Pharmacology & Therapeutics最新文献

{"title":"Metrnl as a secreted protein: Discovery and cardiovascular research","authors":"Zhu-Wei Miao ,&nbsp;Jin Chen ,&nbsp;Can-Xin Chen ,&nbsp;Si-Li Zheng ,&nbsp;Huan-Yu Zhao ,&nbsp;Chao-Yu Miao","doi":"10.1016/j.pharmthera.2024.108730","DOIUrl":"10.1016/j.pharmthera.2024.108730","url":null,"abstract":"<div><div>Secreted proteins have gained more and more attentions, since they can become therapeutic targets, drugs and biomarkers for prevention, diagnosis and treatment of disease and aging. In 2014, Metrnl (also named Meteorin-like, Cometin, Subfatin, Interleukin-39, Interleukin-41, Meteorin-β, and Metrn-β/Metrnβ), as a novel secreted protein released from a certain tissue, was reported by us and others. During the past decade, the number of articles on Metrnl has continued to increase. Different sources of Metrnl have been described with different functions, including Metrnl as an adipokine for insulin sensitization, a cardiokine against cardiac hypertrophy and dysfunction, an endothelium-derived factor against endothelial dysfunction and atherosclerosis, etc. Especially, we show that endothelial Metrnl is a major source for circulating Metrnl levels. Meanwhile, lots of clinical studies have investigated the relationship between blood Metrnl levels and metabolic, inflammatory and cardiovascular diseases. Metrnl appears a protective factor and a promising therapeutic target and/or drug against these diseases, given the relatively consistent conclusion from the preclinical studies. In addition to graphically demonstrating the role of Metrnl in various organs and diseases, this review will mainly describe the discovery of Metrnl, summarize the role of Metrnl in cardiovascular system that is a recently major progress in Metrnl research, and highlight several perspectives for future basic and translational research. Also, we suggest using one name Metrnl instead of other multiple names for the same protein.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"263 ","pages":"Article 108730"},"PeriodicalIF":12.0,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455009","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":"Targeting selective autophagy in CNS disorders by small-molecule compounds","authors":"Yanrong Zheng ,&nbsp;Zhuchen Zhou ,&nbsp;Mengting Liu,&nbsp;Zhong Chen","doi":"10.1016/j.pharmthera.2024.108729","DOIUrl":"10.1016/j.pharmthera.2024.108729","url":null,"abstract":"<div><div>Autophagy functions as the primary cellular mechanism for clearing unwanted intracellular contents. Emerging evidence suggests that the selective elimination of intracellular organelles through autophagy, compared to the increased bulk autophagic flux, is crucial for the pathological progression of central nervous system (CNS) disorders. Notably, autophagic removal of mitochondria, known as mitophagy, is well-understood in an unhealthy brain. Accumulated data indicate that selective autophagy of other substrates, including protein aggregates, liposomes, and endoplasmic reticulum, plays distinctive roles in various pathological stages. Despite variations in substrates, the molecular mechanisms governing selective autophagy can be broadly categorized into two types: ubiquitin-dependent and -independent pathways, both of which can be subjected to regulation by small-molecule compounds. Notably, natural products provide the remarkable possibility for future structural optimization to regulate the highly selective autophagic clearance of diverse substrates. In this context, we emphasize the selectivity of autophagy in regulating CNS disorders and provide an overview of chemical compounds capable of modulating selective autophagy in these disorders, along with the underlying mechanisms. Further exploration of the functions of these compounds will in turn advance our understanding of autophagic contributions to brain disorders and illuminate precise therapeutic strategies for these diseases.