ACS Pharmacology and Translational Science最新文献

{"title":"The Research Deficit and Expert Disagreement Regarding Music Selection for Psychedelic Assisted Therapy","authors":"Milo Moskovitz*,&nbsp;","doi":"10.1021/acsptsci.5c00583","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00583","url":null,"abstract":"<p >Prior research has determined that music plays a central role in psychedelic assisted therapy (PAT). While there is a general consensus of the importance of music during PAT, there are only three empirical studies published to date that directly investigate which type of music might best support PAT. Importantly, no review to date has critically analyzed these studies and identified the gaps. Careful examination reveals these studies have important limitations and the findings lack alignment with other publications and existing recommendations. Additionally, our understanding of guidelines seems to be not much different from when this research started in 1970. This paper summarizes the common impacts of music during PAT, reviews what we know about music selection and guidelines for PAT, and makes suggestions of priorities for future research.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 10","pages":"3684–3690"},"PeriodicalIF":3.7,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.5c00583","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145247807","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":"Para-Cresol and the Brain: Emerging Role in Neurodevelopmental and Neurodegenerative Disorders and Therapeutic Perspectives","authors":"Laura Bertarini,&nbsp;, ,&nbsp;Federico Imbeni,&nbsp;, ,&nbsp;Virginia Brighenti,&nbsp;, ,&nbsp;Isabella Martusciello,&nbsp;, ,&nbsp;Federica Pellati*,&nbsp;, and ,&nbsp;Silvia Alboni*,&nbsp;","doi":"10.1021/acsptsci.5c00289","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00289","url":null,"abstract":"<p ><i>p</i>-Cresol (<i>p</i>C) is a phenolic compound to which humans can be exposed through both environmental sources, such as a pollutant, and endogenous production by the gut microbiota. Among microbial contributors, <i>Clostridioides difficile</i> appears to be a major source of <i>p</i>C within the body. Once absorbed, <i>p</i>C is highly protein-bound in plasma and predominantly circulates in its hepatic conjugated forms: <i>p</i>-cresyl sulfate (<i>p</i>CS) and <i>p</i>-cresol glucuronide (<i>p</i>CG), which are mainly excreted in urine. Accumulation of these metabolites, particularly <i>p</i>CS, classified as a protein-bound uremic toxin, has been associated with the progression of chronic kidney disease (CKD) and related complications, due to its pro-oxidant, pro-inflammatory, and pro-apoptotic properties. CKD patients are at increased risk for cognitive impairment, affective disorders, and central nervous system (CNS) dysfunctions. In recent years, increasing evidence has suggested a potential role of <i>p</i>C and its metabolites in CNS diseases. Here, we summarize current knowledge on the involvement of these compounds in the pathogenesis and progression of autism spectrum disorder, Parkinson’s disease, Alzheimer’s disease, and post-traumatic stress disorder. We also discuss how modulating systemic levels of <i>p</i>C may represent a promising strategy to improve pathological phenotypes in the context of neurodevelopmental and neurodegenerative disorders.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 10","pages":"3432–3452"},"PeriodicalIF":3.7,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.5c00289","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145247806","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":"Role of Colony Stimulating Factor 1 (CSF-1) and Its Receptor CSF1R: Macrophage Repolarization for Glioblastoma Treatment","authors":"Gaurisha alias Resha Ramnath Naik,&nbsp;, ,&nbsp;Rachana S P,&nbsp;, ,&nbsp;Sandesh Ramchandra Jadhav,&nbsp;, ,&nbsp;Rahul Pokale,&nbsp;, ,&nbsp;Paniz Hedayat,&nbsp;, ,&nbsp;Deepanjan Datta,&nbsp;, ,&nbsp;Bhupendra Prajapati,&nbsp;, ,&nbsp;Srinivas Mutalik,&nbsp;, and ,&nbsp;Namdev Dhas*,&nbsp;","doi":"10.1021/acsptsci.5c00007","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00007","url":null,"abstract":"<p >Glioblastoma multiforme (GBM) is the most aggressive and prevailing form of primary brain tumor, illustrated by its rapid growth and invasive nature. GBM continues to be highly incurable despite advancements in treatment due to its complex tumor microenvironment (TME) and the unique characteristics of