bioRxiv - Pharmacology and Toxicology最新文献_第8页

PARP inhibition enhances exemestane efficacy in triple-negative breast cancer PARP 抑制可增强依西美坦对三阴性乳腺癌的疗效

bioRxiv - Pharmacology and Toxicology Pub Date : 2024-07-31 DOI: 10.1101/2024.07.31.605956

Nur Aininie Yusoh, Liping Su, Suet Lin Chia, Xiaohe Tian, Haslina Ahmad, Martin Gill

{"title":"PARP inhibition enhances exemestane efficacy in triple-negative breast cancer","authors":"Nur Aininie Yusoh, Liping Su, Suet Lin Chia, Xiaohe Tian, Haslina Ahmad, Martin Gill","doi":"10.1101/2024.07.31.605956","DOIUrl":"https://doi.org/10.1101/2024.07.31.605956","url":null,"abstract":"Triple negative breast cancer (TNBC) remains the breast cancer subtype with the poorest prognosis and median survival rate. Targeting PARP1/2 with PARP inhibitors (PARPi) and achieving synthetic lethality is an effective strategy for TNBCs with BRCA1/2 mutations, however, the majority of TNBCs are BRCA1/2 wild type. Synergistic drug combinations with PARPi offers the potential to expand the use of PARPi towards BRCA-proficient cancers, including TNBC. To identify new PARPi combinations, we screened a library of 166 FDA-approved oncology drugs for synergy with the PARPi Olaparib in TNBC cells. We found that Exemestane, an aromatase inhibitor, synergised with Olaparib with a significant decrease in IC50 values and clonogenicity accompanied by elevated DNA damage and apoptosis seen in combination treatment. The mechanistic basis for synergy was rationalised by the previously unreported ability of Exemestane to induce replication stress, as evidenced by ATR pathway activation and RPA foci formation. Low impact of this combination towards normal breast epithelial cells was observed and Exemestane has no reported severe toxicity as a monotherapy. This combination was able to achieve enhanced tumor growth inhibition in a murine xenograft model, greater than either drug employed as a single-agent. GO and KEGG enrichment analysis of differential genes indicated alterations in pathways associated with cell death in response to Exemestane and Olaparib treatment.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"172 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141872767","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

Phosphorylation of Zearalenone retains its toxicity 玉米赤霉烯酮的磷酸化作用可保持其毒性

bioRxiv - Pharmacology and Toxicology Pub Date : 2024-07-31 DOI: 10.1101/2024.07.30.605906

Muhammad Asaduzzaman, Ivan Alexandrovitch Pavlov, Guillaume St-Jean, Yan Zhu, Mathieu Castex, Younes Chorfi, Jerome R E del Castillo, Ting Zhou, Imourana Alassane-Kpembi

{"title":"Phosphorylation of Zearalenone retains its toxicity","authors":"Muhammad Asaduzzaman, Ivan Alexandrovitch Pavlov, Guillaume St-Jean, Yan Zhu, Mathieu Castex, Younes Chorfi, Jerome R E del Castillo, Ting Zhou, Imourana Alassane-Kpembi","doi":"10.1101/2024.07.30.605906","DOIUrl":"https://doi.org/10.1101/2024.07.30.605906","url":null,"abstract":"Microbial biotransformation of Zearalenone (ZEN) is a promising deactivation approach. The residual toxicity and stability of Zearalenone-14-phosphate (ZEN-14-P) and Zearalenone-16-phosphate (ZEN-16-P), two novel microbial phosphorylation products of ZEN, remain unknown. We investigated the cytotoxicity, oxidative stress, pro-inflammatory, and estrogenic activity of phosphorylated ZENs using porcine intestinal cells and uterine explants, and human endometrial cells, and traced their metabolic fate by LC-MS/MS analysis. The phosphorylated ZENs significantly decreased the viability of IPEC-J2 and Ishikawa cells. Similar to ZEN, phosphorylation products induced significant oxidative stress, activated the expression of pro-inflammatory cytokines, and demonstrated estrogenic activity through upregulation of estrogen- responsive genes, activation of alkaline phosphatase and proliferation of endometrial glands. LC-MS/MS analysis pointed that although phosphorylated ZENs are partially hydrolyzed to ZEN, their respective metabolic pathways differ. We conclude that phosphorylation might not be sufficient to detoxify ZEN, leaving its cytotoxic, pro-inflammatory and estrogenic properties intact.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141872766","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

