Articoli di riviste: "Fsp1"

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Nwagala, P. N., S. A. Bankole e O. A. F. Ilusanya. "Isolation and molecular characterization of cellulase-producing bacteria from waste dump site". Scientia Africana 23, n. 1 (30 marzo 2024): 73–84. http://dx.doi.org/10.4314/sa.v23i1.6.

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Cellulases are collections of extracellular enzymes and a complex mixture of enzyme proteins with various specificities. Cellulases work together to hydrolyze glycosidic bonds and generate monomers of glucose for fermentation. This investigation aims to isolate and molecularly characterize Bacillus species with cellulolytic ability. Bacillus species were isolated from soil samples retrieved from a dump site and screened for cellulolytic ability on carboxyl methylcellulose (CMC) agar. The percentage hydrolysis efficiency of isolates was determined and cellulase produced was quantified using CMC assay method. Biochemical identification was by Analytical Profile Index (API) Kit 50CHB/20E and API web software while molecular characterization employed 16S rRNA gene sequencing and blast search analysis. Bacillus megaterium (FSP1) and Bacillus zanthoxyli (FSP4) exhibited their cellulolytic potentials by presenting zones of clearance of about 21 ± 2.08 and 7 ± 1.00 mm on CMCA with hydrolysis efficiency of 250 and 600 % respectively. Quantification of crude cellulase revealed cellulase activity of 85 and 74μmol/ml for both bacteria species. Biochemically, the cellulolytic bacteria were identified as Bacillus megaterium (FSP1) and Bacillus zanthoxyli (FSP4) while molecularly, they were identified as Bacillus megaterium 14581 (FSP1) and Bacillus zanthoxyli 1433 (FSP4) with Reference Sequence (RefSeq) accession numbers NR_116873 and NR_164882, and showing maximum sequence similarity of 99 and 96 % respectively. Results obtained from this investigation, suggests that both bacteria species characterised, possesses good cellulolytic ability and hence can be utilized for the production of the enzyme cellulase which has a wide range of industrial application.

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Kong, Ping, Panagiota Christia, Amit Saxena, Ya Su e Nikolaos G. Frangogiannis. "Lack of specificity of fibroblast-specific protein 1 in cardiac remodeling and fibrosis". American Journal of Physiology-Heart and Circulatory Physiology 305, n. 9 (1 novembre 2013): H1363—H1372. http://dx.doi.org/10.1152/ajpheart.00395.2013.

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Understanding the role of fibroblasts in pathologic conditions is hampered by the absence of specific markers. Fibroblast-specific protein (FSP)1 has been suggested as a fibroblast-specific marker in normal and fibrotic tissues; FSP1 reporter mice and FSP1-Cre-driven gene deletion are considered reliable strategies to investigate fibroblast biology. Because fibroblasts are abundant in normal and injured mammalian hearts, we studied the identity of FSP1+ cells in the infarcted and remodeling myocardium using mice with green fluorescent protein (GFP) expression driven by the FSP1 promoter. Neonatal and adult mouse hearts had low numbers of FSP1+ cells. Myocardial infarction induced marked infiltration with FSP1-expressing cells that peaked after 72 h of reperfusion. Using flow cytometry, we identified 50% of FSP1+ cells as hematopoietic cells; many endothelial cells were also FSP1+. Increased infiltration with FSP1+ cells was also noted in the pressure-overloaded myocardium. Although some FSP1+ cells had fibroblast morphology, >30% were identified as hematopoietic cells, endothelial cells, or vascular smooth muscle cells. In contrast, periostin did not stain leukocytes or vascular cells but labeled spindle-shaped interstitial cells and, as a typical matricellular protein, was deposited in the matrix. CD11b+ myeloid cells sorted from the infarcted heart had higher FSP1 expression than corresponding CD11b-negative cells, highlighting the predominant expression by hematopoietic cells. FSP1 is not a specific marker for fibroblasts in cardiac remodeling and fibrosis.

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Hou, Wanyun, Puze Long, Xilin Liu, Fahui Liu, Jiadong Liang, Yunmei Huang, Qunying Su, Lihe Jiang e Chunying Luo. "CISD2 protects against Erastin induced hepatocellular carcinoma ferroptosis by upregulating FSP1". Oncologie 25, n. 3 (30 marzo 2023): 269–79. http://dx.doi.org/10.1515/oncologie-2023-0074.

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Abstract Objectives CDGSH iron sulfur domain 2 (CISD2) is essential to maintain iron (Fe) and reactive oxygen species (ROS) homeostasis, and ferroptosis suppressor protein 1 (FSP1) can protect cells from ferroptosis by inhibiting lipid peroxidation. Here, we investigate the role and potential mechanism of CISD2 and FSP1 in ferroptosis of hepatocellular carcinoma (HCC). Methods Human HCC cells were exposed to ferroptosis inducer Erastin, and the expression changes of CISD2 and FSP1 during ferroptosis were detected. Subsequently, we investigated the effect of overexpression of CISD2 on ferroptosis and FSP1 expression in HCC cells. Finally, we also investigated the effect of overexpression of FSP1 on ferroptosis in HCC cells. Results Erastin induced ferroptosis in hepatoma cells, and HepG2 cells were sensitive to Erastin. In addition, it was found that the expression of CISD2 was significantly upregulated and the expression of FSP1 was significantly downregulated in Erastin treated HepG2 cells. Subsequently, CISD2 was found to be highly expressed in HCC tissues, and overexpression of CISD2 reversed ferroptosis induced by Erastin in HepG2 cells and upregulated the expression of FSP1. Meanwhile, FSP1 showed a low expression level in HCC tissues and cells, and overexpression of FSP1 could reverse the ferroptosis induced by Erastin in HepG2 cells. Conclusion CISD2 and FSP1 are involved in the ferroptosis process of HCC induced by Erastin. CISD2 protects against the ferroptosis of HCC induced by Erastin by upregulating the expression of FSP1.

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Nakamura, Toshitaka, Eikan Mishima, Naoya Yamada, André Santos Dias Mourão, Dietrich Trümbach, Sebastian Doll, Jonas Wanninger et al. "Integrated chemical and genetic screens unveil FSP1 mechanisms of ferroptosis regulation". Nature Structural & Molecular Biology 30, n. 11 (novembre 2023): 1806–15. http://dx.doi.org/10.1038/s41594-023-01136-y.

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AbstractFerroptosis, marked by iron-dependent lipid peroxidation, may present an Achilles heel for the treatment of cancers. Ferroptosis suppressor protein-1 (FSP1), as the second ferroptosis mainstay, efficiently prevents lipid peroxidation via NAD(P)H-dependent reduction of quinones. Because its molecular mechanisms have remained obscure, we studied numerous FSP1 mutations present in cancer or identified by untargeted random mutagenesis. This mutational analysis elucidates the FAD/NAD(P)H-binding site and proton-transfer function of FSP1, which emerged to be evolutionarily conserved among different NADH quinone reductases. Using random mutagenesis screens, we uncover the mechanism of action of next-generation FSP1 inhibitors. Our studies identify the binding pocket of the first FSP1 inhibitor, iFSP1, and introduce the first species-independent FSP1 inhibitor, targeting the NAD(P)H-binding pocket. Conclusively, our study provides new insights into the molecular functions of FSP1 and enables the rational design of FSP1 inhibitors targeting cancer cells.

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Lee, Jaewang, e Jong-Lyel Roh. "Unleashing Ferroptosis in Human Cancers: Targeting Ferroptosis Suppressor Protein 1 for Overcoming Therapy Resistance". Antioxidants 12, n. 6 (5 giugno 2023): 1218. http://dx.doi.org/10.3390/antiox12061218.

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Ferroptosis, a recently identified form of regulated cell death characterized by the iron-dependent accumulation of lethal lipid peroxidation, has gained increasing attention in cancer therapy. Ferroptosis suppressor protein 1 (FSP1), an NAD(P)H-ubiquinone oxidoreductase that reduces ubiquinone to ubiquinol, has emerged as a critical player in the regulation of ferroptosis. FSP1 operates independently of the canonical system xc–/glutathione peroxidase 4 pathway, making it a promising target for inducing ferroptosis in cancer cells and overcoming ferroptosis resistance. This review provides a comprehensive overview of FSP1 and ferroptosis, emphasizing the importance of FSP1 modulation and its potential as a therapeutic target in cancer treatment. We also discuss recent progress in developing FSP1 inhibitors and their implications for cancer therapy. Despite the challenges associated with targeting FSP1, advances in this field may provide a strong foundation for developing innovative and effective treatments for cancer and other diseases.

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Österreicher, Christoph H., Melitta Penz-Österreicher, Sergei I. Grivennikov, Monica Guma, Ekaterina K. Koltsova, Christian Datz, Roman Sasik, Gary Hardiman, Michael Karin e David A. Brenner. "Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liver". Proceedings of the National Academy of Sciences 108, n. 1 (20 dicembre 2010): 308–13. http://dx.doi.org/10.1073/pnas.1017547108.

