Pharmacological Reviews最新文献

{"title":"The pharmacology of vitamin C.","authors":"Jens Lykkesfeldt, Anitra C Carr, Pernille Tveden-Nyborg","doi":"10.1016/j.pharmr.2025.100043","DOIUrl":"10.1016/j.pharmr.2025.100043","url":null,"abstract":"<p><p>Ascorbic acid, the reduced form of vitamin C, is a ubiquitous small carbohydrate. Despite decades of focused research, new metabolic functions of this universal electron donor are still being discovered and add to the complexity of our view of vitamin C in human health. Although praised as an unsurpassed water-soluble antioxidant in plasma and cells, the most interesting functions of vitamin C seem to be its roles as specific electron donor in numerous biological reactions ranging from the well-known hydroxylation of proline to cofactor for the epigenetic master regulators ten-eleven translocation enzymes and Jumonji domain-containing histone-lysine demethylases. Some of these functions may have important implications for disease prevention and treatment and have spiked renewed interest in, eg, vitamin C's potential in cancer therapy. Moreover, some fundamental pharmacokinetic properties of vitamin C remain to be established including if other mechanisms than passive diffusion governs the efflux of ascorbate anions from the cell. Taken together, there still seems to be much to learn about the pharmacology of vitamin C and its role in health and disease. This review explores new avenues of vitamin C and integrates our present knowledge of its pharmacology. SIGNIFICANCE STATEMENT: Vitamin C is involved in multiple biological reactions of which most are essential to human health. Hundreds of millions of people are considered deficient in vitamin C according to accepted guidelines, but little is known about the long-term consequences. Although the complexity of vitamin C's physiology and pharmacology has been widely disregarded in clinical studies for decades, it seems clear that a deeper understanding of particularly its pharmacology holds the key to unravel and possibly exploit the potential of vitamin C in disease prevention and therapy.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 2","pages":"100043"},"PeriodicalIF":19.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476721","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":"Neurobiology of the incubation of drug craving: An update.","authors":"Jonathan J Chow, Kayla M Pitts, Kenichiro Negishi, Rajtarun Madangopal, Yan Dong, Marina E Wolf, Yavin Shaham","doi":"10.1016/j.pharmr.2024.100022","DOIUrl":"10.1016/j.pharmr.2024.100022","url":null,"abstract":"<p><p>Relapse to drug use is often preceded by drug craving. Clinical observations in the 1980s led clinical investigators to postulate that cue-induced cocaine craving may increase during abstinence. Over 2 decades ago, investigators identified an analogous phenomenon in rats of time-dependent increases in drug-seeking behavior during homecage abstinence and termed it incubation of cocaine craving. In 2011, we reviewed the first decade of studies on brain mechanisms of incubation of drug craving. In this review, we provide an update on incubation-related brain mechanisms from studies published since 2011. We first review studies using the standard method of incubation after homecage-forced abstinence from cocaine, methamphetamine, opioid drugs, and nicotine. Next, we review studies using newer methods to study incubation after voluntary abstinence in the drug environment. In these studies, abstinence is achieved by either providing rats alternative nondrug rewards in a choice setting or introducing rats to adverse consequences to drug seeking or taking. We then discuss translational human studies on incubation of cue-induced drug craving. We conclude by discussing several emerging topics, including sex differences in incubation of drug craving, role of sleep patterns, and similarities and differences in mechanisms of incubation of craving across drug classes and abstinence conditions. Our 2 main conclusions are as follows: (1) across drug classes, there are both similarities and differences in mechanisms of incubation of drug craving after forced abstinence, and (2) the method used to achieve abstinence (forced or voluntary) can influence the mechanisms controlling incubation of drug craving or its expression. SIGNIFICANCE STATEMENT: This article reviews results from preclinical and clinical studies published since 2011 on neurobiological mechanisms of incubation of drug craving after homecage-forced abstinence or voluntary abstinence in the drug environment. This article also reviews translational human studies on incubation of cue-induced subjective drug craving and brain response during abstinence. The results of the studies reviewed indicate that multiple brain mechanisms control incubation of drug craving after homecage-forced abstinence or voluntary abstinence.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 2","pages":"100022"},"PeriodicalIF":19.