Unlocking the Potential: FKK6 as a Microbial Mimicry Based Therapy for Chronic Inflammation-Associated Colorectal Cancer in a Murine Model 释放潜能：FKK6 作为一种基于微生物模拟的疗法，在小鼠模型中治疗慢性炎症相关性结直肠癌

bioRxiv - Pharmacology and Toxicology Pub Date : 2024-07-30 DOI: 10.1101/2024.07.30.605845

Lucia Sladekova, Hao Li, Vera M. DesMarais, Amanda P. Beck, Hillary Guzik, Barbora Vyhlidalova, Haiwei Gu, Sridhar Mani, Zdenek Dvorak

{"title":"Unlocking the Potential: FKK6 as a Microbial Mimicry Based Therapy for Chronic Inflammation-Associated Colorectal Cancer in a Murine Model","authors":"Lucia Sladekova, Hao Li, Vera M. DesMarais, Amanda P. Beck, Hillary Guzik, Barbora Vyhlidalova, Haiwei Gu, Sridhar Mani, Zdenek Dvorak","doi":"10.1101/2024.07.30.605845","DOIUrl":"https://doi.org/10.1101/2024.07.30.605845","url":null,"abstract":"Chronic intestinal inflammation significantly contributes to the development of colorectal cancer (CRC) and remains a pertinent clinical challenge, necessitating novel therapeutic approaches. Indole-based microbial metabolite mimics FKK6, which is a ligand and agonist of the pregnane X receptor (PXR), was recently demonstrated to have PXR-dependent anti-inflammatory and protective effects in a mouse model of dextran sodium sulfate (DSS)-induced acute colitis. Here, we examined the therapeutic potential of FKK6 in a mouse model (C57BL/6 FVB humanized PXR mice) of colitis-associated colon cancer (CAC) induced by azoxymethane (AOM) and dextran sodium sulfate (DSS). FKK6 (2 mg/kg) displayed substantial anti-tumor activity, as revealed by reduced size and number of colon tumors, improved colon histopathology, and decreased expression of tumor markers (c-MYC, β-catenin, Ki-67, cyclin D) in the colon. In addition, we carried out the chronic toxicity (30 days) assessment of FKK6 (1 mg/kg and 2 mg/kg) in C57BL/6 mice. Histological examination of tissues, biochemical blood analyses, and immunohistochemical staining for Ki-67 and γ-H2AX showed no difference between FKK6-treated and control mice. Comparative metabolomic analyses in mice exposed for 5 days to DSS and administered with FKK6 (0.4 mg/kg) revealed no significant effects on several classes of metabolites in the mouse fecal metabolome. Ames and micronucleus tests showed no genotoxic and mutagenic potential of FKK6 in vitro. In conclusion, anticancer effects of FKK6 in AOM/DSS-induced CAC, together with FKK6 safety data from in vitro tests and in vivo chronic toxicity study, and comparative metabolomic study, are supportive of the potential therapeutic use of FKK6 in the treatment of CAC.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141872641","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

The structural basis for the selective antagonism of soluble TNF-alpha by shark variable new antigen receptors 鲨鱼可变新抗原受体选择性拮抗可溶性 TNF-α 的结构基础

bioRxiv - Pharmacology and Toxicology Pub Date : 2024-07-30 DOI: 10.1101/2024.07.30.605874

Obinna C Ubah, Eric W. Lake, Stella Priyanka, Ke Shi, Nicholas H. Moeller, Andrew J. Porter, Hideki Aihara, Aaron M. LeBeau, Caroline J. Barelle

