ACS Pharmacology and Translational Science最新文献

{"title":"Tumor Heterogeneity Shapes Survival Dynamics in Drug-Treated Cells, Revealing Size-Drifting Subpopulations.","authors":"Venugopal Vangala, Yu-Chi Chen, Saketh S Dinavahi, Krishne Gowda, Nazir A Lone, Meenhard Herlyn, Joseph Drabick, Klaus Helm, Jiyue Zhu, Rogerio I Neves, Arun K Sharma, Arthur Berg, Marco Archetti, Shantu Amin, Todd D Schell, Gavin P Robertson","doi":"10.1021/acsptsci.4c00453","DOIUrl":"10.1021/acsptsci.4c00453","url":null,"abstract":"<p><p>The goal of this project was to demonstrate that subpopulations of cells in tumors can uniquely fluctuate in size in response to environmental conditions created during drug treatment, thereby acting as a dynamic \"rheostat\" to create a favorable tumor environment for growth. The cancer modeling used for these studies was subpopulations of melanoma cells existing in cultured and tumor systems that differed in aldehyde dehydrogenase (ALDH) activity. However, similar observations were found in other cancer types in addition to melanoma, making them applicable broadly across cancer. The approach was designed to show that either ALDH^high and ALDH^low subpopulations rapidly epigenetically transition between stem-cell-like high into nonstem-like low production states to create an environment during drug treatment that would enable optimal cellular proliferation and tumor expansion to facilitate drug resistance. The controlled experiments showed proportional changes in each cell population to reach an evolutionarily stable equilibrium mediated by the needed levels of ALDH enzyme activity. Mechanistically, cell population size changes served to functionally move the aldehyde and the resulting reactive oxygen species (ROS) levels to those compatible with optimal cellular proliferation with population fluctuations dependent on the levels of drug induced tumor stress. This is the first report documenting fluctuations in the sizes of cell populations in tumors to cooperatively assist in drug resistance development.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 11","pages":"3573-3584"},"PeriodicalIF":4.9,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the Interplay Between Radioimmunoconjugates and Fcγ Receptors in Genetically Engineered Mouse Models of Cancer.","authors":"Cindy Rodriguez, Samantha M Sarrett, Joni Sebastiano, Samantha Delaney, Shane A McGlone, Meena M Hosny, Sarah Thau, Stylianos Bournazos, Brian M Zeglis","doi":"10.1021/acsptsci.4c00275","DOIUrl":"10.1021/acsptsci.4c00275","url":null,"abstract":"<p><p>Fcγ receptors (FcγR) are responsible for many of the interactions between immunoglobulins (IgG) and immune cells. In biomedicine, this interplay is critical to the activity of several types of immunotherapeutics; however, relatively little is known about how FcγRs affect the in vivo performance of radiolabeled antibodies. A handful of recent preclinical studies suggest that binding by FcγR-and particularly FcγRI-can affect the pharmacokinetic profiles of ⁸⁹Zr-labeled radioimmunoconjugates, but there are no extant studies in immunocompetent or genetically engineered mouse models of cancer. In the investigation at hand, we synthesized and characterized ⁸⁹Zr-labeled probes based on wild-type and aglycosylated variants of the CA19-9-targeting antibody 5B1 and evaluated their in vivo behavior in several murine models of cancer, including immunocompetent and FcγR-humanized mice. The aglycosylated desferrioxamine (DFO)-bearing immunoconjugate DFO-^N297A5B1 displayed identical binding to CA19-9-expressing cells compared to its wild-type analogue (DFO-5B1) but exhibited dramatically attenuated affinity for several FcγR. Positron emission tomography imaging and biodistribution studies with [⁸⁹Zr]Zr-DFO-5B1 and [⁸⁹Zr]Zr-DFO-^N297A5B1 were subsequently performed in several strains of mice bearing CA19-9-expressing BxPC3 human pancreatic ductal adenocarcinoma and B16F10-FUT3 murine melanoma xenografts. Significant differences in the pharmacokinetics of the two radioimmunoconjugates were observed in tumor-bearing immunocompromised NSG mice, but these differences failed to materialize in immunocompetent C57BL/6 and FcγR-humanized C57BL/6 mice with B16F10-FUT3 xenografts. We hypothesize that these observations are related to the presence or absence of endogenous IgG. NSG mice completely lack endogenous IgG, and thus their mFcγR are free to bind radioimmunoconjugates and alter their pharmacokinetic behavior. In contrast, C57BL/6 and FcγR-humanized C57BL/6 mice both have endogenous IgG that occupy their FcγR (murine for the former and human for the latter), precluding interactions with radioimmunoconjugates. Ultimately, these data suggest that understanding the interplay between radiolabeled antibodies and FcγR is critical during the preclinical evaluation of radioimmunoconjugates.