Biochemical pharmacology最新文献

The novel use of the CFTR corrector C17 in muscular dystrophy: Pharmacological profile and in vivo efficacy.

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-01-24 DOI: 10.1016/j.bcp.2025.116779

Alberto Benetollo, Sofia Parrasia, Martina Scano, Lucia Biasutto, Andrea Rossa, Leonardo Nogara, Bert Blaauw, Francesco Dalla Barba, Paola Caccin, Marcello Carotti, Alessandro Parolin, Eylem Emek Akyurek, Roberta Sacchetto, Dorianna Sandonà

{"title":"The novel use of the CFTR corrector C17 in muscular dystrophy: Pharmacological profile and in vivo efficacy.","authors":"Alberto Benetollo, Sofia Parrasia, Martina Scano, Lucia Biasutto, Andrea Rossa, Leonardo Nogara, Bert Blaauw, Francesco Dalla Barba, Paola Caccin, Marcello Carotti, Alessandro Parolin, Eylem Emek Akyurek, Roberta Sacchetto, Dorianna Sandonà","doi":"10.1016/j.bcp.2025.116779","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.116779","url":null,"abstract":"Sarcoglycanopathies are rare forms of severe muscular dystrophies currently without a therapy. Mutations in sarcoglycan (SG) genes cause the reduction or absence of the SG-complex, a tetramer located in the sarcolemma that plays a protective role during muscle contraction. Missense mutations in SGCA, which cause α-sarcoglycanopathy, otherwise known as LGMD2D/R3, lead to folding defective forms of α-SG that are discarded by the cell quality control. Recently, we demonstrated how a small molecule called C17, initially identified as a CFTR corrector, can be re-used to ameliorate the dystrophic phenotype of a mouse model of α-sarcoglycanopathy. Here, we have examined the pharmacological profile of C17 by performing ADME (absorption, distribution, metabolism, and elimination) studies. Our data show that C17 is well-distributed to relevant organs like heart and skeletal muscle, and likely metabolized in the small intestine into hydrophilic and hydrophobic derivatives. Elimination occurs through faeces (unmodified and modified C17) and urine (modified forms). Interestingly, we detected a quantifiable amount of C17 in treated muscles 48 h after an acute parenteral administration. This led to design a regimen of chronic treatment with a reduced dosing frequency. The result was the recovery of muscle strength, thanks to the rescue of the SG-complex, despite containing a mutated subunit, at the level of the sarcolemma. Thus, we can conclude that CFTR corrector C17 has a reasonable pharmacological profile and great potential to become a valuable therapeutic option for LGMD2D/R3 and other forms of muscular dystrophy caused by folding defective but potentially functional proteins.","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116779"},"PeriodicalIF":5.3,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Acute myeloid leukemia with t(8;21) translocation: Molecular pathogenesis, potential therapeutics and future directions.

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-01-24 DOI: 10.1016/j.bcp.2025.116774

Pei Han Yu, Ze Yan Zhang, Yuan Yuan Kang, Ping Huang, Chang Yang, Hua Naranmandura

{"title":"Acute myeloid leukemia with t(8;21) translocation: Molecular pathogenesis, potential therapeutics and future directions.","authors":"Pei Han Yu, Ze Yan Zhang, Yuan Yuan Kang, Ping Huang, Chang Yang, Hua Naranmandura","doi":"10.1016/j.bcp.2025.116774","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.116774","url":null,"abstract":"Acute myeloid leukemia (AML) is a highly heterogeneous and aggressive blood cancer. Genetic abnormalities, such as the t(8;21) rearrangement, play a significant role in AML onset. This rearrangement leads to the formation of the RUNX1/RUNX1T1 fusion protein, disrupting gene regulation and genomic stability, ultimately causing full-blown leukemia. Despite a generally favorable prognosis, t(8;21) patients face relapse and chemotherapy resistance, particularly when harboring cooperating mutations. While advances in cellular genetics and molecular biology have improved AML treatment, there are currently no specific targeted therapies against RUNX1/RUNX1T1. Therefore, investigating targeted therapies for this AML subtype holds promise for patients. This review explores the complex landscape of t(8;21) AML, unravels the molecular mechanisms of RUNX1/RUNX1T1-driven leukemogenesis, and discusses recent advancements in target therapies including small molecule drugs and PROTAC. Our goal is to develop more effective and less toxic strategies for managing t(8;21) AML patients.","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116774"},"PeriodicalIF":5.3,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An Introduction to the Special Issue "9th International Conference on Relaxin and Related Peptides".

