Pharmacology & Therapeutics最新文献

{"title":"Disease progression modeling with temporal realignment: An emerging approach to deepen knowledge on chronic diseases","authors":"Hideki Yoshioka ,&nbsp;Ryota Jin ,&nbsp;Akihiro Hisaka ,&nbsp;Hiroshi Suzuki","doi":"10.1016/j.pharmthera.2024.108655","DOIUrl":"10.1016/j.pharmthera.2024.108655","url":null,"abstract":"<div><p>The recent development of the first disease-modifying drug for Alzheimer's disease represents a major advancement in dementia treatment. Behind this breakthrough is a quarter century of research efforts to understand the disease not by a particular symptom at a given moment, but by long-term sequential changes in multiple biomarkers. Disease progression modeling with temporal realignment (DPM-TR) is an emerging computational approach proposed with this biomarker-based disease concept. By integrating short-term clinical observations of multiple disease biomarkers in a data-driven manner, DPM-TR provides a way to understand the progression of chronic diseases over decades and predict individual disease stages more accurately. DPM-TR has been developed primarily in the area of neurodegenerative diseases but has recently been extended to non-neurodegenerative diseases, including chronic obstructive pulmonary, autoimmune, and ophthalmologic diseases. This review focuses on opportunities for DPM-TR in clinical practice and drug development and discusses its current status and challenges.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"259 ","pages":"Article 108655"},"PeriodicalIF":13.5,"publicationDate":"2024-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140847084","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":"The role of lidocaine in cancer progression and patient survival","authors":"Kohei Chida ,&nbsp;Hirofumi Kanazawa ,&nbsp;Hirotaka Kinoshita ,&nbsp;Arya Mariam Roy ,&nbsp;Kenichi Hakamada ,&nbsp;Kazuaki Takabe","doi":"10.1016/j.pharmthera.2024.108654","DOIUrl":"10.1016/j.pharmthera.2024.108654","url":null,"abstract":"<div><p>Since its development in 1943, lidocaine has been one of the most commonly used local anesthesia agents for surgical procedures. Lidocaine alters neuronal signal transmission by prolonging the inactivation of fast voltage-gated sodium channels in the cell membrane of neurons, which are responsible for action potential propagation. Recently, it has attracted attention due to emerging evidence suggesting its potential antitumor properties, particularly in the in vitro setting. Further, local administration of lidocaine around the tumor immediately prior to surgical removal has been shown to improve overall survival in breast cancer patients. However, the exact mechanisms driving these antitumor effects remain largely unclear. In this article, we will review the existing literature on the mechanism of lidocaine as a local anesthetic, its effects on the cancer cells and the tumor microenvironment, involved pathways, and cancer progression. Additionally, we will explore recent reports highlighting its impact on clinical outcomes in cancer patients. Taken together, there remains significant ambiguity surrounding lidocaine's functions and roles in cancer biology, particularly in perioperative setting.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"259 ","pages":"Article 108654"},"PeriodicalIF":13.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140847085","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":"Pharmacological potential of cyclic nucleotide signaling in immunity","authors":"Eirene Marie Q. Ednacot ,&nbsp;Ali Nabhani ,&nbsp;David M. Dinh ,&nbsp;Benjamin R. Morehouse","doi":"10.1016/j.pharmthera.2024.108653","DOIUrl":"10.1016/j.pharmthera.2024.108653","url":null,"abstract":"<div><p>Cyclic nucleotides are important signaling molecules that play many critical physiological roles including controlling cell fate and development, regulation of metabolic processes, and responding to changes in the environment. Cyclic nucleotides are also pivotal regulators in immune signaling, orchestrating intricate processes that maintain homeostasis and defend against pathogenic threats. This review provides a comprehensive examination of the pharmacological potential of cyclic nucleotide signaling pathways within the realm of immunity. Beginning with an overview of the fundamental roles of cAMP and cGMP as ubiquitous second messengers, this review delves into the complexities of their involvement in immune responses. Special attention is given to the challenges associated with modulating these signaling pathways for therapeutic purposes, emphasizing the necessity for achieving cell-type specificity to avert unintended consequences. A major focus of the review is on the recent paradigm-shifting discoveries regarding specialized cyclic nucleotide signals in the innate immune system, notably the cGAS–STING pathway. The significance of cyclic dinucleotides, exemplified by 2′3′-cGAMP, in controlling immune responses