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"263 ","pages":"Article 108729"},"PeriodicalIF":12.0,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455012","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":"A comprehensive review on pharmacokinetic mechanism of herb-herb/drug interactions in Chinese herbal formula","authors":"Mengting Li ,&nbsp;Yanli Wang ,&nbsp;Yi Chen ,&nbsp;Lijinchuan Dong ,&nbsp;Jieyuan Liu ,&nbsp;Yu Dong ,&nbsp;Qing Yang ,&nbsp;Weiyan Cai ,&nbsp;Qi Li ,&nbsp;Bo Peng ,&nbsp;Yujie Li ,&nbsp;Xiaogang Weng ,&nbsp;Yajie Wang ,&nbsp;Xiaoxin Zhu ,&nbsp;Zipeng Gong ,&nbsp;Ying Chen","doi":"10.1016/j.pharmthera.2024.108728","DOIUrl":"10.1016/j.pharmthera.2024.108728","url":null,"abstract":"<div><div>Oral administration of Chinese Herbal Medicine (CHM) faces various challenges in reaching the target organs including absorption and conversion in the gastrointestinal tract, hepatic metabolism <em>via</em> the portal vein, and eventual systemic circulation. During this process, factors such as gut microbes, physical or chemical barriers, metabolic enzymes, and transporters play crucial roles. Particularly, interactions between different herbs in CHM have been observed both <em>in vitro</em> and <em>in vivo</em>. <em>In vitro</em>, interactions typically manifest as detectable physical or chemical changes, such as facilitating solubilization or producing precipitates when decoctions of multiple herbs are administered. <em>In vivo</em>, such interactions cause alterations in the ADME (absorption, distribution, metabolism, and excretion) profile on metabolic enzymes or transporters in the body, leading to competition, antagonism, inhibition, or activation. These interactions ultimately contribute to differences in the therapeutic and pharmacological effects of multi-herb formulas in CHM. Over the past two thousand years, China has cultivated profound expertise and solid theoretical frameworks over the scientific use of herbs. The combination of multiple herbs in one decoction has been frequently employed to synergistically enhance therapeutic efficacy or mitigate toxic and side effects in clinical settings. Additionally combining herbs with increased toxicity or decreased effect is also regarded as a remedy, a practice that should be approached with caution according to Traditional Chinese Medicine (TCM) physicians. Such historical records and practices serve as a foundation for predicting favorable multi-herb combinations and their potential risks. However, systematic data that are available to support the clinical practice and the exploration of novel herbal formulas remain limited. Therefore, this review aims to summarize the pharmacokinetic interactions and mechanisms of herb-herb or herb-drug combinations from existing works, and to offer guidance as well as evidence for optimizing CHM and developing new medicines with CHM characteristics.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"264 ","pages":"Article 108728"},"PeriodicalIF":12.0,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142398997","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 TRPC5 receptor as pharmacological target for pain and metabolic disease","authors":"Pragyanshu Khare ,&nbsp;Jagdish Chand ,&nbsp;Alexandra Ptakova ,&nbsp;Renato Liguori ,&nbsp;Fulvia Ferrazzi ,&nbsp;Mahendra Bishnoi ,&nbsp;Viktorie Vlachova ,&nbsp;Katharina Zimmermann","doi":"10.1016/j.pharmthera.2024.108727","DOIUrl":"10.1016/j.pharmthera.2024.108727","url":null,"abstract":"<div><div>The transient receptor potential canonical (TRPC) channels are a group of highly homologous nonselective cation channels from the larger TRP channel family. They have the ability to form homo- and heteromers with varying degrees of calcium (Ca²⁺) permeability and signalling properties. TRPC5 is the one cold-sensitive among them and likewise facilitates the influx of extracellular Ca²⁺ into cells to modulate neuronal depolarization and integrate various intracellular signalling pathways. Recent research with cryo-electron microscopy revealed its structure, along with clear insight into downstream signalling and protein-protein interaction sites. Investigations using global and conditional deficient mice revealed the involvement of TRPC5 in metabolic diseases, energy balance, thermosensation and conditions such as osteoarthritis, rheumatoid arthritis, and inflammatory pain including opioid-induced hyperalgesia and hyperalgesia following tooth decay and pulpitis. This review provides an update on recent advances in our understanding of the role of TRPC5 with focus on metabolic diseases and pain.