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Cirrhosis is the end result of chronic liver disease. Hepatic stellate cells (HSC) are believed to be the major source of collagen-producing myofibroblasts in cirrhotic livers. Portal fibroblasts, bone marrow-derived cells, and epithelial to mesenchymal transition (EMT) might also contribute to the myofibroblast population in damaged livers. Fibroblast-specific protein 1 (FSP1, also called S100A4) is considered a marker of fibroblasts in different organs undergoing tissue remodeling and is used to identify fibroblasts derived from EMT in several organs including the liver. The aim of this study was to characterize FSP1-positive cells in human and experimental liver disease. FSP1-positive cells were increased in human and mouse experimental liver injury including liver cancer. However, FSP1 was not expressed by HSC or type I collagen-producing fibroblasts. Likewise, FSP1-positive cells did not express classical myofibroblast markers, including αSMA and desmin, and were not myofibroblast precursors in injured livers as evaluated by genetic lineage tracing experiments. Surprisingly, FSP1-positive cells expressed F4/80 and other markers of the myeloid-monocytic lineage as evaluated by double immunofluorescence staining, cell fate tracking, flow cytometry, and transcriptional profiling. Similar results were obtained for bone marrow-derived and peritoneal macrophages. FSP1-positive cells were characterized by increased expression of COX2, osteopontin, inflammatory cytokines, and chemokines but reduced expression of MMP3 and TIMP3 compared with Kupffer cells/macrophages. These findings suggest that FSP1 is a marker of a specific subset of inflammatory macrophages in liver injury, fibrosis, and cancer.

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Strutz, F., H. Okada, C. W. Lo, T. Danoff, R. L. Carone, J. E. Tomaszewski e E. G. Neilson. "Identification and characterization of a fibroblast marker: FSP1." Journal of Cell Biology 130, n. 2 (15 luglio 1995): 393–405. http://dx.doi.org/10.1083/jcb.130.2.393.

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We performed subtractive and differential hybridization for transcript comparison between murine fibroblasts and isogenic epithelium, and observed only a few novel intracellular genes which were relatively specific for fibroblasts. One such gene encodes a filament-associated, calcium-binding protein, fibroblast-specific protein 1 (FSP1). The promoter/enhancer region driving this gene is active in fibroblasts but not in epithelium, mesangial cells or embryonic endoderm. During development, FSP1 is first detected by in situ hybridization after day 8.5 as a postgastrulation event, and is associated with cells of mesenchymal origin or of fibroblastic phenotype. Polyclonal antiserum raised to recombinant FSP1 protein stained the cytoplasm of fibroblasts, but not epithelium. Only occasional cells stain with specific anti-FSP1 antibodies in normal parenchymal tissue. However, in kidneys fibrosing from persistent inflammation, many fibroblasts could be identified in interstitial sites of collagen deposition and also in tubular epithelium adjacent to the inflammatory process. This pattern of anti-FSP1 staining during tissue fibrosis suggests, as a hypothesis, that fibroblasts in some cases arise, as needed, from the local conversion of epithelium. Consistent with this notion that FSP1 may be involved in the transition from epithelium to fibroblasts are experiments in which the in vitro overexpression of FSP1 cDNA in tubular epithelium is accompanied by conversion to a mesenchymal phenotype, as characterized by a more stellate and elongated fibroblast-like appearance, a reduction in cytokeratin, and new expression of vimentin. Similarly, tubular epithelium submerged in type I collagen gels exhibited the conversion to a fibroblast phenotype which includes de novo expression of FSP1 and vimentin. Use of the FSP1 marker, therefore, should further facilitate both the in vivo studies of fibrogenesis and the mapping of cell fate among fibroblasts.

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Okada, Hirokazu, Theodore M. Danoff, Raghuram Kalluri e Eric G. Neilson. "Early role of Fsp1 in epithelial-mesenchymal transformation". American Journal of Physiology-Renal Physiology 273, n. 4 (1 ottobre 1997): F563—F574. http://dx.doi.org/10.1152/ajprenal.1997.273.4.f563.

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A seamless plasticity exists among cells shifting between epithelial and mesenchymal phenotypes during early development and again later, in adult tissues, following wound repair or organ remodeling in response to injury. Fsp1, a gene encoding a fibroblast-specific protein associated with mesenchymal cell morphology and motility, is expressed during epithelial-mesenchymal transformations (EMT) in vivo. In the current study, we identified several cytokines that induce Fsp1 in cultured epithelial cells. A combination of these factors, however, was most efficacious at completing the process of EMT. The optimal combination identified were two of the cytokines classically associated with fibrosis, i.e., transforming growth factor-β1 (TGF-β1) and epidermal growth factor (EGF). To confirm that it was the induction of Fsp1 by these cytokines mediating EMT, we used antisense oligomers to block Fsp1 production and subsequently measured cell motility and markers of EMT phenotype. The antisense oligomers suppressed Fsp1 expression and epithelial transformation; therefore, we conclude that the appearance of Fsp1 is an important early event in the pathway toward EMT.

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Gotorbe, Célia, Jérôme Durivault, Willian Meira, Shamir Cassim, Maša Ždralević, Jacques Pouysségur e Milica Vučetić. "Metabolic Rewiring toward Oxidative Phosphorylation Disrupts Intrinsic Resistance to Ferroptosis of the Colon Adenocarcinoma Cells". Antioxidants 11, n. 12 (6 dicembre 2022): 2412. http://dx.doi.org/10.3390/antiox11122412.

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Glutathione peroxidase 4 (GPX4) has been reported as one of the major targets for ferroptosis induction, due to its pivotal role in lipid hydroperoxide removal. However, recent studies pointed toward alternative antioxidant systems in this context, such as the Coenzyme Q-FSP1 pathway. To investigate how effective these alternative pathways are in different cellular contexts, we used human colon adenocarcinoma (CRC) cells, highly resistant to GPX4 inhibition. Data obtained in the study showed that simultaneous pharmacological inhibition of GPX4 and FSP1 strongly compromised the survival of the CRC cells, which was prevented by the ferroptosis inhibitor, ferrostatin-1. Nonetheless, this could not be phenocopied by genetic deletion of FSP1, suggesting the development of resistance to ferroptosis in FSP1-KO CRC cells. Considering that CRC cells are highly glycolytic, we used CRC Warburg-incompetent cells, to investigate the role metabolism plays in this phenomenon. Indeed, the sensitivity to inhibition of both anti-ferroptotic axes (GPx4 and FSP1) was fully revealed in these cells, showing typical features of ferroptosis. Collectively, data indicate that two independent anti-ferroptotic pathways (GPX4-GSH and CoQ10-FSP1) operate within the overall physiological context of cancer cells and in some instances, their inhibition should be coupled with other metabolic modulators, such as inhibitors of glycolysis/Warburg effect.

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Dixit, Vishwa, Yun-Hee Youm, Hyunwon Yang, Christo Venkov, Nancy Manley, Eric Nielson, Todd Leff e Bolormaa Vandanmagsar. "Origin of Thymic Adipocytes in Aging: Incidental to Thymopoiesis or Instigator of Immunosenescence? (132.22)". Journal of Immunology 184, n. 1_Supplement (1 aprile 2010): 132.22. http://dx.doi.org/10.4049/jimmunol.184.supp.132.22.

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Abstract Vishwa Deep Dixit, Yun-Hee Youm, Hyunwon Yang, Christo Venkov, Nancy R Manley, Eric Nielson, Todd Leff, Bolormaa Vandanmagsar By 50 years of age most of human thymus is replaced with adipocytes of unknown provenance and uncertain function. We investigated the lineage and mechanism of thymic adipocyte formation during aging and asked whether manipulating these pathways regulates thymic function. Using.We demonstrate that indelibly LacZ marked FoxN1 thymic epithelial cells transition to give rise to local tissue fibroblasts via the epithelial-mesenchymal transition(EMT)process. Importantly, we found an age-related increase in pro-EMT regulator FSP1 and pro-adipogenic transcription factor PPARγ in thymus. Consistent with these findings, a subset of FoxN1LacZ+ cells are FSP1+ with large unilocular lipid droplet, typical of adipocyte phenotype. Furthermore, aged FSP1.GFP reporter mice revealed that the sorted FSP1+ thymic fibroblasts lack TEC signatures and express PPARγ, indicative of adipogenic lineage commitment. Notably, overexpression of constitutive-active PPARγ in FSP1+ adipogenic lineage cells led to increased thymic adipogenesis and reduced thymopoiesis. Conversely, inhibition of EMT and thymoadipogenesis via anti-aging intervention, caloric restriction prevented thymic aging and immunosenescence. Future longevity studies using specific genetic manipulation of these pathways may provide a definitive answer to the puzzle of age-related thymic adiposity and involution.

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Bryja, Artur, Wojciech Pieńkowski, Katarzyna Stefańska, Błażej Chermuła, Rut Bryl, Maria Wieczorkiewicz, Jakub Kulus et al. "Analysis of TGFB1, CD105 and FSP1 expression in human granulosa cells during a 7-day primary in vitro culture". Medical Journal of Cell Biology 8, n. 4 (1 dicembre 2020): 152–57. http://dx.doi.org/10.2478/acb-2020-0019.

