Pharmacology & Therapeutics最新文献

{"title":"Recent advances in development and delivery of non-viral nucleic acid therapeutics for brain tumor therapy","authors":"Donat Kögel ,&nbsp;Achim Temme ,&nbsp;Achim Aigner","doi":"10.1016/j.pharmthera.2024.108762","DOIUrl":"10.1016/j.pharmthera.2024.108762","url":null,"abstract":"<div><div>High grade gliomas (HGG) are a group of CNS tumors refractory to currently existing therapies, which routinely leads to early recurrence and a dismal prognosis. Recent advancements in nucleic acid-based therapy using a wide variety of different molecular targets and non-viral nanocarrier systems suggest that this approach holds significant potential to meet the urgent demand for improved therapeutic options for the treatment of these tumors. This review provides a comprehensive and up-to-date overview on the current landscape and progress of preclinical and clinical developments in this rapidly evolving and exciting field of research, including optimized nanocarrier delivery systems, promising therapeutic targets and tailor-made therapeutic strategies for individualized HGG patient treatment.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"266 ","pages":"Article 108762"},"PeriodicalIF":12.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738082","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":"Combinational CAR T-cell therapy for solid tumors: Requisites, rationales, and trials","authors":"Kyohei Misawa ,&nbsp;Hina Bhat ,&nbsp;Prasad S. Adusumilli ,&nbsp;Zhaohua Hou","doi":"10.1016/j.pharmthera.2024.108763","DOIUrl":"10.1016/j.pharmthera.2024.108763","url":null,"abstract":"<div><div>Chimeric antigen receptor (CAR) T-cell therapy has achieved potent antitumor efficacy in hematological malignancies; however, because of limitations in CAR T-cell recruitment, infiltration, activation, and functional persistence in the tumor, its efficacy in solid tumors has been suboptimal. To overcome these challenges, combinational strategies that include chemotherapy, radiation therapy, or immune checkpoint inhibitor agent therapy with CAR T-cell therapy are being investigated. The established functional characteristics of the abovementioned therapies provide a rationale for the use of a combinational approach with CAR T cells. Chemotherapy reshapes the peritumoral stroma, decreases the immunosuppressive cell population, and promotes a proinflammatory milieu, all of which allow for increased recruitment, infiltration, and accumulation of CAR T cells. Radiation therapy promotes a chemokine gradient, which augments tumor infiltration by CAR T cells and further increases expression of tumor-associated antigens, allowing for increased activation of CAR T cells. Immune checkpoint inhibitor agent therapy inactivates T-cell exhaustion pathways—most notably, the PD1/PDL1 pathway—thereby improving the functional persistence of CAR T cells and promoting endogenous immunity. In this review, we discuss the requisites and rationales for combinational therapy, and we review 25 ongoing phase I and II clinical trials, of which 4 use chemotherapy, 3 use radiation therapy, 11 use immunotherapy, and 7 use another agent. While safety, efficacy, and improved outcomes are the primary goals of these ongoing studies, the knowledge gained from them will help pave the way for subsequent studies focused on optimizing combinational regimens and identifying predictive biomarkers.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"266 ","pages":"Article 108763"},"PeriodicalIF":12.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765112","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":"Signaling pathways and targeted therapies in Ewing sarcoma","authors":"Ke Jia ,&nbsp;Li Cao ,&nbsp;Yihan Yu ,&nbsp;Doudou Jing ,&nbsp;Wei Wu ,&nbsp;Brian Andrew Van Tine ,&nbsp;Zengwu Shao","doi":"10.1016/j.pharmthera.2024.108765","DOIUrl":"10.1016/j.pharmthera.2024.108765","url":null,"abstract":"<div><div>Ewing sarcoma, the second most prevalent malignant bone tumor with potential occurrence in soft tissues, exhibits a high level of aggressiveness, primarily afflicting children and adolescents. It is characterized by fusion proteins arising from chromosomal translocations. The fusion proteins induce aberrations in multiple signaling pathways and molecules, constituting a key event in oncogenic transformation. While diagnostic and therapeutic modalities have advanced in recent decades and multimodal treatments, including surgery, radiotherapy, and chemotherapy, have significantly improved survival of patients with localized tumors, patients with metastatic tumors continue to face poor prognoses. There persists a pressing need for novel alternative treatments, yet the translation of our understanding of Ewing sarcoma pathogenesis into improved clinical outcomes remains a critical challenge. Here, we provide a comprehensive review of Ewing sarcoma, including fusion proteins, various signaling pathways, pivotal pathogenetic molecules implicated in its development, and associated targeted therapies and immunotherapies. We summarize past endeavors, current advancements, and deliberate on limitations and future research directions. It is envisaged that this review will furnish novel insights into prospective treatment avenues for Ewing sarcoma.