FASEB bioAdvances最新文献

{"title":"Human inborn errors of long-chain fatty acid oxidation show impaired inflammatory responses to TLR4-ligand LPS","authors":"Signe Mosegaard,&nbsp;Krishna S. Twayana,&nbsp;Simone W. Denis,&nbsp;Jeffrey Kroon,&nbsp;Bauke V. Schomakers,&nbsp;Michel van Weeghel,&nbsp;Riekelt H. Houtkooper,&nbsp;Rikke K. J. Olsen,&nbsp;Christian K. Holm","doi":"10.1096/fba.2024-00060","DOIUrl":"https://doi.org/10.1096/fba.2024-00060","url":null,"abstract":"<p>Stimulation of mammalian cells with inflammatory inducers such as lipopolysaccharide (LPS) leads to alterations in activity of central cellular metabolic pathways. Interestingly, these metabolic changes seem to be important for subsequent release of pro-inflammatory cytokines. This has become particularly clear for enzymes of tricarboxylic acid (TCA) cycle such as succinate dehydrogenase (<i>SDH</i>). LPS leads to inhibition of SDH activity and accumulation of succinate to enhance the LPS-induced formation of IL-1β. If enzymes involved in beta-oxidation of fatty acids are important for sufficient responses to LPS is currently not clear. Using cells from various patients with inborn long-chain fatty acid oxidation disorders (lcFAOD), we report that disease-causing deleterious variants of Electron Transfer Flavoprotein Dehydrogenase (<i>ETFDH</i>) and of Very Long Chain Acyl-CoA Dehydrogenase (<i>ACADVL</i>), both cause insufficient inflammatory responses to stimulation with LPS. The insufficiencies included reduced TLR4 expression levels, impaired TLR4 signaling, and reduced or absent induction of pro-inflammatory cytokines such as IL-6. The insufficient responses to LPS were reproduced in cells from healthy controls by targeted loss-of-function of either <i>ETFDH</i> or <i>ACADVL,</i> supporting that the deleterious <i>ETFDH</i> and <i>ACADVL</i> variants cause the attenuated responses to LPS. <i>ETFDH</i> and <i>ACADVL</i> encode two distinct enzymes both involved in fatty acid beta-oxidation, and patients with these deficiencies cannot sufficiently metabolize long-chain fatty acids. We report that genes important for beta-oxidation of long-chain fatty acids are also important for inflammatory responses to an acute immunogen trigger like LPS, which may have important implications for understanding infection and other metabolic stress induced disease pathology in lcFAODs.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"6 9","pages":"337-350"},"PeriodicalIF":2.5,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2024-00060","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142152321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of nociception-sensitive ionotropic glutamate receptor-expressing rostroventrolateral medulla neurons by stimulation of cardiac afferents in rats","authors":"Matthew R. Zahner,&nbsp;Cade C. Oculam,&nbsp;Eric Beaumont","doi":"10.1096/fba.2024-00040","DOIUrl":"https://doi.org/10.1096/fba.2024-00040","url":null,"abstract":"<p>Myocardial ischemia causes the release of bradykinin, which activates afferent nerve endings in the ventricular epicardium. This elicits a sympathetically mediated increase in arterial pressure and heart rate, referred to as the cardiogenic sympathetic afferent reflex. The rostroventrolateral medulla (RVLM) is a key sympathetic brain stem site for regulating cardiovascular activity. This study aimed to determine the importance of non-barosensitive nociception sympathetic activity and the role of glutamate receptor activation of RVLM neurons in the cardiogenic sympathetic afferent reflex. We tested the hypothesis that inhibition of barosensitive sympathetic activity attenuates but does not abolish the reflex response to cardiac visceral afferents. Renal sympathetic nerve activity (RSNA), arterial pressure, and heart rate responses to epicardial bradykinin application were recorded in anesthetized rats before and after bilateral RVLM microinjection of either GABA_A agonist muscimol, ionotropic glutamate receptor antagonist kynurenic acid, N-methyl-d-aspartate (NMDA) receptor antagonist 2-amino-5- phosphonopentanoic acid (AP5), or non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Baroreceptor loading-induced inhibition of barosensitive activity attenuated the bradykinin-induced RSNA response (93 ± 14% increase) and tachycardia (18 ± 3 bpm). While RVLM muscimol microinjection abolished the RSNA response (1.6 ± 4.2% from baseline, 0.49 ± 0.38 μV*s), surprisingly, it did not abolish the tachycardia (27 ± 4 bpm). Kynurenic acid microinjection blocked the arterial pressure and RSNA responses, while AP5 or CNQX only attenuated the responses. These data suggest that nociception-sensitive sympathetic activity that does not appear to be barosensitive is also involved in the cardiogenic sympathetic afferent reflex. Importantly, while muscimol and kynurenic acid abolished the arterial pressure and RSNA response, neither affected the tachycardia, suggesting an alternate cardiac pathway independent of RVLM.