Pharmacology & Therapeutics最新文献

{"title":"Understanding the molecular bridges between the drugs and immune cell","authors":"Umesh Chandra Dash ,&nbsp;Vinayak Nayak ,&nbsp;Hiten Shanker Navani ,&nbsp;Rashmi Rekha Samal ,&nbsp;Palak Agrawal ,&nbsp;Anup Kumar Singh ,&nbsp;Sanatan Majhi ,&nbsp;Devraj Ganpat Mogare ,&nbsp;Asim K. Duttaroy ,&nbsp;Atala Bihari Jena","doi":"10.1016/j.pharmthera.2025.108805","DOIUrl":"10.1016/j.pharmthera.2025.108805","url":null,"abstract":"<div><div>The interactions of drugs with the host's immune cells determine the drug's efficacy and adverse effects in patients. Nonsteroidal Anti-Inflammatory Drugs (NSAID), such as corticosteroids, NSAIDs, and immunosuppressants, affect the immune cells and alter the immune response. Molecularly, drugs can interact with immune cells via cell surface receptors, changing the antigen presentation by modifying the co-stimulatory molecules and interacting with the signaling pathways of T cells, B cells, Natural killer (NK) cells, mast cells, basophils, and macrophages. Immunotoxicity, resulting from drug-induced changes in redox status, generation of Reactive Oxygen Species (ROS)/Reactive Nitrogen Species (RNS), and alterations in antioxidant enzymes within immune cells, leads to immunodeficiency. This, in turn, causes allergic reactions, autoimmune diseases, and cytokine release syndrome (CRS). The treatment options should include the evaluation of immune status and utilization of the concept of pharmacogenomics to minimize the chances of immunotoxicity. Many strategies in redox, like targeting the redox pathway or using redox-active agents, are available for the modulation of the immune system and developing drugs. Case studies highlight significant drug-immune cell interactions and patient outcomes, underscoring the importance of understanding these complexities. The future direction focuses on the drugs to deliver antiviral therapy, new approaches to immunomodulation, and modern technologies for increasing antidote effects with reduced toxicity. In conclusion, in-depth knowledge of the interaction between drugs and immune cells is critical to protect the patient from the adverse effects of the drug and improve therapeutic outcomes of the treatment process. This review focuses on the multifaceted interactions of drugs and their consequences at the cellular levels of immune cells.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108805"},"PeriodicalIF":12.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143137321","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":"Targeting TAK1: Evolution of inhibitors, challenges, and future directions","authors":"Nika Strašek Benedik ,&nbsp;Matic Proj ,&nbsp;Christian Steinebach ,&nbsp;Matej Sova ,&nbsp;Izidor Sosič","doi":"10.1016/j.pharmthera.2025.108810","DOIUrl":"10.1016/j.pharmthera.2025.108810","url":null,"abstract":"<div><div>The increasing incidence of inflammatory and malignant diseases signifies the need to develop first-in-class drugs with novel mechanisms of action. In this respect, the transforming growth factor (TGF)-β-activated kinase 1 (TAK1), an essential part of several signaling pathways, is considered relevant and promising. This manuscript provides a brief overview of the signal transduction orchestrated by TAK1 within these pathways, followed by an in-depth and thorough analysis of the chemical matter demonstrated to inhibit this kinase. Special attention is given to the selectivity profiling of inhibitors, as well as to the outcomes of their biological characterization. Because published TAK1 inhibitors differ significantly in their kinome selectivity, active-site binding, and biological activity, we hope that this review will allow a judicial estimation of their quality and usefulness for TAK1-addressing assays. Our thoughts on the perspectives and possible developments of the field are also provided to assist scientists who are involved in the design and development of TAK1-targeting modulators.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108810"},"PeriodicalIF":12.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254028","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":"Biased signaling in drug discovery and precision medicine","authors":"Ren-Lei Ji,&nbsp;Ya-Xiong Tao","doi":"10.1016/j.pharmthera.2025.108804","DOIUrl":"10.1016/j.pharmthera.2025.108804","url":null,"abstract":"<div><div>Receptors are crucial for converting chemical and environmental signals into cellular responses, making them prime targets in drug discovery, with about 70% of drugs targeting these receptors. Biased signaling, or functional selectivity, has revolutionized drug development by enabling precise modulation of receptor signaling pathways. This concept is more firmly established in G protein-coupled receptor and has now been applied to other receptor types, including ion channels, receptor tyrosine kinases, and nuclear receptors. Advances in structural biology have further refined our understanding of biased signaling. This targeted approach enhances therapeutic efficacy and potentially reduces side effects. Numerous biased drugs have been developed and approved as therapeutics to treat various diseases, demonstrating their significant therapeutic potential. This review provides a comprehensive overview of biased signaling in drug discovery and disease treatment, highlighting recent advancements and exploring the therapeutic potential of these innovative modulators across various diseases.