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 11","pages":"3452-3461"},"PeriodicalIF":4.9,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: Guardians against Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Heart Diseases.","authors":"Linh Thi Truc Pham, Supachoke Mangmool, Warisara Parichatikanond","doi":"10.1021/acsptsci.4c00240","DOIUrl":"10.1021/acsptsci.4c00240","url":null,"abstract":"<p><p>Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an innovative class of antidiabetic drugs that provide cardiovascular benefits to both diabetic and nondiabetic patients, surpassing those of other antidiabetic drugs. Although the roles of mitochondria and endoplasmic reticulum (ER) in cardiovascular research are increasingly recognized as promising therapeutic targets, the exact molecular mechanisms by which SGLT2 inhibitors influence mitochondrial and ER homeostasis in the heart remain incompletely elucidated. This review comprehensively summarizes and discusses the impacts of SGLT2 inhibitors on mitochondrial dysfunction and ER stress in heart diseases including heart failure, ischemic heart disease/myocardial infarction, and arrhythmia from preclinical and clinical studies. Based on the existing evidence, the effects of SGLT2 inhibitors may potentially involve the restoration of mitochondrial biogenesis and alleviation of ER stress. Such consequences are achieved by enhancing adenosine triphosphate (ATP) production, preserving mitochondrial membrane potential, improving the activity of electron transport chain complexes, maintaining mitochondrial dynamics, mitigating oxidative stress and apoptosis, influencing cellular calcium and sodium handling, and targeting the unfolded protein response (UPR) through three signaling pathways including inositol requiring enzyme 1α (IRE1α), protein kinase R like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). Therefore, SGLT2 inhibitors have emerged as a promising target for treating heart diseases due to their potential to improve mitochondrial functions and ER stress.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 11","pages":"3279-3298"},"PeriodicalIF":4.9,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advanced Spray-Dried Inhalable Microparticles/Nanoparticles of an Innovative Mitophagy Activator for Targeted Lung Delivery: Design, Comprehensive Characterization, Human Lung Cell Culture, and In Vitro Aerosol Dispersion Performance.","authors":"Hasham Shafi, Andrea J Lora, Haley M Donow, Saurabh Aggarwal, Panfeng Fu, Ting Wang, Heidi M Mansour","doi":"10.1021/acsptsci.4c00436","DOIUrl":"10.1021/acsptsci.4c00436","url":null,"abstract":"<p><p>Urolithin A (UA) has demonstrated the ability to stimulate mitophagy and enhance mitochondrial and cellular health in skeletal muscles in humans after oral administration. It is hypothesized that targeted delivery of UA as inhaled dry powders to the lungs will enhance mitochondrial health through mitochondrial biogenesis. This study aimed to engineer inhalable excipient-free powders of UA as dry powder inhalers (DPIs) for targeted pulmonary delivery. The particles were designed by particle engineering from dilute organic solutions of UA using the state-of-the-art spray drying technology in a closed mode. Comprehensive physicochemical characterization and advanced microscopy techniques were conducted to examine phase behavior, molecular properties, and particle properties, which are necessary for the rational design of advanced pulmonary inhalation aerosols. Molecular fingerprinting was conducted by using attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy and Raman spectroscopy. Chemical imaging and mapping were conducted using confocal Raman microscopy (CRM) and IR microscopy. The advanced spray-dried (SD) excipient-free powders were successfully produced at different spraying pump feed rates and exhibited favorable molecular and particle properties. The excipient-free SD powders exhibited outstanding in vitro aerosol dispersion performance with an FDI-approved human DPI device (Neohaler) and correlated with the spray drying pump rate. In vitro<i>,</i> cell viability of various human pulmonary cells from different lung regions demonstrated biocompatibility and safety at different doses of UA. The transepithelial electrical resistance (TEER) assay shows that UA maintains cell membrane integrity and barrier tightness, indicating its potential for safe and effective localized drug delivery without long-term adverse effects. These results demonstrated that UA has favorable physicochemical and in vitro properties for inhalation and can be successfully engineered into excipient-free inhalable microparticles/nanoparticles as DPIs.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 11","pages":"3540-3558"},"PeriodicalIF":4.9,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142627921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted Degradation of Receptor-Interacting Protein Kinase 1 to Modulate the Necroptosis Pathway.","authors":"Hiroyuki Inuzuka, Chao Qian, Yihang Qi, Yan Xiong, Chaoyu Wang, Zhen Wang, Dingpeng Zhang, Can Zhang, Jian Jin, Wenyi Wei","doi":"10.1021/acsptsci.4c00421","DOIUrl":"10.1021/acsptsci.4c00421","url":null,"abstract":"<p><p>Necroptosis is a highly regulated form of necrotic cell death that plays an essential role in pathogen defense and tissue homeostasis. Abnormal regulation of the necroptotic pathway has been implicated in the pathogenesis of various human diseases, including cancer, inflammatory, and neurodegenerative diseases. Receptor-interacting protein kinase 1 (RIPK1) serves as a crucial regulator of the necroptotic signaling pathway and has been identified as a potential therapeutic target. Mechanistically, RIPK1 serves as both a protein kinase and a scaffolding protein, fulfilling its dual function through a combination of kinase activity-dependent and kinase activity-independent mechanisms. Thus, employing a targeted RIPK1 knockdown strategy is a highly effective means of inhibiting RIPK1 functions. To achieve a targeted RIPK1 knockdown, we generated a RIPK1-PROTAC, MS2031, by connecting the ZB-R-55 RIPK1 binder to the VHL ligand, thereby recruiting the CUL2-RING-VHL (CRL2^VHL) E3 ubiquitin ligase complex for targeted degradation of RIPK1 through the 26S proteasome. Notably, MS2031 treatment effectively reduced the abundance of RIPK1 protein in the nanomolar range in various cell lines we examined, including HT-29 and T47D cells, and modulated the necroptosis signaling pathway. These results suggest that MS2031 may hold potential for the treatment of human diseases resulting from aberrant regulation of RIPK1.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 11","pages":"3518-3526"},"PeriodicalIF":4.9,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Curcumin: A Potential Weapon in the Prevention and Treatment of Head and Neck Cancer.","authors":"Kateřina Veselá, Zdeněk Kejík, Michal Masařík, Petr Babula, Petr Dytrych, Pavel Martásek, Milan Jakubek","doi":"10.1021/acsptsci.4c00518","DOIUrl":"10.1021/acsptsci.4c00518","url":null,"abstract":"<p><p>Head and neck cancers (HNC) are aggressive, difficult-to-treat tumors that can be caused by genetic factors but mainly by lifestyle or infection caused by the human papillomavirus. As the sixth most common malignancy, it presents a formidable therapeutic challenge with limited therapeutic modalities. Curcumin, a natural polyphenol, is appearing as a promising multitarget anticancer and antimetastatic agent. Numerous studies have shown that curcumin and its derivatives have the potential to affect signaling pathways (NF-κB, JAK/STAT, and EGFR) and molecular mechanisms that are crucial for the growth and migration of head and neck tumors. Furthermore, its ability to interact with the tumor microenvironment and trigger the immune system may significantly influence the organism's immune response to the tumor. Combining curcumin with conventional therapies such as chemotherapy or radiotherapy may improve the efficacy of treatment and reduce the side effects of treatment, thereby increasing its therapeutic potential. This review is a comprehensive overview that discusses both the benefits and limitations of curcumin and its therapeutic effects in the context of tumor biology, with an emphasis on molecular mechanisms in the context of HNC. This review also includes possibilities to improve the limiting properties of curcumin both in terms of the development of new derivatives, formulations, or combinations with conventional therapies that have potential as a new type of therapy for the treatment of HNC and subsequent use in clinical practice.