Biochemical pharmacology最新文献_第10页

G Protein-coupled receptors: key targets for maintaining the function of basal ganglia-thalamus-cortical circuits in Parkinson’s disease G蛋白偶联受体：维持帕金森病基底神经节-丘脑-皮质回路功能的关键靶点

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-09-03 DOI: 10.1016/j.bcp.2025.117303

Ji Wang , Zhen Qiao , Xiu Cao , Huanhuan Li , Yan Wang , Qian Jiao , Xi Chen , Xixun Du

{"title":"G Protein-coupled receptors: key targets for maintaining the function of basal ganglia-thalamus-cortical circuits in Parkinson’s disease","authors":"Ji Wang , Zhen Qiao , Xiu Cao , Huanhuan Li , Yan Wang , Qian Jiao , Xi Chen , Xixun Du","doi":"10.1016/j.bcp.2025.117303","DOIUrl":"10.1016/j.bcp.2025.117303","url":null,"abstract":"<div><div>Parkinson’s Disease (PD), the second most common neurodegenerative disease after Alzheimer’s disease, is clinically characterized by resting tremor, rigidity and postural balance disorder. Its pathological essence is the progressive degenerative death of dopaminergic neurons in the substantia nigra pars compacta (SNpc), leading to a significant decrease in striatal dopamine (DA) levels. This results in the dysfunction of basal ganglia-thalamus-cortex (BGTC) circuit. This circuit is the core neural circuit of motor control, and its abnormality not only directly causes the motor symptoms of PD, but also participates in the cascade of disease progression through the disorder of neurotransmitter signals. At present, DA replacement therapy and DA receptors (DARs) agonists are still the main methods of clinical treatment, but single therapy cannot fully correct the imbalance of other neurotransmitter systems, which has significant limitations in long-term efficacy and symptom management. G protein-coupled receptors (GPCRs), as the largest family of membrane proteins, have become important targets for PD treatment due to their extensive participation in physiological regulatory networks and excellent drug development potential. These transmembrane signaling molecules play important roles in multiple key nodes in the pathological process of PD by precisely regulating the release of neurotransmitters, the maintenance of synaptic plasticity and the dynamic balance of neural circuits. Here, we review the transition of BGTC in the context of PD and then focus on the pathological cascade of GPCRs mediating PD in this loop. Finally, we update the clinical trials or approvals of GPCR drugs under investigation for the treatment of PD.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117303"},"PeriodicalIF":5.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145005872","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

Overcoming standard-of-care resistance in glioblastoma using nanoparticle-based drug delivery targeting the autophagy pathway 利用靶向自噬途径的纳米颗粒为基础的药物递送克服胶质母细胞瘤的标准治疗耐药性。

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-09-03 DOI: 10.1016/j.bcp.2025.117302

Md Ataur Rahman, Mahesh Kumar Yadab, Meser M. Ali

{"title":"Overcoming standard-of-care resistance in glioblastoma using nanoparticle-based drug delivery targeting the autophagy pathway","authors":"Md Ataur Rahman, Mahesh Kumar Yadab, Meser M. Ali","doi":"10.1016/j.bcp.2025.117302","DOIUrl":"10.1016/j.bcp.2025.117302","url":null,"abstract":"<div><div>Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor in adults, characterized by rapid growth, diffuse infiltration, and a dismal prognosis. Despite aggressive treatment involving maximal surgical resection followed by radiotherapy and temozolomide (TMZ) chemotherapy, therapeutic outcomes remain poor due to intrinsic and acquired resistance. Autophagy, a catabolic process that degrades damaged cellular components, plays a critical role in this resistance by enabling tumor cells to survive under metabolic, hypoxic, and therapeutic stress conditions. Notably, modulation of autophagy has emerged as a promising avenue to overcome drug resistance. Recent advances in nanomedicine offer innovative strategies to enhance drug delivery and therapeutic efficacy. Nanoparticle-based drug delivery systems (NDDS) improve the bioavailability of drug molecules, facilitate blood–brain barrier (BBB) penetration, and enable targeted delivery to tumor tissues. This review explores the synergistic potential of integrating NDDS with autophagy-targeting strategies to treat GBM. Various nanoparticle platforms-including liposomes, dendrimers, polymeric nanoparticles, and lipid-based carriers-are highlighted for their ability to modulate autophagy and deliver anti-cancer agents effectively. Furthermore, we discuss the dual role of autophagy in GBM progression and the importance of context- and time-specific modulation. Thus, combining autophagy inhibitors or modulators with nanoparticle-based systems and standard therapies holds promise as a novel therapeutic strategy to counteract resistance and improve patient survival in GBM.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117302"},"PeriodicalIF":5.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145005905","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