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"266 ","pages":"Article 108765"},"PeriodicalIF":12.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765115","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":"Glucuronidation of orally administered drugs and the value of nanocarriers in strategies for its overcome","authors":"Laura Hervieu ,&nbsp;Anne-Claire Groo ,&nbsp;Jérémy Bellien ,&nbsp;Dominique Guerrot ,&nbsp;Aurélie Malzert-Fréon","doi":"10.1016/j.pharmthera.2024.108773","DOIUrl":"10.1016/j.pharmthera.2024.108773","url":null,"abstract":"<div><div>The gastrointestinal tract (GIT) plays a pivotal role in the absorption of orally administered drugs, with the small intestine serving as the primary site due to its extensive surface area and specialized cell types, including enterocytes and M cells. After oral administration, drugs are generally transported <em>via</em> the portal vein to the liver, where they undergo first-pass metabolism. This process involves various enzymatic reactions, including glucuronidation, facilitated by uridine diphosphate-glucuronosyltransferase (UGT), a major phase 2 reaction in mammalian metabolism.</div><div>UGTs conjugate glucuronic acid to a wide array of endogenous and exogenous substrates, enhancing their solubility and excretion, but significantly affecting the bioavailability and therapeutic efficacy of drugs. UGT enzymes are ubiquitously distributed across tissues, prominently in the liver, but also in the GIT, kidneys, brain, and other organs where they play crucial roles in xenobiotic metabolism.</div><div>Species-specific differences in UGT expression and activity impact the selection of animal models for pharmacological studies. Various experimental models – ranging from computational simulations (<em>in silico</em>) to laboratory experiments (<em>in vitro</em>) and animal studies (<em>in vivo</em>) – are employed throughout drug discovery and development to evaluate drug metabolism, including UGT activity.</div><div>Effective strategies to counter pre-systemic metabolism are critical for improving drug bioavailability. This review explores several approaches including prodrugs, co-administration of specific molecules or use of inhibiting excipients in formulations. Strategies incorporating these excipients in nanoformulations demonstrate notable increases in drug absorption and bioavailability.</div><div>This review highlights the importance of targeted delivery systems and excipient selection in overcoming metabolic barriers, aiming to optimize drug efficacy and patient outcomes.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"266 ","pages":"Article 108773"},"PeriodicalIF":12.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794044","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":"Probiotic supplement for the treatment of polycystic ovarian syndrome","authors":"Habiba Ramzan ,&nbsp;Dilara Abbas Bukhari ,&nbsp;Zuhra Bibi ,&nbsp;Arifullah ,&nbsp;Isha ,&nbsp;Atif Nawaz ,&nbsp;Abdul Rehman","doi":"10.1016/j.pharmthera.2024.108785","DOIUrl":"10.1016/j.pharmthera.2024.108785","url":null,"abstract":"<div><div>Polycystic Ovarian Syndrome is one of the major prevalent causes of infertility reported worldwide nearly 6–26 %, especially in girls hitting puberty and women at their childbearing age. The main clinical manifestations include irregular menstrual cycle, small cysts on one or both ovaries, chronic oligo-anovulation, and hirsutism. The etiological criteria are very complex and related to many factors like obesity, insulin sensitivity, inflammation, hyperandrogenism, diabetes mellitus type II, cardiovascular diseases, and dysbiosis of gut microbiota. The given review focuses on managing PCOS through probiotics by analyzing the effects on the symptoms of the disease. The probiotics effective in treating PCOS belong to <em>Bifidobacterium, Lactobacilli, Clostridium, Enterococcus,</em> and other Lactic acid bacteria. Its significance in PCOS is mainly due to the antagonizing of the growth of pathogenic microorganisms, increasing intestinal mucus layer production, reducing intestinal permeability, and modulating the gastrointestinal immune system. Also, their interaction with certain hormones such as insulin, androgen, and estrogen through short-chain fatty acids influences fertility. More research is necessary to validate these results. Probiotic supplements could be a viable option for treating PCOS in adults.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"266 ","pages":"Article 108785"},"PeriodicalIF":12.