bioRxiv - Pharmacology and Toxicology最新文献_第6页

Proteochemometric modeling strengthens the role of Q299 for GABA transporter subtype selectivity 蛋白化学计量模型强化了 Q299 在 GABA 转运体亚型选择性中的作用

bioRxiv - Pharmacology and Toxicology Pub Date : 2024-08-16 DOI: 10.1101/2024.08.13.607728

Stefanie Kickinger, Anna Seiler, Daniela Digles, Gerhard F Ecker

{"title":"Proteochemometric modeling strengthens the role of Q299 for GABA transporter subtype selectivity","authors":"Stefanie Kickinger, Anna Seiler, Daniela Digles, Gerhard F Ecker","doi":"10.1101/2024.08.13.607728","DOIUrl":"https://doi.org/10.1101/2024.08.13.607728","url":null,"abstract":"Proteochemometric modeling (PCM) combines ligand information as well as target information in order to predict an output variable of interest (e.g. activity of a compound). The big advantage of PCM compared to conventional Quantitative Structure-Activity Relationship (QSAR) modeling is, that by creating a single model one can not only predict the affinity of a diverse set of compounds to a diverse set of targets, but also extrapolate the specific ligand-protein interactions that might be relevant for activity. In this study, we compiled a dataset of 323 compounds and their bioactivity data regarding the inhibition of the four GABA-transporter (GAT1/BGT1/GAT2/GAT3) subtypes, which are potential new drug targets for treating epilepsy. Proteochemometric modeling using partial least squares and random forest provided models which performed equally well than conventional QSAR models for each individual transporter. However, by analyzing the importance of the protein descriptors used in the PCM models, we identified the amino acid Leu300/Q299/L294/L314/ in GAT1/BGT1/GAT2/GAT3 to be relevant for binding and subtype selectivity.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"58 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142184301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Low doses of the food contaminant Deoxynivalenol trigger apoptosis and alter GnRH stimulation of gonadotroph cells 低剂量的食品污染物脱氧雪腐镰刀菌烯醇会引发细胞凋亡并改变促性腺激素对促性腺激素细胞的刺激作用

bioRxiv - Pharmacology and Toxicology Pub Date : 2024-08-16 DOI: 10.1101/2024.08.13.607800

Guodong Cai, Lingchen Yang, Francis Marien-Bourgeois, Derek Boerboom, Gustavo Zamberlam, Imourana Alassane-Kpembi

{"title":"Low doses of the food contaminant Deoxynivalenol trigger apoptosis and alter GnRH stimulation of gonadotroph cells","authors":"Guodong Cai, Lingchen Yang, Francis Marien-Bourgeois, Derek Boerboom, Gustavo Zamberlam, Imourana Alassane-Kpembi","doi":"10.1101/2024.08.13.607800","DOIUrl":"https://doi.org/10.1101/2024.08.13.607800","url":null,"abstract":"The Fusarium mycotoxin Deoxynivalenol (DON) represents a significant threat to both human and animal health. It can cross the blood-brain barrier and disrupt cerebral functions. One of the main mechanisms underlying DON toxicity involves the activation of mitogen-activated protein kinases (MAPKs). Gonadotropin-Releasing Hormone (GnRH) stimulation of pituitary gonadotroph cells to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH) triggers the MAPKs pathway too. Yet, no research investigated the endocrine-disrupting effects of DON on pituitary gonadotropins. To address this gap, our study investigated the effects of DON on gonadotroph cell viability, and its impact on the GnRH-stimulated secretion of FSH and LH, using the murine gonadotroph LβT2 cells. Our results uncovered that low-dose exposure to DON (1nM) significantly impairs viability in gonadotroph cells at both 24 and 48 h. Moreover, exposure to DON shows to induce membrane phosphatidylserine translocation without loss of membrane integrity, supporting a DON-induced cytotoxicity through apoptosis initiation. Furthermore, DON specifically inhibits GnRH-induced Erk phosphorylation, while leaving p38 unaffected. Subsequent experiments with DON-treated LβT2 cells stimulated with GnRH showed a dose-dependent reduction in gene expression associated Gonadotropin-Releasing Hormone receptor (GnRHr), Luteinizing Hormone subunit beta (LHβ), and Glycoprotein Hormones, alpha subunit (Cgα), along with a reduction in LH production. Our findings underscore the induction of DON cytotoxicity through active apoptosis and its impact on LH secretion by inhibiting Erk phosphorylation within the MAPKs pathway. This research contributes to a better understanding of the neurotoxic effects of DON and establishes a foundation for further studies exploring the neuroendocrine impact of mycotoxins.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142184302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development of a preclinical screening platform for clinically relevant therapy of Dravet syndrome 开发临床前筛查平台，用于临床相关的德拉韦特综合征治疗