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 11","pages":"3394-3418"},"PeriodicalIF":4.9,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555516/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142628893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Covalent Modification of p53 by (<i>E</i>)-1-(4-Methylpiperazin-1-yl)-3-(5-nitrofuran-2-yl)prop-2-en-1-one.","authors":"Kate Brown, Marco Robello, Andrew J Perciaccante, Jerry C Dinan, Tapan K Maity, Gaelyn C Lyons, Jay P Kumar, Stewart R Durell, Harichandra D Tagad, Daniel Schilling, Herman Nikolayevskiy, Robert O'Connor, Ettore Appella, Daniel H Appella, Lisa M Jenkins","doi":"10.1021/acsptsci.4c00447","DOIUrl":"10.1021/acsptsci.4c00447","url":null,"abstract":"<p><p><i>TP53</i> is commonly mutated in cancer, giving rise to loss of wild-type tumor suppressor function and increases in gain-of-function oncogenic roles. Thus, inhibition of mutant p53 and reactivation of wild-type function represents a potential means to target diverse tumor types. (<i>E</i>)-1-(4-Methylpiperazin-1-yl)-3-(5-nitrofuran-2-yl)prop-2-en-1-one (NSC59984), first identified from a high-throughput screen, induces wild-type p53 signaling and antiproliferative effects while inhibiting mutant p53 gain-of-function activities. Here, we investigate the specific mechanism of action of NSC59984 against p53. We found that NSC59984 reacts with thiols via an unusual Michael addition at the α-carbon. Covalent modification of p53 Cys124 and Cys229 was observed both following <i>in vitro</i> reaction and upon treatment of cells. Finally, we used a biotinylated form of NSC59984 and, separately, thermal proteome profiling to examine off-target effects, identifying several metabolic proteins involved in cellular metabolism as potential targets. These results demonstrate that covalent modification of p53 by NSC59984 leads to increased wild-type activity and suggest that potential reaction with metabolic enzymes may contribute to antiproliferative function.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 11","pages":"3559-3572"},"PeriodicalIF":4.9,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142628840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Perspectives and Novel Preclinical Models of Malignant Pleural Mesothelioma: A Critical Review.","authors":"Aliakbar Ebrahimi, Güntülü Ak, Ceren Özel, Hüseyin İzgördü, Hamed Ghorbanpoor, Shabir Hassan, Huseyin Avci, Muzaffer Metintaş","doi":"10.1021/acsptsci.4c00324","DOIUrl":"10.1021/acsptsci.4c00324","url":null,"abstract":"<p><p>Pleural mesothelioma (PM), a rare malignant tumor explicitly associated with asbestos and erionite exposures, has become a global health problem due to limited treatment options and a poor prognosis, in which the median life expectancy varies depending on the method of treatment. However, the importance of early diagnosis is emphasized, and the practical methods have not matured yet. This study provides a critical overview of PM, addressing various aspects like epidemiology, etiology, diagnosis, treatment options, and the potential use of advanced technologies like microfluidic chip-based models for research and diagnosis. It initially begins with fundamentals of clinical aspects and then discusses the identification of disease-specific biomarkers in patients' serum or plasma samples, which could potentially be used for early diagnosis. A detailed investigation of the sophisticated preclinical models is highlighted. Recent three-dimensional (3D) model accomplishments, including microarchitecture modeling by transwell coculture, spheroids, organoids, 3D bioprinting constructs, and <i>ex vivo</i> tumor slices, are discussed comprehensively. On-chip models that imitate physiological processes, such as detection chips and therapeutic screening chips, are assessed as potential techniques. The review concludes with a critical and constructive discussion of the growing interest in the topic and its limitations and suggestions.