tumor-associated macrophages (TAMs). This review explores the function of macrophages within the TME of GBM, specifically emphasizing the impact of colony-stimulating Factor-1 (CSF-1) and its receptor CSF1R in macrophage biology. The progression, survival, and differentiation of TAMs, which often rely on immunosuppressive properties that contribute to tumor growth and treatment resistance, are facilitated by elevated CSF-1 levels in GBM. The inhibition of CSF1R presents a promising therapeutic strategy, as it selectively targets tumor-promoting macrophages while sparing antitumor macrophages. Preclinical evidence demonstrates improved survival outcomes through CSF1R inhibition in mouse models, highlighting its potential for clinical application. Ongoing clinical trials further investigate this approach, aiming to enhance treatment efficacy for patients with GBM. This review concludes by emphasizing the significance of repolarizing macrophages as a novel therapeutic opportunity in GBM management, alongside emerging trends and future research directions that could lead to breakthroughs in treatment strategies.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 10","pages":"3391–3410"},"PeriodicalIF":3.7,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.5c00007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145247792","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":"A Perspective on the Role of Metformin in Treating Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID","authors":"David Fineberg,&nbsp;, ,&nbsp;Alain Moreau,&nbsp;, ,&nbsp;Elena K. Schneider-Futschik*,&nbsp;, and ,&nbsp;Christopher W. Armstrong*,&nbsp;","doi":"10.1021/acsptsci.5c00229","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00229","url":null,"abstract":"<p >Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID (LC) are increasingly recognized as debilitating postinfectious conditions that impact both individuals and society. Recent research highlights the potential of metformin, an antidiabetic agent, as a treatment for these syndromes by targeting their underlying mechanisms. This review assesses the effectiveness of metformin in ME/CFS and LC, which involve complex dysfunctions related to cytokines, glycolysis, ATP generation, oxidative stress, gastrointestinal microbiomes, and vascular endothelial function. Metformin, traditionally known for its antihyperglycemic properties may offer broader therapeutic benefits by influencing these pathological pathways. It works by inhibiting complexes I and IV of the electron transport chain, which reduces the strain on malfunctioning complex V and decreases the production of harmful free radicals. Additionally, metformin’s impact on mTOR signaling could improve energy metabolism in ME/CFS and LC by downregulating an overactive but underperforming protein, thereby alleviating symptoms. Beyond the impact on cellular metabolism, metformin has shown to have anti-inflammatory, vascular, gastrointestinal, neuroprotective and epigenetic effects. We explore this impact of metformin and the potential role it could play to help people with ME/CFS. While metformin shows promise, it is unlikely to be a stand-alone solution. Instead, it may be part of a broader treatment strategy that includes other therapies targeting neurocognitive and autonomic impairments.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 10","pages":"3411–3431"},"PeriodicalIF":3.7,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145247770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Psilocybin Enhances Cued Fear Extinction and Extinction Recall in Stress-Naïve, Acutely Stressed, and Chronically Stressed Mice","authors":"John Razidlo,&nbsp;, ,&nbsp;Noelle Cataldo,&nbsp;, and ,&nbsp;Cody J Wenthur*,&nbsp;","doi":"10.1021/acsptsci.5c00462","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00462","url":null,"abstract":"<p >Serotonergic psychedelics have shown promise in clinical trials for treating an array of mental health disorders, including depression, anxiety, and post-traumatic stress disorder. Despite these findings, our understanding of how these drugs mechanistically exert their therapeutic effects remains incomplete. While researchers have regularly employed rodent preclinical models to assess such mechanisms, many of these findings arise from stress-naïve animals. Given that prior environmental stress is a critical component for the mental health disorders being studied in clinical trials of psychedelics, understanding the