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"6 9","pages":"377-389"},"PeriodicalIF":2.5,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2024-00040","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142152322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Osteocalcin binds to a GPRC6A Venus fly trap allosteric site to positively modulate GPRC6A signaling","authors":"Rupesh Agarwal,&nbsp;Ruisong Ye,&nbsp;Micholas Dean Smith,&nbsp;Jeremy C. Smith,&nbsp;L. Darryl Quarles,&nbsp;Min Pi","doi":"10.1096/fba.2024-00025","DOIUrl":"https://doi.org/10.1096/fba.2024-00025","url":null,"abstract":"<p>GPRC6A, a member of the Family C G-protein coupled receptors, regulates energy metabolism and sex hormone production and is activated by diverse ligands, including cations, L-amino acids, the osteocalcin (Ocn) peptide and the steroid hormone testosterone. We sought a structural framework for the ability of multiple distinct classes of ligands to active GPRC6A. We created a structural model of GPRC6A using Alphafold2. Using this model we explored a putative orthosteric ligand binding site in the bilobed Venus fly trap (VFT) domain of GPRC6A and two positive allosteric modulator (PAM) sites, one in the VFT and the other in the 7 transmembrane (7TM) domain. We provide evidence that Ocn peptides act as a PAM for GPRC6A by binding to a site in the VFT that is distinct from the orthosteric site for calcium and L-amino acids. In agreement with this prediction, alternatively spliced GPRC6A isoforms 2 and 3, which lack regions of the VFT, and mutations in the computationally predicted Ocn binding site, K352E and H355P, prevent Ocn activation of GPRC6A. These observations explain how dissimilar ligands activate GPRC6A and set the stage to develop novel molecules to activate and inhibit this previously poorly understood receptor.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"6 9","pages":"365-376"},"PeriodicalIF":2.5,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2024-00025","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142152251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"G protein coupled receptor in apoptosis and apoptotic cell clearance","authors":"Xinyan Li,&nbsp;Chao Li,&nbsp;Yang Kang,&nbsp;Rui Zhang,&nbsp;Peiyao Li,&nbsp;Qian Zheng,&nbsp;Hui Wang,&nbsp;Hui Xiao,&nbsp;Lei Yuan","doi":"10.1096/fba.2024-00067","DOIUrl":"https://doi.org/10.1096/fba.2024-00067","url":null,"abstract":"<p>Apoptosis is a genetically programmed form of cell death that is substantially conserved across the evolutionary tree. Apoptotic cell elimination includes recognition, phagocytosis, and degradation. Failure to clear apoptotic cells can ultimately cause a series of human diseases, such as systemic lupus erythematosus, Alzheimer's disease, atherosclerosis, and cancer. Consequently, the timely and effective removal of apoptotic cells is crucial to maintaining the body's homeostasis. GPCRs belong to the largest membrane receptor family. Its intracellular domain exerts an effect on the trimer G protein. By combining with a variety of ligands, the extracellular domain of G protein initiates the dissociation of G protein trimers and progressively transmits signals downstream. Presently, numerous G protein-coupled receptors (GPCRs) have been identified as participants in the apoptosis signal transduction pathway and the apoptotic cell clearance pathway. Therefore, studies on the mechanism of GPCRs in the clearance of apoptotic cells is important for the development of GPCRs therapeutics.