Pharmacology & Therapeutics最新文献

{"title":"Potential application of natural compounds in ischaemic stroke: Focusing on the mechanisms underlying “lysosomocentric” dysfunction of the autophagy-lysosomal pathway","authors":"Yueyang Liu ,&nbsp;Qingbo Liu ,&nbsp;Hanxiao Shang ,&nbsp;Jichong Li ,&nbsp;He Chai ,&nbsp;Kaixuan Wang ,&nbsp;Zhenkun Guo ,&nbsp;Tianyu Luo ,&nbsp;Shiqi Liu ,&nbsp;Yan Liu ,&nbsp;Xuemei Wang ,&nbsp;Hangyi Zhang ,&nbsp;Chunfu Wu ,&nbsp;Shao-Jiang Song ,&nbsp;Jingyu Yang","doi":"10.1016/j.pharmthera.2024.108721","DOIUrl":"10.1016/j.pharmthera.2024.108721","url":null,"abstract":"<div><p>Ischaemic stroke (IS) is the second leading cause of death and a major cause of disability worldwide. Currently, the clinical management of IS still depends on restoring blood flow via pharmacological thrombolysis or mechanical thrombectomy, with accompanying disadvantages of narrow therapeutic time window and risk of haemorrhagic transformation. Thus, novel pathophysiological mechanisms and targeted therapeutic candidates are urgently needed. The autophagy-lysosomal pathway (ALP), as a dynamic cellular lysosome-based degradative process, has been comprehensively studied in recent decades, including its upstream regulatory mechanisms and its role in mediating neuronal fate after IS. Importantly, increasing evidence has shown that IS can lead to lysosomal dysfunction, such as lysosomal membrane permeabilization, impaired lysosomal acidity, lysosomal storage disorder, and dysfunctional lysosomal ion homeostasis, which are involved in the IS-mediated defects in ALP function. There is tightly regulated crosstalk between transcription factor EB (TFEB), mammalian target of rapamycin (mTOR) and lysosomal function, but their relationship remains to be systematically summarized. Notably, a growing body of evidence emphasizes the benefits of naturally derived compounds in the treatment of IS via modulation of ALP function. However, little is known about the roles of natural compounds as modulators of lysosomes in the treatment of IS. Therefore, in this context, we provide an overview of the current understanding of the mechanisms underlying IS-mediated ALP dysfunction, from a lysosomal perspective. We also provide an update on the effect of natural compounds on IS, according to their chemical structural types, in different experimental stroke models, cerebral regions and cell types, with a primary focus on lysosomes and autophagy initiation. This review aims to highlight the therapeutic potential of natural compounds that target lysosomal and ALP function for IS treatment.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"263 ","pages":"Article 108721"},"PeriodicalIF":12.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142243356","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}

{"title":"Artificial intelligence with mass spectrometry-based multimodal molecular profiling methods for advancing therapeutic discovery of infectious diseases","authors":"Jingjing Liu ,&nbsp;Chaohui Bao ,&nbsp;Jiaxin Zhang ,&nbsp;Zeguang Han ,&nbsp;Hai Fang ,&nbsp;Haitao Lu","doi":"10.1016/j.pharmthera.2024.108712","DOIUrl":"10.1016/j.pharmthera.2024.108712","url":null,"abstract":"<div><p>Infectious diseases, driven by a diverse array of pathogens, can swiftly undermine public health systems. Accurate diagnosis and treatment of infectious diseases—centered around the identification of biomarkers and the elucidation of disease mechanisms—are in dire need of more versatile and practical analytical approaches. Mass spectrometry (MS)-based molecular profiling methods can deliver a wealth of information on a range of functional molecules, including nucleic acids, proteins, and metabolites. While MS-driven omics analyses can yield vast datasets, the sheer complexity and multi-dimensionality of MS data can significantly hinder the identification and characterization of functional molecules within specific biological processes and events. Artificial intelligence (AI) emerges as a potent complementary tool that can substantially enhance the processing and interpretation of MS data. AI applications in this context lead to the reduction of spurious signals, the improvement of precision, the creation of standardized analytical frameworks, and the increase of data integration efficiency. This critical review emphasizes the pivotal roles of MS based omics strategies in the discovery of biomarkers and the clarification of infectious diseases. Additionally, the review underscores the transformative ability of AI techniques to enhance the utility of MS-based molecular profiling in the field of infectious diseases by refining the quality and practicality of data produced from omics analyses. In conclusion, we advocate for a forward-looking strategy that integrates AI with MS-based molecular profiling. This integration aims to transform the analytical landscape and the performance of biological molecule characterization, potentially down to the single-cell level. Such advancements are anticipated to propel the development of AI-driven predictive models, thus improving the monitoring of diagnostics and therapeutic discovery for the ongoing challenge related to infectious diseases.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"263 ","pages":"Article 108712"},"PeriodicalIF":12.0,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142144799","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}