against pathogens and cancer, is explored. The evolutionarily conserved nature of cyclic dinucleotides as antiviral agents, spanning across diverse organisms, underscores their potential as targets for innovative immunotherapies. Findings from the last several years have revealed a striking diversity of novel bacterial cyclic nucleotide second messengers which are involved in antiviral responses. Knowledge of the existence and precise identity of these molecules coupled with accurate descriptions of their associated immune defense pathways will be essential to the future development of novel antibacterial therapeutic strategies. The insights presented herein may help researchers navigate the evolving landscape of immunopharmacology as it pertains to cyclic nucleotides and point toward new avenues or lines of thinking about development of therapeutics against the pathways they regulate.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"258 ","pages":"Article 108653"},"PeriodicalIF":13.5,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140847923","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":"Therapeutic potential of natural products and underlying targets for the treatment of aortic aneurysm","authors":"Wenwen Zhao ,&nbsp;Bufan Li,&nbsp;Jinjun Hao,&nbsp;Ruochen Sun,&nbsp;Peng He,&nbsp;Hongyu Lv,&nbsp;Mou He,&nbsp;Jie Shen,&nbsp;Yantao Han","doi":"10.1016/j.pharmthera.2024.108652","DOIUrl":"10.1016/j.pharmthera.2024.108652","url":null,"abstract":"<div><p>Aortic aneurysm is a vascular disease characterized by irreversible vasodilatation that can lead to dissection and rupture of the aortic aneurysm, a life-threatening condition. Thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) are two main types. The typical treatments for aortic aneurysms are open surgery and endovascular aortic repair, which are only indicated for more severe patients. Most patients with aneurysms have an insidious onset and slow progression, and there are no effective drugs to treat this stage. The inability of current animal models to perfectly simulate all the pathophysiological states of human aneurysms may be the key to this issue. Therefore, elucidating the molecular mechanisms of this disease, finding new therapeutic targets, and developing effective drugs to inhibit the development of aneurysms are the main issues of current research. Natural products have been applied for thousands of years to treat cardiovascular disease (CVD) in China and other Asian countries. In recent years, natural products have combined multi-omics, computational biology, and integrated pharmacology to accurately analyze drug components and targets. Therefore, the multi-component and multi-target complexity of natural products have made them a potentially ideal treatment for multifactorial diseases such as aortic aneurysms. Natural products have regained popularity worldwide. This review provides an overview of the known natural products for the treatment of TAA and AAA and searches for potential cardiovascular-targeted natural products that may treat TAA and AAA based on various cellular molecular mechanisms associated with aneurysm development.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"259 ","pages":"Article 108652"},"PeriodicalIF":13.5,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140766622","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":"Cisplatin in the era of PARP inhibitors and immunotherapy","authors":"Mingrui Duan ,&nbsp;Shuguang Leng ,&nbsp;Peng Mao","doi":"10.1016/j.pharmthera.2024.108642","DOIUrl":"https://doi.org/10.1016/j.pharmthera.2024.108642","url":null,"abstract":"<div><p>Platinum compounds such as cisplatin, carboplatin and oxaliplatin are widely used in chemotherapy. Cisplatin induces cytotoxic DNA damage that blocks DNA replication and gene transcription, leading to arrest of cell proliferation. Although platinum therapy alone is effective against many tumors, cancer cells can adapt to the treatment and gain resistance. The mechanisms for cisplatin resistance are complex, including low DNA damage formation, high DNA repair capacity, changes in apoptosis signaling pathways, rewired cell metabolisms, and others. Drug resistance compromises the clinical efficacy and calls for new strategies by combining cisplatin with other therapies. Exciting progress in cancer treatment, particularly development of poly (ADP-ribose) polymerase (PARP) inhibitors and immune checkpoint inhibitors, opened a new chapter to combine cisplatin with these new cancer therapies. In this Review, we discuss how platinum synergizes with PARP inhibitors and immunotherapy to bring new hope to cancer patients.