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Abstract The human granulosa cells (GCs) surround the oocyte and form the ovarian follicle’s proper architecture. These sub-populations include mural granulosa cells, antral granulosa cells, and cumulus granulosa cells. Their main functions are to support the oocyte’s growth (cumulus granulosa cells) and estradiol production (mural granulosa cells). After ovulation, the granulosa cells transform into the luteal cells of the corpus luteum and produce progesterone. Our study investigated the expression profile of three genes: TGFB1, CD105, and FSP1 during a 7-day in vitro culture. The analysis was conducted using the RT-qPCR technique. Changes in the expression of CD105 and FSP1 could be observed during the 7-day in vitro culture. In the case of TGFB, the expression remained at a similar level, with no statistically significant differences observed. Running title: Expression of TGFB1, CD105 and FSP1 in granulosa cells

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Okada, Hirokazu, Theodore M. Danoff, Andreas Fischer, Jesus M. Lopez-Guisa, Frank Strutz e Eric G. Neilson. "Identification of a novelcis-acting element for fibroblast-specific transcription of theFSP1 gene". American Journal of Physiology-Renal Physiology 275, n. 2 (1 agosto 1998): F306—F314. http://dx.doi.org/10.1152/ajprenal.1998.275.2.f306.

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The FSP1 gene encodes a filament-binding S100 protein with paired EF hands that is specifically expressed in fibroblasts. This led us to look for cis-acting elements in the FSP1 promoter that might engage nuclear transcription factors unique to fibroblasts. The first exon of FSP1 is noncoding, therefore, a series of luciferase reporter minigenes were created containing varying lengths of 5′-flanking sequence, the first intron, and the noncoding region of the second exon. A position and promoter-dependent proximal element between −187 and −88 bp was shown to be active in fibroblasts but not in epithelium. Sequence in the first intron from +777 to +964 had an enhancing effect that was not cell type specific. Hsv TK reporter constructs driven by this promoter/intron cassette in transgenic mice were coexpressed appropriately with FSP1 in tissue fibroblasts. Gel mobility shift competitor assays identified a novel domain, FTS-1 (fibroblast transcription site-1; TTGAT from −177 to −173 bp), that specifically interacts with nuclear extracts from fibroblasts. The necessity of this binding site was confirmed by site-specific mutagenesis. Database searches also turned up putative FTS-1 sites in the early promoter regions of other fibroblast expressed proteins, including the α1 and α2(I), and α1(III) collagens and the αSM-actin gene. We hypothesize that the selective engagement of FTS-1 elements may contribute to the mesenchymal phenotype of fibroblasts and perhaps other dedifferentiated cells.

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Bebber, Christina M., e Silvia von Karstedt. "FSP1 inhibition: pick your pocket". Nature Structural & Molecular Biology 30, n. 11 (novembre 2023): 1618–19. http://dx.doi.org/10.1038/s41594-023-01145-x.

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Lee, Keunwook, Kelli L. Boyd, Diptiben V. Parekh, Thomas E. Kehl-Fie, H. Scott Baldwin, Cord Brakebusch, Eric P. Skaar, Mark Boothby e Roy Zent. "Cdc42 Promotes Host Defenses against Fatal Infection". Infection and Immunity 81, n. 8 (20 maggio 2013): 2714–23. http://dx.doi.org/10.1128/iai.01114-12.

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ABSTRACTThe small Rho GTPase Cdc42 regulates key signaling pathways required for multiple cell functions, including maintenance of shape, polarity, proliferation, invasion, migration, differentiation, and morphogenesis. As the role of Cdc42-dependent signaling in fibroblastsin vivois unknown, we attempted to specifically delete it in these cells by crossing the Cdc42fl/flmouse with an fibroblast-specific protein 1 (FSP1)-Cre mouse, which is thought to mediate recombination exclusively in fibroblasts. Surprisingly, the FSP1-Cre;Cdc42fl/flmice died at 3 weeks of age due to overwhelming suppurative upper airway infections that were associated with neutrophilia and lymphopenia. Even though major aberrations in lymphoid tissue development were present in the mice, the principal cause of death was severe migration and killing abnormalities of the neutrophil population resulting in an inability to control infection. We also show that in addition to fibroblasts, FSP1-Cre deleted Cdc42 very efficiently in all leukocytes. Thus, by using this nonspecific Cre mouse, we inadvertently demonstrated the importance of Cdc42 in host protection from lethal infections and suggest a critical role for this small GTPase in innate immunity.

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Yang, Kezhen, Lingling Zhu, Hongzhe Wang, Min Jiang, Chunwang Xiao, Xiangyang Hu, Steffen Vanneste, Juan Dong e Jie Le. "A conserved but plant-specific CDK-mediated regulation of DNA replication protein A2 in the precise control of stomatal terminal division". Proceedings of the National Academy of Sciences 116, n. 36 (20 agosto 2019): 18126–31. http://dx.doi.org/10.1073/pnas.1819345116.

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The R2R3-MYB transcription factor FOUR LIPS (FLP) controls the stomatal terminal division through transcriptional repression of the cell cycle genes CYCLIN-DEPENDENT KINASE (CDK) B1s (CDKB1s), CDKA;1, and CYCLIN A2s (CYCA2s). We mutagenized the weak mutant allele flp-1 seeds with ethylmethane sulfonate and screened out a flp-1 suppressor 1 (fsp1) that suppressed the flp-1 stomatal cluster phenotype. FSP1 encodes RPA2a subunit of Replication Protein A (RPA) complexes that play important roles in DNA replication, recombination, and repair. Here, we show that FSP1/RPA2a functions together with CDKB1s and CYCA2s in restricting stomatal precursor proliferation, ensuring the stomatal terminal division and maintaining a normal guard-cell size and DNA content. Furthermore, we provide direct evidence for the existence of an evolutionarily conserved, but plant-specific, CDK-mediated RPA regulatory pathway. Serine-11 and Serine-21 at the N terminus of RPA2a are CDK phosphorylation target residues. The expression of the phosphorylation-mimic variant RPA2aS11,21/D partially complemented the defective cell division and DNA damage hypersensitivity in cdkb1;1 1;2 mutants. Thus, our study provides a mechanistic understanding of the CDK-mediated phosphorylation of RPA in the precise control of cell cycle and DNA repair in plants.

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Wang, Fang, Jiaxi Li, Yingjie Zhao, Dong Guo, Dongfan Liu, Su'e Chang, Hao Qiao et al. "miR-672-3p Promotes Functional Recovery in Rats with Contusive Spinal Cord Injury by Inhibiting Ferroptosis Suppressor Protein 1". Oxidative Medicine and Cellular Longevity 2022 (21 febbraio 2022): 1–19. http://dx.doi.org/10.1155/2022/6041612.

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Aberrantly expressed microRNAs (miRNAs) after spinal cord injury (SCI) participate in diverse biological pathways and processes, including apoptosis, inflammation, oxidative stress responses, peroxidation, and ferroptosis. This study was aimed at exploring the mechanisms underlying miRNA-mediated ferroptosis in an SCI rat model. In the present study, a T10 weight-dropping SCI model was established and miRNA profiling was used to detect miRNA expression profiles post-SCI. Basso-Beattie-Bresnahan scores and inclined plane test, hematoxylin and eosin (HE) and Nissl staining, immunohistochemistry and immunofluorescence, western blotting, cell viability, and Annexin V/7-aminoactinomycin D (7-AAD) assays were used to evaluate locomotor activity, histological changes in the injured spinal cords, neuronal ferroptosis, ferroptosis suppressor protein 1 (FSP1) expression, and cell death, respectively. It was observed that many miRNAs were differentially expressed after SCI, and miR-672-3p, which increased significantly, was selected after cross-referencing with predicted target miRNAs. The luciferase reporter assay demonstrated that miR-672-3p downregulated FSP1, a glutathione-independent ferroptosis suppressor, by binding to its 3 ′ untranslated region. Oxygen and glucose deprivation- (OGD-) treated PC12 and AGE1.HN cells were treated with miR-672-3p mimics or inhibitors in vitro. The effect of miR-672-3p mimics or inhibitor on OGD-PC12/AGE1.HN ferroptosis was evaluated by flow cytometry, immunohistochemistry, immunofluorescence, and western blotting. The miR-672-3p mimics promoted ferroptosis after SCI, whereas the miR-672-3p inhibitor inhibited this process. Rats with SCI treated with miR-672-3p mimics or inhibitor showed similar results in vivo. Furthermore, the ferroptosis-related changes caused by SCI or miR-672-3p were reversed by overexpression of FSP1 lentivirus in vivo and in vitro. These results indicated that sh-miR-672-3p exerted a neural restoration effect in vivo and in vitro by inhibiting ferroptosis via the FSP1 pathway.

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Yadav, Anju, Sridevi Vallabu, Dileep Kumar, Guohua Ding, Douglas N. Charney, Praveen N. Chander e Pravin C. Singhal. "HIVAN phenotype: consequence of epithelial mesenchymal transdifferentiation". American Journal of Physiology-Renal Physiology 298, n. 3 (marzo 2010): F734—F744. http://dx.doi.org/10.1152/ajprenal.00415.2009.