{"title":"The structural basis for the selective antagonism of soluble TNF-alpha by shark variable new antigen receptors","authors":"Obinna C Ubah, Eric W. Lake, Stella Priyanka, Ke Shi, Nicholas H. Moeller, Andrew J. Porter, Hideki Aihara, Aaron M. LeBeau, Caroline J. Barelle","doi":"10.1101/2024.07.30.605874","DOIUrl":"https://doi.org/10.1101/2024.07.30.605874","url":null,"abstract":"The pro-inflammatory cytokine tumor necrosis factor-alpha (TNF)-α is synthesized as transmembrane TNF-α (tmTNF-α) where proteolytic processing releases soluble TNF-α (sTNF-α). tmTNF-α can act as either a ligand by activating TNF receptors, or a receptor that transmits outside-to-inside signals (reverse signalling) after binding to native receptors. All TNF-α therapies bind tmTNF-α and induce reverse signalling which can result in immunosuppression leading to infection. We present crystal structures of two anti-TNF-α Variable New Antigen Receptors (VNARs) in complex with sTNF-α via two distinct epitopes. The VNAR-D1 recognized an epitope that selectively engaged sTNF-α while VNAR-C4 bound an epitope that overlapped with other biologic therapies. In activated CD4+ T cells, our VNARs did not bind tmTNF-α in contrast to commercially available therapies that demonstrated induction of reverse signalling. Our findings suggest that neutralisation through a unique mechanism may lead to anti-TNF-α agents with an improved safety profile that will benefit high-risk patients.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141872768","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

Exploring potential targets for quercetin treatment of colorectal cancer through network pharmacology and molecular docking technology 通过网络药理学和分子对接技术探索槲皮素治疗结直肠癌的潜在靶点

bioRxiv - Pharmacology and Toxicology Pub Date : 2024-07-30 DOI: 10.1101/2024.07.29.605708

Yuanyuan Qian, Zhaojunli Wang, Jiancheng Ji, Wenlong Fu

引用次数: 0

In-vitro Metabolite Identification for MEDI7219, an Oral GLP-1 Peptide, using LC-MS/MS with CID and EAD Fragmentation 利用带有 CID 和 EAD 片段的 LC-MS/MS 对口服 GLP-1 肽 MEDI7219 进行体外代谢物鉴定

bioRxiv - Pharmacology and Toxicology Pub Date : 2024-07-27 DOI: 10.1101/2024.07.26.605352

Kate Liu, Yue Huang, Taoqing Wang, Ruipeng Mu, Anton I Rosenbaum

{"title":"In-vitro Metabolite Identification for MEDI7219, an Oral GLP-1 Peptide, using LC-MS/MS with CID and EAD Fragmentation","authors":"Kate Liu, Yue Huang, Taoqing Wang, Ruipeng Mu, Anton I Rosenbaum","doi":"10.1101/2024.07.26.605352","DOIUrl":"https://doi.org/10.1101/2024.07.26.605352","url":null,"abstract":"Oral peptide therapeutics typically suffer from short half-lives as they are readily degraded by digestive enzymes. Systematic peptide engineering along with formulation optimization led to the development of a clinical candidate MEDI7219, an orally-bioavailable GLP-1 peptide, that is much more stable than wild type GLP-1 or semaglutide. In this study, we elucidated peptide biotransformation products using in vitro pancreatin assay that employed both collision-induced dissociation (CID) and electron-activated dissociation (EAD) LC-MS/MS methods. Using this approach, we have confidently identified a total of 13 metabolites. Relative quantification of these metabolites over time showed sequential cleavage pattern as peptides were further digested to smaller fragments. These 13 metabolites mapped to 8 cleavage sites on MEDI7219 structure. Most of these cleavage sites can be explained by the specificity of digestive enzymes, e.g. ,trypsin, pepsin and elastase. α-methyl-L-phenylalanine appeared to be well protected from chymotrypsin and pepsin digestion since no cleavage peptides ending with α-methyl-L-phenylalanine were observed. These study results expand upon previously published stability data and provide new insights on potential GLP1 proteolytic liabilities for future engineering. Furthermore, this study exemplifies the application of pancreatin in vitro system methodology as a valuable tool for understanding metabolism of oral peptide therapeutics in vitro. Additionally, orthogonal MS fragmentation modes offered improved confidence in identification for peptide unknown metabolites.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141781667","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

bioRxiv - Pharmacology and Toxicology Pub Date : 2024-07-26 DOI: 10.1101/2024.07.26.605228