G-protein coupled receptors in neuroinflammation, neuropharmacology, and therapeutics 神经炎症、神经药理学和治疗学中的g蛋白偶联受体

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-09-03 DOI: 10.1016/j.bcp.2025.117301

Aditi Singh, Sucharita Shadangi, Soumendra Rana

{"title":"G-protein coupled receptors in neuroinflammation, neuropharmacology, and therapeutics","authors":"Aditi Singh, Sucharita Shadangi, Soumendra Rana","doi":"10.1016/j.bcp.2025.117301","DOIUrl":"10.1016/j.bcp.2025.117301","url":null,"abstract":"<div><div>The G protein-coupled receptors (GPCRs) represent one of the most pharmacologically targeted classes of seven-transmembrane (7TM) receptors, identified through whole genome sequencing of humans. GPCRs transduce extracellular stimuli and signals into intracellular responses, enabling precise cellular communication for physiology and homeostasis. Given their ability to sense a variety of ligands, GPCRs regulate a plethora of physiological functions, such as sensory perception, hormonal regulation and metabolism, growth and development, cardiovascular and reproductive regulation. GPCRs also orchestrate immune responses, triggering a balanced pro- and anti-inflammatory signaling, which is linked to the development, differentiation, and regulation of B-cells that are responsible for the secretion of infection-fighting antibodies. However, an imbalance in inflammatory signaling is also linked to disruption of B-cell differentiation, leading to autoimmune diseases due to increased levels of autoantibodies. Additionally, GPCRs modulate neurotransmission and synaptic plasticity, influencing behaviour, mood, and cognitive functions. Due to their diverse functionality, ∼40 % of FDA-approved, currently marketed drugs are reported to target different GPCRs for therapeutic benefit. A focal point of this review is GPCR-driven neuroinflammation, particularly in neurodegenerative diseases like Alzheimer’s and Parkinson’s disease, including others. The review highlights the contribution of the pro- and anti-inflammatory GPCRs in modulating the disease pathophysiology, including the existing and emerging therapies. It also provides a future roadmap for alternative drug discovery for suppressing neuroinflammation-mediated neurodegenerative disease.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117301"},"PeriodicalIF":5.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144996702","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

STAT1–VAMP8 axis drives nasopharyngeal carcinoma progression via autophagy enhancement STAT1-VAMP8轴通过自噬增强驱动鼻咽癌进展。

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-09-03 DOI: 10.1016/j.bcp.2025.117299

Li Liu , Wentao Yu , Hua Liu , Yuxiang He , Lin Zhu , Chaoying Yang , Xiaoling Su , Pengfei Cao , Han Gong , Jing Liu , Jun He , Hui Li , Ji Zhang