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Human immunodeficiency virus (HIV)-1-associated nephropathy (HIVAN) is characterized by proliferation of glomerular and tubular epithelial cells. We studied the role of epithelial mesenchymal transdifferentiation (EMT) in the development of HIVAN phenotype. Renal cortical sections from six FVB/N (control) and six Tg26 (HIVAN) mice were immunolabeled for PCNA, α-smooth muscle actin (α-SMA), fibroblast-specific protein-1 (FSP1), CD3, and F4/80. Since periglomerular cells (PGCs) and peritubular cells (PTCs) did not show any labeling for CD3 and F4/80 but showed labeling for α-SMA or FSP1, it appears that these were myofibroblasts that migrated from either glomerular or tubular sites, respectively. Occurrence of EMT was also supported by diminished expression of E-cadherin by renal epithelial cells in Tg26 mice. Interestingly, Tg26 mice also showed enhanced renal tissue expression of ZEB2; henceforth, it appears that transcription of molecules required for maintenance of de novo renal epithelial cell phenotype was suppressed. To evaluate the role of ANG II, Tg26 mice in groups of three were administered either normal saline or telmisartan (an AT1 receptor blocker) for 2 wk, followed by evaluation for renal cell EMT. Renal cortical section of Tg26 mice showed a sevenfold increase ( P < 0.001) in parietal epithelial cell (PEC)-PGC and a threefold increase ( P < 0.01) in tubular cell (TC)-PTC proliferation (PCNA-positive cells). Similarly, both PECs-PGCs and TCs-PTCs in Tg26 mice showed enhanced expression of α-SMA and FSP1. Both PECs and podocytes contributed to the glomerular proliferative phenotype, but the contribution of PECs was much greater. Telmisartan-receiving Tg26 mice (TRM) showed attenuated number of proliferating PECs-PGCs and TCs-PTCs compared with saline-receiving Tg26 mice (SRM). Similarly, TRM showed diminished expression of α-SMA and FSP1 by both PECs-PGCs and TCs-PTCs compared with SRM. We conclude that EMT contributes to the manifestation of the proliferative phenotype in HIVAN mice.

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Doll, Sebastian, Florencio Porto Freitas, Ron Shah, Maceler Aldrovandi, Milene Costa da Silva, Irina Ingold, Andrea Goya Grocin et al. "FSP1 is a glutathione-independent ferroptosis suppressor". Nature 575, n. 7784 (21 ottobre 2019): 693–98. http://dx.doi.org/10.1038/s41586-019-1707-0.

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Wei, Xiang, Xin Yi, Xue-Hai Zhu e Ding-Sheng Jiang. "Posttranslational Modifications in Ferroptosis". Oxidative Medicine and Cellular Longevity 2020 (26 novembre 2020): 1–12. http://dx.doi.org/10.1155/2020/8832043.

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Ferroptosis was first coined in 2012 to describe the form of regulated cell death (RCD) characterized by iron-dependent lipid peroxidation. To date, ferroptosis has been implicated in many diseases, such as carcinogenesis, degenerative diseases (e.g., Huntington’s, Alzheimer’s, and Parkinson’s diseases), ischemia-reperfusion injury, and cardiovascular diseases. Previous studies have identified numerous targets involved in ferroptosis; for example, acyl-CoA synthetase long-chain family member 4 (ACSL4) and p53 induce while glutathione peroxidase 4 (GPX4) and apoptosis-inducing factor mitochondria-associated 2 (AIFM2, also known as FSP1) inhibit ferroptosis. At least three major pathways (the glutathione-GPX4, FSP1-coenzyme Q10 (CoQ10), and GTP cyclohydrolase-1- (GCH1-) tetrahydrobiopterin (BH4) pathways) have been identified to participate in ferroptosis regulation. Recent advances have also highlighted the crucial roles of posttranslational modifications (PTMs) of proteins in ferroptosis. Here, we summarize the recently discovered knowledge regarding the mechanisms underlying ferroptosis, particularly the roles of PTMs in ferroptosis regulation.

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Cheng, Hao, Pengfei Wang, Ning Wang, Wenwen Dong, Ziyuan Chen, Mingzhe Wu, Ziwei Wang et al. "Neuroprotection of NRF2 against Ferroptosis after Traumatic Brain Injury in Mice". Antioxidants 12, n. 3 (16 marzo 2023): 731. http://dx.doi.org/10.3390/antiox12030731.

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Ferroptosis and iron-related redox imbalance aggravate traumatic brain injury (TBI) outcomes. NRF2 is the predominant transcription factor regulating oxidative stress and neuroinflammation in TBI, but its role in iron-induced post-TBI damage is unclear. We investigated ferroptotic neuronal damage in the injured cortex and observed neurological deficits post-TBI. These were ameliorated by the iron chelator deferoxamine (DFO) in wild-type mice. In Nrf2-knockout (Nrf2−/−) mice, more sever ferroptosis and neurological deficits were detected. Dimethyl fumarate (DMF)-mediated NRF2 activation alleviated neural dysfunction in TBI mice, partly due to TBI-induced ferroptosis mitigation. Additionally, FTH-FTL and FSP1 protein levels, associated with iron metabolism and the ferroptotic redox balance, were highly NRF2-dependent post-TBI. Thus, NRF2 is neuroprotective against TBI-induced ferroptosis through both the xCT-GPX4- and FTH-FTL-determined free iron level and the FSP1-regulated redox status. This yields insights into the neuroprotective role of NRF2 in TBI-induced neuronal damage and its potential use in TBI treatment.

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Iwano, Masayuki, Yukinari Yamaguchi, Takaaki Iwamoto, Kimihiko Nakatani, Masaru Matsui, Atsushi Kubo, Yasuhiro Akai, Toshio Mori e Yoshihiko Saito. "Urinary FSP1 Is a Biomarker of Crescentic GN". Journal of the American Society of Nephrology 23, n. 2 (17 novembre 2011): 209–14. http://dx.doi.org/10.1681/asn.2011030229.

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Mishima, Eikan, Toshitaka Nakamura, Jiashuo Zheng, Weijia Zhang, André Santos Dias Mourão, Peter Sennhenn e Marcus Conrad. "DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition". Nature 619, n. 7968 (5 luglio 2023): E9—E18. http://dx.doi.org/10.1038/s41586-023-06269-0.

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Deng, Chun, Jin Wang, Youfu Zou, Qianqian Zhao, Jie Feng, Zhou Fu e Chunbao Guo. "Characterization of fibroblasts recruited from bone marrow-derived precursor in neonatal bronchopulmonary dysplasia mice". Journal of Applied Physiology 111, n. 1 (luglio 2011): 285–94. http://dx.doi.org/10.1152/japplphysiol.00201.2010.

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We sought to determine whether the extrapulmonary origin of fibroblasts derived from bone marrow (BM) progenitor cells is essential to lung fibrosis in bronchopulmonary dysplasia (BPD). Neonate mice were durably engrafted with BM isolated from transgenic reporter mice that expressed green fluorescent protein (GFP). Such chimera mice were subjected to 60% O2 exposure for 14 days. A large number of fibroblast-specific protein-1 (FSP1) and GFP-positive fibroblasts were identified in active fibrotic lesions. More surprisingly, however, FSP1+ fibroblasts also arose in considerable numbers from BM-derived alveolar type II cells (AT2) through epithelial-mesenchymal transition (EMT) during lung fibrogenesis. Cultured lung fibroblasts could express the CXC chemokine receptor (CXCR4) and responded chemotactically to their cognate ligand, chemokine (C-X-C motif) ligand 12 (CXCL12), which were elevated in the serum of BPD mice. These data suggest that lung fibroblasts in BPD fibrosis could variably arise from BM progenitor cells. This finding, which suggests the pathophysiological process of fibrosis, could contribute to a therapy for BPD that is characterized by extensive interstitial fibrosis.

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Yang, Kun, Jiaran Shi, Zhujun Hu e Xiaosheng Hu. "The deficiency of miR-214-3p exacerbates cardiac fibrosis via miR-214-3p/NLRC5 axis". Clinical Science 133, n. 17 (settembre 2019): 1845–56. http://dx.doi.org/10.1042/cs20190203.

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Abstract Cardiac fibrosis is a common pathological feature of many cardiovascular diseases. The regulatory mechanisms of miRNAs in cardiac fibrosis are still unknown. Previous studies on miR-214-3p in cardiac fibroblasts reached contradictory conclusions. Thus the role of miR-214-3p in cardiac fibrosis deserves further exploration. Using a combination of in vitro and in vivo studies, we identified miR-214-3p as an important regulator of cardiac fibrosis, and the proliferation and activation of cardiac fibroblasts. We demonstrated that the expression of miR-214-3p is down-regulated in TGF-β1-treated myofibroblasts and transverse aortic constriction (TAC)-induced murine model. Additionally, miR-214-3pflox/flox/FSP1-cre mice and miR-214-3pwt/wt/FSP1-cre mice were subjected to TAC operation or sham operation, and the conditional knockout of miR-214-3p in cardiac fibroblasts aggravates TAC-induced cardiac fibrosis. In vitro, our results indicate that miR-214-3p is an important repressor for fibroblasts proliferation and fibroblast-to-myofibroblast transition by functionally targeting NOD-like receptor family CARD domain containing 5 (NLRC5). In conclusion, our findings show that the deficiency of miR-214-3p exacerbates cardiac fibrosis and reveal a novel miR-214-3p/NLRC5 axis in the regulation of cardiac fibrosis.

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Adamiec-Organisciok, Malgorzata, Magdalena Wegrzyn, Lukasz Cienciala, Damian Sojka, Joanna Nackiewicz e Magdalena Skonieczna. "Compensative Resistance to Erastin-Induced Ferroptosis in GPX4 Knock-Out Mutants in HCT116 Cell Lines". Pharmaceuticals 16, n. 12 (10 dicembre 2023): 1710. http://dx.doi.org/10.3390/ph16121710.

