Pharmacology & Therapeutics最新文献_第3页

Therapeutic implications of impaired nuclear receptor function and dysregulated metabolism in Wilson's disease Wilson病核受体功能受损和代谢失调的治疗意义。

IF 13.5 1区医学

Pharmacology & Therapeutics Pub Date : 2023-11-01 DOI: 10.1016/j.pharmthera.2023.108529

Clavia Ruth Wooton-Kee

{"title":"Therapeutic implications of impaired nuclear receptor function and dysregulated metabolism in Wilson's disease","authors":"Clavia Ruth Wooton-Kee","doi":"10.1016/j.pharmthera.2023.108529","DOIUrl":"10.1016/j.pharmthera.2023.108529","url":null,"abstract":"<div><p><span><span>Copper is an essential trace element that is required for the activity of many enzymes and cellular processes<span>, including energy homeostasis and neurotransmitter biosynthesis; however, excess copper accumulation results in significant cellular toxicity. The liver is the major organ for maintaining copper homeostasis. Inactivating mutations of the copper-transporting P-type ATPase, ATP7B, result in Wilson's disease, an </span></span>autosomal recessive disorder<span> that requires life-long medicinal therapy or liver transplantation. Current treatment protocols are limited to either sequestration of copper via chelation or reduction of copper absorption in the gut (zinc therapy). The goal of these strategies is to reduce free copper, redox stress, and cellular toxicity. Several lines of evidence in Wilson's disease animal models and patients have revealed altered hepatic metabolism and impaired hepatic nuclear receptor activity. Nuclear receptors are transcription factors that coordinate hepatic metabolism in normal and diseased livers, and several hepatic nuclear receptors have decreased activity in Wilson's disease and </span></span><em>Atp7b</em><sup><em>−/−</em></sup> models. In this review, we summarize the basic physiology that underlies Wilson's disease pathology, Wilson's disease animal models, and the possibility of targeting nuclear receptor activity in Wilson's disease patients.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"251 ","pages":"Article 108529"},"PeriodicalIF":13.5,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41176859","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

Severe hypertriglyceridemia: Existing and emerging therapies 严重高甘油三酯血症：现有和新兴的治疗方法。

IF 13.5 1区医学

Pharmacology & Therapeutics Pub Date : 2023-11-01 DOI: 10.1016/j.pharmthera.2023.108544

Waqas A. Malick , Ron Do , Robert S. Rosenson

{"title":"Severe hypertriglyceridemia: Existing and emerging therapies","authors":"Waqas A. Malick , Ron Do , Robert S. Rosenson","doi":"10.1016/j.pharmthera.2023.108544","DOIUrl":"10.1016/j.pharmthera.2023.108544","url":null,"abstract":"<div><p>Severe hypertriglyceridemia<span><span><span> (sHTG), defined as a triglyceride (TG) concentration ≥ 500 mg/dL (≥ 5.7 mmol/L) is an important risk factor for </span>acute pancreatitis<span><span>. Although lifestyle, some medications, and certain conditions such as diabetes may lead to HTG, sHTG results from a combination of major and minor genetic defects in proteins that regulate TG lipolysis. Familial chylomicronemia syndrome (FCS) is a rare disorder caused by complete loss of function in lipoprotein lipase (LPL) or LPL activating proteins due to two homozygous recessive traits or compound heterozygous traits. Multifactorial chylomicronemia syndrome (MCS) and sHTG are due to the accumulation of rare heterozygous variants and polygenic defects that predispose individuals to sHTG phenotypes. Until recently, treatment of sHTG focused on lifestyle interventions, control of secondary factors, and nonselective </span>pharmacotherapies that had modest TG-lowering efficacy and no corresponding reductions in </span></span>atherosclerotic cardiovascular disease events. Genetic discoveries have allowed for the development of novel pathway-specific therapeutics targeting LPL modulating proteins. New targets directed towards inhibition of apolipoprotein C-III (apoC-III), angiopoietin-like protein 3 (ANGPTL3), angiopoietin-like protein 4 (ANGPTL4), and fibroblast growth factor-21 (FGF21) offer far more efficacy in treating the various phenotypes of sHTG and opportunities to reduce the risk of acute pancreatitis and atherosclerotic cardiovascular disease events.</span></p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"251 ","pages":"Article 108544"},"PeriodicalIF":13.5,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41231236","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