{"title":"STAT1–VAMP8 axis drives nasopharyngeal carcinoma progression via autophagy enhancement","authors":"Li Liu , Wentao Yu , Hua Liu , Yuxiang He , Lin Zhu , Chaoying Yang , Xiaoling Su , Pengfei Cao , Han Gong , Jing Liu , Jun He , Hui Li , Ji Zhang","doi":"10.1016/j.bcp.2025.117299","DOIUrl":"10.1016/j.bcp.2025.117299","url":null,"abstract":"<div><div>Nasopharyngeal carcinoma (NPC) is a malignant tumor with a high risk of invasion and metastasis. Elucidating the molecular underpinnings of NPC may uncover new diagnostic and therapeutic targets. Vesicle associated membrane protein 8 (VAMP8) is overexpressed and plays an oncogenic role in various tumors. However, its role and underlying mechanism in NPC remains unclear. In this study, we identified that VAMP8 is significantly overexpressed in NPC public databases (GSE150430 and GSE162025) and NPC tissues compared to adjacent tissues in NPC patients, and VAMP8 overexpression markedly accelerated tumor growth. Lysosome associated genes play major carcinogenic roles in this tumor. Further mechanistic investigations revealed that VAMP8 was involved in the development of NPC by promoting autophagy. Furthermore, we demonstrate that STAT1 transcriptionally up-regulates VAMP8, and VAMP8 overexpression rescued the tumor progression-related phenotypes mediated by STAT1 knocking down. Drug sensitive analysis based on NPC indicated that STAT1 is sensitive to fludarabine. Pharmacologically inhibiting STAT1/VAMP8 axis by fludarabine significantly suppressed the NPC cell proliferation and metastasis. Collectively, our findings establish the STAT1–VAMP8 axis as a critical driver of NPC proliferation and metastasis through autophagy activation. Fludarabine is expected to be a potential therapeutic agent in NPC patients.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117299"},"PeriodicalIF":5.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145005840","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

Design of peptide-based PAC1 antagonists combining molecular dynamics simulations and a biologically relevant cell-based assay 基于肽的PAC1拮抗剂的设计，结合分子动力学模拟和生物学相关的基于细胞的测定。

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-09-03 DOI: 10.1016/j.bcp.2025.117300

Wenqin Xu , Abigail M. Keith , Wenjuan Ye , Xin Hu , Noel Southall , Juan J. Marugan , Marc Ferrer , Mark J. Henderson , Patrick M. Sexton , Giuseppe Deganutti , Lee E. Eiden

{"title":"Design of peptide-based PAC1 antagonists combining molecular dynamics simulations and a biologically relevant cell-based assay","authors":"Wenqin Xu , Abigail M. Keith , Wenjuan Ye , Xin Hu , Noel Southall , Juan J. Marugan , Marc Ferrer , Mark J. Henderson , Patrick M. Sexton , Giuseppe Deganutti , Lee E. Eiden","doi":"10.1016/j.bcp.2025.117300","DOIUrl":"10.1016/j.bcp.2025.117300","url":null,"abstract":"<div><div>The PACAP receptor PAC1 is a G<sub>s</sub>-coupled family B1 GPCR for which the highest-affinity endogenous peptide ligands are the pituitary adenylate cyclase-activating peptides PACAP38 and PACAP27, and whose most abundant endogenous ligand is PACAP38. PACAP action at PAC1 is implicated in neuropsychiatric disorders, atherosclerosis, pain chronification, and protection from neurodegeneration and ischemia. As PACAP also interacts with two related receptors, VPAC1 and VPAC2, highly selective ligands, both agonists and antagonists, for PAC1 have been sought. To date, the peptide PACAP(6–38) and polypeptide M65, which is related to maxadilan, a sandfly vasodilator peptide, have been identified as selective for PAC1. Several non-peptide small molecule compounds (SMOLs) have been reported to be specific antagonists at PAC1, albeit there is only limited literature detailing their pharmacology across different systems and within different laboratories. Here, we present a platform of cellular assays for the screening of biologically relevant antagonists at PAC1 and show that some currently proposed SMOL antagonists do not have activity in this cell reporter assay, while we confirm that PACAP(6–38) and M65 are competitive antagonists. We have used this assay system to explore other peptide antagonists at PAC1, guided by molecular dynamics analysis of the PACAP-PAC1 interaction based on cryo-EM structural models of PAC1 complexed with a number of biologically active ligands. The affinity-trap model for the PAC1-ligand interaction successfully predicts the engagement behavior of PACAP27 and PACAP38 peptide-based PAC1 inhibitors. In particular, C-terminal deletants of PACAP(6–38) that maintain equipotency to PACAP(6–38) allow the shorter sequence to function as a scaffold for further peptide-based antagonist exploration.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117300"},"PeriodicalIF":5.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145005877","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