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"268 ","pages":"Article 108804"},"PeriodicalIF":12.0,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187876","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":"Annexin A1 in neurological disorders: Neuroprotection and glial modulation","authors":"Luiz Philipe de Souza Ferreira ,&nbsp;Rafael André da Silva ,&nbsp;Pâmela Pacassa Borges ,&nbsp;Luana Filippi Xavier ,&nbsp;Pablo Scharf ,&nbsp;Silvana Sandri ,&nbsp;Sonia M. Oliani ,&nbsp;Sandra H.P. Farsky ,&nbsp;Cristiane D. Gil","doi":"10.1016/j.pharmthera.2025.108809","DOIUrl":"10.1016/j.pharmthera.2025.108809","url":null,"abstract":"<div><div>Neurological disorders, such as neurodegenerative and neuroinflammatory diseases, have contributed significantly to global disability, even considering the rising life years expectations. Therefore, prevention, early diagnosis, and therapeutic alternatives have been essential to avoid the future collapse of health public systems. Annexin A1 (ANXA1), a Ca2 + −dependent protein, is a promising therapeutic candidate for neurological disorders. ANXA1, found in neurons and glia, displays roles in physiological and pathological processes. Despite ANXA1 undoubtedly maintains the blood-brain barrier (BBB) integrity, this review will focus on ANXA1 roles in neurons and glial cells. In neurons, the cytoplasmic expression of ANXA1 is associated with apoptosis, while its nuclear translocation is linked to ischemic neuronal death. Interactions with S100A11, the Tat-NTS peptide, and other molecules, modulate this translocation, suggesting potential therapeutic interventions. ANXA1 expressed on microglia modulates inflammation and efferocytosis. Post-translational modifications, such as SUMOylation, guide the role of ANXA1 in microglia polarization and neuroprotection. In addition, ANXA1 in astrocytes responds to inflammatory stimuli by influencing cytokine release. A comprehensive understanding of the intricate mechanisms of ANXA1 in neurons and glial cells reveals promising therapeutic strategies to alleviate neuronal damage in neurological diseases.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108809"},"PeriodicalIF":12.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121688","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":"Uncovering the intricacies of O-GlcNAc modification in cognitive impairment: New insights from regulation to therapeutic targeting","authors":"Jianhui Wang ,&nbsp;Ning Jiang ,&nbsp;Feng Liu ,&nbsp;Chenran Wang ,&nbsp;Wenxia Zhou","doi":"10.1016/j.pharmthera.2024.108761","DOIUrl":"10.1016/j.pharmthera.2024.108761","url":null,"abstract":"<div><div>O-linked β-<em>N</em>-acetylglucosamine (O-GlcNAc) represents a post-translational modification that occurs on serine or threonine residues on various proteins. This conserved modification interacts with vital cellular pathways. Although O-GlcNAc is widely distributed throughout the body, it is particularly enriched in the brain, where most proteins are O-GlcNAcylated. Recent studies have established a causal link between O-GlcNAc regulation in the brain and alterations in neurophysiological function. Alterations in O-GlcNAc levels in the brain are associated with the pathogenesis of several neurogenic diseases that can lead to cognitive impairment. Remarkably, manipulation of O-GlcNAc levels demonstrated a protective effect on cognitive function. Although the precise molecular mechanism of O-GlcNAc modification in the nervous system remains elusive, its regulation is fundamental to multiple neural and cognitive functions, fluctuating levels during normal and pathological cognitive processes. In this review, we highlight the significant functional importance of O-GlcNAc modification in pathological cognitive impairments and the potential application of O-GlcNAc as a promising target for the intervention or amelioration of cognitive impairments.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"266 ","pages":"Article 108761"},"PeriodicalIF":12.