David Manuel Schuster, Danielle P M LeBlanc, Gu Zhou, Matt J Meier, Annette E Dodge, Paul A White, Alexandra S Long, Andrew Williams, Cheryl Hobbs, Alex Diesing, Stephanie L. Smith-Roe, Jesse J Salk, Francesco Marchetti, Carole L Yauk

{"title":"Dose-related Mutagenic and Clastogenic Effects of Benzo[b]fluoranthene in Mouse Somatic Tissues Detected by Duplex Sequencing and the Micronucleus Assay","authors":"David Manuel Schuster, Danielle P M LeBlanc, Gu Zhou, Matt J Meier, Annette E Dodge, Paul A White, Alexandra S Long, Andrew Williams, Cheryl Hobbs, Alex Diesing, Stephanie L. Smith-Roe, Jesse J Salk, Francesco Marchetti, Carole L Yauk","doi":"10.1101/2024.07.26.605228","DOIUrl":"https://doi.org/10.1101/2024.07.26.605228","url":null,"abstract":"Polycyclic aromatic hydrocarbons (PAHs) are common environmental pollutants that originate from the incomplete combustion of organic materials. We investigated the clastogenicity and mutagenicity of benzo[b]fluoranthene (BbF), one of 16 priority PAHs, in MutaMouse males after a 28-day oral exposure. BbF causes robust dose-dependent increases in micronucleus frequency in peripheral blood, indicative of chromosome damage. Duplex Sequencing (DS), an error-corrected sequencing technology, reveals that BbF induces dose-dependent increases in mutation frequencies in bone marrow (BM) and liver. Mutagenicity is increased in intergenic relative to genic regions, suggesting a role for transcription-coupled repair of BbF-induced DNA damage. At higher doses, the maximum mutagenic response to BbF is higher in liver, which has a lower mitotic index but higher metabolic capacity than BM; however, mutagenic potency is comparable between the two tissues. BbF induces primarily C:G>A:T mutations, followed by C:G>T:A and C:G>G:C, indicating that BbF metabolites mainly target guanines and cytosines. The mutation spectrum of BbF correlates with cancer mutational signatures associated with tobacco exposure, supporting its contribution to the carcinogenicity of combustion-derived PAHs in humans. Overall, BbF's mutagenic effects are similar to benzo[a]pyrene, a well-studied mutagenic PAH. Our work showcases the utility of DS for effective mutagenicity assessment of environmental pollutants.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"8654 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141781665","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

Differential biotransformation ability may alter fish biodiversity in polluted waters 不同的生物转化能力可能会改变受污染水域的鱼类生物多样性

bioRxiv - Pharmacology and Toxicology Pub Date : 2024-07-26 DOI: 10.1101/2024.07.26.605280

Marco E Franco, Juliane Hollender, Kristin Schirmer

{"title":"Differential biotransformation ability may alter fish biodiversity in polluted waters","authors":"Marco E Franco, Juliane Hollender, Kristin Schirmer","doi":"10.1101/2024.07.26.605280","DOIUrl":"https://doi.org/10.1101/2024.07.26.605280","url":null,"abstract":"Divergence in the activity of biotransformation pathways could lead to species sensitivity differences to chemical stress. To explore this hypothesis, we evaluated the biotransformation capacity of five fish species that are representatives of Swiss biodiversity assemblages and that inhabit watercourses surrounded by different land use. We report important interspecific differences regarding the presence and activity of major biotransformation pathways, such as the invasive pumpinkseed (Lepomis gibbosus) displaying micropollutant clearance between 3- and 7-fold higher than native species (e.g. Salmo trutta, Squalius cephalus) collected in the same areas. These differences were exacerbated by urban and agricultural influence, which increased biotransformation potential at the enzyme level by as much as 11-fold and micropollutant clearance by approximately 2-fold compared to biotransformation levels in areas with minimal human influence. In the context of the chemical defensome, we argue that fish with low biotransformation activity carry a greater burden on chemical stress, making them less likely to cope with additional stressors and sustain their population in competition with species with a higher biotransformation capacity.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"45 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141781700","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

Gz Enhanced Signal Transduction assaY (GZESTY) for GPCR deorphanization 用于 GPCR 非形态化的 Gz Enhanced Signal Transduction assaY (GZESTYY)

bioRxiv - Pharmacology and Toxicology Pub Date : 2024-07-26 DOI: 10.1101/2024.07.26.605282

