Medicinal Research Reviews最新文献

{"title":"A Bright Future for Photopharmaceuticals Addressing Central Nervous System Disorders: State of the Art and Challenges Toward Clinical Translation.","authors":"Rudolf L Z Ganzoni, Sofie S Bournons, Erick M Carreira, Dimitri De Bundel, Ilse Smolders","doi":"10.1002/med.22105","DOIUrl":"https://doi.org/10.1002/med.22105","url":null,"abstract":"<p><p>Photopharmacology is an innovative approach that uses light to activate drugs. This method offers the potential for highly localized and precise drug activation, making it particularly promising for the treatment of neurological disorders. Despite the enticing prospects of photopharmacology, its application to treat human central nervous system (CNS) diseases remains to be demonstrated. In this review, we provide an overview of prominent strategies for the design and activation of photopharmaceutical agents in the field of neuroscience. Photocaged and photoswitchable drugs and bioactive molecules are discussed, and an instructive list of examples is provided to highlight compound design strategies. Special emphasis is placed on photoactivatable compounds for the modulation of glutamatergic, GABAergic, dopaminergic, and serotonergic neurotransmission for the treatment of neurological conditions, as well as various photoresponsive molecules with potential for improved pain management. Compounds holding promise for clinical translation are discussed in-depth and their potential for future applications is assessed. Neurophotopharmaceuticals have yet to achieve breakthrough in the clinic, as both light delivery and drug design have not reached full maturity. However, by describing the current state of the art and providing illustrative case studies, we offer a perspective on future opportunities in the field of neurophotopharmacology focused on addressing CNS disorders.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787421","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":"Recent Developments in the Optical Control of Adrenergic Signaling.","authors":"Shuang Shi, Yangzhi Cao, Maikel Wijtmans, Henry F Vischer, Rob Leurs","doi":"10.1002/med.22110","DOIUrl":"https://doi.org/10.1002/med.22110","url":null,"abstract":"<p><p>Adrenoceptors (ARs) play a vital role in various physiological processes and are key therapeutic targets. The advent of optical control techniques, including optogenetics and photopharmacology, offers the potential to modulate AR signaling with precise temporal and spatial resolution. In this review, we summarize the latest advancements in the optical control of AR signaling, encompassing optogenetics, photocaged compounds, and photoswitchable compounds. We also discuss the limitations of current tools and provide an outlook on the next generation of optogenetic and photopharmacological tools. These emerging optical technologies not only enhance our understanding of AR signaling but also pave the way for potential therapeutic developments.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778511","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":"Light-Activated Pharmacological Tools for Exploring the Cholinergic System.","authors":"Alessio Colleoni, Giulia Galli, Clelia Dallanoce, Marco De Amici, Pau Gorostiza, Carlo Matera","doi":"10.1002/med.22108","DOIUrl":"https://doi.org/10.1002/med.22108","url":null,"abstract":"<p><p>Cholinergic transmission plays a critical role in both the central and peripheral nervous systems, affecting processes such as learning, memory, and inflammation. Conventional cholinergic drugs generally suffer from poor selectivity and temporal precision, leading to undesired effects and limited therapeutic efficacy. Photopharmacology aims to overcome the limitations of traditional drugs using photocleavable or photoswitchable ligands and spatiotemporal patterns of illumination. Spanning from muscarinic and nicotinic modulators to cholinesterase inhibitors, this review explores the development and application of light-activated compounds as tools for unraveling the role of cholinergic signaling in both physiological and pathological contexts, while also paving the way for innovative phototherapeutic approaches.