performance of these drugs in animals previously exposed to acute or chronic stress is of strong translational relevance. In this study, we examined the effects of psilocybin in male mice that were stress-naïve, as well as in those that underwent either single-prolonged stress (SPS) or chronic restraint stress (CRS). The effects of these treatments on corticosterone release, extinction of freezing behavior, and recall of extinction in Pavlovian fear conditioning were examined for each group. We observed that psilocybin challenge transiently increased serum corticosterone in stress-naïve mice relative to saline; however, this effect was not observed in SPS and CRS animals. Interestingly, psilocybin treatment enhanced fear extinction and promoted extinction recall 24 h later not only in stress-naïve animals but also in stressed animals. These findings indicate psilocybin’s ability to acutely enhance fear extinction and promote enhanced extinction recall across animals with diverse environmental stress experiences prior to exposure.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 10","pages":"3631–3640"},"PeriodicalIF":3.7,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.5c00462","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145247773","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":"Genetic Deletion of the Purinergic Receptor P2rx7 Worsens the Phenotype of α-Sarcoglycan Muscular Dystrophy","authors":"Cecilia Astigiano,&nbsp;, ,&nbsp;Elisa Principi,&nbsp;, ,&nbsp;Sara Pintus,&nbsp;, ,&nbsp;Andrea Benzi,&nbsp;, ,&nbsp;Serena Baratto,&nbsp;, ,&nbsp;Chiara Panicucci,&nbsp;, ,&nbsp;Mario Passalacqua,&nbsp;, ,&nbsp;Juan Sierra-Marquez,&nbsp;, ,&nbsp;Annette Nicke,&nbsp;, ,&nbsp;Francesca Antonini,&nbsp;, ,&nbsp;Genny Del Zotto,&nbsp;, ,&nbsp;Annunziata Gaetana Cicatiello,&nbsp;, ,&nbsp;Lizzia Raffaghello,&nbsp;, ,&nbsp;Tanja Rezzonico Jost,&nbsp;, ,&nbsp;Fabio Grassi,&nbsp;, ,&nbsp;Santina Bruzzone,&nbsp;, ,&nbsp;Claudio Bruno*,&nbsp;, and ,&nbsp;Elisabetta Gazzerro*,&nbsp;","doi":"10.1021/acsptsci.5c00138","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00138","url":null,"abstract":"<p >Limb-girdle muscular dystrophy R3 (LGMDR3), a rare genetic disorder characterized by progressive impairment of limb, diaphragmatic, and respiratory muscles, is caused by loss-of-function mutations in the α-sarcoglycan gene (<i>SGCA</i>) and aggravated by immune-mediated damage and fibrotic tissue replacement. Pharmacological inhibition of purinergic receptor P2X7 (P2X7R) reduced inflammation and fibrosis in <i>Sgca</i>^–/– mice. To further define the role of P2X7R, we generated a double knockout mouse model <i>Sgca</i>^{<i>–/–</i>}<i>P2rx7</i>^<i>-/</i>-. We compared diaphragms isolated from 24-week-old <i>Sgca</i>^–/–<i>P2rx7</i>^+/+ and <i>Sgca</i>^{<i>–/–</i>}<i>P2rx7<i>^–/–</i></i>mice since the diaphragmatic muscle is early and severely damaged by <i>Sgca</i> genetic loss-of-function. Unexpectedly, <i>Sgca</i>^{<i>–/–</i>}<i>P2rx7^–/–</i> mice displayed increased extracellular matrix deposition and augmented cellularity in fibrotic areas, in particular, a higher number of CD3⁺ lymphocytes and Iba1⁺ macrophages compared to <i>Sgca</i>^–/–<i>P2rx7</i>^<i>+/+</i> mice. Moreover, intense P2X4R signal colocalized with CD3⁺ and Iba1⁺ cells, confirming its expression by these infiltrating immune cells. Absence of an improvement of the dystrophic phenotype was histologically confirmed in <i>Sgca</i>^{<i>–/–</i>}<i>P2rx7^–/–</i> quadriceps, although the fibrotic reaction was milder than that in diaphragms, suggesting a differential influence of the tissue microenvironment on the receptor functions. Flow cytometric analysis of limb muscle-infiltrating immune cells revealed a decrease in NK cells. Motor performance tests did not reveal any difference between the two genotypes. In conclusion, this study identified a divergent outcome of genetic deletion of the <i>P2rx7</i> gene as compared to P2X7R blockade in α-sarcoglycan dystrophic tissue, suggesting that pharmacological interventions targeting the P2X7R in dystrophic immune-mediated damage require careful definition of a precise time window and dosage.