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11964951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143731015","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 transporting polypeptides: Pharmacology, toxicology, structure, and transport mechanisms.","authors":"Bruno Hagenbuch, Bruno Stieger, Kaspar P Locher","doi":"10.1016/j.pharmr.2024.100023","DOIUrl":"10.1016/j.pharmr.2024.100023","url":null,"abstract":"<p><p>Organic anion transporting polypeptides (OATPs) are membrane proteins that mediate the uptake of a wide range of substrates across the plasma membrane of various cells and tissues. They are classified into 6 subfamilies, OATP1 through OATP6. Humans contain 12 OATPs encoded by 11 solute carrier of organic anion transporting polypeptide (SLCO) genes: OATP1A2, OATP1B1, OATP1B3, the splice variant OATP1B3-1B7, OATP1C1, OATP2A1, OATP2B1, OATP3A1, OATP4A1, OATP4C1, OATP5A1, and OATP6A1. Most of these proteins are expressed in epithelial cells, where they mediate the uptake of structurally unrelated organic anions, cations, and even neutral compounds into the cytoplasm. The best-characterized members are OATP1B1 and OATP1B3, which have an important role in drug metabolism by mediating drug uptake into the liver and are involved in drug-drug interactions. In this review, we aimed to (1) provide a historical perspective on the identification of OATPs and their nomenclature and discuss their phylogenic relationships and molecular characteristics; (2) review the current knowledge of the broad substrate specificity and their role in drug disposition and drug-drug interactions, with a special emphasis on human hepatic OATPs; (3) summarize the different experimental systems that are used to study the function of OATPs and discuss their advantages and disadvantages; (4) review the available experimental 3-dimensional structures and examine how they can help elucidate the transport mechanisms of OATPs; and (5) finally, summarize the current knowledge of the regulation of OATP expression, discuss clinically important single-nucleotide polymorphisms, and outline challenges of physiologically based pharmacokinetic modeling and in vitro to in vivo extrapolation. SIGNIFICANCE STATEMENT: Organic anion transporting polypeptides (OATPs) are a family of 12 uptake transporters in the solute carrier superfamily. Several members, particularly the liver-expressed OATP1B1 and OATP1B3, are important drug transporters. They mediate the uptake of several endobiotics and xenobiotics, including statins and numerous other drugs, into hepatocytes, and their inhibition by other drugs or reduced expression due to single-nucleotide polymorphisms can lead to adverse drug effects. Their recently solved 3-dimensional structures should help to elucidate their transport mechanisms and broad substrate specificities.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 2","pages":"100023"},"PeriodicalIF":19.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143731016","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":"Polypharmacological strategies for infectious bacteria.","authors":"Miguel M Leitão, Ariana S C Gonçalves, Fernanda Borges, Manuel Simões, Anabela Borges","doi":"10.1016/j.pharmr.2025.100038","DOIUrl":"10.1016/j.pharmr.2025.100038","url":null,"abstract":"<p><p>Polypharmacological approaches have significant potential for the treatment of various complex diseases, including infectious bacteria-related diseases. Actually, multitargeting agents can achieve better therapeutic effects and overcome the drawbacks of monotherapy. Although multidrug multitarget strategies have demonstrated the ability to inactivate infectious bacteria, several challenges have been pointed out. In this way, multitarget direct ligands approaches appear to be a rational and sustainable strategy to combat antibiotic resistance. By combining different pharmacophores, antibiotic hybrids stand out as a promising application in the field of bacterial infections. These new chemical entities can achieve synergistic interactions that allow to extend the spectrum of action and target multiple pathways. In addition, antibiotic hybrids can reduce the likelihood of resistance development and provide improved chemical stability. It is worth highlighting that despite the efforts of the scientific community to discover new solutions for the most complex diseases, there is a significant lack of studies on biofilm-associated infections. This review describes the different polypharmacological approaches that can be used to treat bacterial infections with a particular focus, whenever possible, on those promoted by biofilms. By exploring these innovative approaches, we aim to inspire further research and progress in the search for effective treatments for infectious bacteria-related diseases, including biofilm-related ones. SIGNIFICANCE STATEMENT: The importance of the proposed topic lies in the escalating challenge of antibiotic resistance, particularly in the context of infectious bacteria-related infections. Polypharmacological approaches, such as antibiotic hybrids, represent innovative strategies to combat bacterial infections. By targeting multiple signaling pathways, these approaches not only enhance therapeutic effect but also reduce the development of resistance while improving the drug's chemical stability. Despite the urgent need to combat bacterial infectious diseases, there is a notable research gap, in particular in biofilm-related ones. This review highlights the critical importance of exploring polypharmacological approaches with the aim of motivating further research and advances in effective treatments for infectious bacteria, including biofilm related infections.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 2","pages":"100038"},"PeriodicalIF":19.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537739","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":"Pharmacological strategies to bridge the gap between cancer and cardiovascular therapeutics.","authors":"Ali H Eid","doi":"10.1016/j.pharmr.2024.100035","DOIUrl":"https://doi.org/10.1016/j.pharmr.2024.100035","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 2","pages":"100035"},"PeriodicalIF":19.