NLRP3 and cancer: Pathogenesis and therapeutic opportunities NLRP3和癌症：发病机制和治疗机会。

IF 13.5 1区医学

Pharmacology & Therapeutics Pub Date : 2023-11-01 DOI: 10.1016/j.pharmthera.2023.108545

Isak W. Tengesdal, Charles A. Dinarello, Carlo Marchetti

引用次数: 0

Signaling pathways in brain ischemia: Mechanisms and therapeutic implications 脑缺血的信号通路：机制和治疗意义。

IF 13.5 1区医学

Pharmacology & Therapeutics Pub Date : 2023-11-01 DOI: 10.1016/j.pharmthera.2023.108541

Wen Lin , Xiang-Yu Zhao , Jia-wen Cheng , Li-tao Li , Quan Jiang , Yi-Xuan Zhang , Feng Han

{"title":"Signaling pathways in brain ischemia: Mechanisms and therapeutic implications","authors":"Wen Lin , Xiang-Yu Zhao , Jia-wen Cheng , Li-tao Li , Quan Jiang , Yi-Xuan Zhang , Feng Han","doi":"10.1016/j.pharmthera.2023.108541","DOIUrl":"10.1016/j.pharmthera.2023.108541","url":null,"abstract":"<div><p>Ischemic stroke<span> occurs when the arteries supplying blood to the brain are narrowed or blocked, inducing damage to brain tissue due to a lack of blood supply. One effective way to reduce brain damage and alleviate symptoms is to reopen blocked blood vessels in a timely manner and reduce neuronal damage. To achieve this, researchers have focused on identifying key cellular signaling pathways that can be targeted with drugs. These pathways include oxidative/nitrosative stress, excitatory amino acids and their receptors, inflammatory signaling molecules, metabolic pathways, ion channels, and other molecular events involved in stroke pathology. However, evidence suggests that solely focusing on protecting neurons may not yield satisfactory clinical results. Instead, researchers should consider the multifactorial and complex mechanisms underlying stroke pathology, including the interactions between different components of the neurovascular unit. Such an approach is more representative of the actual pathological process observed in clinical settings. This review summarizes recent research on the multiple molecular mechanisms and drug targets in ischemic stroke, as well as recent advances in novel therapeutic strategies. Finally, we discuss the challenges and future prospects of new strategies based on the biological characteristics of stroke.</span></p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"251 ","pages":"Article 108541"},"PeriodicalIF":13.5,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41092368","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

Sulfoconjugation of protein peptides and glycoproteins in physiology and diseases 生理学和疾病中蛋白质肽和糖蛋白的硫酸偶联。

IF 13.5 1区医学

Pharmacology & Therapeutics Pub Date : 2023-11-01 DOI: 10.1016/j.pharmthera.2023.108540

Pengfei Xu , Xinran Cai , Xiuchen Guan , Wen Xie

{"title":"Sulfoconjugation of protein peptides and glycoproteins in physiology and diseases","authors":"Pengfei Xu , Xinran Cai , Xiuchen Guan , Wen Xie","doi":"10.1016/j.pharmthera.2023.108540","DOIUrl":"10.1016/j.pharmthera.2023.108540","url":null,"abstract":"<div><p><span>Protein sulfoconjugation, or sulfation, represents a critical post-translational modification (PTM) process that involves the attachment of sulfate groups to various positions of substrates within the protein peptides or glycoproteins<span>. This process plays a dynamic and complex role in many physiological and pathological processes. Here, we summarize the importance of sulfation in the fields of oncology, virology, drug-induced liver injury (DILI), inflammatory bowel disease (IBD), and </span></span>atherosclerosis<span>. In oncology, sulfation is involved in tumor initiation, progression, and migration. In virology, sulfation influences viral entry, replication, and host immune response. In DILI, sulfation is associated with the incidence of DILI, where altered sulfation affects drug metabolism and toxicity. In IBD, dysregulation of sulfation compromises mucosal barrier and immune response. In atherosclerosis, sulfation influences the development of atherosclerosis by modulating the accumulation of lipoprotein, and the inflammation, proliferation, and migration of smooth muscle cells. The current review underscores the importance of further research to unravel the underlying mechanisms and therapeutic potential of targeting sulfoconjugation in various diseases. A better understanding of sulfation could facilitate the emergence of innovative diagnostic or therapeutic strategies.</span></p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"251 ","pages":"Article 108540"},"PeriodicalIF":13.5,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41094639","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

