Pharmacology & Therapeutics最新文献_第10页

From physiology to pathology: Emerging roles of GPER in cardiovascular disease 从生理学到病理学：GPER在心血管疾病中的新作用。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-03-01 Epub Date: 2025-01-29 DOI: 10.1016/j.pharmthera.2025.108801

Zixuan Wang , Junren Liu , Ying Chen , Yi Tang , Ting Chen , Chang Zhou , Shuo Wang , Ranbo Chang , Zhongshuai Chen , Wenqing Yang , Zhen Guo , Ting Chen

{"title":"From physiology to pathology: Emerging roles of GPER in cardiovascular disease","authors":"Zixuan Wang , Junren Liu , Ying Chen , Yi Tang , Ting Chen , Chang Zhou , Shuo Wang , Ranbo Chang , Zhongshuai Chen , Wenqing Yang , Zhen Guo , Ting Chen","doi":"10.1016/j.pharmthera.2025.108801","DOIUrl":"10.1016/j.pharmthera.2025.108801","url":null,"abstract":"<div><div>Cardiovascular diseases (CVDs) are among the leading causes of death globally and pose a significant threat to public health. Factors such as prolonged high cholesterol levels, diabetes, smoking, unhealthy diet, and genetic predisposition could contribute to the occurrence and development of CVDs. Common CVDs include hypertension (HTN), atherosclerosis (AS), myocardial infarction (MI), myocardial ischemia-reperfusion injury (MIRI), heart failure (HF) and arrhythmia. Estrogen is recognized for its cardiovascular protective effects, resulting in lower incidence and mortality rates of CVDs in premenopausal women compared to men. The G protein-coupled estrogen receptor (GPER), a G protein-coupled receptor with a seven-transmembrane structure, exhibits unique structural characteristics and widespread tissue distribution. GPER activates intracellular signaling pathways through its interaction with G proteins, mediating estrogen's biological effects and participating in the regulation of cardiovascular function, metabolic balance, and nervous system. Although recent research has highlighted the significant role of GPER in the cardiovascular system, its specific mechanisms remain unclear. Therefore, this review summarizes the latest research on GPER in CVDs, including its fundamental characteristics, physiological functions in the cardiovascular system, and its roles and potential therapeutic applications in common CVDs such as HTN, AS, MI, MIRI, HF and arrhythmia. Exploring GPER's positive effects on cardiovascular health will provide new strategies and research directions for the treatment of CVDs.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108801"},"PeriodicalIF":12.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Bridging the gap: The endocannabinoid system as a functional fulcrum for benzodiazepines in a novel frontier of anxiety pharmacotherapy 缩小差距：内源性大麻素系统作为苯二氮卓类药物的功能支点，开辟了焦虑症药物治疗的新领域。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-03-01 Epub Date: 2025-01-23 DOI: 10.1016/j.pharmthera.2025.108799

Sina Pakkhesal , Mohammad Shakouri , Reza Mosaddeghi-Heris , Sepideh Kiani Nasab , Negin Salehi , AmirMohammad Sharafi , Ali Ahmadalipour