Molecular glues and PROTACs in targeted protein degradation: mechanisms, advances, and therapeutic potential 靶向蛋白降解中的分子胶和PROTACs：机制、进展和治疗潜力

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-09-02 DOI: 10.1016/j.bcp.2025.117297

Omar Eladl

{"title":"Molecular glues and PROTACs in targeted protein degradation: mechanisms, advances, and therapeutic potential","authors":"Omar Eladl","doi":"10.1016/j.bcp.2025.117297","DOIUrl":"10.1016/j.bcp.2025.117297","url":null,"abstract":"<div><div>Targeted protein degradation (TPD) is a transformative approach to drug discovery that enables the modulation of proteins previously considered “undruggable.” Unlike traditional inhibitors, which transiently suppress protein activity, TPD harnesses the ubiquitin–proteasome system to selectively eliminate specific proteins and thereby fully abolish their activities. Two prominent approaches within TPD, Molecular Glues and PROteolysis TArgeting Chimeras (PROTACs), differ in both mechanism and therapeutic application.</div><div>Molecular Glues are small molecules with low molecular weight that act as a molecular bridge, facilitating interaction between a target protein and an E3 ubiquitin ligase to enable degradation without requiring classical binding pockets. PROTACs are heterobifunctional small molecules that simultaneously engage a target protein and an E3 ligase to induce selective degradation through a catalytic mechanism. Both strategies have vastly expanded the druggable proteome and hold great promise for therapeutic interventions.</div><div>This review provides a comparative overview of Molecular Glues and PROTACs, including their mechanisms, design principles, and therapeutic applications. We highlight their physicochemical properties, advantages, and limitations, as well as recent advances that are fueling the discovery of novel degraders. Through clinical advancements and case studies, we examine how these modalities are reshaping drug discovery and enabling new treatments for a variety of diseases.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117297"},"PeriodicalIF":5.6,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144996701","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

Alteration of alanine-327 in LXRα to LXRβ-type histidine deteriorates its subtype-selective activation by riccardin C LXRα中alanine-327对lxr β型组氨酸的改变使其在riccardin C作用下的亚型选择性活化恶化。

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-09-02 DOI: 10.1016/j.bcp.2025.117304

Norimasa Tamehiro , Yukari Shigemoto-Mogami , Hongyan Cui , Yoshinori Asakawa , Norihito Shibata , Tomoko Nishimaki-Mogami

{"title":"Alteration of alanine-327 in LXRα to LXRβ-type histidine deteriorates its subtype-selective activation by riccardin C","authors":"Norimasa Tamehiro , Yukari Shigemoto-Mogami , Hongyan Cui , Yoshinori Asakawa , Norihito Shibata , Tomoko Nishimaki-Mogami","doi":"10.1016/j.bcp.2025.117304","DOIUrl":"10.1016/j.bcp.2025.117304","url":null,"abstract":"<div><div>Liver X receptors (LXRα and LXRβ) are nuclear receptors critical for lipid homeostasis and inflammation regulation, making them potential therapeutic targets for atherosclerosis and inflammatory diseases. While LXR agonists hold promise, their use is limited by adverse effects on hepatic lipogenesis. Riccardin C (RC) has shown promise as an LXRα partial agonist/ LXRβ antagonist with cell-type-selective properties. This study investigates the molecular mechanisms behind RC-induced LXRα activation. A series of LXRα/β chimera and point-mutated receptors was generated to identify the domains and residues required for RC-induced transactivation. Functional analysis revealed that mutating alanine-327 of LXRα to LXRβ-type histidine in helix 6 impaired RC-induced association with coactivator peptides, reducing transactivation. Conversely, mutating histidine-341 of LXRβ or the inactive chimera to the LXRα-type alanine partially restored the response to RC, highlighting the significance of the A327H mutation in selective LXRα activation by RC. Furthermore, in vivo experiments revealed that when administered orally to mice, RC selectively induced hepatic and intestinal <em>Abca1</em> expression without stimulating hepatic lipogenic gene expression, thereby elevating HDL levels without increasing plasma and hepatic triglycerides. These findings offer valuable insights for the development of novel therapeutic agents.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117304"},"PeriodicalIF":5.6,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999560","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