Neuropathic pain: From actual pharmacological treatments to new therapeutic horizons 神经性疼痛：从实际的药物治疗到新的治疗视野。

IF 13.5 1区医学

Pharmacology & Therapeutics Pub Date : 2023-11-01 DOI: 10.1016/j.pharmthera.2023.108546

Maxime Thouaye , Ipek Yalcin

{"title":"Neuropathic pain: From actual pharmacological treatments to new therapeutic horizons","authors":"Maxime Thouaye , Ipek Yalcin","doi":"10.1016/j.pharmthera.2023.108546","DOIUrl":"10.1016/j.pharmthera.2023.108546","url":null,"abstract":"<div><p>Neuropathic pain<span><span><span>, caused by a lesion or disease affecting the somatosensory system, affects between 3 and 17% of the general population. The treatment of neuropathic pain is challenging due to its heterogeneous etiologies, lack of objective diagnostic tools and resistance to classical analgesic drugs. First-line treatments recommended by the Special Interest Group on Neuropathic Pain (NeuPSIG) and European Federation of Neurological Societies (EFNS) include gabapentinoids, </span>tricyclic antidepressants (TCAs) and selective serotonin </span>noradrenaline reuptake inhibitors (SNRIs). Nevertheless these treatments have modest efficacy or dose limiting side effects. There is therefore a growing number of preclinical and clinical studies aim at developing new treatment strategies to treat neuropathic pain with better efficacy, selectivity, and less side effects. In this review, after a brief description of the mechanisms of action, efficacy, and limitations of current therapeutic drugs, we reviewed new preclinical and clinical targets currently under investigation, as well as promising non-pharmacological alternatives and their potential co-use with pharmacological treatments.</span></p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"251 ","pages":"Article 108546"},"PeriodicalIF":13.5,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41187315","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: 1

Obesity and its comorbidities, current treatment options and future perspectives: Challenging bariatric surgery? 肥胖及其合并症，目前的治疗选择和未来前景：挑战减肥手术？

IF 13.5 1区医学

Pharmacology & Therapeutics Pub Date : 2023-11-01 DOI: 10.1016/j.pharmthera.2023.108549

Simon Kloock , Christian G. Ziegler , Ulrich Dischinger

{"title":"Obesity and its comorbidities, current treatment options and future perspectives: Challenging bariatric surgery?","authors":"Simon Kloock , Christian G. Ziegler , Ulrich Dischinger","doi":"10.1016/j.pharmthera.2023.108549","DOIUrl":"10.1016/j.pharmthera.2023.108549","url":null,"abstract":"<div><p>Obesity and its comorbidities, including type 2 diabetes mellitus, cardiovascular disease, heart failure and non-alcoholic liver disease are a major health and economic burden with steadily increasing numbers worldwide. The need for effective pharmacological treatment options is strong, but, until recently, only few drugs have proven sufficient efficacy and safety. This article provides a comprehensive overview of obesity and its comorbidities, with a special focus on organ-specific pathomechanisms. Bariatric surgery as the so far most-effective therapeutic strategy, current pharmacological treatment options and future treatment strategies will be discussed. An increasing knowledge about the gut-brain axis and especially the identification and physiology of incretins unfolds a high number of potential drug candidates with impressive weight-reducing potential. Future multi-modal therapeutic concepts in obesity treatment may surpass the effectivity of bariatric surgery not only with regard to weight loss, but also to associated comorbidities.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"251 ","pages":"Article 108549"},"PeriodicalIF":13.5,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0163725823002139/pdfft?md5=3db00c13c3ab618b50ce8d8e26a26802&pid=1-s2.0-S0163725823002139-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50160197","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: 2

Modulating glucocorticoid receptor actions in physiology and pathology: Insights from coregulators 调节糖皮质激素受体在生理学和病理学中的作用：来自协同调节因子的见解。

IF 13.5 1区医学

Pharmacology & Therapeutics Pub Date : 2023-11-01 DOI: 10.1016/j.pharmthera.2023.108531

Lina Fadel , Marija Dacic , Vlera Fonda , Baila A. Sokolsky , Fabiana Quagliarini , Inez Rogatsky , N. Henriette Uhlenhaut