{"title":"Bridging the gap: The endocannabinoid system as a functional fulcrum for benzodiazepines in a novel frontier of anxiety pharmacotherapy","authors":"Sina Pakkhesal , Mohammad Shakouri , Reza Mosaddeghi-Heris , Sepideh Kiani Nasab , Negin Salehi , AmirMohammad Sharafi , Ali Ahmadalipour","doi":"10.1016/j.pharmthera.2025.108799","DOIUrl":"10.1016/j.pharmthera.2025.108799","url":null,"abstract":"<div><div>While benzodiazepines have been a mainstay of the pharmacotherapy of anxiety disorders, their short-term efficacy and risk of abuse have driven the exploration of alternative treatment approaches. The endocannabinoid (eCB) system has emerged as a key modulator of anxiety-related processes, with evidence suggesting dynamic interactions between the eCB system and the GABAergic system, the primary target of benzodiazepines. According to the existing literature, the activation of the cannabinoid receptors has been shown to exert anxiolytic effects, while their blockade or genetic deletion results in heightened anxiety-like responses. Moreover, studies have provided evidence of interactions between the eCB system and benzodiazepines in anxiety modulation. For instance, the attenuation of benzodiazepine-induced anxiolysis by cannabinoid receptor antagonism or genetic variations in the eCB system components in animal studies, have been associated with variations in benzodiazepine response and susceptibility to anxiety disorders. The combined use of cannabinoid-based medications, such as cannabinoid receptor agonists and benzodiazepine co-administration, has shown promise in augmenting anxiolytic effects and reducing benzodiazepine dosage requirements. This article aims to comprehensively review and discuss the current evidence on the involvement of the eCB system as a key modulator of benzodiazepine-related anxiolytic effects, and further, the possible mechanisms by which the region-specific eCB system-GABAergic connectivity modulates the neuro-endocrine/behavioral stress response, providing an inclusive understanding of the complex interplay between the eCB system and benzodiazepines in the context of anxiety regulation, to inform future research and clinical practice.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108799"},"PeriodicalIF":12.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Cannabinoid receptor 1 ligands: Biased signaling mechanisms driving functionally selective drug discovery 大麻素受体1配体：偏倚信号机制驱动功能选择性药物发现。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-03-01 Epub Date: 2025-01-17 DOI: 10.1016/j.pharmthera.2025.108795

Lei Tian , Taotao Qiang , Sundian Liu , Boxin Zhang , Yunfei Zhang , Bingxing Zhang , Jinrong Hu , Jiayun Zhang , Qi Lu , Changhua Ke , Juan Xia , Chengyuan Liang

{"title":"Cannabinoid receptor 1 ligands: Biased signaling mechanisms driving functionally selective drug discovery","authors":"Lei Tian , Taotao Qiang , Sundian Liu , Boxin Zhang , Yunfei Zhang , Bingxing Zhang , Jinrong Hu , Jiayun Zhang , Qi Lu , Changhua Ke , Juan Xia , Chengyuan Liang","doi":"10.1016/j.pharmthera.2025.108795","DOIUrl":"10.1016/j.pharmthera.2025.108795","url":null,"abstract":"<div><div>G protein-coupled receptors (GPCRs) adopt conformational states that activate or inhibit distinct signaling pathways, including those mediated by G proteins or β-arrestins. Biased signaling through GPCRs may offer a promising strategy to enhance therapeutic efficacy while reducing adverse effects. Cannabinoid receptor 1 (CB1), a key GPCR in the endocannabinoid system, presents therapeutic potential for conditions such as pain, anxiety, cognitive impairment, psychiatric disorders, and metabolic diseases. This review examines the structural conformations of CB1 coupling to different signaling pathways and explores the mechanisms underlying biased signaling, which are critical for the design of functionally selective ligands. We discuss the structure-function relationships of endogenous cannabinoids (eCBs), phytocannabinoids, and synthetic cannabinoid ligands with biased properties. Challenges such as the complexity of ligand bias screening, the limited availability of distinctly biased ligands, and the variability in receptor signaling profiles <em>in vivo</em> have hindered clinical progress. Although the therapeutic potential of biased ligands in various clinical conditions remains in its infancy, retrospective identification of such molecules provides a strong foundation for further development. Recent advances in CB1 crystallography, particularly insights into its conformations with G proteins and β-arrestins, now offer a framework for structure-based drug design. While there is still a long way to go before biased CB1 ligands can be widely used in clinical practice, ongoing multidisciplinary research shows promise for achieving functional selectivity in targeting specific pathways. These progress could lead to the development of safer and more effective cannabinoid-based therapies in the future.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108795"},"PeriodicalIF":12.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Attributes novel drug candidate: Constitutive GPCR signal bias mediated by purinergic receptors 新候选药物：嘌呤能受体介导的组成型GPCR信号偏倚。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-03-01 Epub Date: 2025-01-23 DOI: 10.1016/j.pharmthera.2025.108802

Li Yin , Kexin Ni , Tianqi Mao , Sheng Tian , Chunxiao Liu , Jiayao Chen , Mengze Zhou , Huanqiu Li , Qinghua Hu