{"title":"CircRNAs as upstream regulators of miRNA//HMGA2 axis in human cancer","authors":"Qiqi Sun ,&nbsp;Xiaoyong Lei ,&nbsp;Xiaoyan Yang","doi":"10.1016/j.pharmthera.2024.108711","DOIUrl":"10.1016/j.pharmthera.2024.108711","url":null,"abstract":"<div><div>High mobility group protein A2 (HMGA2) is widely recognized as a chromatin-binding protein, whose overexpression is observed in nearly all human cancers. It exerts its oncogenic effects by influencing various cellular processes such as the epithelial-mesenchymal transition, cell differentiation, and DNA damage repair. MicroRNA (miRNA) serves as a pivotal gene expression regulator, concurrently modulating multiple genes implicated in cancer progression, including HMGA2. It also serves as a significant biomarker for cancer. Circular RNA (circRNA) plays a crucial role in gene regulation primarily by sequestering miRNAs and impeding their ability to enhance the expression of other genes, including HMGA2. Increasingly, studies have underscored the vital role of miRNA/HMGA2 interactions in cancer. Given the significance of circRNA as an upstream regulatory mediator and the complexity of regulatory mechanisms, we hereby present a comprehensive overview of the pivotal role of circRNAs as upstream regulators of the miRNA//HMGA2 axis in human cancers. This insight may herald a novel direction for future cancer research.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"263 ","pages":"Article 108711"},"PeriodicalIF":12.0,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118640","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}

{"title":"microRNAs in kidney diseases: Regulation, therapeutics, and biomarker potential","authors":"Zhiwen Liu ,&nbsp;Ying Fu ,&nbsp;Mingjuan Yan ,&nbsp;Subing Zhang ,&nbsp;Juan Cai ,&nbsp;Guochun Chen ,&nbsp;Zheng Dong","doi":"10.1016/j.pharmthera.2024.108709","DOIUrl":"10.1016/j.pharmthera.2024.108709","url":null,"abstract":"<div><p>MicroRNAs (miRNAs) are small, non-coding RNA molecules that play a crucial role in regulating gene expression by inhibiting the translation of their specific target messenger RNAs. To date, numerous studies have demonstrated changes in the expression of miRNAs in the kidneys throughout the progression of both acute kidney injury (AKI) and chronic kidney disease (CKD) in both human patients and experimental models. The role of specific microRNAs in the pathogenesis of kidney diseases has also been demonstrated. Further studies have elucidated the regulation of these microRNAs in diseased kidneys. Besides, certain miRNAs are detected in plasma and/or urine in kidney diseases and are potential diagnostic biomarkers. In this review, we provide an overview of recent developments in our understanding of how miRNAs contribute to kidney diseases. We also explore the potential of miRNAs as both biomarkers and therapeutic targets for these conditions, and highlight future research directions.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"262 ","pages":"Article 108709"},"PeriodicalIF":12.0,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054567","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}

{"title":"Targeting organ-specific mitochondrial dysfunction to improve biological aging","authors":"Corina T. Madreiter-Sokolowski ,&nbsp;Ursula Hiden ,&nbsp;Jelena Krstic ,&nbsp;Katrin Panzitt ,&nbsp;Martin Wagner ,&nbsp;Christian Enzinger ,&nbsp;Michael Khalil ,&nbsp;Mahmoud Abdellatif ,&nbsp;Ernst Malle ,&nbsp;Tobias Madl ,&nbsp;Elena Osto ,&nbsp;Markus Schosserer ,&nbsp;Christoph J. Binder ,&nbsp;Andrea Olschewski","doi":"10.1016/j.pharmthera.2024.108710","DOIUrl":"10.1016/j.pharmthera.2024.108710","url":null,"abstract":"<div><p>In an aging society, unveiling new anti-aging strategies to prevent and combat aging-related diseases is of utmost importance. Mitochondria are the primary ATP production sites and key regulators of programmed cell death. Consequently, these highly dynamic organelles play a central role in maintaining tissue function, and mitochondrial dysfunction is a pivotal factor in the progressive age-related decline in cellular homeostasis and organ function.</p><p>The current review examines recent advances in understanding the interplay between mitochondrial dysfunction and organ-specific aging. Thereby, we dissect molecular mechanisms underlying mitochondrial impairment associated with the deterioration of organ function, exploring the role of mitochondrial DNA, reactive oxygen species homeostasis, metabolic activity, damage-associated molecular patterns, biogenesis, turnover, and dynamics.</p><p>We also highlight emerging therapeutic strategies in preclinical and clinical tests that are supposed to rejuvenate mitochondrial function, such as antioxidants, mitochondrial biogenesis stimulators, and modulators of mitochondrial turnover and dynamics. Furthermore, we discuss potential benefits and challenges associated with the use of these interventions, emphasizing the need for organ-specific approaches given the unique mitochondrial characteristics of different tissues.</p><p>In conclusion, this review highlights the therapeutic potential of addressing mitochondrial dysfunction to mitigate organ-specific aging, focusing on the skin, liver, lung, brain, skeletal muscle, and lung, as well as on the reproductive, immune, and cardiovascular systems. Based on a comprehensive understanding of the multifaceted roles of mitochondria, innovative therapeutic strategies may be developed and optimized to combat biological aging and promote healthy aging across diverse organ systems.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"262 ","pages":"Article 108710"},"PeriodicalIF":12.0,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S016372582400130X/pdfft?md5=8f87dab5dd66f3b5f2112c8e90a66766&pid=1-s2.0-S016372582400130X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046094","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}