{"title":"Modulating glucocorticoid receptor actions in physiology and pathology: Insights from coregulators","authors":"Lina Fadel , Marija Dacic , Vlera Fonda , Baila A. Sokolsky , Fabiana Quagliarini , Inez Rogatsky , N. Henriette Uhlenhaut","doi":"10.1016/j.pharmthera.2023.108531","DOIUrl":"10.1016/j.pharmthera.2023.108531","url":null,"abstract":"<div><p>Glucocorticoids (GCs) are a class of steroid hormones that regulate key physiological processes such as metabolism, immune function, and stress responses. The effects of GCs are mediated by the glucocorticoid receptor (GR), a ligand-dependent transcription factor that activates or represses the expression of hundreds to thousands of genes in a tissue- and physiological state-specific manner. The activity of GR is modulated by numerous coregulator proteins that interact with GR in response to different stimuli assembling into a multitude of DNA-protein complexes and facilitate the integration of these signals, helping GR to communicate with basal transcriptional machinery and chromatin. Here, we provide a brief overview of the physiological and molecular functions of GR, and discuss the roles of GR coregulators in the immune system, key metabolic tissues and the central nervous system. We also present an analysis of the GR interactome in different cells and tissues, which suggests tissue-specific utilization of GR coregulators, despite widespread functions shared by some of them.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"251 ","pages":"Article 108531"},"PeriodicalIF":13.5,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S016372582300195X/pdfft?md5=35115605c8fbdbcd6f444bf2476b765d&pid=1-s2.0-S016372582300195X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10286424","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

Biologics for severe asthma and beyond 用于严重哮喘及其他疾病的生物制品。

IF 13.5 1区医学

Pharmacology & Therapeutics Pub Date : 2023-10-30 DOI: 10.1016/j.pharmthera.2023.108551

Carlo Mümmler , Katrin Milger

引用次数: 0

Multitarget antibacterial drugs: An effective strategy to combat bacterial resistance 多靶点抗菌药物:对抗细菌耐药性的有效策略

IF 13.5 1区医学

Pharmacology & Therapeutics Pub Date : 2023-10-30 DOI: 10.1016/j.pharmthera.2023.108550

Jin Feng , Youle Zheng , Wanqing Ma , Awais Ihsan , Haihong Hao , Guyue Cheng , Xu Wang

{"title":"Multitarget antibacterial drugs: An effective strategy to combat bacterial resistance","authors":"Jin Feng , Youle Zheng , Wanqing Ma , Awais Ihsan , Haihong Hao , Guyue Cheng , Xu Wang","doi":"10.1016/j.pharmthera.2023.108550","DOIUrl":"https://doi.org/10.1016/j.pharmthera.2023.108550","url":null,"abstract":"<div><p>The rise of antibiotic resistance and the decrease in the discovery of new antibiotics have caused a global health crisis. Of particular concern is the fact that despite efforts to develop new antibiotics, drug discovery is unable to keep up with the rapid development of resistance. This ongoing crisis highlights the fact that single-target drugs may not always exhibit satisfactory therapeutic effects and are prone to target mutations and resistance due to the complexity of bacterial mechanisms. Retrospective studies have shown that most successful antibiotics have multiple targets. Compared with single-target drugs, successfully designed multitarget drugs can simultaneously regulate multiple targets to reduce resistance caused by single-target mutations or expression changes. In addition to a lower risk of drug–drug interactions, multitarget drugs show superior pharmacokinetics and higher patient compliance compared with combination therapies. Therefore, to reduce resistance, many efforts have been made to discover and design multitarget drugs with different chemical structures and functions. Although there have been numerous studies on how to develop drugs and slow down the development of drug resistance, the reduction of bacterial resistance by multitarget antibacterial drugs has not received widespread attention and is rarely mentioned in the peer-reviewed literature. This review summarises the development of antibiotic resistance and the mechanisms proposed for its emergence, examines the potential of multitarget drugs as an effective strategy to slow the development of resistance, and discusses the rationale for multitarget drug therapy. We also describe multitarget antibacterial compounds with the potential to reduce drug resistance and the available strategies to develop multitarget drugs.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"252 ","pages":"Article 108550"},"PeriodicalIF":13.5,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71726204","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