bioRxiv - Pharmacology and Toxicology Pub Date : 2024-08-16 DOI: 10.1101/2024.08.13.607806

Jeffrey Amoako Mensah, Kyle E. Thomson, Jennifer L. Huff, Tia Freeman, Christopher A Reilly, Joseph E. Rower, Cameron S Metcalf, Karen S Wilcox

{"title":"Development of a preclinical screening platform for clinically relevant therapy of Dravet syndrome","authors":"Jeffrey Amoako Mensah, Kyle E. Thomson, Jennifer L. Huff, Tia Freeman, Christopher A Reilly, Joseph E. Rower, Cameron S Metcalf, Karen S Wilcox","doi":"10.1101/2024.08.13.607806","DOIUrl":"https://doi.org/10.1101/2024.08.13.607806","url":null,"abstract":"Background: Patients with drug-resistant epilepsy, including Dravet syndrome (DS), are frequently prescribed multiple antiseizure medications (ASMs). Nevertheless, people with DS often have inadequate seizure control, and there is an ongoing unmet clinical need to identify novel therapeutics. As a proof-of-principle study to further validate and characterize the Scn1aA1783V/WT mouse model and identify a drug screening paradigm with face, construct, and predictive value, we assessed the efficacy of subchronic administration of stiripentol add-on to clobazam and valproic acid at clinically relevant doses using the Scn1aA1783V/WT mouse model. Methods: We evaluated the efficacy of STP add-on to CLB and VPA using hyperthermia-induced and video-EEG monitoring of spontaneous seizure tests following a 14-day treatment. VPA was delivered via osmotic minipump, while STP and CLB were administered via food pellets delivered through automatic feeders. Bioanalytical assays were performed to evaluate drug concentrations in plasma and brain using liquid chromatography-tandem mass spectrometry. Results: STP, CLB, N-desmethylclobazam, and VPA all yielded plasma concentrations within the human therapeutic plasma concentrations range. STP added to CLB and VPA significantly elevated the seizing temperatures in the hyperthermia-induced seizure assay. CLB, VPA, and STP coadministration significantly reduced spontaneous seizure frequency compared to CLB and VPA combined. Significance: This research lays the groundwork for exploring effective add-on compounds to CLB and VPA in treating DS. The study further highlights the utility of the Scn1aA1783V/WT mice in discovering therapies for DS-associated pharmacoresistant seizures.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142184300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Protamine Protects Against Vancomycin Induced Kidney Injury 质胺能防止万古霉素引起的肾损伤

bioRxiv - Pharmacology and Toxicology Pub Date : 2024-08-15 DOI: 10.1101/2024.08.12.607677

Justin Shiau, Patti Engel, Mark Olsen, Gwendolyn Pais, Jack Chang, Marc H. Scheetz