Aloperine ameliorates radiation enteritis by driving the TAS2R138-PLCβ/GAPDH axis-mediated glucose metabolic reprogramming to inhibit ferroptosis in intestinal epithelial cells Aloperine通过驱动TAS2R138-PLCβ/GAPDH轴介导的糖代谢重编程来抑制肠上皮细胞的铁下垂，从而改善放射性肠炎

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-09-01 DOI: 10.1016/j.bcp.2025.117292

Xi Zeng , Suwen Pang , Hong Lu , Jingchao Zhu , Ze Li , Ni Liu , Xifeng Zhang , Yun Wang , Zhifeng Wei

{"title":"Aloperine ameliorates radiation enteritis by driving the TAS2R138-PLCβ/GAPDH axis-mediated glucose metabolic reprogramming to inhibit ferroptosis in intestinal epithelial cells","authors":"Xi Zeng , Suwen Pang , Hong Lu , Jingchao Zhu , Ze Li , Ni Liu , Xifeng Zhang , Yun Wang , Zhifeng Wei","doi":"10.1016/j.bcp.2025.117292","DOIUrl":"10.1016/j.bcp.2025.117292","url":null,"abstract":"<div><div>Radiation enteritis (RE) is a common side effect of radiotherapy, with no specific therapeutic agents available. <em>Sophora alopecuroides L.</em> (KDZ) has been used in China for many years to treat gastrointestinal disorders, and matrine, oxymatrine, and aloperine (ALO) are its main alkaloid components. We found that ALO significantly attenuated the damage of ionizing radiation (IR) to the viability of intestinal epithelial cells (IECs), outperforming matrine and oxymatrine. The IR-induced Fe<sup>2+</sup> accumulation, lipid peroxidation and down-regulated glutathione peroxidase 4 and solute carrier family 7 member 11 levels were restored, and ferroptosis but not apoptosis or necrosis was further indicated. Untargeted metabolomic analysis showed that ALO shifted the glucose flux from glycolysis to the hexosamine biosynthetic pathway to elevate the UDP-GlcNAc level. Notably, ALO could directly bind with taste 2 receptor member 138 (TAS2R138) as one of its potential targets, and promoted the activation of downstream signaling molecules phospholipase C β (PLCβ) and α-gustducin. Furthermore, ALO enhanced the association of PLCβ and GAPDH at MET56 and LYS271, and inhibiting the latter’s acetylation and activity <em>via</em> activating TAS2R138. In addition, after triggering the metabolic reprogramming, ALO promoted the <em>O/N</em>-glycosylation to prevent the lysosomal degradation of ferritin heavy chain 1 and transferrin receptor, modulating iron storage and transport, thus alleviating ferroptosis. <em>In vivo</em>, the above-mentioned effect and mechanisms of ALO were demonstrated using the model of RE in mice. Collectively, ALO activated TAS2R138 to promote the interaction of PLCβ and GAPDH to induce metabolic reprogramming and alleviate IR-induced ferroptosis of IECs to improve RE.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117292"},"PeriodicalIF":5.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144931784","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

Non-coding RNAs-glycolysis axis in cancer therapy resistance: Insight into mechanism to therapeutic solution 非编码rna -糖酵解轴在癌症治疗耐药中的作用：对治疗方案机制的洞察。

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-09-01 DOI: 10.1016/j.bcp.2025.117286

Jiachen Tan , Qinzheng Xu , Nuruliarizki Shinta Pandupuspitasari , Faheem Ahmed Khan , Di Wu , Fei Sun , Chunjie Huang

