Pharmacology & Therapeutics最新文献

{"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}

{"title":"Characteristics of anticancer activity of CBP/p300 inhibitors – Features of their classes, intracellular targets and future perspectives of their application in cancer treatment","authors":"Magdalena Strachowska ,&nbsp;Agnieszka Robaszkiewicz","doi":"10.1016/j.pharmthera.2024.108636","DOIUrl":"10.1016/j.pharmthera.2024.108636","url":null,"abstract":"<div><p>Due to the contribution of highly homologous acetyltransferases CBP and p300 to transcription elevation of oncogenes and other cancer promoting factors, these enzymes emerge as possible epigenetic targets of anticancer therapy. Extensive efforts in search for small molecule inhibitors led to development of compounds targeting histone acetyltransferase catalytic domain or chromatin-interacting bromodomain of CBP/p300, as well as dual BET and CBP/p300 inhibitors. The promising anticancer efficacy in <em>in vitro</em> and mice models led CCS1477 and NEO2734 to clinical trials. However, none of the described inhibitors is perfectly specific to CBP/p300 since they share similarity of a key functional domains with other enzymes, which are critically associated with cancer progression and their antagonists demonstrate remarkable clinical efficacy in cancer therapy. Therefore, we revise the possible and clinically relevant off-targets of CBP/p300 inhibitors that can be blocked simultaneously with CBP/p300 thereby improving the anticancer potential of CBP/p300 inhibitors and pharmacokinetic predicting data such as absorption, distribution, metabolism, excretion (ADME) and toxicity.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"257 ","pages":"Article 108636"},"PeriodicalIF":13.5,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0163725824000561/pdfft?md5=56be2af5b36c1256bfa4b880c50388dd&pid=1-s2.0-S0163725824000561-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140192971","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":"CYP2J2-mediated metabolism of arachidonic acid in heart: A review of its kinetics, inhibition and role in heart rhythm control","authors":"Jacqueline Wen Hui Leow,&nbsp;Eric Chun Yong Chan","doi":"10.1016/j.pharmthera.2024.108637","DOIUrl":"10.1016/j.pharmthera.2024.108637","url":null,"abstract":"<div><p>Cytochrome P450 2 J2 (CYP2J2) is primarily expressed extrahepatically and is the predominant epoxygenase in human cardiac tissues. This highlights its key role in the metabolism of endogenous substrates. Significant scientific interest lies in cardiac CYP2J2 metabolism of arachidonic acid (AA), an omega-6 polyunsaturated fatty acid, to regioisomeric bioactive epoxyeicosatrienoic acid (EET) metabolites that show cardioprotective effects including regulation of cardiac electrophysiology. From an <em>in vitro</em> perspective, the accurate characterization of the kinetics of CYP2J2 metabolism of AA including its inhibition and inactivation by drugs could be useful in facilitating <em>in vitro-in vivo</em> extrapolations to predict drug-AA interactions in drug discovery and development. In this review, background information on the structure, regulation and expression of CYP2J2 in human heart is presented alongside AA and EETs as its endogenous substrate and metabolites. The <em>in vitro</em> and <em>in vivo</em> implications of the kinetics of this endogenous metabolic pathway as well as its perturbation <em>via</em> inhibition and inactivation by drugs are elaborated. Additionally, the role of CYP2J2-mediated metabolism of AA to EETs in cardiac electrophysiology will be expounded.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"258 ","pages":"Article 108637"},"PeriodicalIF":13.5,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140192972","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":"Musculoskeletal crosstalk in chronic obstructive pulmonary disease and comorbidities: Emerging roles and therapeutic potentials","authors":"Kevin Mou,&nbsp;Stanley M.H. Chan,&nbsp;Ross Vlahos","doi":"10.1016/j.pharmthera.2024.108635","DOIUrl":"10.1016/j.pharmthera.2024.108635","url":null,"abstract":"<div><p>Chronic Obstructive Pulmonary Disease (COPD) is a multifaceted respiratory disorder characterized by progressive airflow limitation and systemic implications. It has become increasingly apparent that COPD exerts its influence far beyond the respiratory system, extending its impact