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Ferroptosis results from the accumulation of oxidized and damaged lipids which then leads to programmed cell death. This programmed process is iron-dependent, and as a fundamental biological process, plays a crucial role in tissue homeostasis. The ferroptosis molecular pathway depends on self-regulatory genes: GPX4; TFRC; ACSL4; FSP1; SLC7A11, and PROM2. Some of them were considered here as ferro-sensitive or ferro-resistance markers. We examined the impact of GPX4 gene knock-out, using the CRISPR/Cas-9 technique, on ferroptosis induction in the HCT116 colorectal cancer cell line. The results confirmed that cells lacking the GPX4 gene (GPX4 KO) should be more susceptible to ferroptosis after erastin treatment. However, the decrease in cell viability was not as significant as we initially assumed. Based on the lipid peroxidation markers profile and RT-qPCR gene expression analysis, we revealed the activation of an alternative antioxidant system supporting GPX4 KO cells, mostly for cellular ferroptotic death avoidance. Increased expression of FSP1 and PRDX1 genes in knock-out mutants was associated with their function—recognized here as ferroptosis suppressors. For such reasons, studies on the role of GPX4 and other crucial genes from the ferroptotic pathway should be explored. Despite promising prospects, the utilization of ferroptosis mechanisms in cancer therapy remains at the stage of experimental and in vitro preclinical studies.

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Lemberger, U. J., M. Penz-Österreicher, D. Brenner, M. Trauner e C. H. Österreicher. "P167 LACK OF FSP1/S100A4 ATTENUATES LIVER FIBROSIS IN MICE". Journal of Hepatology 60, n. 1 (aprile 2014): S122. http://dx.doi.org/10.1016/s0168-8278(14)60329-9.

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Zhang, Rui, Yuan Gao, Xiaotong Zhao, Mei Gao, Yanjun Wu, Yingying Han, Yuemei Qiao et al. "FSP1-positive fibroblasts are adipogenic niche and regulate adipose homeostasis". PLOS Biology 16, n. 8 (6 agosto 2018): e2001493. http://dx.doi.org/10.1371/journal.pbio.2001493.

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Yamaki, Shogo, Takuo Omachi, Yuji Kawai e Koji Yamazaki. "Characterization of a novelMorganella morganiibacteriophage FSP1 isolated from river water". FEMS Microbiology Letters 359, n. 2 (28 agosto 2014): 166–72. http://dx.doi.org/10.1111/1574-6968.12560.

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Xavier da Silva, Thamara Nishida, e José Pedro Friedmann Angeli. "Sabotaging the breaks: FSEN1 expands the toolbox of FSP1 inhibitors". Cell Chemical Biology 30, n. 9 (settembre 2023): 1006–8. http://dx.doi.org/10.1016/j.chembiol.2023.08.015.

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Mao, Chao, Xiaoguang Liu, Yuelong Yan, Kellen Olszewski e Boyi Gan. "Reply to: DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition". Nature 619, n. 7968 (5 luglio 2023): E19—E23. http://dx.doi.org/10.1038/s41586-023-06270-7.

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Li, Zihao, Siwen Chen, Haowen Cui, Xiang Li, Dongying Chen, Wenjun Hao, Jianru Wang et al. "Tenascin-C-mediated suppression of extracellular matrix adhesion force promotes entheseal new bone formation through activation of Hippo signalling in ankylosing spondylitis". Annals of the Rheumatic Diseases 80, n. 7 (15 aprile 2021): 891–902. http://dx.doi.org/10.1136/annrheumdis-2021-220002.

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ObjectivesThe aim of this study was to identify the role of tenascin-C (TNC) in entheseal new bone formation and to explore the underlying molecular mechanism.MethodsLigament tissue samples were obtained from patients with ankylosing spondylitis (AS) during surgery. Collagen antibody-induced arthritis and DBA/1 models were established to observe entheseal new bone formation. TNC expression was determined by immunohistochemistry staining. Systemic inhibition or genetic ablation of TNC was performed in animal models. Mechanical properties of extracellular matrix (ECM) were measured by atomic force microscopy. Downstream pathway of TNC was analysed by RNA sequencing and confirmed with pharmacological modulation both in vitro and in vivo. Cellular source of TNC was analysed by single-cell RNA sequencing (scRNA-seq) and confirmed by immunofluorescence staining.ResultsTNC was aberrantly upregulated in ligament and entheseal tissues from patients with AS and animal models. TNC inhibition significantly suppressed entheseal new bone formation. Functional assays revealed that TNC promoted new bone formation by enhancing chondrogenic differentiation during endochondral ossification. Mechanistically, TNC suppressed the adhesion force of ECM, resulting in the activation of downstream Hippo/yes-associated protein signalling, which in turn increased the expression of chondrogenic genes. scRNA-seq and immunofluorescence staining further revealed that TNC was majorly secreted by fibroblast-specific protein-1 (FSP1)+fibroblasts in the entheseal inflammatory microenvironment.ConclusionInflammation-induced aberrant expression of TNC by FSP1+fibroblasts promotes entheseal new bone formation by suppressing ECM adhesion forces and activating Hippo signalling.

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Yuan, Bin, Xu-Dong Zhao, Jun-Da Shen, Shu-Juan Chen, Han-Yu Huang, Xiao-Ming Zhou, Yan-Ling Han, Long-Jiang Zhou, Xiao-Jie Lu e Qi Wu. "Activation of SIRT1 Alleviates Ferroptosis in the Early Brain Injury after Subarachnoid Hemorrhage". Oxidative Medicine and Cellular Longevity 2022 (9 luglio 2022): 1–19. http://dx.doi.org/10.1155/2022/9069825.

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Ferroptosis is a regulated cell death that characterizes the lethal lipid peroxidation and iron overload, which may contribute to early brain injury (EBI) pathogenesis after subarachnoid hemorrhage (SAH). Although Sirtuin 1 (SIRT1), a class III histone deacetylase, has been proved to have endogenous neuroprotective effects on the EBI following SAH, the role of SIRT1 in ferroptosis has not been studied. Hence, we designed the current study to determine the role of ferroptosis in the EBI and explore the correlation between SIRT1 and ferroptosis after SAH. The pathways of ferroptosis were examined after experimental SAH in vivo (prechiasmatic cistern injection mouse model) and in HT-22 cells stimulated by oxyhemoglobin (oxyHb) in vitro. Then, ferrostatin-1 (Fer-1) was used further to determine the role of ferroptosis in EBI. Finally, we explored the correlation between SIRT1 and ferroptosis via regulating the expression of SIRT1 by resveratrol (RSV) and selisistat (SEL). Our results showed that ferroptosis was involved in the pathogenesis of EBI after SAH through multiple pathways, including acyl-CoA synthetase long-chain family member 4 (ACSL4) activation, iron metabolism disturbance, and the downregulation of glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1). Inhibition of ferroptosis by Fer-1 significantly alleviated oxidative stress-mediated brain injury. SIRT1 activation could suppress SAH-induced ferroptosis by upregulating the expression of GPX4 and FSP1. Therefore, ferroptosis could be a potential therapeutic target for SAH, and SIRT1 activation is a promising method to inhibit ferroptosis.

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Bruneval, Patrick, Jerome Rossert e Jean Bariety. "Renewal of FSP1: A marker of fibrogenesis on human renal biopsies". Kidney International 68, n. 3 (settembre 2005): 1366–67. http://dx.doi.org/10.1111/j.1523-1755.2005.00546.x.

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Bersuker, Kirill, Joseph M. Hendricks, Zhipeng Li, Leslie Magtanong, Breanna Ford, Peter H. Tang, Melissa A. Roberts et al. "The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis". Nature 575, n. 7784 (21 ottobre 2019): 688–92. http://dx.doi.org/10.1038/s41586-019-1705-2.

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Hadian, Kamyar. "Ferroptosis Suppressor Protein 1 (FSP1) and Coenzyme Q10 Cooperatively Suppress Ferroptosis". Biochemistry 59, n. 5 (31 gennaio 2020): 637–38. http://dx.doi.org/10.1021/acs.biochem.0c00030.

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Huang, Long Shuang, Tara Sudhadevi, Panfeng Fu, Prasanth-Kumar Punathil-Kannan, David Lenin Ebenezer, Ramaswamy Ramchandran, Vijay Putherickal et al. "Sphingosine Kinase 1/S1P Signaling Contributes to Pulmonary Fibrosis by Activating Hippo/YAP Pathway and Mitochondrial Reactive Oxygen Species in Lung Fibroblasts". International Journal of Molecular Sciences 21, n. 6 (17 marzo 2020): 2064. http://dx.doi.org/10.3390/ijms21062064.