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"6 9","pages":"289-297"},"PeriodicalIF":2.5,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2024-00067","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142152316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights on pathophysiology of hydrocephalus rats induced by kaolin injection","authors":"Kuo Zhang,&nbsp;Wanqi Zhou,&nbsp;Huijie Yu,&nbsp;Meijun Pang,&nbsp;Huixin Gao,&nbsp;Faheem Anwar,&nbsp;Kai Yu,&nbsp;Ziwei Zhou,&nbsp;Fang Guo,&nbsp;Xiuyun Liu,&nbsp;Dong Ming","doi":"10.1096/fba.2024-00070","DOIUrl":"https://doi.org/10.1096/fba.2024-00070","url":null,"abstract":"<p>Hydrocephalus can affect brain function and motor ability. Current treatments mostly involve invasive surgeries, with a high risk of postoperative infections and failure. A successful animal model plays a significant role in developing new treatments for hydrocephalus. Hydrocephalus was induced in Sprague–Dawley rats by injecting 25% kaolin into the subarachnoid space at the cerebral convexities with different volumes of 30, 60 and 90 μL. Magnetic resonance imaging (MRI) was performed 1 month and 4 months after kaolin injection. The behavioral performance was assessed weekly, lasting for 7 weeks. The histopathological analyses were conducted to the lateral ventricles by hematoxylin–eosin (HE) staining. Transcriptomic analysis was used between Normal Pressure Hydrocephalus (NPH) patients and hydrocephalus rats. MRI showed a progressive enlargement of ventricles in hydrocephalus group. Kaolin-60 μL and kaolin-90 μL groups showed larger ventricular size, higher anxiety level, bigger decline in body weight, motor ability and cognitive competence. These symptoms may be due to higher-grade inflammatory infiltrate and the damage of the structure of ependymal layer of the ventricles, indicated by HE staining. The overlap upregulated genes and pathways mainly involve immunity and inflammation. Transcriptomic revealed shared pathogenic genes CD40, CD44, CXCL10, and ICAM1 playing a dominance role. 60 μL injection might be recommended for the establishment of hydrocephalus animal model, with a high successful rate and high stability. The hydrocephalus model was able to resemble the inflammatory mechanism and behavioral performance observed in human NPH patients, providing insights for identifying therapeutic targets for hydrocephalus.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"6 9","pages":"351-364"},"PeriodicalIF":2.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2024-00070","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142152292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene expression analysis identifies hub genes and pathways distinguishing fatal from survivor outcomes of Ebola virus disease","authors":"Melvin Mensah-Bonsu,&nbsp;Christopher Doss,&nbsp;Clay Gloster,&nbsp;Perpetua Muganda","doi":"10.1096/fba.2024-00055","DOIUrl":"https://doi.org/10.1096/fba.2024-00055","url":null,"abstract":"<p>The Ebola virus poses a severe public health threat, yet understanding factors influencing disease outcomes remains incomplete. Our study aimed to identify critical pathways and hub genes associated with fatal and survivor Ebola disease outcomes. We analyzed differentially expressed hub genes (DEGs) between groups with fatal and survival outcomes, as well as a healthy control group. We conducted additional analysis to determine the functions and pathways associated with these DEGs. We found 13,198 DEGs in the fatal and 12,039 DEGs in the survival group compared to healthy controls, and 1873 DEGs in the acute fatal and survivor groups comparison. Upregulated DEGs in the comparison between the acute fatal and survivor groups were linked to ECM receptor interaction, complement and coagulation cascades, and PI3K-Akt signaling. Upregulated hub genes identified from the acute fatal and survivor comparison (FGB, C1QA, SERPINF2, PLAT, C9, SERPINE1, F3, VWF) were enriched in complement and coagulation cascades; the downregulated hub genes (IL1B, 1L17RE, XCL1, CXCL6, CCL4, CD8A, CD8B, CD3D) were associated with immune cell processes. Hub genes CCL2 and F2 were unique to fatal outcomes, while CXCL1, HIST1H4F, and IL1A were upregulated hub genes unique to survival outcomes compared to healthy controls. Our results demonstrate for the first time the association of EVD outcomes to specific hub genes and their associated pathways and biological processes. The identified hub genes and pathways could help better elucidate Ebola disease pathogenesis and contribute to the development of targeted interventions and personalized treatment for distinct EVD outcomes.