{"title":"Attributes novel drug candidate: Constitutive GPCR signal bias mediated by purinergic receptors","authors":"Li Yin , Kexin Ni , Tianqi Mao , Sheng Tian , Chunxiao Liu , Jiayao Chen , Mengze Zhou , Huanqiu Li , Qinghua Hu","doi":"10.1016/j.pharmthera.2025.108802","DOIUrl":"10.1016/j.pharmthera.2025.108802","url":null,"abstract":"<div><div>G protein-coupled receptors (GPCRs) can transmit signals via G protein-dependent or independent pathways due to the conformational changes of receptors and ligands, which is called biased signaling. This concept posits that ligands can selectively activate a specific signaling pathway after receptor activation, facilitating downstream signaling along a preferred pathway. Biased agonism enables the development of ligands that prioritize therapeutic signaling pathways while mitigating on-target undesired effects. As a class of GPCRs located on the surface of cell membranes, the discovery and clinical implementation of adenosine and P2Y receptors purinergic signaling modulators have progressed dramatically. However, many preclinical drug candidates targeting purinergic receptors have failed in clinical trials due to limited efficacy and/or severe on-target undesired effects. To overcome the key barriers typically encountered when transitioning ligands into the clinic, the renewed impetus has focused on the modulation of purinergic receptor function by exogenous agonists/antagonists and allosteric modulators to exploit biased agonism. This article provides a brief overview of the research progress on the mechanism of purinergic biased signal transduction from the conformational changes of purinergic GPCRs and biased ligands primarily, and highlights therapeutically relevant biased agonism at purinergic receptors.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108802"},"PeriodicalIF":12.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Roles of NLRC4 inflammasome in neurological disorders: Mechanisms, implications, and therapeutic potential NLRC4 炎性体在神经系统疾病中的作用：机制、影响和治疗潜力

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-03-01 Epub Date: 2025-01-22 DOI: 10.1016/j.pharmthera.2025.108803

Wen Zhang , Li Zhang , Shuo Fu , Rong Yan , Xue Zhang , Junke Song , Yang Lu

{"title":"Roles of NLRC4 inflammasome in neurological disorders: Mechanisms, implications, and therapeutic potential","authors":"Wen Zhang , Li Zhang , Shuo Fu , Rong Yan , Xue Zhang , Junke Song , Yang Lu","doi":"10.1016/j.pharmthera.2025.108803","DOIUrl":"10.1016/j.pharmthera.2025.108803","url":null,"abstract":"<div><div>The nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 4 (NLRC4) inflammasome, a vital component of the innate immune system, is known for defending against bacterial infections. However, recent insights have revealed its significant impact on neurological disorders. This comprehensive review discussed the mechanisms underlying the activation and regulation of the NLRC4 inflammasome, highlighting the complexity of its response to cellular stress and damage signals. The biological functions of NLRC4 were explored, particularly its influence on cytokine production and the induction of pyroptosis, a form of inflammatory cell death. This review further emphasized the role of the NLRC4 inflammasome in brain injuries and neurodegenerative disorders. In the realm of brain injuries such as stroke and traumatic brain injury, as well as in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, the NLRC4 inflammasome played a pivotal role in modulating neuroinflammatory responses, which was crucial for understanding the progression and potential therapeutic targeting of these conditions. The emerging role of NLRC4 in psychiatric disorders and its potential impact on glioma progression were also examined. Additionally, this review presented a thorough summary of the latest research on inhibitors that impeded the assembly and activation of the NLRC4 inflammasome, pointing to new therapeutic possibilities in neurological disorders. In conclusion, by integrating current knowledge on the activation and regulation of NLRC4 with its biological functions and clinical implications, this article underscored the importance of NLRC4 inflammasome in neurological pathologies, which opened new possibilities for the treatment of challenging neurological conditions.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108803"},"PeriodicalIF":12.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Conformationally adaptive therapeutic peptides for diseases caused by intrinsically disordered proteins (IDPs). New paradigm for drug discovery: Target the target, not the arrow 构象适应性治疗肽对内在无序蛋白（IDPs）引起的疾病。药物发现的新范例：瞄准目标，而不是箭头。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-03-01 Epub Date: 2025-01-17 DOI: 10.1016/j.pharmthera.2025.108797

