Zhu et al. report that reduced expression of cold-inducible RNA-binding protein (CIRBP) in aged donor hearts promotes ferroptosis and blunts cardioprotective effects of hypothermia during heart transplantation in a rat model. Image credit: Shanghai Bangtu Culture Media Co.
Dicarboxylic fatty acids are generated in the liver and kidney in a minor pathway called fatty acid ω-oxidation. The effects of consuming dicarboxylic fatty acids as an alternative source of dietary fat have not been explored. Here, we fed dodecanedioic acid, a 12-carbon dicarboxylic (DC12), to mice at 20% of daily caloric intake for nine weeks. DC12 increased metabolic rate, reduced body fat, reduced liver fat, and improved glucose tolerance. We observed DC12-specific breakdown products in liver, kidney, muscle, heart, and brain, indicating that oral DC12 escaped first-pass liver metabolism and was utilized by many tissues. In tissues expressing the “a” isoform of acyl-CoA oxidase-1 (ACOX1), a key peroxisomal fatty acid oxidation enzyme, DC12 was chain shortened to the TCA cycle intermediate succinyl-CoA. In tissues with low peroxisomal fatty acid oxidation capacity, DC12 was oxidized by mitochondria. In vitro, DC12 was catabolized even by adipose tissue and was not stored intracellularly. We conclude that DC12 and other dicarboxylic acids may be useful for combatting obesity and for treating metabolic disorders.
Eric S. Goetzman, Bob B. Zhang, Yuxun Zhang, Sivakama S. Bharathi, Joanna Bons, Jacob Rose, Samah Shah, Keaton J. Solo, Alexandra V. Schmidt, Adam C. Richert, Steven J. Mullett, Stacy L. Gelhaus, Krithika S. Rao, Sruti S. Shiva, Katherine E. Pfister, Anne Silva Barbosa, Sunder Sims-Lucas, Steven F. Dobrowolski, Birgit Schilling
One critical mechanism through which prostate cancer (PCa) adapts to treatments targeting androgen receptor (AR) signaling is the emergence of ligand-binding domain-truncated and constitutively active AR splice variants, particularly AR-V7. While AR-V7 has been intensively studied, its ability to activate distinct biological functions compared to the full-length AR (AR-FL), and its role in regulating the metastatic progression of castration-resistant PCa (CRPC), remains unclear. Our study found that, under castrated conditions, AR-V7 strongly induced osteoblastic bone lesions, a response not observed with AR-FL overexpression. Through combined ChIP-seq, ATAC-seq, and RNA-seq analyses, we demonstrated that AR-V7 uniquely accesses the androgen-responsive elements in compact chromatin regions, activating a distinct transcription program. This program was highly enriched for genes involved in epithelial-mesenchymal transition and metastasis. Notably, we discovered that SOX9, a critical metastasis driver gene, was a direct target and downstream effector of AR-V7. Its protein expression was dramatically upregulated in AR-V7-induced bone lesions. Moreover, we found that Ser81 phosphorylation enhanced AR-V7’s pro-metastasis function by selectively altering its specific transcription program. Blocking this phosphorylation with CDK9 inhibitors impaired the AR-V7-mediated metastasis program. Overall, our study has provided molecular insights into the role of AR splice variants in driving the metastatic progression of CRPC.
Dong Han, Maryam Labaf, Yawei Zhao, Jude Owiredu, Songqi Zhang, Krishna Patel, Kavita Venkataramani, Jocelyn S. Steinfeld, Wanting Han, Muqing Li, Mingyu Liu, Zifeng Wang, Anna Besschetnova, Susan Patalano, Michaela J. Mulhearn, Jill A. Macoska, Xin Yuan, Steven P. Balk, Peter S. Nelson, Stephen R. Plymate, Shuai Gao, Kellee R. Siegfried, Ruihua Liu, Mary M. Stangis, Gabrielle Foxa, Piotr J. Czernik, Bart O. Williams, Kourosh Zarringhalam, Xiaohong Li, Changmeng Cai
Neuroinflammation is a recognized complication of immunotherapeutic approaches such as immune checkpoint inhibitor treatment, chimeric antigen receptor therapy, and graft versus host disease (GVHD) occurring after allogeneic hematopoietic stem cell transplantation. While T cells and inflammatory cytokines play a role in this process, the precise interplay between the adaptive and innate arms of the immune system that propagates inflammation in the central nervous system remains incompletely understood. Using a murine model of GVHD, we demonstrate that type 2 cannabinoid receptor (CB2R) signaling plays a critical role in the pathophysiology of neuroinflammation. In these studies, we identify that CB2R expression on microglial cells induces an activated inflammatory phenotype which potentiates the accumulation of donor-derived proinflammatory T cells, regulates chemokine gene regulatory networks, and promotes neuronal cell death. Pharmacological targeting of this receptor with a brain penetrant CB2R inverse agonist/antagonist selectively reduces neuroinflammation without deleteriously affecting systemic GVHD severity. Thus, these findings delineate a therapeutically targetable neuroinflammatory pathway and has implications for the attenuation of neurotoxicity after GVHD and potentially other T cell-based immunotherapeutic approaches.