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The sphingosine kinase 1 (SPHK1)/sphingosine–1–phosphate (S1P) signaling axis is emerging as a key player in the development of idiopathic pulmonary fibrosis (IPF) and bleomycin (BLM)-induced lung fibrosis in mice. Recent evidence implicates the involvement of the Hippo/Yes-associated protein (YAP) 1 pathway in lung diseases, including IPF, but its plausible link to the SPHK1/S1P signaling pathway is unclear. Herein, we demonstrate the increased co-localization of YAP1 with the fibroblast marker FSP1 in the lung fibroblasts of BLM-challenged mice, and the genetic deletion of Sphk1 in mouse lung fibroblasts (MLFs) reduced YAP1 localization in fibrotic foci. The PF543 inhibition of SPHK1 activity in mice attenuated YAP1 co-localization with FSP1 in lung fibroblasts. In vitro, TGF-β stimulated YAP1 translocation to the nucleus in primary MLFs, and the deletion of Sphk1 or inhibition with PF543 attenuated TGF-β-mediated YAP1 nuclear localization. Moreover, the PF543 inhibition of SPHK1, or the verteporfin inhibition of YAP1, decreased the TGF-β- or BLM-induced mitochondrial reactive oxygen species (mtROS) in human lung fibroblasts (HLFs) and the expression of fibronectin (FN) and alpha-smooth muscle actin (α-SMA). Furthermore, scavenging mtROS with MitoTEMPO attenuated the TGF-β-induced expression of FN and α-SMA. The addition of the S1P antibody to HLFs reduced TGF-β- or S1P-mediated YAP1 activation, mtROS, and the expression of FN and α-SMA. These results suggest a role for SPHK1/S1P signaling in TGF-β-induced YAP1 activation and mtROS generation, resulting in fibroblast activation, a critical driver of pulmonary fibrosis.

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den Boon, Johan A., Dohun Pyeon, Sophia S. Wang, Mark Horswill, Mark Schiffman, Mark Sherman, Rosemary E. Zuna et al. "Molecular transitions from papillomavirus infection to cervical precancer and cancer: Role of stromal estrogen receptor signaling". Proceedings of the National Academy of Sciences 112, n. 25 (8 giugno 2015): E3255—E3264. http://dx.doi.org/10.1073/pnas.1509322112.

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To study the multistep process of cervical cancer development, we analyzed 128 frozen cervical samples spanning normalcy, increasingly severe cervical intraepithelial neoplasia (CIN1– CIN3), and cervical cancer (CxCa) from multiple perspectives, revealing a cascade of progressive changes. Compared with normal tissue, expression of many DNA replication/repair and cell proliferation genes was increased in CIN1/CIN2 lesions and further sustained in CIN3, consistent with high-risk human papillomavirus (HPV)-induced tumor suppressor inactivation. The CIN3-to-CxCa transition showed metabolic shifts, including decreased expression of mitochondrial electron transport complex components and ribosomal protein genes. Significantly, despite clinical, epidemiological, and animal model results linking estrogen and estrogen receptor alpha (ERα) to CxCa, ERα expression declined >15-fold from normalcy to cancer, showing the strongest inverse correlation of any gene with the increasing expression of p16, a marker for HPV-linked cancers. This drop in ERα in CIN and tumor cells was confirmed at the protein level. However, ERα expression in stromal cells continued throughout CxCa development. Our further studies localized stromal ERα to FSP1+, CD34+, SMA− precursor fibrocytes adjacent to normal and precancerous CIN epithelium, and FSP1−, CD34−, SMA+ activated fibroblasts in CxCas. Moreover, rank correlations with ERα mRNA identified IL-8, CXCL12, CXCL14, their receptors, and other angiogenesis and immune cell infiltration and inflammatory factors as candidates for ERα-induced stroma–tumor signaling pathways. The results indicate that estrogen signaling in cervical cancer has dramatic differences from ERα+ breast cancers, and imply that estrogen signaling increasingly proceeds indirectly through ERα in tumor-associated stromal fibroblasts.

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Davis, Jennifer L., Roman Thaler, Linda Cox, Biancamaria Ricci, Heather M. Zannit, Fei Wan, Roberta Faccio, Amel Dudakovic, Andre J. van Wijnen e Deborah J. Veis. "Constitutive activation of NF-κB inducing kinase (NIK) in the mesenchymal lineage using Osterix (Sp7)- or Fibroblast-specific protein 1 (S100a4)-Cre drives spontaneous soft tissue sarcoma". PLOS ONE 16, n. 7 (22 luglio 2021): e0254426. http://dx.doi.org/10.1371/journal.pone.0254426.

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Aberrant NF-κB signaling fuels tumor growth in multiple human cancer types including both hematologic and solid malignancies. Chronic elevated alternative NF-κB signaling can be modeled in transgenic mice upon activation of a conditional NF-κB-inducing kinase (NIK) allele lacking the regulatory TRAF3 binding domain (NT3). Here, we report that expression of NT3 in the mesenchymal lineage with Osterix (Osx/Sp7)-Cre or Fibroblast-Specific Protein 1 (FSP1)-Cre caused subcutaneous, soft tissue tumors. These tumors displayed significantly shorter latency and a greater multiple incidence rate in Fsp1-Cre;NT3 compared to Osx-Cre;NT3 mice, regardless of sex. Histological assessment revealed poorly differentiated solid tumors with some spindled patterns, as well as robust RelB immunostaining, confirming activation of alternative NF-κB. Even though NT3 expression also occurs in the osteolineage in Osx-Cre;NT3 mice, we observed no bony lesions. The staining profiles and pattern of Cre expression in the two lines pointed to a mesenchymal tumor origin. Immunohistochemistry revealed that these tumors stain strongly for alpha-smooth muscle actin (αSMA), although vimentin staining was uniform only in Osx-Cre;NT3 tumors. Negative CD45 and S100 immunostains precluded hematopoietic and melanocytic origins, respectively, while positive staining for cytokeratin 19 (CK19), typically associated with epithelia, was found in subpopulations of both tumors. Principal component, differential expression, and gene ontology analyses revealed that NT3 tumors are distinct from normal mesenchymal tissues and are enriched for NF-κB related biological processes. We conclude that constitutive activation of the alternative NF-κB pathway in the mesenchymal lineage drives spontaneous sarcoma and provides a novel mouse model for NF-κB related sarcomas.

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Wang, Zhikui, Zhongqi Zhou, Wenjie Ji, Lina Sun, Yulin Man, Jifeng Wang e Hongjuan Zhang. "Silencing of lncRNA 6030408B16RIK prevents ultrafiltration failure in peritoneal dialysis via microRNA-326-3p-mediated WISP2 down-regulation". Biochemical Journal 477, n. 10 (29 maggio 2020): 1907–21. http://dx.doi.org/10.1042/bcj20190877.

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Continuous exposure to peritoneal dialysis (PD) fluid results in peritoneal fibrosis and ultimately causes ultrafiltration failure. Noncoding RNAs, including long noncoding RNAs (lncRNAs) and microRNAs (miRNAs), have been reported to participate in ultrafiltration failure in PD. Therefore, our study aimed to investigate the mechanism of lncRNA 6030408B16RIK in association with miR-326-3p in ultrafiltration failure in PD. Peritoneal tissues were collected from uremic patients with or without PD. A uremic rat model with PD was first established by 5/6 nephrectomy. The relationship between lncRNA 6030408B16RIK, miR-326-3p and WISP2 was identified using luciferase reporter, RNA pull-down and RIP assays. After ectopic expression and depletion treatments in cells, expression of α-SMA, phosphorylated β-catenin, FSP1, E-cadherin and Vimentin was evaluated by RT-qPCR and Western blot analyses, and Collagen III and CD31 expression by immunohistochemistry. Ultrafiltration volume and glucose transport capacity were assessed by the peritoneal equilibration test. Expression of lncRNA 6030408B16RIK and WISP2 was up-regulated and miR-326-3p expression was poor in peritoneal tissues of uremic PD patients and model rats. LncRNA 6030408B16RIK competitively bound to miR-326-3p and then elevated WISP2 expression. Silencing of lncRNA 6030408B16RIK and WISP2 or overexpression of miR-326-3p was shown to decrease the expression of α-SMA, phosphorylated β-catenin, FSP1, Vimentin, Collagen III and CD31, while reducing glucose transport capacity and increasing E-cadherin expression and ultrafiltration volume in uremic PD rats. In summary, lncRNA 6030408B16RIK silencing exerts an anti-fibrotic effect on uremic PD rats with ultrafiltration failure by inactivating the WISP2-dependent Wnt/β-catenin pathway via miR-326-3p.

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Poly, Frédéric, Cheryl Ewing, Scarlett Goon, Thomas E. Hickey, David Rockabrand, Gary Majam, Lanfong Lee, Julie Phan, Nicholas J. Savarino e Patricia Guerry. "Heterogeneity of a Campylobacter jejuni Protein That Is Secreted through the Flagellar Filament". Infection and Immunity 75, n. 8 (21 maggio 2007): 3859–67. http://dx.doi.org/10.1128/iai.00159-07.

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ABSTRACTCj0859c, or FspA, is a small, acidic protein ofCampylobacter jejunithat is expressed by a σ28promoter. Analysis of thefspAgene in 41 isolates ofC. jejunirevealed two overall variants of the predicted protein, FspA1 and FspA2. Secretion of FspA occurs in broth-grown bacteria and requires a minimum flagellar structure. The addition of recombinant FspA2, but not FspA1, to INT407 cells in vitro resulted in a rapid induction of apoptosis. These data define a novelC. jejunivirulence factor, and the observed heterogeneity amongfspAalleles suggests alternate virulence potential among different strains.