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"263 ","pages":"Article 108727"},"PeriodicalIF":12.0,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387016","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":"Microtubule dynamics in cancer metastasis: Harnessing the underappreciated potential for therapeutic interventions","authors":"Snehal Mangaonkar ,&nbsp;Sangeeta Nath ,&nbsp;Biswa Prasun Chatterji","doi":"10.1016/j.pharmthera.2024.108726","DOIUrl":"10.1016/j.pharmthera.2024.108726","url":null,"abstract":"<div><div>Microtubules, dynamic cytoskeletal structures crucial for cellular processes, have surfaced as promising targets for cancer therapy owing to their pivotal role in cancer progression and metastasis. This review comprehensively explores the multifaceted landscape of microtubule-targeting drugs and their potential to inihibit cancer metastasis. Although the role of Actin cytoskeleton is well known in controlling metastasis, only recently Microtubules are emerging as a potential controller of metastasis. We delve into the processes at the core of antimetastatic impacts of microtubule-targeting agents, both through direct modulation of microtubules and via alternative pathways. Drawing from in vitro and in vivo studies, we analyze the cytotoxic and antimetastatic doses of various compounds, shedding light on their therapeutic potential. Furthermore, we discuss the emerging class of microtubule targeting drugs, and their role in metastasis inhibition, such as microtubules acetylation inhibitory drugs, particularly histone deacetylase inihibitors and antibody-drug conjugates. Histone deacetylase (HDAC) strengthens the microtubule cytoskeleton through acetylation. Recently, HDAC inhibitors have been discovered to have antimetastatic properties. Here, the role of HDAC inhibitors in stopping metastasis is discussed with respect to microtubule cytoskeleton. Surprisingly, novel antibody conjugates of microtubule-targeting agents, which are in clinical trials, were found to be antimetastatic. This review discusses these antibody conjugates in detail. Additionally, we elucidate the intricate crosstalk between microtubules and other cytoskeletal proteins, unveiling novel therapeutic strategies for metastasis suppression. By providing a wide-ranging overview of the complex interplay between microtubules and cancer metastasis, this review contributes to the comprehension of cancer's biological mechanisms and the development of innovative therapeutic interventions to mitigate metastatic progression.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"263 ","pages":"Article 108726"},"PeriodicalIF":12.0,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142338472","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":"Powering up targeted protein degradation through active and passive tumour-targeting strategies: Current and future scopes","authors":"Janarthanan Venkatesan ,&nbsp;Dhanashree Murugan ,&nbsp;Kalaiarasu Lakshminarayanan ,&nbsp;Alexis R. Smith ,&nbsp;Harashkumar Vasanthakumari Thirumalaiswamy ,&nbsp;Hariprasath Kandhasamy ,&nbsp;Boutheina Zender ,&nbsp;Guangrong Zheng ,&nbsp;Loganathan Rangasamy","doi":"10.1016/j.pharmthera.2024.108725","DOIUrl":"10.1016/j.pharmthera.2024.108725","url":null,"abstract":"<div><div>Targeted protein degradation (TPD) has emerged as a prominent and vital strategy for therapeutic intervention of cancers and other diseases. One such approach involves the exploration of proteolysis targeting chimeras (PROTACs) for the selective elimination of disease-causing proteins through the innate ubiquitin-proteasome pathway. Due to the unprecedented achievements of various PROTAC molecules in clinical trials, researchers have moved towards other physiological protein degradation approaches for the targeted degradation of abnormal proteins, including lysosome-targeting chimeras (LYTACs), autophagy-targeting chimeras (AUTACs), autophagosome-tethering compounds (ATTECs), molecular glue degraders, and other derivatives for their precise mode of action. Despite numerous advantages, these molecules face challenges in solubility, permeability, bioavailability, and potential off-target or on-target off-tissue effects. Thus, an urgent need arises to direct the action of these degrader molecules specifically against cancer cells, leaving the proteins of non-cancerous cells intact. Recent advancements in TPD have led to innovative delivery methods that ensure the degraders are delivered in a cell- or tissue-specific manner to achieve cell/tissue-selective degradation of target proteins. Such receptor-specific active delivery or nano-based passive delivery of the PROTACs could be achieved by conjugating them with targeting ligands (antibodies, aptamers, peptides, or small molecule ligands) or nano-based carriers. These techniques help to achieve precise delivery of PROTAC payloads to the target sites. Notably, the successful entry of a Degrader Antibody Conjugate (DAC), ORM-5029, into a phase 1 clinical trial underscores the therapeutic potential of these conjugates, including LYTAC-antibody conjugates (LACs) and aptamer-based targeted protein degraders. Further, using bispecific antibody-based degraders (AbTACs) and delivering the PROTAC pre-fused with E3 ligases provides a solution for cell type-specific protein degradation. Here, we highlighted the current advancements and challenges associated with developing new tumour-specific protein degrader approaches and summarized their potential as single agents or combination therapeutics for cancer.