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"6 9","pages":"298-310"},"PeriodicalIF":2.5,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2024-00055","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142152369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mouse developmental defects, but not paraganglioma tumorigenesis, upon conditional Complex II loss in early Sox10+ cells","authors":"Elizabeth P. Lewis,&nbsp;Fatimah Al Khazal,&nbsp;Brandon Wilbanks,&nbsp;Naomi M. Gades,&nbsp;Patricia Ortega-Sáenz,&nbsp;José López-Barneo,&nbsp;Igor Adameyko,&nbsp;L. James Maher III","doi":"10.1096/fba.2024-00056","DOIUrl":"10.1096/fba.2024-00056","url":null,"abstract":"<p>In humans, loss of heterozygosity for defective alleles of any of the four subunits of mitochondrial tricarboxylic acid cycle enzyme succinate dehydrogenase (SDH, also Complex II of the electron transport chain) can lead to paraganglioma tumors in neuroendocrine cells. With the goal of developing mouse models of this rare disorder, we have developed various SDH conditional loss strategies. Based on recent lineage tracing studies, we hypothesized that conditional SDHC loss in early embryogenesis during migration of primordial neural crest cells that form the susceptible chromaffin cells of the adrenal medulla might induce paraganglioma. We triggered low levels of detectable SDHC loss in Sox10⁺ cells at E11.5 of mouse development. We report that, rather than developing adrenal medulla paraganglioma (pheochromocytoma), offspring survived with evidence of neural crest cell dysfunction. Phenotypes included mild lower extremity gait anomalies suggestive of neural tube closure defects and patches of unpigmented fur consistent with neural crest-derived melanocyte dysfunction. These defects were not observed in mice lacking <i>Sdhc</i> knockout. Our results add to existing data suggesting that, unlike humans, even early embryonic (Sox10-driven) SDHx loss is inadequate to trigger paraganglioma in mice of the genetic backgrounds that have been investigated. Instead, low levels of tricarboxylic acid cycle-deficient neural crest cells cause mild developmental defects in hind limb and melanocyte function. This new model may be of interest for studies of metabolism during early neural crest cell development.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"6 9","pages":"327-336"},"PeriodicalIF":2.5,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2024-00056","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141808605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reduction of pathological retinal neovascularization, vessel obliteration, and artery tortuosity by PEDF protein in an oxygen-induced ischemic retinopathy rat model","authors":"Shiying Zhao,&nbsp;Alexander V. Tschulakow,&nbsp;Subha S. Karthikeyan,&nbsp;Kun Wang,&nbsp;Stefan Kochanek,&nbsp;Ulrich Schraermeyer,&nbsp;Sylvie Julien-Schraermeyer","doi":"10.1096/fba.2024-00059","DOIUrl":"10.1096/fba.2024-00059","url":null,"abstract":"<p>Retinopathy of prematurity (ROP) is a severe retinal disease in premature infants characterized by pathological neovascularization, obliteration of retinal vessels and increased vessel tortuosity. Currently, there are no completely satisfactory treatments for ROP. Pigment epithelium-derived factor (PEDF), a potent inhibitor of angiogenesis, appears late in gestation and its deficiency may be linked to development of ROP. This study investigates the preclinical efficacy of PEDF protein alone or in combination with VEGF antagonists for treating ROP. The safety of PEDF protein in the rat eye was assessed using functional in vivo measurements and histology. The efficacy of intravitreal injections (IVI) of various treatments was evaluated in a rat oxygen-induced retinopathy (OIR) model using in vivo imaging and flatmount analyses. No functional or histological side-effects were found in rat eyes after intravitreal PEDF protein injection. PEDF protein alone or combined with anti-VEGF drugs significantly reduced pathological neovascularization and vessel obliteration, comparable to the effects of anti-VEGF drugs alone. Regarding arterial tortuosity, treatment with a combination of PEDF, and VEGF antagonist was more effective than treatment with anti-VEGF alone. IVI of PEDF protein is safe. PEDF protein alone or combined with VEGF antagonists shows similar efficacy in reducing pathological neovascularization and vessel obliteration as anti-VEGF agents. Furthermore, only treatments involving PEDF protein, alone or with VEGF antagonists, significantly improved the quality of retinal vasculature. Thus, PEDF protein alone or combined with anti-VEGF agents presents a promising alternative to current anti-VEGF treatments for ROP.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"6 9","pages":"311-326"},"PeriodicalIF":2.