{"title":"C-type natriuretic peptide (CNP): The cardiovascular system and beyond","authors":"Yasmin A. Dickinson,&nbsp;Amie J. Moyes,&nbsp;Adrian J. Hobbs","doi":"10.1016/j.pharmthera.2024.108708","DOIUrl":"10.1016/j.pharmthera.2024.108708","url":null,"abstract":"<div><p>C-type natriuretic peptide (CNP) represents the ‘local’ member of the natriuretic peptide family, functioning in an autocrine or paracrine capacity to modulate a hugely diverse portfolio of physiological processes. Whilst the best-characterised of these regulatory roles are in the cardiovascular system, akin to its predominantly endocrine siblings atrial (ANP) and brain (BNP) natriuretic peptides, CNP governs many additional, unrelated mechanisms including bone growth, gamete maturation, auditory processing, and neuronal integrity. Furthermore, there is currently great interest in mimicking the biological activity of CNP for therapeutic gain in many of these disparate organ systems. Herein, we provide an overview of the physiology, pathophysiology and pharmacology of CNP in both cardiovascular and non-cardiovascular settings.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"262 ","pages":"Article 108708"},"PeriodicalIF":12.0,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0163725824001281/pdfft?md5=a6600f580a45edf02b1283f72e0e53df&pid=1-s2.0-S0163725824001281-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999177","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}

{"title":"Overview of the role of purinergic signaling and insights into its role in cancer therapy","authors":"Francesco Di Virgilio,&nbsp;Valentina Vultaggio-Poma,&nbsp;Mario Tarantini,&nbsp;Anna Lisa Giuliani","doi":"10.1016/j.pharmthera.2024.108700","DOIUrl":"10.1016/j.pharmthera.2024.108700","url":null,"abstract":"<div><p>Innovation of cancer therapy has received a dramatic acceleration over the last fifteen years thanks to the introduction of the novel immune checkpoint inhibitors (ICI). On the other hand, the conspicuous scientific knowledge accumulated in purinergic signaling since the early seventies is finally being transferred to the clinic. Several Phase I/II clinical trials are currently underway to investigate the effect of drugs interfering with purinergic signaling as stand-alone or combination therapy in cancer. This is supporting the novel concept of “purinergic immune checkpoint” (PIC) in cancer therapy.</p><p>In the present review we will address a) the basic pharmacology and cell biology of the purinergic system; b) principles of its pathophysiology in human diseases; c) implications for cell death, cell proliferation and cancer; d) novel molecular tools to investigate nucleotide homeostasis in the extracellular environment; e) recent developments in the pharmacology of P1, P2 receptors and related ecto-enzymes; f) P1 and P2 ligands as novel diagnostic tools; g) current issues in PIC-based anti-cancer therapy.</p><p>This review will provide an appraisal of the current status of purinergic signaling in cancer and will help identify future avenues of development.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"262 ","pages":"Article 108700"},"PeriodicalIF":12.0,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0163725824001207/pdfft?md5=a1daa6b93f0294c43639514fa72fb4a9&pid=1-s2.0-S0163725824001207-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141900437","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}