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-01-23 DOI: 10.1016/j.bcp.2025.116775

Robert G Bennett, Sabine Hombach-Klonisch, Thomas Klonisch, Brian C Wilson

引用次数: 0

The natural product micheliolide promotes the nuclear translocation of GAPDH via binding to Cys247 and induces glioblastoma cell death in combination with temozolomide.

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-01-23 DOI: 10.1016/j.bcp.2025.116759

Jian-Shuang Guo, Ji-Yan Wang, Sheng-Hua Chen, Yang-Ping Deng, Qian-Yu Gao, Zi-Xiao Liu, Ju Liu, Ke Lv, Ning Liu, Gui-Ying Bai, Chang-Liang Shan, Xue-Quan Feng, Jing Li, Yue Chen

{"title":"The natural product micheliolide promotes the nuclear translocation of GAPDH via binding to Cys247 and induces glioblastoma cell death in combination with temozolomide.","authors":"Jian-Shuang Guo, Ji-Yan Wang, Sheng-Hua Chen, Yang-Ping Deng, Qian-Yu Gao, Zi-Xiao Liu, Ju Liu, Ke Lv, Ning Liu, Gui-Ying Bai, Chang-Liang Shan, Xue-Quan Feng, Jing Li, Yue Chen","doi":"10.1016/j.bcp.2025.116759","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.116759","url":null,"abstract":"Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is significantly upregulated in glioblastoma (GBM) and plays a crucial role in cell apoptosis and drug resistance. Micheliolide (MCL) is a natural product with a variety of antitumour activities, and the fumarate salt form of dimethylamino MCL (DMAMCL; commercial name ACT001) has been tested in clinical trials for recurrent GBM; this compound suppresses the proliferation of GBM cells by rewiring aerobic glycolysis. Herein, we demonstrated that MCL directly targets GAPDH through covalent binding to the cysteine 247 (Cys247) residue. Intriguingly, MCL does not affect the enzyme activity of GAPDH but facilitates the nuclear translocation of the GAPDH/Siah1 (E3 ligase) complex. Furthermore, MCL/DMAMCL can exacerbate temozolomide (TMZ)-induced DNA damage. This treatment synergistically induced GBM cell death and suppressed tumour growth in a GBM xenograft mouse model. Collectively, our results reveal that MCL triggers non-glycolysis-related functions of GAPDH and that MCL promotes GBM cell death, especially when combined with TMZ, thus providing a novel strategy for clinical GBM treatment.","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116759"},"PeriodicalIF":5.3,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143036294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The AHR-NRF2-JDP2 gene battery: Ligand-induced AHR transcriptional activation.

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-01-22 DOI: 10.1016/j.bcp.2025.116761

Kenly Wuputra, Wen-Hung Hsu, Chia-Chen Ku, Ya-Han Yang, Kung-Kai Kuo, Fang-Jung Yu, Hsin-Su Yu, Kyosuke Nagata, Deng-Chyang Wu, Chao-Hung Kuo, Kazunari K Yokoyama

{"title":"The AHR-NRF2-JDP2 gene battery: Ligand-induced AHR transcriptional activation.","authors":"Kenly Wuputra, Wen-Hung Hsu, Chia-Chen Ku, Ya-Han Yang, Kung-Kai Kuo, Fang-Jung Yu, Hsin-Su Yu, Kyosuke Nagata, Deng-Chyang Wu, Chao-Hung Kuo, Kazunari K Yokoyama","doi":"10.1016/j.bcp.2025.116761","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.116761","url":null,"abstract":"Aryl hydrocarbon receptor (AHR) and nuclear factor-erythroid 2-related factor 2 (NRF2) can regulate a series of genes encoding the detoxifying phase I and II enzymes, via a signaling crosstalk known as the \"AHR-NRF2 gene battery\". The chromatin transcriptional regulator Jun dimerization protein 2 (JDP2) plays a central role in thetranscription of AHR gene in response to the phase I enzyme ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin. It forms a transcriptional complex with AHR-AHR nuclear translocator (ARNT) and NRF2-small musculoaponeurotic fibrosarcoma proteins (sMAF), which are then recruited to the respective cis-elements, such as dioxin response elements and antioxidant response elements, respectively, in the AHR promoter. Here, we present a revised description of the AHR-NRF2 gene battery as the AHR-NRF2-JDP2 gene battery for transactivating the AHR promoter by phase I enzyme ligands. The chromatin regulator JDP2 was found to be involved in the movement of AHR-NRF2 complexes from the dioxin response element to the antioxidant response element in the AHR promoter, during its activation in a spatiotemporal manner. This new epigenetic and chromatin remodeling role of AHR-NRF2-JDP2 axis is useful for identifying new therapeutic targets for various diseases, including immunological response, detoxification, development, and cancer-related diseases.","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116761"},"PeriodicalIF":5.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143036280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Downregulation of RSAD2 ameliorates keratinocyte hyperproliferation and skin inflammation in psoriasis via the TAK1/NF-κB axis.