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 11","pages":"3299-3333"},"PeriodicalIF":4.9,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142628556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of Protocols to Test Peptide Stability in Blood Plasma and Cell Culture Supernatants.","authors":"Anna Kohler, Eva-Maria Jülke, Jan Stichel, Annette G Beck-Sickinger","doi":"10.1021/acsptsci.4c00503","DOIUrl":"10.1021/acsptsci.4c00503","url":null,"abstract":"<p><p>Due to their high specificity, peptides are promising candidates in drug development, but fast degradation often limits their biological activity. Thus, a short half-life is one of the major challenges in the development of new peptide therapeutics. Moreover, the enzymatic cleavage of peptides can be a reason for misleading results in biological assays. Peptide stability assays typically consist of incubation, precipitation, and detection steps. However, the current methods differ greatly regarding these three steps, thus limiting the compatibility. Here, we systematically evaluate different parameters of peptide stability assays. First, we quantified and compared the analyte loss during the precipitation of plasma proteins. Especially, broadly used precipitation by strong acids was found to be unsuitable, while mixtures of organic solvents preserved more peptides for further analysis. Next, the stability of four fluorescently labeled model peptides was analyzed in blood plasma and two different cell culture supernatants. Strong variation in the degradation dynamics and patterns was found. Finally, we evaluated the role of fluorescent labeling on peptide stability and compared results to peptides with isotopic labels, underlining the individual advantages of both methods. Altogether, the data provide important parameters for analyzing and comparing the peptide stability.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 11","pages":"3618-3625"},"PeriodicalIF":4.9,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142628642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Cognitive Restoration Effects of Resveratrol: Insight Molecular through Behavioral Studies in Various Cognitive Impairment Models.","authors":"Yingrak Boondam, Chaianan Saefoong, Natjanan Niltup, Arnaud Monteil, Worawan Kitphati","doi":"10.1021/acsptsci.4c00373","DOIUrl":"10.1021/acsptsci.4c00373","url":null,"abstract":"<p><p>Cognition is essential for daily activities and progressively deteriorates with age due to various factors leading to cognitive decline. This decline often begins with memory impairment and advances to broader cognitive dysfunctions. Resveratrol (RES), a natural phenolic compound found in red wine, has garnered significant attention for its potential to prevent cognitive decline. This review aims to synthesize the latest preclinical data on the cognitive restorative effects of RES. We highlight RES activities from cellular mechanisms to behavioral outcomes. Evidence from various cognitive impairment models demonstrates that RES exerts neuroprotective effects through multiple mechanisms, including anti-inflammatory, antioxidative, anti-apoptotic, and neurotrophic actions, all of which contribute to cognitive enhancement in behavioral studies. Despite the established role of RES in mitigating memory decline, our review identifies a critical gap in behavioral studies regarding cognitive flexibility. Further research in this domain is recommended. Additionally, species-specific pharmacokinetic differences may account for the inconsistencies between preclinical and clinical outcomes, particularly in rats and humans. We propose that formulations designed to delay gut metabolism through enterohepatic circulation could enhance the translational potential of RES. Furthermore, long-term studies are needed to determine the optimal dose capable of maximizing health benefits without raising toxicity during chronic use.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 11","pages":"3334-3357"},"PeriodicalIF":4.9,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}