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 10","pages":"3477–3489"},"PeriodicalIF":3.7,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.5c00138","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145247771","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":"An Orally Available Grafted Peptide Targeting Epidermal Growth Factor Receptor Dimers Reduces Non-Small Cell Lung Cancer Tumors in Mouse Models","authors":"Prajesh Shrestha,&nbsp;, ,&nbsp;Sitanshu S. Singh,&nbsp;, ,&nbsp;Achyut Dahal,&nbsp;, ,&nbsp;Vivitri Prasasty,&nbsp;, ,&nbsp;Arpan Chowdhury,&nbsp;, ,&nbsp;Debajyoti Majumdar,&nbsp;, ,&nbsp;Xin Gu,&nbsp;, ,&nbsp;William Johnson,&nbsp;, ,&nbsp;Dachuan Zhang,&nbsp;, ,&nbsp;Daniel D. Billadeau,&nbsp;, and ,&nbsp;Seetharama Jois*,&nbsp;","doi":"10.1021/acsptsci.5c00336","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00336","url":null,"abstract":"<p >Epidermal growth factor receptors, such as human epidermal growth factor receptors (EGFR, HER1) and HER2, HER3, are essential in cell growth and differentiation. EGFR, HER2, and HER3 dimerize to generate signaling for cell growth, and in cancer cells, these receptors are either overexpressed or harbor mutations, resulting in uncontrolled signaling. The dimerization of these receptors is required for signaling and can be inhibited by peptides and antibodies. We have designed a grafted peptide, SFTI-G5, that targets the HER2 protein and inhibits dimerization of both EGFR:HER2 and HER2:HER3. To develop the grafted peptide as an orally bioavailable peptide, we evaluated the stability of the peptide against enzymatic degradation. Oral administration of SFTI-G5 at 50 mg/kg suppressed the growth of lung cancer cell lines that overexpress the HER2 protein in a mouse xenograft model. To evaluate the specificity of the peptide for the HER2 protein, a patient-derived xenograft (PDX) model of mice with low HER2 expression was used. The peptide did not have any effect on tumor growth in the low HER2 expression model, suggesting the specificity of the peptide for the HER2 protein. Pharmacokinetic studies via the IV route indicated that the peptide is stable in serum, with a terminal half-life of more than 40 h. These studies suggest that stable grafted cyclic peptides can be designed to target protein–protein interactions and that these peptides can be made orally bioavailable.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 10","pages":"3531–3545"},"PeriodicalIF":3.7,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145247757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A First-in-Class Chemical-Induced Proximity System Achieves Dose-Dependent Control of Tumor Protein P53 Gene Activation in Preclinical Models of Gastric Cancer","authors":"Travis J. Nelson,&nbsp;, ,&nbsp;Ryan M. Kemper,&nbsp;, ,&nbsp;Anna M. Chiarella,&nbsp;, ,&nbsp;Stephany Gonzalez Tineo,&nbsp;, ,&nbsp;Michell Carroll,&nbsp;, ,&nbsp;Surya Tripathi,&nbsp;, ,&nbsp;Brandon J. Clarke,&nbsp;, ,&nbsp;Xufen Yu,&nbsp;, ,&nbsp;Xiaoping Hu,&nbsp;, ,&nbsp;Aidan J. Cooke,&nbsp;, ,&nbsp;Bhavika C. Chirumamilla,&nbsp;, ,&nbsp;Alicia Chandler,&nbsp;, ,&nbsp;Evan McGilvary,&nbsp;, ,&nbsp;Samantha G. Pattenden,&nbsp;, ,&nbsp;Jian Jin,&nbsp;, ,&nbsp;Daniel J. Crona,&nbsp;, and ,&nbsp;Nathaniel A. Hathaway*,&nbsp;","doi":"10.1021/acsptsci.5c00402","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00402","url":null,"abstract":"<p >The tumor protein P53 (<i>TP53</i>) gene has long been studied in cancer research with genomic and epigenetic aberrations playing a driving role in cancer pathology, yet even after decades of work, only a few methods have been developed to specifically target <i>TP53</i> therapeutically. Some cancers are driven by loss-of-function <i>TP53</i> mutations, while others have wild-type <i>TP53</i> in a transcriptionally repressed state; the latter is exploitable by advances in epigenome editing. In our previous work, we demonstrated that deactivated CRISPR/Cas9 systems (dCas9), combined with an FK-506-binding protein (FKBP) recruitment protein tag and chemical epigenetic modifier (CEM) small molecules, can elicit gene-specific changes in expression in a dose-dependent manner. Here, we describe the development, application, and characterization of the dCas9-FKBP-CEM technology to increase <i>TP53</i> expression. We demonstrate that catalyzing increased <i>TP53</i> expression via dCas9-FKBP-CEM87 induced apoptosis, cell cycle arrest, and tumor growth inhibition in a dose-dependent manner in preclinical models of gastric cancer.