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Li, Yilan, Jingru Yan, Heng Sun, Yating Liang, Qianqian Zhao, Shan Yu e Yao Zhang. "Ferroptosis inhibitor alleviates sorafenib-induced cardiotoxicity by attenuating KLF11-mediated FSP1-dependent ferroptosis". International Journal of Biological Sciences 20, n. 7 (2024): 2622–39. http://dx.doi.org/10.7150/ijbs.86479.

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Chen, Yiling, Derek Lee, Misty Shuo Zhang, Jacinth Wing-Sum Cheu e Carmen Chak-Lui Wong. "Abstract 3675: Targeting the mevalonate pathway, a novel anti-ferroptosis pathway, in hepatocellular carcinoma (HCC) treatment". Cancer Research 83, n. 7_Supplement (4 aprile 2023): 3675. http://dx.doi.org/10.1158/1538-7445.am2023-3675.

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Abstract Ferroptosis is a novel immunogenic and regulated cell death caused by iron-dependent lipid peroxidation. Glutathione peroxidase 4(GPX4)/glutathione and ferroptosis suppressor protein 1(FSP1)/Coenzyme Q10(CoQ10) are two major anti-ferroptosis systems that prevent lipid ROS-induced cell death. Our current study unprecedentedly uncovered that the Mevalonate pathway (MVA) protects HCC from ferroptosis by two parallel mechanisms: 1) by providing the lipophilic antioxidant CoQ10 for FSP1; 2) by generating isopentenyl pyrophosphate (IPP), a substrate for Selenocysteine (Sec)-tRNA modification for selenoprotein GPX4 translation. Selenoproteins are a class of proteins composed of selenocysteine, the 21st amino acid not found in the codon table. Selenocysteine is recoded by the stop codon UGA and synthesized on its tRNA. The Sec-tRNA incorporates Sec into selenoproteins such as GPX4. We showed that perturbation of the MVA pathway by genetic knockdown or pharmacologic inhibition repressed CoQ10 synthesis and the translation of selenoproteins, thereby leading to lipid-derived ROS and ferroptotic cell death. Furthermore, we showed that Mevalonate diphosphate decarboxylase (MVD), a MVA enzyme, was a transcriptional target of Nuclear Factor Erythroid 2- related factor 2 (NRF2), a master regulator of oxidative stress response. High expression of MVD was associated with poor prognosis in HCC. Strikingly, MVD inhibitor treatment profoundly suppressed HCC. Reduced tumor size and increased tumor-infiltrated effector T cells and macrophages were found in vivo. To conclude, our study has provided novel mechanistic insight about how NRF2/MVA pathway promotes HCC and suggested that MVD might be a good prognostic indicator and therapeutic target in human HCC. Funding Support: RGC Postdoctoral Fellowship Scheme 2021/22 (Project #102010048) Citation Format: Yiling Chen, Derek Lee, Misty Shuo Zhang, Jacinth Wing-Sum Cheu, Carmen Chak-Lui Wong. Targeting the mevalonate pathway, a novel anti-ferroptosis pathway, in hepatocellular carcinoma (HCC) treatment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3675.

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Anne, Gajanan, Ramesh S, Priyaranjan Sharma, Maruthi Prashanth B H, Aditya Kudva S, K. Prakash, Sandeep Sahu e Nagaraj Bhat. "Enhancing wear resistance of AZ61 alloy through friction stir processing: experimental study and prediction model". Materials Research Express, 20 maggio 2024. http://dx.doi.org/10.1088/2053-1591/ad4e0a.

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Abstract In this study, the friction stir technique is proposed to process AZ61 alloy and artificial neural network is built to predict and compare the experimental wear results. The effects of different processing parameters, including spindle speed (800–1200 rpm), travelling speed (05–15 mm/min), and depth of press (0.8-1.2 mm) on the microstructural evolution, mechanical properties and wear behaviour investigated. The grain size of the FSP1 samples found to be 14 ± 2 µm and shifting of peaks are observed in the X ray diffraction analysis chiefly due to texture development. As the spindle speed, travelling speed increases the surface roughness increases, it is observed that Ra – for FSP1 and FSP9 is found to be 68.4 nm and 116.3 nm respectively. Highest micro-hardness (113.36 Hv) values were observed for FSP1 sample and least is FSP9 sample (79. 51 Hv) and BM sample (65.92 Hv). Due to increased heat input into the processed regime, the hardness decreased as rotational and traveling speed increased, resulting in the development of coarse microstructure and a reduction in hardness. Based on wear results it has been observed that specimen FSP1 sample (0.003 g and 0.28) had the lowest weight loss and COF values compared to other FSP conditions. This is due to the combination of process parameters resulted in sufficient heat generation, grain refinement, and strain hardening of the stir zone, which enhanced the wear resistance of the specimen. Coefficient of friction is reduced to 0.28 from 0.68, and weight loss has been reduced to about 58% as compared to BM sample. This work shows that enhancing the wear resistance of magnesium alloys using friction stir processing is a successful approach.

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Nakamura, Toshitaka, Clara Hipp, André Santos Dias Mourão, Jan Borggräfe, Maceler Aldrovandi, Bernhard Henkelmann, Jonas Wanninger et al. "Phase separation of FSP1 promotes ferroptosis". Nature, 28 giugno 2023. http://dx.doi.org/10.1038/s41586-023-06255-6.

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AbstractFerroptosis is evolving as a highly promising approach to combat difficult-to-treat tumour entities including therapy-refractory and dedifferentiating cancers1–3. Recently, ferroptosis suppressor protein-1 (FSP1), along with extramitochondrial ubiquinone or exogenous vitamin K and NAD(P)H/H+ as an electron donor, has been identified as the second ferroptosis-suppressing system, which efficiently prevents lipid peroxidation independently of the cyst(e)ine–glutathione (GSH)–glutathione peroxidase 4 (GPX4) axis4–6. To develop FSP1 inhibitors as next-generation therapeutic ferroptosis inducers, here we performed a small molecule library screen and identified the compound class of 3-phenylquinazolinones (represented by icFSP1) as potent FSP1 inhibitors. We show that icFSP1, unlike iFSP1, the first described on-target FSP1 inhibitor5, does not competitively inhibit FSP1 enzyme activity, but instead triggers subcellular relocalization of FSP1 from the membrane and FSP1 condensation before ferroptosis induction, in synergism with GPX4 inhibition. icFSP1-induced FSP1 condensates show droplet-like properties consistent with phase separation, an emerging and widespread mechanism to modulate biological activity7. N-terminal myristoylation, distinct amino acid residues and intrinsically disordered, low-complexity regions in FSP1 were identified to be essential for FSP1-dependent phase separation in cells and in vitro. We further demonstrate that icFSP1 impairs tumour growth and induces FSP1 condensates in tumours in vivo. Hence, our results suggest that icFSP1 exhibits a unique mechanism of action and synergizes with ferroptosis-inducing agents to potentiate the ferroptotic cell death response, thus providing a rationale for targeting FSP1-dependent phase separation as an efficient anti-cancer therapy.

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Miyauchi, Wataru, Yuji Shishido, Yoshiaki Matsumi, Tomoyuki Matsunaga, Masahiro Makinoya, Shota Shimizu, Kozo Miyatani et al. "Simultaneous regulation of ferroptosis suppressor protein 1 and glutathione peroxidase 4 as a new therapeutic strategy of ferroptosis for esophageal squamous cell carcinoma". Esophagus, 28 dicembre 2022. http://dx.doi.org/10.1007/s10388-022-00982-x.

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Abstract Background Ferroptosis suppressor protein 1 and glutathione peroxidase 4 have been identified as key molecules in two independent pathways associated with ferroptosis inhibition. This study investigated the prognostic significance and clinical associations of FSP1 and GPX4 expression in esophageal squamous cell carcinoma (ESCC) and assessed the therapeutic potential of regulating these molecules in ESCC cells. Methods Immunohistochemical analysis was performed on surgical specimens of 97 patients with ESCC for FSP1 and GPX4 expression. To identify the change in ESCC cell viability, FSP1 and GPX4 inhibitors were administered to three cell lines. In addition, ferroptosis as the cause of reduced cell viability by FSP1 and GPX4 inhibition was confirmed. Results Prognosis was significantly worse for patients in the group positive for both FSP1 and GPX4 compared with the other groups (p < 0.001). In multivariate analysis, positivity for both FSP1 and GPX4 was an independent poor prognostic factor (p = 0.002). The combination of FSP1 and GPX4 inhibitors induced cell death more potently than each inhibitor did alone. Furthermore, the ferroptosis inhibitor markedly canceled this cell death. Conclusions Overexpression of FSP1 and GPX4 is a poor prognostic factor for patients with ESCC. Simultaneous suppression of both FSP1 and GPX4 caused potent cell death, which was markedly abrogated by ferroptosis inhibitors. These findings indicate that simultaneous regulation of FSP1 and GPX4 may be a new therapeutic target in ESCC.

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Liu, Man-ru, Ce Shi, Qiu-ya Song, Meng-jie Kang, Xin Jiang, Hui Liu e Dong-sheng Pei. "Sorafenib induces ferroptosis by promoting TRIM54-mediated FSP1 ubiquitination and degradation in hepatocellular carcinoma". Hepatology Communications 7, n. 10 (11 settembre 2023). http://dx.doi.org/10.1097/hc9.0000000000000246.