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690748","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":"Danshensu Derivatives: A Series of Promising Drugs With Protective Effects Against Cardiocerebrovascular Diseases and Cancers.","authors":"Yang Yang, Luyang Du, Huadong Zhao, Ye Zhao, Sha Liao, Zhe Zhang, Shaofei Zhang, Yajun Bai, Xiaohui Zheng","doi":"10.1002/med.22102","DOIUrl":"https://doi.org/10.1002/med.22102","url":null,"abstract":"<p><p>Salvia miltiorrhiza (Danshen in Chinese) is a traditional medicinal plant with an extensive range of cardiocerebrovascular protective effects widely used in China and other Asian countries. Danshensu (DSS) is the most important water-soluble component of Danshen and has significant antioxidant, anti-inflammatory, antiplatelet aggregation, antitumor, and other pharmacological activities. However, DSS has poor fat solubility and is unstable due to its o-phenol hydroxyl and α-hydroxy carboxylic acids. Therefore, it is necessary to develop new DSS derivatives through reasonable structural modifications to obtain new drugs with better activity, preferable stability, and higher bioavailability. Our team has previously investigated the effect of Danshen on chronic diseases. Through nearly two decades of research, we have made considerable research progress on the impact of DSS derivatives on cardiocerebrovascular diseases. Based on the published literature and our previous work, it was confirmed that DSS derivatives have a wide range of cardiocerebrovascular protective and other pharmacological effects. Here, this review summarized recent research progress on DSS derivatives in terms of design, synthesis, pharmacological effects, and molecular mechanisms to provide new insights for further research.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603274","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":"Breaking Barriers; Phytoestrogens in the Fight Against Triple-Negative Breast Cancer: A Comprehensive Review.","authors":"Md Sohel","doi":"10.1002/med.22107","DOIUrl":"https://doi.org/10.1002/med.22107","url":null,"abstract":"<p><p>The development of standard drugs for some unusual cancers, including estrogen-nonresponsive breast cancer, is somewhat difficult within a very short time. So, considering the current situation, phytoestrogen may be a potential candidate for unraveling chemotherapeutics agents. The reason for this review article is to manifest overall information regarding the effects of phytoestrogen on triple-negative breast cancer (TNBC), along with its related cellular and molecular pathways in different TNBC models. Data was retrieved by systematic searches according to PRISMA guidelines, and commonly used tools and servers are BioRender, ChemDraw professional 16.0, Schrodinger, and ADMETlab 2.0. TNBC may be caused due to dysregulation of several signaling mechanisms such as Wnt/β-catenin, hedgehog, MAPK, notch, PI3K/AKT/mTOR, hippo, NF-κB, and JAK/STAT signaling cascades. Among all phytoestrogens (n = 150), 48 compounds are therapeutically effective on TNBC in some in vitro and preclinical models. Chemotherapeutics activities are regulated through varieties of mechanisms, including targeting signaling pathways such as phosphor-Akt, PI3K/AKT/mTOR, NF-κB, TNF-α; apoptosis such as FASL, Bcl2, Bax, Bak, Bad, apfa1, ASK1, Capase, and PARP; metastasis such as MMPs (1,2,3,9), Wnt/-β catenin, angiogenesis (E&N Cadherin, Vimentin), cell proliferation (cyclins-A, B1, D1, E1, and CDKs 1, 6,7), inflammatory molecules (TNF-α, NF-κB, IL-1β, IL-8), regulating tumor suppressor genes (p21, p27, p51, p53) and some nonspecific pathways like DNA damage and repair (γH2AX, RAD51, and surviving), autophagy (mTOR, ULK1, and cathepsin B), epigenetic (HDAC1, DNMT1, telomerase production) and metabolism regulation (glucose regulation-GLUT1 and GLUT4), showing antioxidant and many other pathways. Some selective phytoestrogens exert synergistic activities with conventional cancer drugs as well radiotherapy like as conventional mechanism and reverse drug resistance through regulation of the EMT process, signaling pathways, drug sensitizing, miRNA regulation, and improving drug uptake. Nano-based phytoestrogen can target TNBC cells, stimulate drug accumulation, and improve drug efficacies, making phytoestrogens more effective agents in treating TNBC. Additionally, an in-silico pharmacokinetics study reveals that phytoestrogen possesses suitable pharmacokinetic characteristics with minor toxicity. So, phytoestrogen can be a potential candidate drug against TNBC until standard and fully effective pharma drugs are available at markets.