{"title":"Protamine Protects Against Vancomycin Induced Kidney Injury","authors":"Justin Shiau, Patti Engel, Mark Olsen, Gwendolyn Pais, Jack Chang, Marc H. Scheetz","doi":"10.1101/2024.08.12.607677","DOIUrl":"https://doi.org/10.1101/2024.08.12.607677","url":null,"abstract":"Introduction: Vancomycin causes kidney injury by accumulating in the proximal tubule, likely mediated by megalin uptake. Protamine is a putative megalin inhibitor that shares binding sites with heparin and is approved for heparin overdose in patients. Methods: We employed a well characterized Sprague Dawley rat model to assess kidney injury and function in animals that received vancomycin, protamine alone, or vancomycin plus protamine over 5 days. Urinary KIM-1 was used as the primary measure for kidney injury while iohexol clearance was calculated to assess kidney function. Animals had samples drawn pre-treatment to serve as their own controls. Additionally, since protamine is not a known nephrotoxin, the protamine group also served as a control. Cellular inhibition studies were performed to assess the ability of protamine to inhibit OAT1, OAT3, and OCT2. Results: Rats that received vancomycin had significantly increased urinary KIM-1 on day 2 (24.9 ng/24h, 95% CI 1.87 to 48.0) compared to the protamine alone group. By day 4, animals that received protamine with vancomycin had urinary KIM-1 amounts that were elevated compared to protamine alone (KIM-1 29.0 ng/24h, 95% CI 5.0 to 53.0). No statistically significant differences were identified for iohexol clearance changes between drug groups or when comparing clearance change from baseline (P>0.05). No substantial inhibition of OAT1, OAT3, or OCT2 was observed with protamine. IC50 values for protamine were 1e-4 M for OAT1 and OAT3 and 4.3e-5 M for OCT2. Conclusion: Protamine, when added to vancomycin therapy, delays vancomycin induced kidney injury as defined by urinary KIM-1 in the rat model by one to three days. Protamine putatively acts through blockade of megalin and does not appear to have significant inhibition on OAT1, OAT3, or OCT2. Since protamine is an approved FDA medication, it has clinical potential as a therapeutic to reduce vancomycin related kidney injury; however, greater utility may be found by pursuing compounds with fewer adverse event liabilities.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142184334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A hollow fiber membrane-based liver organoid-on-a-chip model for examining drug metabolism and transport 基于中空纤维膜的肝脏片上类器官模型，用于检测药物代谢和转运

bioRxiv - Pharmacology and Toxicology Pub Date : 2024-08-15 DOI: 10.1101/2024.08.12.607504

Adam Myszczyszyn, Anna Muench, Vivian Lehmann, Theo Sinnige, Frank G. van Steenbeek, Manon Bouwmeester, Roos-Anne Samsom, Marit Keuper-Navis, Thomas K. van der Made, Daniel Kogan, Sarah Braem, Luc J. W. van der Laan, Hossein Eslami Amirabadi, Evita van de Steeg, Rosalinde Masereeuw, Bart Spee

{"title":"A hollow fiber membrane-based liver organoid-on-a-chip model for examining drug metabolism and transport","authors":"Adam Myszczyszyn, Anna Muench, Vivian Lehmann, Theo Sinnige, Frank G. van Steenbeek, Manon Bouwmeester, Roos-Anne Samsom, Marit Keuper-Navis, Thomas K. van der Made, Daniel Kogan, Sarah Braem, Luc J. W. van der Laan, Hossein Eslami Amirabadi, Evita van de Steeg, Rosalinde Masereeuw, Bart Spee","doi":"10.1101/2024.08.12.607504","DOIUrl":"https://doi.org/10.1101/2024.08.12.607504","url":null,"abstract":"Liver-on-a-chip models predictive for both metabolism as well as canalicular and blood transport of drug candidates in humans are lacking. Here, we established an advanced, bioengineered and animal component-free hepatocyte-like millifluidic system based on 3D hollow fiber membranes (HFMs), recombinant human laminin 332 coating and adult human stem cell-derived organoids. Organoid fragments formed polarized and tight monolayers on HFMs with improved hepatocyte-like maturation, as compared to standard 3D organoid cultures in Matrigel from matched donors. Gene expression profiling and immunofluorescence revealed that hepatocyte-like monolayers expressed a broad panel of phase I (e.g., CYP3A4, CYP2D6) and II (UGTs, SULTs) drug-metabolizing enzymes and drug transporters (e.g., OATP1B3, MDR1 and MRP3). Moreover, statically cultured monolayers displayed phase I and II metabolism of a cocktail of six relevant compounds, including midazolam and 7-hydroxycoumarin. We also demonstrated the disposition of midazolam in the basal/blood-like circulation and apical/canalicular-like compartment of the millifluidic chip. Finally, we connected the system to the other two PK/ADME-most relevant organ systems, i.e. small intestine- and kidney proximal tubule-like to study the bioavailability of midazolam and coumarin, and excretion of metformin. In conclusion, we generated a proof-of-concept liver organoid-on-a-chip model for examining metabolism and transport of drugs, which can be further developed to predict PK/ADME profiles in humans.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142184303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Celastrol binds to pyruvate kinase and imitates the metabolic reprogramming of ATP Celastrol 可与丙酮酸激酶结合，并模仿 ATP 的代谢重构过程

bioRxiv - Pharmacology and Toxicology Pub Date : 2024-08-10 DOI: 10.1101/2024.08.09.607407