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Background: Ferroptosis is a unique form of regulated cell death that provided a new opportunity for cancer therapy. Ferroptosis suppressor protein 1 (FSP1) is a key regulator in the NAD(P)H/FSP1/CoQ10 antioxidant system, which sever as an oxide redox enzyme to scavenge harmful lipid hydroperoxides and escape from ferroptosis in cells. This study aimed to investigate the role of FSP1 on sorafenib-induced ferroptosis and disclosed the underlying mechanisms. Methods: Cell viability, malondialdehyde (MDA), glutathione (GSH), and lipid reactive oxygen species levels were assessed using indicated assay kits. The levels of FSP1 and glutathione peroxidase 4 (GPX4) in the patients with HCC were analyzed based on the database. Western blot and quantitative real-time PCR were performed to detect the protein and mRNA expression. Co-immunoprecipitation was applied to detect the interaction between proteins. Tumor xenograft experiments were used to evaluate whether overexpression of FSP1-inhibited sorafenib-induced ferroptosis in vivo. Results: We verified that sorafenib-induced ferroptosis in HCC. Furthermore, we found that sorafenib decreased the protein level of FSP1, and knockdown FSP1 rendered HCC cells susceptible to sorafenib-induced ferroptosis. Co-immunoprecipitation and ubiquitination assays showed that sorafenib accelerated the TRIM54-mediated FSP1 ubiquitination and degradation. Sorafenib-induced ferroptosis was abrogated by TRIM54 suppression. Mechanically, sorafenib-promoted TRIM54 ubiquitinated and degraded FSP1 by means of the ERK pathway. Moreover, FSP1 enhanced tumor development and decreased HCC cellular susceptibility to sorafenib in vivo. Conclusions: Sorafenib facilitated the TRIM54-mediated FSP1 ubiquitination through the ERK pathway, thereby inducing ferroptosis in HCC cells.

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Takahashi, Naoki, Seiji Yokoi, Hideki Kimura, Hironobu Naiki, Taiji Matsusaka, Yasuhiko Yamamoto, Kimihiko Nakatani, Kenji Kasuno e Masayuki Iwano. "Renoprotective effects of extracellular fibroblast specific protein 1 via nuclear factor erythroid 2-related factor-mediated antioxidant activity". Scientific Reports 13, n. 1 (18 dicembre 2023). http://dx.doi.org/10.1038/s41598-023-49863-y.

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AbstractPodocyte expression of fibroblast specific protein 1 (FSP1) is observed in various types of human glomerulonephritis. Considering that FSP1 is secreted extracellularly and has been shown to have multiple biological effects on distant cells, we postulated that secreted FSP1 from podocytes might impact renal tubules. Our RNA microarray analysis in a tubular epithelial cell line (mProx) revealed that FSP1 induced the expression of heme oxygenase 1, sequestosome 1, solute carrier family 7, member 11, and cystathionine gamma-lyase, all of which are associated with nuclear factor erythroid 2-related factor (Nrf2) activation. Therefore, FSP1 is likely to exert cytoprotective effects through Nrf2-induced antioxidant activity. Moreover, in mProx, FSP1 facilitated Nrf2 translocation to the nucleus, increased levels of reduced glutathione, inhibited the production of reactive oxygen species (ROS), and reduced cisplatin-induced cell death. FSP1 also ameliorated acute tubular injury in mice with cisplatin nephrotoxicity, which is a representative model of ROS-mediated tissue injury. Similarly, in transgenic mice that express FSP1 specifically in podocytes, tubular injury associated with cisplatin nephrotoxicity was also mitigated. Extracellular FSP1 secreted from podocytes acts on downstream tubular cells, exerting renoprotective effects through Nrf2-mediated antioxidant activity. Consequently, podocytes and tubular epithelial cells have a remote communication network to limit injury.

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Lv, Yun, Chunhui Liang, Qichao Sun, Jing Zhu, Haiyan Xu, Xiaoqing Li, Yao-yao Li et al. "Structural insights into FSP1 catalysis and ferroptosis inhibition". Nature Communications 14, n. 1 (22 settembre 2023). http://dx.doi.org/10.1038/s41467-023-41626-7.

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AbstractFerroptosis suppressor protein 1 (FSP1, also known as AIMF2, AMID or PRG3) is a recently identified glutathione-independent ferroptosis suppressor1–3, but its underlying structural mechanism remains unknown. Here we report the crystal structures of Gallus gallus FSP1 in its substrate-free and ubiquinone-bound forms. The structures reveal a FAD-binding domain and a NAD(P)H-binding domain, both of which are shared with AIF and NADH oxidoreductases4–9, and a characteristic carboxy-terminal domain as well. We demonstrate that the carboxy-terminal domain is crucial for the catalytic activity and ferroptosis inhibition of FSP1 by mediating the functional dimerization of FSP1, and the formation of two active sites located on two sides of FAD, which are responsible for ubiquinone reduction and a unique FAD hydroxylation respectively. We also identify that FSP1 can catalyze the production of H2O2 and the conversion of FAD to 6-hydroxy-FAD in the presence of oxygen and NAD(P)H in vitro, and 6-hydroxy-FAD directly inhibits ferroptosis in cells. Together, these findings further our understanding on the catalytic and ferroptosis suppression mechanisms of FSP1 and establish 6-hydroxy-FAD as an active cofactor in FSP1 and a potent radical-trapping antioxidant in ferroptosis inhibition.

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Müller, Fabienne, Jonathan K. M. Lim, Christina M. Bebber, Eric Seidel, Sofya Tishina, Alina Dahlhaus, Jenny Stroh et al. "Elevated FSP1 protects KRAS-mutated cells from ferroptosis during tumor initiation". Cell Death & Differentiation, 29 novembre 2022. http://dx.doi.org/10.1038/s41418-022-01096-8.

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AbstractOncogenic KRAS is the key driver oncogene for several of the most aggressive human cancers. One key feature of oncogenic KRAS expression is an early increase in cellular reactive oxygen species (ROS) which promotes cellular transformation if cells manage to escape cell death, mechanisms of which remain incompletely understood. Here, we identify that expression of oncogenic as compared to WT KRAS in isogenic cellular systems renders cells more resistant to ferroptosis, a recently described type of regulated necrosis. Mechanistically, we find that cells with mutant KRAS show a specific lack of ferroptosis-induced lipid peroxidation. Interestingly, KRAS-mutant cells upregulate expression of ferroptosis suppressor protein 1 (FSP1). Indeed, elevated levels of FSP1 in KRAS-mutant cells are responsible for mediating ferroptosis resistance and FSP1 is upregulated as a consequence of MAPK and NRF2 pathway activation downstream of KRAS. Strikingly, FSP1 activity promotes cellular transformation in soft agar and its overexpression is sufficient to promote spheroid growth in 3D in KRAS WT cells. Moreover, FSP1 expression and its activity in ferroptosis inhibition accelerates tumor onset of KRAS WT cells in the absence of oncogenic KRAS in vivo. Consequently, we find that pharmacological induction of ferroptosis in pancreatic organoids derived from the LsL-KRASG12D expressing mouse model is only effective in combination with FSP1 inhibition. Lastly, FSP1 is upregulated in non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) as compared to the respective normal tissue of origin and correlates with NRF2 expression in PDAC patient datasets. Based on these data, we propose that KRAS-mutant cells must navigate a ferroptosis checkpoint by upregulating FSP1 during tumor establishment. Consequently, ferroptosis-inducing therapy should be combined with FSP1 inhibitors for efficient therapy of KRAS-mutant cancers.

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Kim, Jong Woo, Min-Ju Kim, Tae-Hee Han, Ji-Yoon Lee, Sangok Kim, Hyerin Kim, Kyoung-Jin Oh et al. "FSP1 confers ferroptosis resistance in KEAP1 mutant non-small cell lung carcinoma in NRF2-dependent and -independent manner". Cell Death & Disease 14, n. 8 (26 agosto 2023). http://dx.doi.org/10.1038/s41419-023-06070-x.

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AbstractFerroptosis, a type of cell death induced by lipid peroxidation, has emerged as a novel anti-cancer strategy. Cancer cells frequently acquire resistance to ferroptosis. However, the underlying mechanisms are poorly understood. To address this issue, we conducted a thorough investigation of the genomic and transcriptomic data derived from hundreds of human cancer cell lines and primary tissue samples, with a particular focus on non-small cell lung carcinoma (NSCLC). It was observed that mutations in Kelch-like ECH-associated protein 1 (KEAP1) and subsequent nuclear factor erythroid 2-related factor 2 (NRF2, also known as NFE2L2) activation are strongly associated with ferroptosis resistance in NSCLC. Additionally, AIFM2 gene, which encodes ferroptosis suppressor protein 1 (FSP1), was identified as the gene most significantly correlated with ferroptosis resistance, followed by multiple NRF2 targets. We found that inhibition of NRF2 alone was not sufficient to reduce FSP1 protein levels and promote ferroptosis, whereas FSP1 inhibition effectively sensitized KEAP1-mutant NSCLC cells to ferroptosis. Furthermore, we found that combined inhibition of FSP1 and NRF2 induced ferroptosis more intensely. Our findings imply that FSP1 is a crucial suppressor of ferroptosis whose expression is partially dependent on NRF2 and that synergistically targeting both FSP1 and NRF2 may be a promising strategy for overcoming ferroptosis resistance in cancer.

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