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-01-21 DOI: 10.1016/j.bcp.2025.116764

Xueqing Li, Fuqiang Chen, Yunqian Li, Yunyue Zhen, Jiaoying Ju, Zhengjun Li, Shan Huang, Qing Sun

{"title":"Downregulation of RSAD2 ameliorates keratinocyte hyperproliferation and skin inflammation in psoriasis via the TAK1/NF-κB axis.","authors":"Xueqing Li, Fuqiang Chen, Yunqian Li, Yunyue Zhen, Jiaoying Ju, Zhengjun Li, Shan Huang, Qing Sun","doi":"10.1016/j.bcp.2025.116764","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.116764","url":null,"abstract":"Immune cell infiltration and keratinocyte (KC) hyperproliferation are characteristics of psoriasis. Radical S-adenosyl methionine domain-containing 2 (RSAD2) plays an integral role in the innate immune response and is associated with various immune-related diseases. However, RSAD2's expression and role in modulating immune responses in psoriasis remain unexplored. In this study, we demonstrated a significant upregulation of RSAD2 expression in both psoriatic lesions and psoriasis-like mouse epidermis, with its expression positively correlated with psoriasis severity. In psoriatic cell models, RSAD2 was shown to promote the proliferation and secretion of pro-inflammatory cytokines by activating the transforming growth factor-β-activated kinase 1 (TAK1)-mediated nuclear factor kappa-B (NF-κB) signaling pathway. Additionally, it was found that the expression of RSAD2 is increased by the action of interferon regulatory factor-1 (IRF1), which binds to the promoter region of RSAD2. Therefore, the function of RSAD2 in psoriasis is regulated by IRF1. Notably, RSAD2 inhibition decreased epidermal hyperplasia and alleviated imiquimod (IMQ)-induced psoriatic dermatitis. In summary, our study highlights the modulation of the IRF1-RSAD2-TAK1 axis as a potential innovative therapeutic approach for psoriasis, offering new insights into the molecular mechanisms by which KCs drive inflammation in psoriasis.","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116764"},"PeriodicalIF":5.3,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting GSDMD JX06 inhibits PANoptosis and multiple organ injury.

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-01-21 DOI: 10.1016/j.bcp.2025.116765

Shiyi Chen, Guodong Wu, Tongfu Li, Jiacheng Jiang, Yuqing Zhong, Dong Sun, Feng Qian, Long Shuang Huang

{"title":"Targeting GSDMD JX06 inhibits PANoptosis and multiple organ injury.","authors":"Shiyi Chen, Guodong Wu, Tongfu Li, Jiacheng Jiang, Yuqing Zhong, Dong Sun, Feng Qian, Long Shuang Huang","doi":"10.1016/j.bcp.2025.116765","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.116765","url":null,"abstract":"Multiple organ dysfunction syndrome (MODS) is the major cause of mortality of patients in intensive care units. The elusive mechanisms of tissue damage in MODS and limited therapeutic options encourage us to seek effective therapies to MODS. PANoptosis has recently been proven to be the key player in both heat stress and sepsis-mediated MODS. Therefore, we initially investigated the role of gasdermin D (GSDMD) in heat stress and sepsis-induced MODS. We found that GSDMD deficiency attenuates heat stress or sepsis mediated cell death, tissue inflammation and severe multiple organ injury (MOI). Next, we screened out and proved that JX06 effectively inhibited GSDMD-NT mediated cell death, by covalently modifying the Cys39/192 residue in GSDMD, inhibiting the accumulation of GSDMD-NT and pore formation in cell membrane. In vivo, JX06 administration attenuated heat stress and sepsis-mediated cell death, inflammation, MODS and animal mortality via suppressing GSDMD-mediated PANoptosis. Overall, our results indicated that GSDMD is critical for MODS by executing PANoptosis; administrating its inhibitor, JX06, effectively suppresses MODS by inhibiting PANoptosis, and suggesting that JX06 would be an effective drug candidate for MODS and related death.","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116765"},"PeriodicalIF":5.3,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

^{Evolution and therapeutic potential of glucagon-like peptide 2 analogs}.

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-01-20 DOI: 10.1016/j.bcp.2025.116758

Binbin Gong, Ting Wang, Lidan Sun

引用次数: 0

LILRB4 as a novel immunotherapeutic target for multiple diseases.