Luca Franchini, Joseph J Porter, John D Lueck, Cesare Orlandi

{"title":"Gz Enhanced Signal Transduction assaY (GZESTY) for GPCR deorphanization","authors":"Luca Franchini, Joseph J Porter, John D Lueck, Cesare Orlandi","doi":"10.1101/2024.07.26.605282","DOIUrl":"https://doi.org/10.1101/2024.07.26.605282","url":null,"abstract":"G protein-coupled receptors (GPCRs) are key pharmacological targets, yet many remain underutilized due to unknown activation mechanisms and ligands. Orphan GPCRs, lacking identified natural ligands, are a high priority for research, as identifying their ligands will aid in understanding their functions and potential as drug targets. Most GPCRs, including orphans, couple to Gi/o/z family members, however current assays to detect their activation are limited, hindering ligand identification efforts. We introduce GZESTY, a highly sensitive, cell-based assay developed in an easily deliverable format designed to study the pharmacology of Gi/o/z-coupled GPCRs and assist in deorphanization. We optimized assay conditions and developed an all-in-one vector employing novel cloning methods to ensure the correct expression ratio of GZESTY components. GZESTY successfully assessed activation of a library of ligand-activated GPCRs, detecting both full and partial agonism, as well as responses from endogenous GPCRs. Notably, with GZESTY we established the presence of endogenous ligands for GPR176 and GPR37 in brain extracts, validating its use in deorphanization efforts. This assay enhances the ability to find ligands for orphan GPCRs, expanding the toolkit for GPCR pharmacologists.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141781544","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

Compromised chronic efficacy of a Glucokinase Activator AZD1656 in mouse models for common human GCKR variants 葡萄糖激酶激活剂 AZD1656 在常见人类 GCKR 变异小鼠模型中的慢性疗效受损

bioRxiv - Pharmacology and Toxicology Pub Date : 2024-07-24 DOI: 10.1101/2024.07.24.604910

Brian E Ford, Shruti S Chachra, Ahmed Alshawi, Fiona Oakley, Rebecca J Fairclough, David M Smith, Dina Tiniakos, Loranne Agius

{"title":"Compromised chronic efficacy of a Glucokinase Activator AZD1656 in mouse models for common human GCKR variants","authors":"Brian E Ford, Shruti S Chachra, Ahmed Alshawi, Fiona Oakley, Rebecca J Fairclough, David M Smith, Dina Tiniakos, Loranne Agius","doi":"10.1101/2024.07.24.604910","DOIUrl":"https://doi.org/10.1101/2024.07.24.604910","url":null,"abstract":"Glucokinase activators (GKAs) have been developed as blood glucose lowering drugs for type 2 diabetes. Despite good short-term efficacy, several GKAs showed a decline in efficacy chronically during clinical trials. The underlying mechanisms remain incompletely understood. We tested the hypothesis that deficiency in the liver glucokinase regulatory protein (GKRP) as occurs with common human GCKR variants affects chronic GKA efficacy. We used a Gckr-P446L mouse model for the GCKR exonic rs1260326 (P446L) variant and the Gckr-del/wt mouse to model transcriptional deficiency to test for chronic efficacy of the GKA, AZD1656 in GKRP-deficient states. In the Gckr-P446L mouse, the blood glucose lowering efficacy of AZD1656 (3 mg/kg body wt) after 2 weeks was independent of genotype. However after 19 weeks, efficacy was maintained in wild-type but declined in the LL genotype, in conjunction with raised hepatic glucokinase activity and without raised liver lipids. Sustained blood glucose lowering efficacy in wild-type mice was associated with qualitatively similar but more modest changes in the liver transcriptome compared with the P446L genotype, consistent with GKA therapy representing a more modest glucokinase excess than the P446L genotype. Chronic treatment with AZD1656 in the Gckr-del/wt mouse was associated with raised liver triglyceride and hepatocyte microvesicular steatosis. The results show that in mouse models of liver GKRP deficiency in conjunction with functional liver glucokinase excess as occurs in association with common human GCKR variants, GKRP-deficiency predisposes to declining efficacy of the GKA in lowering blood glucose and to GKA induced elevation in liver lipids.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141781659","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