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884950","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":"Peripheral GABAA receptors - Physiological relevance and therapeutic implications","authors":"Milica Gajić Bojić ,&nbsp;Jovana Aranđelović ,&nbsp;Ranko Škrbić ,&nbsp;Miroslav M. Savić","doi":"10.1016/j.pharmthera.2024.108759","DOIUrl":"10.1016/j.pharmthera.2024.108759","url":null,"abstract":"<div><div>The role of γ- aminobutyric acid (GABA) and GABA_A receptors is not only essential for neurotransmission in the central nervous system (CNS), but they are also involved in communication in various peripheral tissues such as the pancreas, liver, kidney, gastrointestinal tract, trachea, immune cells and blood vessels. GABA_A receptors located outside the CNS (“peripheral GABA_A receptors”) enable both neuronal and non-neuronal GABA-ergic signaling in various physiological processes and are generally thought to have similar properties to the extrasynaptic receptors in the CNS. By activating these peripheral receptors, GABA and various GABA_A receptor modulators, including drugs such as benzodiazepines and general anesthetics, may contribute to or otherwise affect the maintenance of general body homeostasis. However, the existing data in the literature on the role of non-neuronal GABA-ergic signaling in insulin secretion, glucose metabolism, renal function, intestinal motility, airway tone, immune response and blood pressure regulation are far from complete. In fact, they mainly focus on the identification of components for the local synthesis and utilization of GABA and on the expression repertoire of GABA_A receptor subunits rather than on subunit composition, activation effects and (sub)cellular localization. A deeper understanding of how modulation of peripheral GABA_A receptors can have significant therapeutic effects on a range of pathological conditions such as multiple sclerosis, diabetes, irritable bowel syndrome, asthma or hypertension could contribute to the development of more specific pharmacological strategies that would provide an alternative or complement to existing therapies. Selective GABA_A receptor modulators with improved peripheral efficacy and reduced central side effects would therefore be highly desirable first-in-class drug candidates. This review updates recent advances unraveling the molecular components and cellular determinants of the GABA signaling machinery in peripheral organs, tissues and cells of both, humans and experimental animals.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"266 ","pages":"Article 108759"},"PeriodicalIF":12.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765114","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":"EGFL7: An emerging biomarker with great therapeutic potential","authors":"Carina Fabian ,&nbsp;Sukrit Mahajan ,&nbsp;Mirko H.H. Schmidt","doi":"10.1016/j.pharmthera.2024.108764","DOIUrl":"10.1016/j.pharmthera.2024.108764","url":null,"abstract":"<div><div>EGFL7 is a factor involved in the regulation of various essential biological mechanisms. Endothelial cells and neurons secrete the EGFL7 protein into the extracellular matrix, where it interacts with other matrix proteins, thereby regulating several important signaling pathways. To date, extensive <em>in vitro</em> and <em>in vivo</em> studies have illuminated the central role of EGFL7 in governing major biological processes involving blood vessels and the central nervous system. Notably, EGFL7 has also emerged as a key factor in a spectrum of diseases including cancer, stroke, multiple sclerosis and preeclampsia. Its influence on various diseases and multiple regulatory pathways highlights EGFL7 as an emerging biomarker and therapeutic target. Thus, the multifaceted regulatory functions of EGFL7 will be discussed in the physiological context before delving into its involvement in the progression of different diseases. Finally, the review will provide an insight into the broad therapeutic potential of EGFL7 by describing its role as a powerful biomarker and discussing potential strategies to therapeutically target EGFL7 function in a plethora of human diseases.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"266 ","pages":"Article 108764"},"PeriodicalIF":12.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142778835","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":"Non-canonical signaling initiated by hormone-responsive G protein-coupled receptors from subcellular compartments","authors":"Li-Kun Yang ,&nbsp;Wei Wang ,&nbsp;Dong-Yu Guo ,&nbsp;Bo Dong","doi":"10.1016/j.pharmthera.2024.108788","DOIUrl":"10.1016/j.pharmthera.2024.108788","url":null,"abstract":"<div><div>G protein-coupled receptors (GPCRs), the largest family of membrane receptors in the mammalian genomes, regulate almost all known physiological processes by transducing numerous extracellular stimuli including almost two-thirds of endogenous hormones and neurotransmitters. The traditional view held that GPCR signaling occurs exclusively at the cell surface, where the receptors bind with the ligands and undergo conformational changes to recruit and activate heterotrimeric G proteins. However, with the application of advanced biochemical and biophysical techniques, this conventional model is challenged by the elucidation of spatiotemporal GPCR activation with the evidence that receptors