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"258 ","pages":"Article 108642"},"PeriodicalIF":13.5,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140554252","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":"Ultramicronized N-palmitoylethanolamine associated with analgesics: Effects against persistent pain","authors":"Stefania Nobili ,&nbsp;Laura Micheli ,&nbsp;Elena Lucarini,&nbsp;Alessandra Toti,&nbsp;Carla Ghelardini,&nbsp;Lorenzo Di Cesare Mannelli","doi":"10.1016/j.pharmthera.2024.108649","DOIUrl":"10.1016/j.pharmthera.2024.108649","url":null,"abstract":"<div><p>Current epidemiological data estimate that one in five people suffers from chronic pain with considerable impairment of health-related quality of life. The pharmacological treatment is based on first- and second-line analgesic drugs, including COX-2 selective and nonselective nonsteroidal anti-inflammatory drugs, paracetamol, antidepressants, anti-seizure drugs and opioids, that are characterized by important side effects.</p><p><em>N</em>-palmitoylethanolamine (PEA) is a body's own fatty-acid ethanolamide belonging to the family of autacoid local injury antagonist amides. The anti-inflammatory and pain-relieving properties of PEA have been recognized for decades and prompted to depict its role in the endogenous mechanisms of pain control. Together with its relative abundance in food sources, this opened the way to the use of PEA as a pain-relieving nutritional intervention.</p><p>Naïve PEA is a large particle size lipid molecule with low solubility and bioavailability. Reducing particle size is a useful method to increase surface area, thereby improving dissolution rate and bioavailability accordingly. Micron-size formulations of PEA (e.g., ultramicronized and co-(ultra)micronized) have shown higher oral efficacy compared to naïve PEA. In particular, ultramicronized PEA has been shown to efficiently cross the intestinal wall and, more importantly, the blood-brain and blood-spinal cord barrier. Several preclinical and clinical studies have shown the efficacy, safety and tolerability of ultramicronized PEA.</p><p>This narrative review summarizes the available pharmacokinetic/pharmacodynamic data on ultramicronized PEA and focuses to its contribution to pain control, in particular as ‘add-on’ nutritional intervention. Data showing the ability of ultramicronized PEA to limit opioid side effects, including the development of tolerance, have also been reviewed.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"258 ","pages":"Article 108649"},"PeriodicalIF":13.5,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S016372582400069X/pdfft?md5=5ac0e4b197e65d33a3b7c1edb7627f9f&pid=1-s2.0-S016372582400069X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140766459","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":"Psilocybin for dementia prevention? The potential role of psilocybin to alter mechanisms associated with major depression and neurodegenerative diseases","authors":"Zarah R. Haniff ,&nbsp;Mariia Bocharova ,&nbsp;Tim Mantingh ,&nbsp;James J. Rucker ,&nbsp;Latha Velayudhan ,&nbsp;David M. Taylor ,&nbsp;Allan H. Young ,&nbsp;Dag Aarsland ,&nbsp;Anthony C. Vernon ,&nbsp;Sandrine Thuret","doi":"10.1016/j.pharmthera.2024.108641","DOIUrl":"https://doi.org/10.1016/j.pharmthera.2024.108641","url":null,"abstract":"<div><p>Major depression is an established risk factor for subsequent dementia, and depression in late life may also represent a prodromal state of dementia. Considering current challenges in the clinical development of disease modifying therapies for dementia, the focus of research is shifting towards prevention and modification of risk factors to alter the neurodegenerative disease trajectory. Understanding mechanistic commonalities underlying affective symptoms and cognitive decline may reveal biomarkers to aid early identification of those at risk of progressing to dementia during the preclinical phase of disease, thus allowing for timely intervention. Adult hippocampal neurogenesis (AHN) is a phenomenon that describes the birth of new neurons in the dentate gyrus throughout life and it is associated with spatial learning, memory and mood regulation. Microglia are innate immune system macrophages in the central nervous system that carefully regulate AHN via multiple mechanisms. Disruption in AHN is associated with both dementia and major depression and microgliosis is a hallmark of several neurodegenerative diseases.</p><p>Emerging evidence suggests that psychedelics promote neuroplasticity, including neurogenesis, and may also be immunomodulatory. In this context, psilocybin, a serotonergic agonist with rapid-acting antidepressant properties has the potential to ameliorate intersecting pathophysiological processes relevant for both major depression and neurodegenerative diseases. In this narrative review, we focus on the evidence base for the effects of psilocybin on adult hippocampal neurogenesis and microglial form and function; which may suggest that psilocybin has the potential to modulate multiple mechanisms of action, and may have implications in altering the progression from major depression to dementia in those at risk.