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"263 ","pages":"Article 108725"},"PeriodicalIF":12.0,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142338473","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":"Opportunities and challenges in the therapeutic exploitation of histamine and histamine receptor pharmacology in inflammation-driven disorders","authors":"Ekaterini Tiligada ,&nbsp;Charikleia Stefanaki ,&nbsp;Madeleine Ennis ,&nbsp;Detlef Neumann","doi":"10.1016/j.pharmthera.2024.108722","DOIUrl":"10.1016/j.pharmthera.2024.108722","url":null,"abstract":"<div><div>Inflammation-driven diseases encompass a wide array of pathological conditions characterised by immune system dysregulation leading to tissue damage and dysfunction. Among the myriad of mediators involved in the regulation of inflammation, histamine has emerged as a key modulatory player. Histamine elicits its actions through four rhodopsin-like G-protein-coupled receptors (GPCRs), named chronologically in order of discovery as histamine H₁, H₂, H₃ and H₄ receptors (H₁_–₄R). The relatively low affinity H₁R and H₂R play pivotal roles in mediating allergic inflammation and gastric acid secretion, respectively, whereas the high affinity H₃R and H₄R are primarily linked to neurotransmission and immunomodulation, respectively. Importantly, however, besides the H₄R, both H₁R and H₂R are also crucial in driving immune responses, the H₂R tending to promote yet ill-defined and unexploited suppressive, protective and/or resolving processes. The modulatory action of histamine <em>via</em> its receptors on inflammatory cells is described in detail. The potential therapeutic value of the most recently discovered H₄R in inflammatory disorders is illustrated <em>via</em> a selection of preclinical models. The clinical trials with antagonists of this receptor are discussed and possible reasons for their lack of success described.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"263 ","pages":"Article 108722"},"PeriodicalIF":12.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142278246","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 influence of glutamate receptors on insulin release and diabetic neuropathy","authors":"Enza Palazzo,&nbsp;Ida Marabese,&nbsp;Federica Ricciardi,&nbsp;Francesca Guida,&nbsp;Livio Luongo,&nbsp;Sabatino Maione","doi":"10.1016/j.pharmthera.2024.108724","DOIUrl":"10.1016/j.pharmthera.2024.108724","url":null,"abstract":"<div><p>Diabetes causes macrovascular and microvascular complications such as peripheral neuropathy. Glutamate regulates insulin secretion in pancreatic β-cells, and its increased activity in the central nervous system is associated with peripheral neuropathy in animal models of diabetes. One strategy to modulate glutamatergic activity consists in the pharmacological manipulation of metabotropic glutamate receptors (mGluRs), which, compared to the ionotropic receptors, allow for a fine-tuning of neurotransmission that is compatible with therapeutic interventions. mGluRs are a family of eight G-protein coupled receptors classified into three groups (I-III) based on sequence homology, transduction mechanisms, and pharmacology. Activation of group II and III or inhibition of group I represents a strategy to counteract the glutamatergic hyperactivity associated with diabetic neuropathy. In this review article, we will discuss the role of glutamate receptors in the release of insulin and the development/treatment of diabetic neuropathy, with particular emphasis on their manipulation to prevent the glutamatergic hyperactivity associated with diabetic neuropathy.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"263 ","pages":"Article 108724"},"PeriodicalIF":12.