{"title":"Non-coding RNAs-glycolysis axis in cancer therapy resistance: Insight into mechanism to therapeutic solution","authors":"Jiachen Tan , Qinzheng Xu , Nuruliarizki Shinta Pandupuspitasari , Faheem Ahmed Khan , Di Wu , Fei Sun , Chunjie Huang","doi":"10.1016/j.bcp.2025.117286","DOIUrl":"10.1016/j.bcp.2025.117286","url":null,"abstract":"<div><div>Despite advancements in cancer therapy, including radiotherapy and chemotherapy, resistance to cancer treatment remains a significant clinical challenge. Metabolic reprogramming and dysfunctional glycolysis, a defining characteristic of cancer cells, are commonly observed in drug-resistant cancer cells. Besides glycolytic enzymes, several signaling molecules—including EGFR, HIF-1α, AMPK, and β-catenin—are involved in the regulation of glycolysis and play crucial roles in mediating resistance to cancer therapy. Numerous studies have elucidated the pivotal role of non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), in the modulation of cancer drug resistance. miRNAs dually regulate glycolysis—some inhibit glycolysis to overcome therapy resistance, while others promote glycolysis, inducing resistance in cancer cells. Recent investigations have underscored the critical function of competitive endogenous RNAs (ceRNAs) in modulating glycolytic pathways, indicating circRNA/lncRNA–miRNA–mRNA as an important regulatory network in cancer therapy resistance. Exosomal ncRNAs are another mediator of cancer therapy resistance; depending on the specific ncRNAs they carry, they can either promote or suppress glycolysis. In the final section, we demonstrated that herbal medicine can successfully mitigate drug resistance in cancer by modulating the ncRNA-glycolysis axis.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117286"},"PeriodicalIF":5.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991320","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

Pharmacological characterization of ubrogepant and atogepant in cAMP assays at human, rat, and mouse calcitonin family receptors in transfected cells 人、大鼠和小鼠降钙素家族受体在转染细胞中的cAMP测定中增厚剂和增厚剂的药理学特征。

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-08-30 DOI: 10.1016/j.bcp.2025.117295

Mhairi Nimick , Tyla I Alexander , Michael L Garelja , Christopher S Walker , Pradeep Banerjee , Debbie L Hay

{"title":"Pharmacological characterization of ubrogepant and atogepant in cAMP assays at human, rat, and mouse calcitonin family receptors in transfected cells","authors":"Mhairi Nimick , Tyla I Alexander , Michael L Garelja , Christopher S Walker , Pradeep Banerjee , Debbie L Hay","doi":"10.1016/j.bcp.2025.117295","DOIUrl":"10.1016/j.bcp.2025.117295","url":null,"abstract":"<div><div>Calcitonin gene-related peptide (CGRP) is involved in migraine pathophysiology, and can activate multiple receptors belonging to the calcitonin receptor family; this includes the CGRP receptor, adrenomedullin and amylin (AMY) receptors. Ubrogepant and atogepant, which were designed to target the CGRP receptor, are therapeutically approved for the management of migraine. However, there are limited data on their ability to antagonize members of the wider calcitonin receptor family. We therefore defined the receptor pharmacology of ubrogepant and atogepant at each of the seven calcitonin family receptors from rat, mouse and human. Cos7 cells transiently transfected with each receptor were exposed to species-matched agonists in the absence or presence of ubrogepant and atogepant. As all receptors robustly couple to the G<sub>αs</sub> G protein, cyclic adenosine monophosphate production was measured and antagonist potency quantified. Ubrogepant and atogepant antagonized multiple rodent receptors, although the exact profile differed between compound and species. Both compounds were relatively non-selective between rat receptors, suggesting it may be difficult to interpret results in rat models. Selectivity was distinct at mouse receptors. For human receptors, both compounds were most potent at the CGRP receptor, however there was also some affinity at other receptors from this family, especially the AMY<sub>1</sub> receptor. Collectively, our data show that while these compounds are most potent at the CGRP receptor, they have activity at other receptors from the calcitonin receptor family, and this activity differs between species. Our data provide a framework for understanding the activity of ubrogepant and atogepant in rat, mouse and human studies.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117295"},"PeriodicalIF":5.6,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940683","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