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738083","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":"Biased signaling in GPCRs: Structural insights and implications for drug development","authors":"Yuanyuan Ma,&nbsp;Brandon Patterson,&nbsp;Lan Zhu","doi":"10.1016/j.pharmthera.2024.108786","DOIUrl":"10.1016/j.pharmthera.2024.108786","url":null,"abstract":"<div><div>G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors in humans, playing a crucial role in regulating diverse cellular processes and serving as primary drug targets. Traditional drug design has primarily focused on ligands that uniformly activate or inhibit GPCRs. However, the concept of biased agonism—where ligands selectively stabilize distinct receptor conformations, leading to unique signaling outcomes—has introduced a paradigm shift in therapeutic development. Despite the promise of biased agonists to enhance drug efficacy and minimize side effects, a comprehensive understanding of the structural and biophysical mechanisms underlying biased signaling is essential. Recent advancements in GPCR structural biology have provided unprecedented insights into ligand binding, conformational dynamics, and the molecular basis of biased signaling. These insights, combined with improved techniques for characterizing ligand efficacy, have driven the development of biased ligands for several GPCRs, including opioid, angiotensin, and adrenergic receptors. This review synthesizes these developments, from mechanisms to drug discovery in biased signaling, emphasizing the role of structural insights in the rational design of next-generation biased agonists with superior therapeutic profiles. Ultimately, these advances hold the potential to revolutionize GPCR-targeted drug discovery, paving the way for more precise and effective treatments.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"266 ","pages":"Article 108786"},"PeriodicalIF":12.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884948","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":"Is there a place for natural agents with anti-inflammatory and antioxidative properties in critically ill patients? Potential usefulness of Xanthohumol","authors":"Wojciech Dabrowski ,&nbsp;Carmen Andrea Pfortmueller ,&nbsp;Katarzyna Kotfis ,&nbsp;Andrzej Jaroszynski ,&nbsp;Mariusz Gagos ,&nbsp;Wlodzimierz Plotek ,&nbsp;Manu L.N.G. Malbrain","doi":"10.1016/j.pharmthera.2024.108766","DOIUrl":"10.1016/j.pharmthera.2024.108766","url":null,"abstract":"<div><div>Multi-organ dysfunction is a major issue in critically ill patients, where a significant inflammatory response appears to be the primary factor driving the degree of organ impairment, which correlates with the extent of organ injury. The management of inflammation requires a multidisciplinary approach, including antibiotics for infection control, circulatory and respiratory support, and correction of coagulation abnormalities. However, the use of anti-inflammatory treatments is typically restricted to a selected group of medications, with their effectiveness remaining the subject of extensive debate. Xanthohumol (Xn), a natural compound extracted from hops, possesses strong anti-inflammatory and antioxidative properties, with a mild anti-coagulation effect. Its biological activity is related to the inhibition of different inflammatory pathways, reduction in cytokine production and secretion, and an increase in antioxidative enzyme activity. This review examined the potential use of Xn as an adjuvant in the treatment of various pathologies in critically ill patients.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"266 ","pages":"Article 108766"},"PeriodicalIF":12.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783793","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":"Biased agonism at free-fatty acid receptor-4 (FFA4/GPR120)","authors":"Razan L. Teyani ,&nbsp;Nader H. Moniri","doi":"10.1016/j.pharmthera.2024.108784","DOIUrl":"10.1016/j.pharmthera.2024.108784","url":null,"abstract":"<div><div>Free-fatty acid receptor-4 (FFA4), previously known as GPR120, is a G protein-coupled receptor (GPCR) activated by medium-to-long chain free fatty acids (FFAs), including saturated, monounsaturated, and polyunsaturated fats, many of which (e.g., omega-3 fatty acids) are critical contributors to human health and disease. FFA4 is widely expressed across human tissues, and its activation supports a range of physiological functions, including the release of gastrointestinal incretin hormones like glucagon-like peptide-1 (GLP-1), regulation of pancreatic hormone secretion, peripheral glucose uptake, adipose regulation, and anti-inflammatory responses in macrophages. Due to its pivotal role in energy metabolism and inflammation, FFA4 has emerged as a major target in drug discovery. Historically, FFA4 signaling was linked to the Gαq/11 family of intracellular heterotrimeric G proteins, which mediate its GLP-1 releasing effects. However, emerging evidence indicates that FFA4 can signal through other Gα proteins in various cellular contexts. Notably, its anti-inflammatory effects are also dependent on interactions with β-arrestin proteins, further broadening the receptor's signaling versatility. This review explores the concept of biased agonism at FFA4, emphasizing how this receptor selectively signals through distinct transduction pathways, including Gα proteins and β-arrestins. We also examine the key structural elements of FFA4 that govern its interactions with different signaling partners, the elucidation of which has laid the groundwork for the development of biased agonists aimed at selectively modulating these FFA4-mediated pathways for therapeutic application.