Jacques Fantini , Fodil Azzaz , Coralie Di Scala , Anaïs Aulas , Henri Chahinian , Nouara Yahi

{"title":"Conformationally adaptive therapeutic peptides for diseases caused by intrinsically disordered proteins (IDPs). New paradigm for drug discovery: Target the target, not the arrow","authors":"Jacques Fantini , Fodil Azzaz , Coralie Di Scala , Anaïs Aulas , Henri Chahinian , Nouara Yahi","doi":"10.1016/j.pharmthera.2025.108797","DOIUrl":"10.1016/j.pharmthera.2025.108797","url":null,"abstract":"<div><div>The traditional model of protein structure determined by the amino acid sequence is today seriously challenged by the fact that approximately half of the human proteome is made up of proteins that do not have a stable 3D structure, either partially or in totality. These proteins, called intrinsically disordered proteins (IDPs), are involved in numerous physiological functions and are associated with severe pathologies, e.g. Alzheimer, Parkinson, Creutzfeldt-Jakob, amyotrophic lateral sclerosis (ALS), and type 2 diabetes. Targeting these proteins is challenging for two reasons: i) we need to preserve their physiological functions, and ii) drug design by molecular docking is not possible due to the lack of reliable starting conditions. Faced with this challenge, the solutions proposed by artificial intelligence (AI) such as AlphaFold are clearly unsuitable. Instead, we suggest an innovative approach consisting of mimicking, in short synthetic peptides, the conformational flexibility of IDPs. These peptides, which we call adaptive peptides, are derived from the domains of IDPs that become structured after interacting with a ligand. Adaptive peptides are designed with the aim of selectively antagonizing the harmful effects of IDPs, without targeting them directly but through selected ligands, without affecting their physiological properties. This “target the target, not the arrow” strategy is promised to open a new route to drug discovery for currently undruggable proteins.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108797"},"PeriodicalIF":12.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unfolded protein responses: Dynamic machinery in wound healing 未折叠蛋白反应：伤口愈合的动态机制。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-03-01 Epub Date: 2025-01-17 DOI: 10.1016/j.pharmthera.2025.108798

Morgan Minjares , Pattaraporn Thepsuwan , Kezhong Zhang , Jie-Mei Wang

{"title":"Unfolded protein responses: Dynamic machinery in wound healing","authors":"Morgan Minjares , Pattaraporn Thepsuwan , Kezhong Zhang , Jie-Mei Wang","doi":"10.1016/j.pharmthera.2025.108798","DOIUrl":"10.1016/j.pharmthera.2025.108798","url":null,"abstract":"<div><div>Skin wound healing is a dynamic process consisting of multiple cellular and molecular events that must be tightly coordinated to repair the injured tissue efficiently. The healing pace is decided by the type of injuries, the depth and size of the wounds, and whether wound infections occur. However, aging, comorbidities, genetic factors, hormones, and nutrition also impact healing outcomes. During wound healing, cells undergo robust processes of synthesizing new proteins and degrading multifunctional proteins. This imposes an increasing burden on the endoplasmic reticulum (ER), causing ER stress. Unfolded protein response (UPR) represents a collection of highly conserved stress signaling pathways originated from the ER to maintain protein homeostasis and modulate cell physiology. UPR is known to be beneficial for tissue healing. However, when excessive ER stress exceeds ER's folding potential, UPR pathways trigger cell apoptosis, interrupting tissue regeneration. Understanding how UPR pathways modulate the skin's response to injuries is critical for new interventions toward the control of acute and chronic wounds. Herein, in this review, we focus on the participation of the canonical and noncanonical UPR pathways during different stages of wound healing, summarize the available evidence demonstrating UPR's unique position in balancing homeostasis and pathophysiology of healing tissues, and highlight the understudied areas where therapeutic opportunities may arise.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108798"},"PeriodicalIF":12.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 TAK1: Evolution of inhibitors, challenges, and future directions 靶向TAK1：抑制剂的发展、挑战和未来方向。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-03-01 Epub Date: 2025-02-03 DOI: 10.1016/j.pharmthera.2025.108810