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2024-00059","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141823452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxidative stress mediates nucleocytoplasmic shuttling of KPNA2 via AKT1-CDK1 axis-regulated S62 phosphorylation","authors":"Jie-Xin Huang,&nbsp;Chun-I Wang,&nbsp;Chia-Yu Kuo,&nbsp;Ting-Wei Chang,&nbsp;Yu-Chin Liu,&nbsp;Ting-Feng Hsiao,&nbsp;Chih-Liang Wang,&nbsp;Chia-Jung Yu","doi":"10.1096/fba.2024-00078","DOIUrl":"10.1096/fba.2024-00078","url":null,"abstract":"<p>Karyopherin α 2 (KPNA2, importin α1), a transport factor shuttling between the nuclear and cytoplasmic compartments, is involved in the nuclear import of proteins and participates in cellular processes such as cell cycle regulation, apoptosis, and transcriptional regulation. However, it is still unclear which signaling regulates the nucleocytoplasmic distribution of KPNA2 in response to cellular stress. In this study, we report that oxidative stress increases nuclear retention of KPNA2 through alpha serine/threonine-protein kinase (AKT1)-mediated reduction of serine 62 (S62) phosphorylation. We first found that AKT1 activation was required for H₂O₂-induced nuclear accumulation of KPNA2. Immunoprecipitation and quantitative proteomic analysis revealed that the phosphorylation of KPNA2 at S62 was decreased under H₂O₂-induced oxidative stress. We showed that cyclin-dependent kinase 1 (CDK1), a kinase responsible for KPNA2 S62 phosphorylation, contributes to the localization of KPNA2 in the cytoplasm. AKT1 knockdown increased KPNA2 S62 phosphorylation and inhibited CDK1 activation. Furthermore, H₂O₂-induced AKT1 activation promoted nuclear KPNA2 interaction with nucleophosmin 1 (NPM1), resulting in attenuation of NPM1-mediated cyclin D1 gene transcription. Thus, we infer that the AKT1-CDK1 axis regulates the nucleocytoplasmic shuttling and function of KPNA2 through spatiotemporal regulation of KPNA2 S62 phosphorylation under oxidative stress conditions.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"6 8","pages":"276-288"},"PeriodicalIF":2.5,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2024-00078","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141673676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Social defeat stress impairs systemic iron metabolism by activating the hepcidin–ferroportin axis","authors":"Emiko Kasahara,&nbsp;Ayumi Nakamura,&nbsp;Kenki Morimoto,&nbsp;Shiho Ito,&nbsp;Mika Hori,&nbsp;Atsuo Sekiyama","doi":"10.1096/fba.2024-00071","DOIUrl":"10.1096/fba.2024-00071","url":null,"abstract":"<p>Chronic psychological stress has been reported to decrease circulating iron concentrations and impair hematopoiesis. However, the underlying mechanisms remain unclear. This study aimed to investigate the effects of psychological stress on biological iron metabolism by using the social defeat stress (SDS) model, a widely used model of depression. Compared with control mice, mice subjected to SDS (SDS mice) had lower social interaction (SI) behavior. The SDS mice also showed impaired hematopoiesis, as evidenced by reduced circulating red blood cell counts, elevated reticulocyte counts, and decreased plasma iron levels. In the SDS mice, the iron contents in the bone marrow decreased, whereas those in the spleen increased, suggesting dysregulation in systemic iron metabolism. The concentrations of plasma hepcidin, an important regulator of systemic iron homeostasis, increased in the SDS mice. Meanwhile, the concentrations of ferroportin, an iron transport protein negatively regulated by hepcidin, were lower in the spleen and duodenum of the SDS mice than in those of the control mice. Treatment with dalteparin, a hepcidin inhibitor, prevented the decrease in plasma iron levels in the SDS mice. The gene expression and enzyme activity of furin, which converts the precursor hepcidin to active hepcidin, were high and positively correlated with plasma hepcidin concentration. Thus, furin activation might be responsible for the increased plasma hepcidin concentration. This study is the first to show that psychological stress disrupts systemic iron homeostasis by activating the hepcidin–ferroportin axis. Consideration of psychological stressors might be beneficial in the treatment of diseases with iron-refractory anemia.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"6 8","pages":"263-275"},"PeriodicalIF":2.5,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2024-00071","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141687049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}