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"258 ","pages":"Article 108641"},"PeriodicalIF":13.5,"publicationDate":"2024-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0163725824000615/pdfft?md5=862308f7cd3837dabdd6124f68df8bf8&pid=1-s2.0-S0163725824000615-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140551523","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":"Therapeutic targeting of DNA methylation alterations in cancer","authors":"Abigail V. Lee ,&nbsp;Kevin A. Nestler ,&nbsp;Katherine B. Chiappinelli","doi":"10.1016/j.pharmthera.2024.108640","DOIUrl":"https://doi.org/10.1016/j.pharmthera.2024.108640","url":null,"abstract":"<div><p>DNA methylation is a critical component of gene regulation and plays an important role in the development of cancer. Hypermethylation of tumor suppressor genes and silencing of DNA repair pathways facilitate uncontrolled cell growth and synergize with oncogenic mutations to perpetuate cancer phenotypes. Additionally, aberrant DNA methylation hinders immune responses crucial for antitumor immunity. Thus, inhibiting dysregulated DNA methylation is a promising cancer therapy. Pharmacologic inhibition of DNA methylation reactivates silenced tumor suppressors and bolster immune responses through induction of viral mimicry. Now, with the advent of immunotherapies and discovery of the immune-modulatory effects of DNA methylation inhibitors, there is great interest in understanding how targeting DNA methylation in combination with other therapies can enhance antitumor immunity. Here, we describe the role of aberrant DNA methylation in cancer and mechanisms by which it promotes tumorigenesis and modulates immune responses. Finally, we review the initial discoveries and ongoing efforts to target DNA methylation as a cancer therapeutic.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"258 ","pages":"Article 108640"},"PeriodicalIF":13.5,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140350299","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":"SIRT3: A potential therapeutic target for liver fibrosis","authors":"Yan Ning ,&nbsp;Xinyue Dou ,&nbsp;Zhichao Wang ,&nbsp;Kao Shi ,&nbsp;Zeping Wang ,&nbsp;Chuan Ding ,&nbsp;Xianan Sang ,&nbsp;Xiang Zhong ,&nbsp;Meiyu Shao ,&nbsp;Xin Han ,&nbsp;Gang Cao","doi":"10.1016/j.pharmthera.2024.108639","DOIUrl":"10.1016/j.pharmthera.2024.108639","url":null,"abstract":"<div><p>Sirtuin3 (SIRT3) is a nicotinamide adenine dinucleotide (NAD⁺)-dependent protein deacetylase located in the mitochondria, which mainly regulates the acetylation of mitochondrial proteins. In addition, SIRT3 is involved in critical biological processes, including oxidative stress, inflammation, DNA damage, and apoptosis, all of which are closely related to the progression of liver disease. Liver fibrosis characterized by the deposition of extracellular matrix is a result of long termed or repeated liver damage, frequently accompanied by damaged hepatocytes, the recruitment of inflammatory cells, and the activation of hepatic stellate cells. Based on the functions and pharmacology of SIRT3, we will review its roles in liver fibrosis from three aspects: First, the main functions and pharmacological effects of SIRT3 were investigated based on its structure. Second, the roles of SIRT3 in major cells in the liver were summarized to reveal its mechanism in developing liver fibrosis. Last, drugs that regulate SIRT3 to prevent and treat liver fibrosis were discussed. In conclusion, exploring the pharmacological effects of SIRT3, especially in the liver, may be a potential strategy for treating liver fibrosis.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"257 ","pages":"Article 108639"},"PeriodicalIF":13.5,"publicationDate":"2024-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140334154","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":"Epigenetic determinants and non-myocardial signaling pathways contributing to heart growth and regeneration","authors":"Jihyun Jang ,&nbsp;Federica Accornero ,&nbsp;Deqiang Li","doi":"10.1016/j.pharmthera.2024.108638","DOIUrl":"10.1016/j.pharmthera.2024.108638","url":null,"abstract":"<div><p>Congenital heart disease is the most common birth defect worldwide. Defective cardiac myogenesis is either a major presentation or associated with many types of congenital heart disease. Non-myocardial tissues, including endocardium and epicardium, function as a supporting hub for myocardial growth and maturation during heart development. Recent research findings suggest an emerging role of epigenetics in nonmyocytes supporting myocardial development. Understanding how growth signaling pathways in non-myocardial tissues are regulated by epigenetic factors will likely identify new disease mechanisms for congenital heart diseases and shed lights for novel therapeutic strategies for heart regeneration.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"257 ","pages":"Article 108638"},"PeriodicalIF":13.5,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140317528","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}