Xuan Zhang, Xudong Jiang, Xiaobin Wu, Youhao Yang, Jintian Wang, Junfeng Zheng, Miao Zhou, Chen Qian

引用次数: 0

Qing-Luo-Yin eases angiogenesis in adjuvant-induced arthritis rats by activating PPARγ 清络饮通过激活 PPARγ 缓解佐剂诱导性关节炎大鼠的血管生成

bioRxiv - Pharmacology and Toxicology Pub Date : 2024-08-10 DOI: 10.1101/2024.08.01.606254

jian zuo, Zhe Yang

{"title":"Qing-Luo-Yin eases angiogenesis in adjuvant-induced arthritis rats by activating PPARγ","authors":"jian zuo, Zhe Yang","doi":"10.1101/2024.08.01.606254","DOIUrl":"https://doi.org/10.1101/2024.08.01.606254","url":null,"abstract":"Objective: Qing-Luo-Yin (QLY) is an anti-rheumatic herbal formula with potentials activating PPARγ. This study investigated if its anti-angiogenesis effects are related to immune modulation. Method: Adjuvant-induced arthritis (AIA) rats were orally treated by QLY or rosiglitazone (a PPARγ agonist) for 30 days. Their immune and metabolism statues were investigated afterward. Isolated monocytes and lymphocytes were co-cultured reciprocally, and treated by different serums. Healthy rats received blood transfusion from QLY-treated or AIA model rats. Two days ahead of sacrifice, a matrigel plug was planted. The plug and some blood immune indicators were examined. AIA rat serum-incubated THP-1 and Jurkat cells were treated by sinomenine, berberine and palmatine. The medium and T0070907 (a PPARγ inhibitor) were used to stimulate HUVEC cells. Results: QLY showed similar therapeutic effects on AIA to rosiglitazone, alleviating joint injuries, synovial angiogenesis, and metabolic disorders. Although QLY impaired inflammatory phenotype of AIA monocytes in vivo, the effect was hardly achieved or sustained in vitro. T cells from QLY-treated AIA rats showed the weakened inflammatory phenotype, and were unable to induce monocytes inflammatory polarization. AIA rat lymphocytes induced angiogenesis in the matrigel plug in healthy recipients. In lymphocytes enrichment site, QLY reduced the secretion of IL-17A, IFNγ, and many angiogenesis-related cytokines. QLY-related components affected Jurkat but not THP-1 cells. Jurkat T cells induced angiogenesis of HUVEC cells when cultured by AIA rat serum. Inhibitory effects of the compounds on it were abolished by T0070907. Conclusion: PPARγ activation in T cells is a foundation for the anti-angiogenesis property of QLY.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"85 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141933278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Multi-Coloured Sequential Resonance Energy Transfer for Simultaneous Ligand Binding at G Protein-Coupled Receptors 在 G 蛋白偶联受体上同时进行配体结合的多色序列共振能量转移

bioRxiv - Pharmacology and Toxicology Pub Date : 2024-08-09 DOI: 10.1101/2024.08.07.606978

Alice Valentini, Bethany Dibnah, Marija Ciba, Trond Ulven, Brian D Hudson, Elisabeth Rexen Ulven

引用次数: 0

Caution when using network partners for target identification in drug discovery 在药物发现中使用网络伙伴进行靶点识别时要谨慎

bioRxiv - Pharmacology and Toxicology Pub Date : 2024-08-09 DOI: 10.1101/2024.08.08.607024

Dandan Tan, Yiheng Chen, Yann Ilboudo, Kevin Y.H. Liang, Guillaume Butler-Laporte, J Brent Richards