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"266 ","pages":"Article 108784"},"PeriodicalIF":12.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884947","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":"Essential role of sulfide oxidation in brain health and neurological disorders","authors":"Eiki Kanemaru,&nbsp;Fumito Ichinose","doi":"10.1016/j.pharmthera.2024.108787","DOIUrl":"10.1016/j.pharmthera.2024.108787","url":null,"abstract":"<div><div>Hydrogen sulfide (H₂S) is an environmental hazard well known for its neurotoxicity. In mammalian cells, H₂S is predominantly generated by transsulfuration pathway enzymes. In addition, H₂S produced by gut microbiome significantly contributes to the total sulfide burden in the body. Although low levels of H₂S is believed to exert various physiological functions such as neurotransmission and vasomotor control, elevated levels of H₂S inhibit the activity of cytochrome <em>c</em> oxidase (i.e., mitochondrial complex IV), thereby impairing oxidative phosphorylation. To protect the electron transport chain from respiratory poisoning by H₂S, the compound is actively oxidized to form persulfides and polysulfides by a mitochondrial resident sulfide oxidation pathway. The reaction, catalyzed by sulfide:quinone oxidoreductase (SQOR), is the initial and critical step in sulfide oxidation. The persulfide species are subsequently oxidized to sulfite, thiosulfate, and sulfate by persulfide dioxygenase (ETHE1 or SDO), thiosulfate sulfurtransferase (TST), and sulfite oxidase (SUOX). While SQOR is abundantly expressed in the colon, liver, lung, and skeletal muscle, its expression is notably low in the brains of most mammals. Consequently, the brain's limited capacity to oxidize H₂S renders it particularly sensitive to the deleterious effects of H₂S accumulation. Impaired sulfide oxidation can lead to fatal encephalopathy, and the overproduction of H₂S has been implicated in the developmental delays observed in Down syndrome. Our recent findings indicate that the brain's limited capacity to oxidize sulfide exacerbates its sensitivity to oxygen deprivation. The beneficial effects of sulfide oxidation are likely to be mediated not only by the detoxification of H₂S but also by the formation of persulfide, which exerts cytoprotective effects through multiple mechanisms. Therefore, pharmacological agents designed to scavenge H₂S and/or enhance persulfide levels may offer therapeutic potential against neurological disorders characterized by impaired or insufficient sulfide oxidation or excessive H₂S production.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"266 ","pages":"Article 108787"},"PeriodicalIF":12.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884949","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":"Non-vesicular extracellular RNA: A potential drug target to intervene cell-cell communication","authors":"Takeshi Tomita","doi":"10.1016/j.pharmthera.2024.108774","DOIUrl":"10.1016/j.pharmthera.2024.108774","url":null,"abstract":"<div><div>The importance of non-vesicular extracellular RNA in the mammalian system is becoming increasingly apparent. Non-vesicular extracellular RNA is defined as RNA molecules not included in a lipid bilayer such as exosomes. Because non-vesicular extracellular RNA is not protected from RNases and is therefore rapidly degraded, they were not easily captured by conventional biofluid analyses. Recent publications showed that some non-vesicular extracellular RNAs are relatively stable in biofluids or tissue culture media, and they have unique biological functions. Major RNAs (rRNA, mRNA, and tRNA) and other non-cording RNAs play important roles in transcription or translation in the cell. In contrast, non-vesicular extracellular RNA has functions related to intercellular communication rather than protein synthesis. This review discusses the basics of non-vesicular extracellular RNA, including its definition, purification, receptors, and future prospects as a drug target.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"266 ","pages":"Article 108774"},"PeriodicalIF":12.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790903","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}