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603273","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":"Cutting-Edge Therapy and Immune Escape Mechanisms in EBV-Associated Tumors.","authors":"Jie Wang, Rong Wang, Meifeng Wang, Junshang Ge, Yian Wang, Yanhan Li, Changan Chen, Jiale He, Boshu Zheng, Meifang Xu, Xianjie Jiang, Yuhang Liu, Mingfen Chen, Jun Long","doi":"10.1002/med.22104","DOIUrl":"https://doi.org/10.1002/med.22104","url":null,"abstract":"<p><p>Epstein-Barr virus (EBV), the first identified human tumor virus, significantly influences the immune microenvironment of associated cancers. EBV-induced expression of viral antigens by tumor cells triggers immune recognition and elicits a pro-inflammatory response. While mild inflammation may help eliminate malignant cells, intense inflammation can accelerate tumor progression. Moreover, EBV can establish lifelong latency in human hosts, characterized by low immunogenicity of its proteins and noncoding RNAs. This enables tumor cells to evade immune detection and impair immune cell function, disrupting immune homeostasis. Consequently, EBV-associated malignancies pose a considerable public health challenge globally, often complicating the prognosis of cancer patients under conventional treatment. With deeper research into the oncogenic expressions and mechanisms of EBV, novel targeted therapies against EBV are gaining prominence. This review discusses recent advancements in understanding how EBV helps tumor cells evade immune surveillance and induce immune dysfunction. It also examines the clinical potential of targeting EBV-associated tumors, providing fresh perspectives on the mechanisms and therapeutic strategies for these cancers.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612710","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":"Controlling Protein Functionalities With Temporal and Cellular/Subcellular Dimensions of Spatial Resolution With Molecular Photoswitches.","authors":"Saugata Sahu, Ammathnadu S Amrutha, Nobuyuki Tamaoki","doi":"10.1002/med.22106","DOIUrl":"https://doi.org/10.1002/med.22106","url":null,"abstract":"<p><p>The use of photoswitchable ligand to control the protein functionalities and related downstream effects in an on-off manner is an active research area in photopharmacology and medicinal chemistry. Temporal control grants a privilege to identify the crucial role of a particular receptor in biological occurrences without destroying the protein permanently. Additionally, light can be applied site-selectively to regulate protein functionality with cellular and sub-cellular levels of spatial resolutions. The spatiotemporal resolution enables the probing of a specific receptor, a receptor isoform, or a particular signalling pathway. This reversible and fast spatiotemporal control is highly beneficial in studying protein functionalities in highly dynamic biological processes, including but not limited to signal transduction, neurotransmission, cell divisions, immune response, protein folding, and protein degradation. Though several light-active ligands have been developed to control protein functionality in an on-off manner efficiently, only a few reports on protein functionality with spatial resolution exist in the literature. Major challenges to achieve efficient photoswitches to study protein functionalities are efficient synthesis strategy, photostability of the ligand, bidirectional visible light switching ability and most importantly precise controlling of the local concentration of desired photoisomer using light. The site-specific localization of the active photoisomer depends on multiple factors like the nature of the photoswitch, the binding affinity of both photoisomers, molecular diffusion and light irradiation conditions. The present review discusses suitable techniques and the role of different factors in achieving cellular and subcellular dimension control in protein functionality. Multiple strategies are discussed, along with their advantages and limitations, to explore the enormous potentiality of these approaches in manipulating protein functionality.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565718","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":"Energy Metabolism Supports Molecular and Functional Heterogeneity of Reactive Astrocytes in Central Nervous System Disorders.","authors":"Jie Song, Jianning Kang, Ying Zhang, Yinghui Wang, Rui Yang, Bin Ning","doi":"10.1002/med.22103","DOIUrl":"https://doi.org/10.1002/med.22103","url":null,"abstract":"<p><p>Astrocytes undergo a reactive transformation in central nervous system (CNS) disorders, manifesting significant heterogeneity in morphology, molecules, function, and spatial distribution. Just like all cells, astrocytes necessitate energy for their basic functions. Energy production proves critical for the survival and development of astrocytes, as well as their fate determination and functional diversity. The activation process of astrocytes involves a metabolic shift in energy, yet our understanding of how this change impacts