{"title":"Caution when using network partners for target identification in drug discovery","authors":"Dandan Tan, Yiheng Chen, Yann Ilboudo, Kevin Y.H. Liang, Guillaume Butler-Laporte, J Brent Richards","doi":"10.1101/2024.08.08.607024","DOIUrl":"https://doi.org/10.1101/2024.08.08.607024","url":null,"abstract":"Identifying novel, high-yield drug targets is challenging and often results in a high failure rate. However, recent data indicates that leveraging human genetic evidence to identify and validate these targets significantly increases the likelihood of success in drug development. Two recent papers from Open Targets claimed that around half of FDA-approved drugs had targets with direct human genetic evidence. By expanding target identification to include protein network partners—molecules in physical contact—the proportion of drug targets with genetic evidence support increased to two-thirds. However, the efficacy of using these network partners for target identification was not formally tested. To address this, we tested the approach on a list of robust positive control genes. We used the IntAct database to find molecular interacting proteins of genes identified by exome-wide association studies (ExWAS) and genome-wide association studies (GWAS) combined with a locus-to-gene mapping algorithm called the Effector Index (Ei). We assessed how accurately including interacting genes with the ExWAS and Effector Index selected genes identified positive controls, focusing on precision, sensitivity, and specificity. Our results indicated that although molecular interactions led to higher sensitivity in identifying positive control genes, their practical application is limited by low precision. Hence, expanding genetically identified targets to include network partners did not increase the chance of identifying drug targets, suggesting that such results should be interpreted with caution.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141933276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DMT1 knockout abolishes ferroptosis induced mitochondrial dysfunction in C. elegans amyloid beta proteotoxicity DMT1 基因敲除可消除优雅鼠淀粉样蛋白 beta 蛋白毒性中铁蛋白沉积诱导的线粒体功能障碍

bioRxiv - Pharmacology and Toxicology Pub Date : 2024-08-09 DOI: 10.1101/2024.08.08.607074

Wilson Peng, Kaitlin B Chung, B. Paige Lawrence, M. Kerry O'Banion, Robert T Dirksen, Andrew P Wojtovich, John O Onukwufor

{"title":"DMT1 knockout abolishes ferroptosis induced mitochondrial dysfunction in C. elegans amyloid beta proteotoxicity","authors":"Wilson Peng, Kaitlin B Chung, B. Paige Lawrence, M. Kerry O'Banion, Robert T Dirksen, Andrew P Wojtovich, John O Onukwufor","doi":"10.1101/2024.08.08.607074","DOIUrl":"https://doi.org/10.1101/2024.08.08.607074","url":null,"abstract":"Iron is critical for neuronal activity and metabolism, and iron dysregulation alters these functions in age-related neurodegenerative disorders, such as Alzheimers disease (AD). AD is a chronic neurodegenerative disease characterized by neuronal dysfunction, memory loss and decreased cognitive function. AD patients exhibit elevated iron levels in the brain compared to age-matched non-AD individuals. However, the degree to which iron overload contributes to AD pathogenesis is unclear. Here, we evaluated the involvement of ferroptosis, an iron-dependent cell death process, in mediating AD-like pathology in C. elegans. Results showed that iron accumulation occurred prior to the loss of neuronal function as worms age. In addition, energetic imbalance was an early event in iron-induced loss of neuronal function. Furthermore, the loss of neuronal function was, in part, due to increased mitochondrial reactive oxygen species mediated oxidative damage, ultimately resulting in ferroptotic cell death. Mitochondrial redox environment and ferroptosis were modulated by pharmacologic processes that exacerbate or abolish iron accumulation both in wild-type worms and worms with increased levels of neuronal amyloid beta. However, neuronal amyloid beta worms were more sensitive to ferroptosis-mediated neuronal loss, and this increased toxicity was ameliorated by limiting the uptake of ferrous iron through knockout of divalent metal transporter 1 (DMT1). In addition, the loss of DMT1 completely suppressed phenotypic measures of amyloid beta toxicity with age. Overall, our findings suggest that iron-induced ferroptosis alters the mitochondrial redox environment to drive oxidative damage when neuronal amyloid beta is overexpressed. DMT1 knockout abolishes neuronal amyloid beta pathology by reducing neuronal iron uptake","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141933277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0