can signal from subcellular compartments to exhibit various molecular and cellular responses with physiological and pathophysiological relevance. Thus, this ‘location bias’ of GPCR signaling has become another layer of complexity of GPCR signal transduction. In this review, we generally introduce the development of the concept of compartmentalized GPCR signaling and comprehensively summarize the receptors reported to be localized on the membranes of different intracellular organelles. We review the physiological functions of these compartmentalized GPCRs with emphasis on some well-characterized prototypical hormone/neurotransmitter-binding receptors, including β₂-adrenergic receptor, opioid receptors, parathyroid hormone type 1 receptor, thyroid-stimulating hormone receptor, cannabinoid receptor type 1, and metabotropic glutamate receptor 5, as examples. In addition, the therapeutic implications of compartmentalized GPCR signaling by introducing lipophilic or hydrophilic ligands for intracellular targeting, lipid conjugation anchor drugs, and strategy to modulate receptor internalization/resensitization, are highlighted and open new avenues in GPCR pharmacology and therapeutics.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"266 ","pages":"Article 108788"},"PeriodicalIF":12.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891176","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":"Single-cell RNA sequencing in autoimmune diseases: New insights and challenges","authors":"Jialing Huang ,&nbsp;Yuelin Hu ,&nbsp;Shuqing Wang ,&nbsp;Yuefang Liu ,&nbsp;Xin Sun ,&nbsp;Xin Wang ,&nbsp;Hongsong Yu","doi":"10.1016/j.pharmthera.2025.108807","DOIUrl":"10.1016/j.pharmthera.2025.108807","url":null,"abstract":"<div><div>Autoimmune diseases involve a variety of cell types, yet the intricacies of their individual roles within molecular mechanisms and therapeutic strategies remain poorly understood. Single-cell RNA sequencing (scRNA-seq) offers detailed insights into transcriptional diversity at the single-cell level, significantly advancing research in autoimmune diseases. This article explores how scRNA-seq enhances the understanding of cellular heterogeneity and its potential applications in the etiology, diagnosis, treatment, and prognosis of autoimmune diseases. By revealing a comprehensive cellular landscape, scRNA-seq illuminates the functional regulation of different cell subtypes during disease progression. It aids in identifying diagnostic and prognostic markers, and analyzing cell communication networks to uncover potential therapeutic targets. Despite its valuable contributions, addressing the limitations of scRNA-seq is essential for making further advancements.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108807"},"PeriodicalIF":12.0,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078371","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":"From physiology to pathology: Emerging roles of GPER in cardiovascular disease","authors":"Zixuan Wang ,&nbsp;Junren Liu ,&nbsp;Ying Chen ,&nbsp;Yi Tang ,&nbsp;Ting Chen ,&nbsp;Chang Zhou ,&nbsp;Shuo Wang ,&nbsp;Ranbo Chang ,&nbsp;Zhongshuai Chen ,&nbsp;Wenqing Yang ,&nbsp;Zhen Guo ,&nbsp;Ting Chen","doi":"10.1016/j.pharmthera.2025.108801","DOIUrl":"10.1016/j.pharmthera.2025.108801","url":null,"abstract":"<div><div>Cardiovascular diseases (CVDs) are among the leading causes of death globally and pose a significant threat to public health. Factors such as prolonged high cholesterol levels, diabetes, smoking, unhealthy diet, and genetic predisposition could contribute to the occurrence and development of CVDs. Common CVDs include hypertension (HTN), atherosclerosis (AS), myocardial infarction (MI), myocardial ischemia-reperfusion injury (MIRI), heart failure (HF) and arrhythmia. Estrogen is recognized for its cardiovascular protective effects, resulting in lower incidence and mortality rates of CVDs in premenopausal women compared to men. The G protein-coupled estrogen receptor (GPER), a G protein-coupled receptor with a seven-transmembrane structure, exhibits unique structural characteristics and widespread tissue distribution. GPER activates intracellular signaling pathways through its interaction with G proteins, mediating estrogen's biological effects and participating in the regulation of cardiovascular function, metabolic balance, and nervous system. Although recent research has highlighted the significant role of GPER in the cardiovascular system, its specific mechanisms remain unclear. Therefore, this review summarizes the latest research on GPER in CVDs, including its fundamental characteristics, physiological functions in the cardiovascular system, and its roles and potential therapeutic applications in common CVDs such as HTN, AS, MI, MIRI, HF and arrhythmia. Exploring GPER's positive effects on cardiovascular health will provide new strategies and research directions for the treatment of CVDs.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108801"},"PeriodicalIF":12.0,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}