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-01-20 DOI: 10.1016/j.bcp.2025.116762

Xu Wang, Lanying Li, Dan Liu, Yuhang Jin, Xuan Zhao, Sijin Li, Rui Hou, Zhangchun Guan, Wen Ma, Junnian Zheng, Ming Lv, Ming Shi

{"title":"LILRB4 as a novel immunotherapeutic target for multiple diseases.","authors":"Xu Wang, Lanying Li, Dan Liu, Yuhang Jin, Xuan Zhao, Sijin Li, Rui Hou, Zhangchun Guan, Wen Ma, Junnian Zheng, Ming Lv, Ming Shi","doi":"10.1016/j.bcp.2025.116762","DOIUrl":"10.1016/j.bcp.2025.116762","url":null,"abstract":"Immune checkpoints are critical for maintaining autoimmune homeostasis and are implicated in various autoimmune diseases, with their significance increasingly recognized. Investigating the functions and mechanisms of these checkpoints is essential for the development of more effective treatments. Leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4) stands out as a unique immune checkpoint, with limited expression in most normal tissues but prominent presence in various hematological and solid tumors. It is also expressed on numerous immune and stromal cells, functioning as both a \"Tumor Immune Checkpoint\" and a \"Tumor Stromal Immune Checkpoint.\" Due to its distinct expression profile, LILRB4 plays a pivotal role in tumors, autoimmune diseases, allergic reactions, and the maintenance of immune homeostasis during transplantation and pregnancy. A thorough understanding of its ligands, functions, mechanisms, and ongoing therapeutic strategies targeting LILRB4 will be crucial for the development of advanced therapeutic options. This review examines LILRB4 expression and function across multiple diseases and discusses therapeutic approaches targeting LILRB4 in various contexts. Additionally, the potential of combining current drugs with LILRB4-targeted therapies is explored. Challenges in developing LILRB4-targeting drugs are also addressed, offering valuable insights for future research.","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116762"},"PeriodicalIF":5.3,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cotargeting of thioredoxin 1 and glutamate-cysteine ligase in both imatinib-sensitive and imatinib-resistant CML cells. 硫氧还蛋白1和谷氨酸-半胱氨酸连接酶在伊马替尼敏感和伊马替尼耐药CML细胞中的共靶向

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-01-18 DOI: 10.1016/j.bcp.2025.116763

Xiaoyan Sun, Chunli Zhang, Bo Fan, Qingyu Liu, Xiaofeng Shi, Shuxia Wang, Ting Chen, Xueting Cai, Chunping Hu, Handong Sun, Pematenzin Puno, Peng Cao

{"title":"Cotargeting of thioredoxin 1 and glutamate-cysteine ligase in both imatinib-sensitive and imatinib-resistant CML cells.","authors":"Xiaoyan Sun, Chunli Zhang, Bo Fan, Qingyu Liu, Xiaofeng Shi, Shuxia Wang, Ting Chen, Xueting Cai, Chunping Hu, Handong Sun, Pematenzin Puno, Peng Cao","doi":"10.1016/j.bcp.2025.116763","DOIUrl":"10.1016/j.bcp.2025.116763","url":null,"abstract":"Chronic myeloid leukemia (CML) is a type of malignancy characterized by harboring the oncogene Bcr-Abl, which encodes the constitutively activated tyrosine kinase BCR-ABL. Although tyrosine kinase inhibitors targeting BCR-ABL have revolutionized CML therapy, native and acquired drug resistance commonly remains a great challenge. Thioredoxin 1 (Trx1) and glutamate-cysteine ligase (GCL), which are two major antioxidants that maintain cellular redox homeostasis, are potential targets for cancer therapy and overcoming drug resistance. However, how their inhibition is implicated in CML is still unclear. Here, our results revealed that Trx1 was overexpressed in patients with CML compared with healthy donors. Trx1 expression was greater in imatinib-resistant CML cells than in imatinib-sensitive cells. Pharmacological inhibitors of Trx1 attenuated cell growth and reduced colony formation in both imatinib-sensitive and imatinib-resistant CML cells. Furthermore, decreased Trx1 expression enhanced the cytotoxicity of the GCL inhibitor buthionine sulfoximine (BSO). We surmise that the combined inhibition of Trx1 and GCL promotes the induction of hydrogen peroxide and depletes GPX4 expression in CML cells, resulting in ferroptosis in cancerous cells. Finally, the combined inhibition of Trx1 and GCL had a synergistic effect on CML cells in murine xenograft models. These findings offer crucial informationregarding the combined roles ofTrx1 and GCL in triggering ferroptosis in CML and suggestefficacioustherapeutic uses for these systems in this disease.","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116763"},"PeriodicalIF":5.3,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0