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S016372582400144X/pdfft?md5=240c691a52afc25d35d265a343409431&pid=1-s2.0-S016372582400144X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142272513","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":"Gene editing in common cardiovascular diseases","authors":"Anna-Maria Lauerer ,&nbsp;Xurde M. Caravia ,&nbsp;Lars S. Maier ,&nbsp;Francesco Chemello ,&nbsp;Simon Lebek","doi":"10.1016/j.pharmthera.2024.108720","DOIUrl":"10.1016/j.pharmthera.2024.108720","url":null,"abstract":"<div><p>Cardiovascular diseases are the leading cause of morbidity and mortality worldwide, highlighting the high socioeconomic impact. Current treatment strategies like compound-based drugs or surgeries are often limited. On the one hand, systemic administration of substances is frequently associated with adverse side effects; on the other hand, they typically provide only short-time effects requiring daily intake. Thus, new therapeutic approaches and concepts are urgently needed. The advent of CRISPR-Cas9 genome editing offers great promise for the correction of disease-causing hereditary mutations. As such mutations are often very rare, gene editing strategies to correct them are not broadly applicable to many patients. Notably, there is recent evidence that gene editing technology can also be deployed to disrupt common pathogenic signaling cascades in a targeted, specific, and efficient manner, which offers a more generalizable approach. However, several challenges remain to be addressed ranging from the optimization of the editing strategy itself to a suitable delivery strategy up to potential immune responses to the editing components. This review article discusses important CRISPR-Cas9-based gene editing approaches with their advantages and drawbacks and outlines opportunities in their application for treatment of cardiovascular diseases.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"263 ","pages":"Article 108720"},"PeriodicalIF":12.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0163725824001402/pdfft?md5=49e1c0d6b1b7b1b23e4d7305dafc4eca&pid=1-s2.0-S0163725824001402-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142272435","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":"Organic anion transporters in remote sensing and organ crosstalk","authors":"Jeffry C. Granados ,&nbsp;Sanjay K. Nigam","doi":"10.1016/j.pharmthera.2024.108723","DOIUrl":"10.1016/j.pharmthera.2024.108723","url":null,"abstract":"<div><p>The organic anion transporters, OAT1 and OAT3, regulate the movement of drugs, toxins, and endogenous metabolites. In 2007, we proposed that OATs and other SLC22 transporters are involved in “remote sensing” and organ crosstalk. This is now known as the Remote Sensing and Signaling Theory (RSST). In the proximal tubule of the kidney, OATs regulate signaling molecules such as fatty acids, bile acids, indoxyl sulfate, kynurenine, alpha-ketoglutarate, urate, flavonoids, and antioxidants. OAT1 and OAT3 function as key hubs in a large homeostatic network involving multi-, oligo- and monospecific transporters, enzymes, and nuclear receptors. The Remote Sensing and Signaling Theory emphasizes the functioning of OATs and other “drug” transporters in the network at multiple biological scales (inter-organismal, organism, organ, cell, organelle). This network plays an essential role in the homeostasis of urate, bile acids, prostaglandins, sex steroids, odorants, thyroxine, gut microbiome metabolites, and uremic toxins. The transported metabolites have targets in the kidney and other organs, including nuclear receptors (e.g., HNF4a, AHR), G protein-coupled receptors (GPCRs), and protein kinases. Feed-forward and feedback loops allow OAT1 and OAT3 to mediate organ crosstalk as well as modulate energy metabolism, redox state, and remote sensing. Furthermore, there is intimate inter-organismal communication between renal OATs and the gut microbiome. Extracellular vesicles containing microRNAs and proteins (exosomes) play a key role in the Remote Sensing and Signaling System as does the interplay with the neuroendocrine, hormonal, and immune systems. Perturbation of function with OAT-interacting drugs (e.g., probenecid, diuretics, antivirals, antibiotics, NSAIDs) can lead to drug-metabolite interactions. The RSST has general applicability to other multi-specific SLC and ABC “drug” transporters (e.g., OCT1, OCT2, SLCO1B1, SLCO1B3, ABCG2, P-gp, ABCC2, ABCC3, ABCC4). Recent high-resolution structures of SLC22 and other transporters, together with chemoinformatic and artificial intelligence methods, will aid drug development and also lead to a deeper mechanistic understanding of polymorphisms.</p></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"263 ","pages":"Article 108723"},"PeriodicalIF":12.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142272437","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}