Pharmacology & Therapeutics最新文献

{"title":"Healing action of Interleukin-4 (IL-4) in acute and chronic inflammatory conditions: Mechanisms and therapeutic strategies.","authors":"Kai Pan, Qiong Li, Zhikun Guo, Zongjin Li","doi":"10.1016/j.pharmthera.2024.108760","DOIUrl":"10.1016/j.pharmthera.2024.108760","url":null,"abstract":"<p><p>Interleukin-4 (IL-4), which is traditionally associated with inflammation, has emerged as a key player in tissue regeneration. Produced primarily by T-helper 2 (Th2) and other immune cells, IL-4 activates endogenous lymphocytes and promotes M2 macrophage polarization, both of which are crucial for tissue repair. Moreover, IL-4 stimulates the proliferation and differentiation of various cell types, contributing to efficient tissue regeneration, and shows promise for promoting tissue regeneration after injury. This review explores the multifaceted roles of IL-4 in tissue repair, summarizing its mechanisms and potential for clinical application. This review delves into the multifaceted functions of IL-4, including its immunomodulatory effects, its involvement in tissue regeneration, and its potential therapeutic applications. We discuss the mechanisms underlying IL-4-induced M2 macrophage polarization, a crucial process for tissue repair. Additionally, we explore innovative strategies for delivering IL-4, including gene therapy, protein-based therapies, and cell-based therapies. By leveraging the regenerative properties of IL-4, we can potentially develop novel therapies for various diseases, including chronic inflammatory disorders, autoimmune diseases, and organ injuries. While early research has shown promise for the application of IL-4 in regenerative medicine, further studies are needed to fully elucidate its therapeutic potential and optimize its use.</p>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":" ","pages":"108760"},"PeriodicalIF":12.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765113","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 intricate interactions between inflammasomes and bacterial pathogens: Roles, mechanisms, and therapeutic potentials.","authors":"Jin Kyung Kim, Asmita Sapkota, Taylor Roh, Eun-Kyeong Jo","doi":"10.1016/j.pharmthera.2024.108756","DOIUrl":"10.1016/j.pharmthera.2024.108756","url":null,"abstract":"<p><p>Inflammasomes are intracellular multiprotein complexes that consist of a sensor, an adaptor, and a caspase enzyme to cleave interleukin (IL)-1β and IL-18 into their mature forms. In addition, caspase-1 and -11 activation results in the cleavage of gasdermin D to form pores, thereby inducing pyroptosis. Activation of the inflammasome and pyroptosis promotes host defense against pathogens, whereas dysregulation of the inflammasome can result in various pathologies. Inflammasomes exhibit versatile microbial signal detection, directly or indirectly, through cellular processes, such as ion fluctuations, reactive oxygen species generation, and the disruption of intracellular organelle function; however, bacteria have adaptive strategies to manipulate the inflammasome by altering microbe-associated molecular patterns, intercepting innate pathways with secreted effectors, and attenuating inflammatory and cell death responses. In this review, we summarize recent advances in the diverse roles of the inflammasome during bacterial infections and discuss how bacteria exploit inflammasome pathways to establish infections or persistence. In addition, we highlight the therapeutic potential of harnessing bacterial immune subversion strategies against acute and chronic bacterial infections. A more comprehensive understanding of the significance of inflammasomes in immunity and their intricate roles in the battle between bacterial pathogens and hosts will lead to the development of innovative strategies to address emerging threats posed by the expansion of drug-resistant bacterial infections.</p>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":" ","pages":"108756"},"PeriodicalIF":12.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708548","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":"Glucuronidation of orally administered drugs and the value of nanocarriers in strategies for its overcome.","authors":"Laura Hervieu, Anne-Claire Groo, Jérémy Bellien, Dominique Guerrot, Aurélie Malzert-Fréon","doi":"10.1016/j.pharmthera.2024.108773","DOIUrl":"10.1016/j.pharmthera.2024.108773","url":null,"abstract":"<p><p>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 via 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. 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. Species-specific differences in UGT expression and activity impact the selection of animal models for pharmacological studies. Various experimental models - ranging from computational simulations (in silico) to laboratory experiments (in vitro) and animal studies (in vivo) - are employed throughout drug discovery and development to evaluate drug metabolism, including UGT activity. 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. This review highlights the importance of targeted delivery systems and excipient selection in overcoming metabolic barriers, aiming to optimize drug efficacy and patient outcomes.</p>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":" ","pages":"108773"},"PeriodicalIF":12.0,"publicationDate":"2024-12-06","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":"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":"<p><p>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.</p>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":" ","pages":"108774"},"PeriodicalIF":12.0,"publicationDate":"2024-12-05","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}

{"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, Carmen Andrea Pfortmueller, Katarzyna Kotfis, Andrzej Jaroszynski, Mariusz Gagos, Wlodzimierz Plotek, Manu L N G Malbrain","doi":"10.1016/j.pharmthera.2024.108766","DOIUrl":"10.1016/j.pharmthera.2024.108766","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":" ","pages":"108766"},"PeriodicalIF":12.0,"publicationDate":"2024-12-03","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":"EGFL7: An emerging biomarker with great therapeutic potential.","authors":"Carina Fabian, Sukrit Mahajan, Mirko H H Schmidt","doi":"10.1016/j.pharmthera.2024.108764","DOIUrl":"https://doi.org/10.1016/j.pharmthera.2024.108764","url":null,"abstract":"<p><p>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 in vitro and in vivo 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.</p>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":" ","pages":"108764"},"PeriodicalIF":12.0,"publicationDate":"2024-12-02","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Signaling pathways and targeted therapies in Ewing sarcoma.","authors":"Ke Jia, Li Cao, Yihan Yu, Doudou Jing, Wei Wu, Brian Andrew Van Tine, Zengwu Shao","doi":"10.1016/j.pharmthera.2024.108765","DOIUrl":"10.1016/j.pharmthera.2024.108765","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":" ","pages":"108765"},"PeriodicalIF":12.0,"publicationDate":"2024-11-30","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":"","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, Hina Bhat, Prasad S Adusumilli, Zhaohua Hou","doi":"10.1016/j.pharmthera.2024.108763","DOIUrl":"10.1016/j.pharmthera.2024.108763","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":" ","pages":"108763"},"PeriodicalIF":12.0,"publicationDate":"2024-11-29","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":"Peripheral GABA_A receptors - Physiological relevance and therapeutic implications.","authors":"Milica Gajić Bojić, Jovana Aranđelović, Ranko Škrbić, Miroslav M Savić","doi":"10.1016/j.pharmthera.2024.108759","DOIUrl":"10.1016/j.pharmthera.2024.108759","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":" ","pages":"108759"},"PeriodicalIF":12.0,"publicationDate":"2024-11-28","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":"Uncovering the intricacies of O-GlcNAc modification in cognitive impairment: New insights from regulation to therapeutic targeting.","authors":"Jianhui Wang, Ning Jiang, Feng Liu, Chenran Wang, Wenxia Zhou","doi":"10.1016/j.pharmthera.2024.108761","DOIUrl":"10.1016/j.pharmthera.2024.108761","url":null,"abstract":"<p><p>O-linked β-N-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.</p>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":" ","pages":"108761"},"PeriodicalIF":12.0,"publicationDate":"2024-11-26","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}