Nika Strašek Benedik , Matic Proj , Christian Steinebach , Matej Sova , Izidor Sosič

{"title":"Targeting TAK1: Evolution of inhibitors, challenges, and future directions","authors":"Nika Strašek Benedik , Matic Proj , Christian Steinebach , Matej Sova , Izidor Sosič","doi":"10.1016/j.pharmthera.2025.108810","DOIUrl":"10.1016/j.pharmthera.2025.108810","url":null,"abstract":"<div><div>The increasing incidence of inflammatory and malignant diseases signifies the need to develop first-in-class drugs with novel mechanisms of action. In this respect, the transforming growth factor (TGF)-β-activated kinase 1 (TAK1), an essential part of several signaling pathways, is considered relevant and promising. This manuscript provides a brief overview of the signal transduction orchestrated by TAK1 within these pathways, followed by an in-depth and thorough analysis of the chemical matter demonstrated to inhibit this kinase. Special attention is given to the selectivity profiling of inhibitors, as well as to the outcomes of their biological characterization. Because published TAK1 inhibitors differ significantly in their kinome selectivity, active-site binding, and biological activity, we hope that this review will allow a judicial estimation of their quality and usefulness for TAK1-addressing assays. Our thoughts on the perspectives and possible developments of the field are also provided to assist scientists who are involved in the design and development of TAK1-targeting modulators.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108810"},"PeriodicalIF":12.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Semaphorin 3s signaling in the central nervous system: Mechanisms and therapeutic implication for brain diseases 中枢神经系统信号素3s信号：脑疾病的机制和治疗意义。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-03-01 Epub Date: 2025-01-23 DOI: 10.1016/j.pharmthera.2025.108800

Ya-Ping Lu , Yi-Ling Luo , Zhou-Yue Wu , Chao Han , Yin-Zhi Jin , Jun-Ming Han , Shu-Yang Chen , Fei Teng , Feng Han , Xiu-Xiu Liu , Ying-Mei Lu

引用次数: 0

Uncovering the intricacies of O-GlcNAc modification in cognitive impairment: New insights from regulation to therapeutic targeting 揭示认知障碍中 O-GlcNAc 修饰的复杂性：从调控到靶向治疗的新见解。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-02-01 Epub Date: 2024-11-26 DOI: 10.1016/j.pharmthera.2024.108761

Jianhui Wang , Ning Jiang , Feng Liu , Chenran Wang , Wenxia Zhou

{"title":"Uncovering the intricacies of O-GlcNAc modification in cognitive impairment: New insights from regulation to therapeutic targeting","authors":"Jianhui Wang , Ning Jiang , Feng Liu , Chenran Wang , Wenxia Zhou","doi":"10.1016/j.pharmthera.2024.108761","DOIUrl":"10.1016/j.pharmthera.2024.108761","url":null,"abstract":"<div><div>O-linked β-<em>N</em>-acetylglucosamine (O-GlcNAc) represents a post-translational modification that occurs on serine or threonine residues on various proteins. This conserved modification interacts with vital cellular pathways. Although O-GlcNAc is widely distributed throughout the body, it is particularly enriched in the brain, where most proteins are O-GlcNAcylated. Recent studies have established a causal link between O-GlcNAc regulation in the brain and alterations in neurophysiological function. Alterations in O-GlcNAc levels in the brain are associated with the pathogenesis of several neurogenic diseases that can lead to cognitive impairment. Remarkably, manipulation of O-GlcNAc levels demonstrated a protective effect on cognitive function. Although the precise molecular mechanism of O-GlcNAc modification in the nervous system remains elusive, its regulation is fundamental to multiple neural and cognitive functions, fluctuating levels during normal and pathological cognitive processes. In this review, we highlight the significant functional importance of O-GlcNAc modification in pathological cognitive impairments and the potential application of O-GlcNAc as a promising target for the intervention or amelioration of cognitive impairments.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"266 ","pages":"Article 108761"},"PeriodicalIF":12.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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