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143731021","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":"Vitamin D and its analogs in immune system regulation.","authors":"Patricio Artusa, John H White","doi":"10.1016/j.pharmr.2024.100032","DOIUrl":"10.1016/j.pharmr.2024.100032","url":null,"abstract":"<p><p>Vitamin D was discovered as the cure for nutritional rickets, a disease of bone growth arising from inadequate intestinal calcium absorption, and for much of the 20th century, it was studied for its critical role in calcium homeostasis. However, we now recognize that the vitamin D receptor and vitamin D metabolic enzymes are expressed in numerous tissues unrelated to calcium homeostasis. Notably, vitamin D signaling can induce cellular differentiation and cell cycle arrest. Moreover, the vitamin D receptor and the enzyme CYP27B1, which produces the hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25D), are expressed throughout the immune system. In addition, CYP27B1 expression in immune cells is regulated by physiological inputs independent of those controlling its expression in calcium homeostatic tissues. These observations have driven the development of 1,25D-like secosteroidal analogs and nonsecosteroidal analogs to separate the effects of vitamin D on cell differentiation and function from its calcemic activities. Notably, some of these analogs have had considerable success in the clinic in the treatment of inflammatory and immune-related disorders. In this review, we described in detail the mechanisms of vitamin D signaling and the physiological signals controlling 1,25D synthesis and catabolism, with a focus on the immune system. We also surveyed the effects of 1,25D and its analogs on the regulation of immune system function and their implications for human immune-related disorders. Finally, we described the potential of vitamin D analogs as anticancer therapeutics, in particular, their use as adjuncts to cancer immunotherapy. SIGNIFICANCE STATEMENT: Vitamin D signaling is active in both the innate and adaptive arms of the immune system. Numerous vitamin D analogs, developed primarily to minimize the dose-limiting hypercalcemia of the active form of vitamin D, have been used widely in preclinical and clinical studies of immune system regulation. This review presents a description of the mechanisms of action of vitamin D signaling, an overview of analog development, and an in-depth discussion of the immunoregulatory roles of vitamin D analogs.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 2","pages":"100032"},"PeriodicalIF":19.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143731133","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":"Beyond the stomach stall: Current and emerging pharmacotherapeutics for gastroparesis.","authors":"Ali H Eid","doi":"10.1016/j.pharmr.2024.100021","DOIUrl":"https://doi.org/10.1016/j.pharmr.2024.100021","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 2","pages":"100021"},"PeriodicalIF":19.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143731069","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":"Shared molecular, cellular, and environmental hallmarks in cardiovascular disease and cancer: Any place for drug repurposing?","authors":"Elisa Avolio, Barbara Bassani, Marzia Campanile, Khaled Ak Mohammed, Paola Muti, Antonino Bruno, Gaia Spinetti, Paolo Madeddu","doi":"10.1016/j.pharmr.2024.100033","DOIUrl":"10.1016/j.pharmr.2024.100033","url":null,"abstract":"<p><p>Cancer and cardiovascular disease (CVD) are the 2 biggest killers worldwide. Specific treatments have been developed for the 2 diseases. However, mutual therapeutic targets should be considered because of the overlap of cellular and molecular mechanisms. Cancer research has grown at a fast pace, leading to an increasing number of new mechanistic treatments. Some of these drugs could prove useful for treating CVD, which realizes the concept of cancer drug repurposing. This review provides a comprehensive outline of the shared hallmarks of cancer and CVD, primarily ischemic heart disease and heart failure. We focus on chronic inflammation, altered immune response, stromal and vascular cell activation, and underlying signaling pathways causing pathological tissue remodeling. There is an obvious scope for targeting those shared mechanisms, thereby achieving reciprocal preventive and therapeutic benefits. Major attention is devoted to illustrating the logic, advantages, challenges, and viable examples of drug repurposing and discussing the potential influence of sex, gender, age, and ethnicity in realizing this approach. Artificial intelligence will help to refine the personalized application of drug repurposing for patients with CVD. SIGNIFICANCE STATEMENT: Cancer and cardiovascular disease (CVD), the 2 biggest killers worldwide, share several underlying cellular and molecular mechanisms. So far, specific therapies have been developed to tackle the 2 diseases. However, the development of new cardiovascular drugs has been slow compared with cancer drugs. Understanding the intersection between pathological mechanisms of the 2 diseases provides the basis for repurposing cancer therapeutics for CVD treatment. This approach could allow the rapid development of new drugs for patients with CVDs.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 2","pages":"100033"},"PeriodicalIF":19.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143731119","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":"Carbonic anhydrase inhibitors: \"Old\" drugs with new potential in unexpected areas.","authors":"Ali H Eid","doi":"10.1016/j.pharmr.2024.100007","DOIUrl":"https://doi.org/10.1016/j.pharmr.2024.100007","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 1","pages":"100007"},"PeriodicalIF":19.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425940","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":"Drugs from the ocean floor.","authors":"Maha Khachab, Amirhossein Sahebkar, Ali H Eid","doi":"10.1016/j.pharmr.2024.100009","DOIUrl":"https://doi.org/10.1016/j.pharmr.2024.100009","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 1","pages":"100009"},"PeriodicalIF":19.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425944","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}