), the most aggressive brain tumor, the interactions between the genetically distinct GBM cells and the surrounding TME are not fully understood. To address this, we analyzed matched primary and recurrent GBM archival tumor tissues with imaging-based techniques aimed to simultaneously evaluate tumor tissues for presence of hypoxic, angiogenic, and inflammatory niches, extracellular matrix organization, TERT promoter mutational status, and several oncogenic amplifications on the same slide and location. We found that the relationships between genetic and TME diversity are different in primary and matched recurrent tumors. Interestingly, the texture of the extracellular matrix (ECM), identified by label-free reflectance imaging, was predictive of single-cell genetic traits present in the tissue. Moreover, reflectance of ECM revealed structured organization of the perivascular niche in recurrent GBM, enriched in immunosuppressive macrophages. Single-cell spatial transcriptomics further confirmed the presence of the niche-specific macrophage populations and identified interactions between endothelial cells, perivascular fibroblasts, and immunosuppressive macrophages. Our results underscore the importance of GBM tissue organization in tumor evolution and highlight novel genetic and spatial dependencies.
Ugoma Onubogu, Chandler D. Gatenbee, Sandhya Prabhakaran, Kelsey Wolfe, Benjamin Oakes, Roberto Salatino, Rachael Vaubel, Oszkar Szentirmai, Alexander R. A. Anderson, Michalina Janiszewska
Prenatal exposure to viral pathogens has been known to cause the development of neuropsychiatric disorders in adulthood. Furthermore, COVID-19 has been associated with a variety of neurological manifestations, raising the question of whether in utero SARS-CoV-2 exposure can affect neurodevelopment, resulting in long-lasting behavioral and cognitive deficits. Using a human ACE-2-knock-in mouse model, we have previously shown that prenatal exposure to SARS-CoV-2 at later stages of development leads to fetal brain infection and gliosis in the hippocampus and cortex. In this study, we aimed to determine if infection of the fetal brain results in long-term neuroanatomical alterations of the cortex and hippocampus, as well as any cognitive deficits in adulthood. Here, we show that infected mice developed slower and weighed less in adulthood. We also found altered hippocampal and amygdala volume and aberrant newborn neuron morphology in the hippocampus of adult mice infected in utero. Furthermore, we observed sex-dependent alterations in anxiety-like behavior and locomotion, as well as hippocampal-dependent spatial memory. Taken together, our study revealed long-lasting neurological and cognitive changes as a result of prenatal SARS-CoV-2 infection, identifying a window for early intervention and highlighting the importance of immunization and antiviral intervention in pregnant women.
Courtney L. McMahon, Erin M. Hurley, Aranis Muniz Perez, Manuel Estrada, Daniel J. Lodge, Jenny Hsieh
We present a transcriptomic analysis that provides a better understanding of regulatory mechanisms within the healthy and injured periosteum. The focus of this work is on characterizing early events controlling bone healing during formation of periosteal callus on day 3 post fracture. Building upon our previous findings showing that induced Notch1 signaling in osteoprogenitors leads to better healing, we compared samples in which Notch 1 intracellular domain is overexpressed by periosteal stem/progenitor cells with control intact and fractured periosteum. Molecular mechanisms and changes in skeletal stem/progenitor cells (SSPCs) and other cell populations within the callus, including hematopoietic lineages were determined. Notably, Notch ligands were differentially expressed in endothelial and mesenchymal populations, with Dll4 restricted to endothelial cells, whereas Jag1 was expressed by mesenchymal populations. Targeted deletion of Dll4 in endothelial cells using Cdh5CreER resulted in negative effects on early fracture healing, while deletion in SSPCs using α-smooth muscle actin-CreER did not impact bone healing. Translating these observations into clinically relevant model of bone healing revealed the beneficial effects of delivering Notch ligands alongside osteogenic inducer, BMP2. These findings provide insights into the regulatory mechanisms within the healthy and injured periosteum, paving the way for novel translational approaches to bone healing.
Sanja Novak, Hitoshi Tanigawa, Vijender Singh, Sierra H. Root, Tannin A. Schmidt, Kurt D. Hankenson, Ivo Kalajzic
Dendritic cell inhibitory receptor (DCIR) is a C-type lectin receptor selectively expressed on myeloid cells, including monocytes, macrophage, dendritic cells, and neutrophils. Its role in immune regulation has been implicated in murine models and human genome-wide association studies (GWAS), suggesting defective DCIR function associates with increased susceptibility to autoimmune diseases such as rheumatoid arthritis, lupus and Sjogren’s syndrome. However, little is known about the mechanisms underlying DCIR activation to dampen inflammation. Here, we developed anti-DCIR agonistic antibodies that promote phosphorylation on DCIR’s immune receptor tyrosine-based inhibitory motifs (ITIM) and recruitment of SH2 containing protein tyrosine phosphatase-2 (SHP2) for reducing inflammation. We also explored the inflammation resolution by depleting DCIR+ cells with antibodies. Utilizing a human DCIR knock-in mouse model, we validated the anti-inflammatory properties of the agonistic anti-DCIR antibody in experimental peritonitis and colitis. These findings provide critical evidence for targeting DCIR to develop transformative therapies for inflammatory diseases.
Liang Chen, Suresh Patil, Jeffrey Barbon, James Waire, F. Stephen Laroux, Donna McCarthy, Mishra Pratibha, Suju Zhong, Feng Dong, Karin Orsi, Gunarso Nguyen, Yingli Yang, Nancy Crosbie, Eric Dominguez, Arun Deora, Geertruida Veldman, Susan V. Westmoreland, Liang Jin, Timothy Radstake, Kevin White, Hsi-Ju Wei
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