the heterogeneity of reactive astrocytes remains limited. In this comprehensive review, we begin by outlining the advancements in research on reactive astrocytes in CNS disorders, establishing a crucial association between the energy metabolism of reactive astrocytes and their molecular and functional aspects. Following this, we delve into a thorough analysis of the energy metabolic transitions of reactive astrocytes within the context of CNS diseases. Starting from the essential pathways of energy metabolism, we present a novel perspective, shedding light on the molecular and functional heterogeneity of reactive astrocytes by considering the heterogeneity in energy metabolism. In conclusion, we propose that the modulation of energy metabolism in reactive astrocytes, coupled with the promotion of their functionality toward disease recovery, represents a cutting-edge and promising strategy for the treatment of CNS diseases.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539726","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 Emerging Landscape of Tubercular Targets: A Medicinal Chemistry Approach.","authors":"Baji Baba Shaik, Kimeshni Moodley, Safiyah Ghumran, Muhammad D Bala, Parvesh Singh, Rajshekhar Karpoormath","doi":"10.1002/med.22100","DOIUrl":"https://doi.org/10.1002/med.22100","url":null,"abstract":"<p><p>Antitubercular drug discovery progress in the last decade, especially research on the biological function, target inhibition and diagnosis of tuberculosis (TB) diagnosis has considerably advanced. The application of target-based drug discovery techniques have become a more powerful tool for medicinal chemists in developing new therapeutic strategies, such as its application in the identification/validation of new targets, new leads, and drug candidates with optimized efficacy. This has been further evidenced by the recent approval of delamanid and bedaquiline for the treatment of MDR-TB and XDR-TB, respectively. While a TB drug pipeline has shown great development, high attrition rates must constantly replenish the pipeline with high-quality leads acting through the inhibition of new targets. This review provides a critical analysis of the approaches used to advance hit compounds into viable lead candidates as well as the possible influence of new targets on drug development in the near future. Finally, we concluded with the present challenges that are faced in TB drug development.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363207","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":"Unleashing the Power of Covalent Drugs for Protein Degradation.","authors":"Meng-Jie Fu, Hang Jin, Shao-Peng Wang, Liang Shen, Hong-Min Liu, Ying Liu, Yi-Chao Zheng, Xing-Jie Dai","doi":"10.1002/med.22101","DOIUrl":"https://doi.org/10.1002/med.22101","url":null,"abstract":"<p><p>Targeted protein degradation (TPD) has emerged as a significant therapeutic approach for a variety of diseases, including cancer. Advances in TPD techniques, such as molecular glue (MG) and lysosome-dependent strategies, have shown substantial progress since the inception of the first PROTAC in 2001. The PROTAC methodology represents the forefront of TPD technology, with ongoing evaluation in more than 20 clinical trials for the treatment of diverse medical conditions. Two prominent PROTACs, ARV-471 and ARV-110, are currently undergoing phase III and II clinical trials, respectively. Traditional PROTACs are encountering obstacles such as limited binding affinity and a restricted range of E3 ligase ligands for facilitating the protein of interest (POI) degradation. Covalent medicines offer the potential to enhance PROTAC efficacy by enabling the targeting of previously considered \"undruggable\" shallow binding sites. Strategic alterations allow PROTAC to establish covalent connections with particular target proteins, including Kirsten rat sarcoma viral oncogene homolog (KRAS), Bruton's tyrosine kinase (BTK), epidermal growth factor receptor (EGFR), as well as E3 ligases such as DDB1 and CUL4 associated factor 16 (DCAF16) and Kelch-like ECH-associated protein 1 (Keap1). The concept of covalent degradation has also been utilized in various new forms of degraders, including covalent molecule glue (MG), in-cell click-formed proteolysis targeting chimera (CLIPTAC), HaloPROTAC, lysosome-targeting chimera (LYTAC) and GlueTAC. This review focuses on recent advancements in covalent degraders beyond covalent PROTACs and examines obstacles and future directions pertinent to this field.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997127","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}