to various organ systems. Among these, the musculoskeletal system emerges as a central player in both the pathogenesis and management of COPD and its associated comorbidities. Muscle dysfunction and osteoporosis are prevalent musculoskeletal disorders in COPD patients, leading to a substantial decline in exercise capacity and overall health. These manifestations are influenced by systemic inflammation, oxidative stress, and hormonal imbalances, all hallmarks of COPD. Recent research has uncovered an intricate interplay between COPD and musculoskeletal comorbidities, suggesting that muscle and bone tissues may cross-communicate through the release of signalling molecules, known as “myokines” and “osteokines”. We explored this dynamic relationship, with a particular focus on the role of the immune system in mediating the cross-communication between muscle and bone in COPD. Moreover, we delved into existing and emerging therapeutic strategies for managing musculoskeletal disorders in COPD. It underscores the development of personalized treatment approaches that target both the respiratory and musculoskeletal aspects of COPD, offering the promise of improved well-being and quality of life for individuals grappling with this complex condition. This comprehensive review underscores the significance of recognizing the profound impact of COPD on the musculoskeletal system and its comorbidities. By unravelling the intricate connections between these systems and exploring innovative treatment avenues, we can aspire to enhance the overall care and outcomes for COPD patients, ultimately offering hope for improved health and well-being.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"257 ","pages":"Article 108635"},"PeriodicalIF":13.5,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S016372582400055X/pdfft?md5=26febba9eb277ff475f01cb8434dc262&pid=1-s2.0-S016372582400055X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140178914","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":"Efficacy and safety of transarterial chemoembolization combined with lenvatinib and PD-1 inhibitor in the treatment of advanced hepatocellular carcinoma: A meta-analysis","authors":"Lei Wang ,&nbsp;Li Lin ,&nbsp;Wei Zhou","doi":"10.1016/j.pharmthera.2024.108634","DOIUrl":"10.1016/j.pharmthera.2024.108634","url":null,"abstract":"<div><p>The study aims to evaluate the benefits and potential adverse effects of transarterial chemoembolization (TACE) combined with lenvatinib and programmed cell death 1 (PD-1) protein inhibitors in the treatment of advanced hepatocellular carcinoma (HCC). A systematic literature search of several databases for relevant studies, published from inception up to May 2023, was performed. Clinical trials investigating TACE combined with lenvatinib and PD-1 inhibitors compared with other treatment regimens for advanced HCC were included. Data were pooled using fixed- or random-effects models and expressed as hazard ratios (HRs) or risk ratios (RRs) with corresponding 95% confidence interval (CI). Trial sequential analysis was used to determine whether the study results were sufficiently conclusive. Totally thirteen cohort studies comprising 1279 patients were included. The combined use of TACE, lenvatinib, and PD-1 inhibitors significantly improved overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) compared with other treatment regimens. The incidences of all-grade or grade ≥ 3 adverse events were comparable and did not differ significantly between the two groups. Prognostic factor analysis identified treatment options, portal vein tumor thrombus, extrahepatic metastasis, and Barcelona Clinic Liver Cancer (BCLC) stage as independent prognostic factors for OS. Extrahepatic metastasis, Child–Pugh score, and hepatic vein invasion emerged as independent prognostic factors for PFS. TSA suggested that the available data were adequate for drawing numerical conclusions regarding ORR and DCR. An approach combining TACE, lenvatinib, and PD-1 inhibitors appeared to offer significant improvements in OS, PFS, ORR, and DCR in patients with advanced HCC without significantly increasing the risk for all-grade adverse events.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"257 ","pages":"Article 108634"},"PeriodicalIF":13.5,"publicationDate":"2024-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140157320","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}