{"title":"Tissue-specific activation of insulin signaling as a potential target for obesity-related metabolic disorders","authors":"Hideyuki Okuma,&nbsp;Kyoichiro Tsuchiya","doi":"10.1016/j.pharmthera.2024.108699","DOIUrl":"10.1016/j.pharmthera.2024.108699","url":null,"abstract":"<div><p>The incidence of obesity is rapidly increasing worldwide. Obesity-associated insulin resistance has long been established as a significant risk factor for obesity-related disorders such as type 2 diabetes and atherosclerosis. Insulin plays a key role in systemic glucose metabolism, with the liver, skeletal muscle, and adipose tissue as the major acting tissues. Insulin receptors and the downstream insulin signaling-related molecules are expressed in various tissues, including vascular endothelial cells, vascular smooth muscle cells, and monocytes/macrophages. In obesity, decreased insulin action is considered a driver for associated disorders. However, whether insulin action has a positive or negative effect on obesity-related disorders depends on the tissue in which it acts. While an enhancement of insulin signaling in the liver increases hepatic fat accumulation and exacerbates dyslipidemia, enhancement of insulin signaling in adipose tissue protects against obesity-related dysfunction of various organs by increasing the capacity for fat accumulation in the adipose tissue and inhibiting ectopic fat accumulation. Thus, this “healthy adipose tissue expansion” by enhancing insulin sensitivity in adipose tissue, but not in the liver, may be an effective therapeutic strategy for obesity-related disorders. To effectively address obesity-related metabolic disorders, the mechanisms of insulin resistance in various tissues of obese patients must be understood and drugs that enhance insulin action must be developed. In this article, we review the potential of interventions that enhance insulin signaling as a therapeutic strategy for obesity-related disorders, focusing on the molecular mechanisms of insulin action in each tissue.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"262 ","pages":"Article 108699"},"PeriodicalIF":12.0,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0163725824001190/pdfft?md5=e581979ebbd453ee2ff079fb7585ccff&pid=1-s2.0-S0163725824001190-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141900438","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}

{"title":"Entering the TiME machine: How age-related changes in the tumor immune microenvironment impact melanoma progression and therapy response","authors":"Alexis E. Carey ,&nbsp;Ashani T. Weeraratna","doi":"10.1016/j.pharmthera.2024.108698","DOIUrl":"10.1016/j.pharmthera.2024.108698","url":null,"abstract":"<div><p>Melanoma is the deadliest form of skin cancer in the United States, with its incidence rates rising in older populations. As the immune system undergoes age-related changes, these alterations can significantly influence tumor progression and the effectiveness of cancer treatments. Recent advancements in understanding immune checkpoint molecules have paved the way for the development of innovative immunotherapies targeting solid tumors. However, the aging tumor microenvironment can play a crucial role in modulating the response to these immunotherapeutic approaches. This review seeks to examine the intricate relationship between age-related changes in the immune system and their impact on the efficacy of immunotherapies, particularly in the context of melanoma. By exploring this complex interplay, we hope to elucidate potential strategies to optimize treatment outcomes for older patients with melanoma, and draw parallels to other cancers.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"262 ","pages":"Article 108698"},"PeriodicalIF":12.0,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888040","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}

{"title":"Overcoming cancer drug-resistance calls for novel strategies targeting abnormal alternative splicing","authors":"Ji Zhang ,&nbsp;Xinyu Xu ,&nbsp;Hongwei Deng ,&nbsp;Li Liu ,&nbsp;Yuancai Xiang ,&nbsp;Jianguo Feng","doi":"10.1016/j.pharmthera.2024.108697","DOIUrl":"10.1016/j.pharmthera.2024.108697","url":null,"abstract":"<div><p>Abnormal gene alternative splicing (AS) events are strongly associated with cancer progression. Here, we summarize AS events that contribute to the development of drug resistance and classify them into three categories: alternative <em>cis</em>-splicing (ACS), alternative <em>trans</em>-splicing (ATS), and alternative back-splicing (ABS). The regulatory mechanisms underlying AS processes through <em>cis-</em>acting regulatory elements and <em>trans</em>-acting factors are comprehensively described, and the distinct functions of spliced variants, including linear spliced variants derived from ACS, chimeric spliced variants arising from ATS, and circRNAs generated through ABS, are discussed. The identification of dysregulated spliced variants, which contribute to drug resistance and hinder effective cancer treatment, suggests that abnormal AS processes may together serve as a precise regulatory mechanism enabling drug-resistant cancer cell survival or, alternatively, represent an evolutionary pathway for cancer cells to adapt to changes in the external environment. Moreover, this review summarizes recent advancements in treatment approaches targeting AS-associated drug resistance, focusing on <em>cis</em>-acting regulatory elements, <em>trans</em>-acting factors, and specific spliced variants. Collectively, gaining an in-depth understanding of the mechanisms underlying aberrant alternative splicing events and developing strategies to target this process hold great promise for overcoming cancer drug resistance.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"261 ","pages":"Article 108697"},"PeriodicalIF":12.0,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141722806","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}