Alison Moe, Aditya Rayasam, Garrett Sauber, Ravi K. Shah, Ashley Doherty, Cheng-Yin Yuan, Aniko Szabo, Bob M. Moore II, Marco Colonna, Weiguo Cui, Julian Romero, Anthony E. Zamora, Cecilia J. Hillard, William R. Drobyski
Widespread alterations in RNA alternative splicing (AS) have been identified in adult gliomas. However, their regulatory mechanism, biological significance, and therapeutic potential remain largely elusive. Here, using a computational approach with both bulk and single cell RNA-sequencing, we uncover a prognostic AS signature linked with neural developmental hierarchies. Using advanced iPSC glioma models driven by glioma driver mutations, we show that this AS signature could be enhanced by EGFRvIII and inhibited by in situ IDH1 mutation. Functional validation of two isoform switching events in CERS5 and MPZL1 shows regulations of sphingolipid metabolism and SHP2 signaling, respectively. Analysis of upstream RNA binding proteins reveals PTBP1 as a key regulator of the AS signature where targeting of PTBP1 suppresses tumor growth and promotes the expression of a neuron marker TUJ1 in glioma stem-like cells. Overall, our data highlights the role of AS in impacting glioma malignance and heterogeneity and its potential as a therapeutic vulnerability for treating adult gliomas.
Xiao Song, Deanna Tiek, Shunichiro Miki, Tianzhi Huang, Minghui Lu, Anshika Goenka, Rebeca P. Iglesia, Xiaozhou Yu, Runxin Wu, Maya N. Walker, Chang Zeng, Hardik Shah, Shao Huan Samuel Weng, Allen Huff, Wei Zhang, Tomoyuki Koga, Christopher G. Hubert, Craig M. Horbinski, Frank F. Furnari, Bo Hu, Shi-Yuan Cheng
Cancer cells exhibit heightened secretory states that drive tumor progression. Here, we identify a chromosome 3q amplicon that serves as a platform for secretory regulation in cancer. The 3q amplicon encodes multiple Golgi-resident proteins, including the scaffold Golgi integral membrane protein 4 (GOLIM4) and the ion channel ATPase Secretory Pathway Ca2+ Transporting 1 (ATP2C1). We show that GOLIM4 recruits ATP2C1 and Golgi phosphoprotein 3 (GOLPH3) to coordinate calcium-dependent cargo loading and Golgi membrane bending and vesicle scission. GOLIM4 depletion disrupts the protein complex, resulting in a secretory blockade that inhibits the progression of 3q-amplified malignancies. In addition to its role as a scaffold, GOLIM4 maintains intracellular manganese (Mn) homeostasis by binding excess Mn in the Golgi lumen, which initiates the routing of Mn-bound GOLIM4 to lysosomes for degradation. We show that Mn treatment inhibits the progression of multiple types of 3q-amplified malignancies by degrading GOLIM4, resulting in a secretory blockade that interrupts pro-survival autocrine loops and attenuates pro-metastatic processes in the tumor microenvironment. Potentially underlying the selective activity of Mn against 3q-amplified malignancies, ATP2C1 co-amplification increases Mn influx into the Golgi lumen, resulting in a more rapid degradation of GOLIM4. These findings show that functional cooperativity between co-amplified genes underlies heightened secretion and a targetable secretory addiction in 3q-amplified malignancies.
Xiaochao Tan, Shike Wang, Guan-Yu Xiao, Chao Wu, Xin Liu, Biyao Zhou, Jiang Yu, Dzifa Yawa Duose, Yuanxin Xi, Jing Wang, Kunika Gupta, Apar Pataer, Jack A. Roth, Michael P. Kim, Fengju Chen, Chad J. Creighton, William K. Russell, Jonathan M. Kurie
JCI celebrates a century of publishing scientific discoveries with a special collection highlighting major innovations in medicine and key contributing mechanistic studies.
Vascular malformations in arteries, veins, and lymphatic vessels occur in a broad range of conditions that vary widely in severity and presentation. Leveraging the mechanisms specific to each type of malformation will be essential for optimizing disease management. This review series, developed with series editor Miikka Vikkula, will span hemangioma, hereditary hemorrhagic telangiectasia, lymphatic abnormalities, cerebral small vessel disease, capillary malformations, and more, with reviews contributed by leading experts in each condition.
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