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 10","pages":"3585–3599"},"PeriodicalIF":3.7,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145247754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical Positron Emission Tomography Imaging of B7–H3 Expression Using Affibody Molecules Labeled with Gallium-68","authors":"Vladimir Tolmachev,&nbsp;, ,&nbsp;Ekaterina A. Bezverkhniaia,&nbsp;, ,&nbsp;Eleftherios Papalanis,&nbsp;, ,&nbsp;Abdullah Mujahid Bin Muhammad,&nbsp;, ,&nbsp;Anzhelika Vorobyeva,&nbsp;, ,&nbsp;Elin Gunneriusson,&nbsp;, ,&nbsp;Susanne Klint,&nbsp;, ,&nbsp;Eva Ryer,&nbsp;, ,&nbsp;Matilda Carlqvist,&nbsp;, ,&nbsp;Wojciech Kazmierczak,&nbsp;, ,&nbsp;Anna Orlova,&nbsp;, ,&nbsp;Fredrik Y. Frejd*,&nbsp;, and ,&nbsp;Maryam Oroujeni,&nbsp;","doi":"10.1021/acsptsci.5c00320","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00320","url":null,"abstract":"<p >Affibody molecules, nonimmunoglobulin scaffold proteins, have a high potential as probes for molecular imaging of different molecular targets. One of the molecular targets for radionuclide diagnosis and therapy is B7–H3 (known as CD276), which is overexpressed in various cancers, whereas its expression is low in most normal organs and tissues. The visualization of expression levels of B7–H3 has been performed using Affibody molecules labeled with Tc-99m. However, radionuclide molecular imaging using PET offers several advantages such as superior sensitivity, quantitation accuracy, and better spatial resolution compared to SPECT. In this study, we aimed to introduce a radiotracer for PET imaging of B7–H3. To design imaging agents for labeling with the generator-produced positron-emitting radionuclide ⁶⁸Ga, the macrocyclic triaza chelator (2-[4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl]acetic acid) (NOTA) was site-specifically coupled to the C-terminal cysteine of the anti–B7-H3 Affibody molecules. Four different variants of Affibody molecules, Z_B7–H3_₂, Z_B7–H3_₃, Z_B7–H3_₄, and Z_AC12 (as control), were produced, characterized, and successfully labeled with ⁶⁸Ga. ⁶⁸Ga-labeled conjugates bound specifically to B7–H3-expressing cells <i>in vitro</i> and <i>in vivo</i>. Biodistribution showed that [⁶⁸Ga]Ga-Z_B7–H3_₂ had the highest tumor accumulation only 2 h after administration, which was 2.8-fold higher than that for the control Z_AC12. There was a tendency for higher tumor-to-organ ratios compared to the other variants, resulting in higher imaging contrast using [⁶⁸Ga]Ga-Z_B7–H3_₂ for preclinical PET imaging of B7–H3-expressing tumors. Thus, [⁶⁸Ga]Ga-Z_B7–H3_₂ could be a promising candidate for further development aimed at clinical PET in the future.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 10","pages":"3509–3522"},"PeriodicalIF":3.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.5c00320","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145247787","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":"Targeting Insulin Resistance in Hepatocytes: A Novel Insulin-Mimetic Agent Delivered via an Advanced Nanocarrier System","authors":"Mihaela Turtoi*,&nbsp;Mariana Deleanu,&nbsp;Maria Anghelache,&nbsp;Geanina Voicu,&nbsp;Ruxandra Anton,&nbsp;Florentina Safciuc and Manuela Calin,&nbsp;","doi":"10.1021/acsptsci.5c00483","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00483","url":null,"abstract":"<p >Hepatic insulin resistance (IR) is a key contributor to the onset and progression of type 2 diabetes mellitus (T2DM), characterized by reduced insulin sensitivity, impaired glucose uptake, decreased glycogen synthesis, and excessive lipid accumulation in hepatocytes. Many vanadium compounds exhibit promising antidiabetic properties; however, their clinical application remains limited due to concerns about toxicity. Here, we investigate the impact of our newly developed Schiff base-binuclear oxidovanadium(V) complex (abbreviated as Van) in reversing IR and elucidate its pharmacological mechanism using an <i>in vitro</i> experimental model of hepatocarcinoma (HepG2) subjected to IR (IR-HepG2). We propose incorporating Van into liposomes as a nanotherapeutic strategy to increase its cellular uptake and maximize its therapeutic effectiveness. Our data show that Van effectively reverses IR in the IR-HepG2 cell model by increasing glucose uptake, promoting glycogen synthesis, and reducing lipid accumulation. The mechanism underlying Van’s ability to reverse IR involves the inhibition of protein tyrosine phosphatase (PTP)-1B protein expression and total PTPs’ activity, leading to the activation of the insulin receptor (InsR)/protein kinase B (AKT)/glycogen synthase kinase (GSK)3αβ pathway and a reduction in glucose-6-phosphatase (G6Pase) protein expression while maintaining unchanged phosphoenolpyruvate carboxykinase (PCK1) and glucose transporter (GLUT)2 synthesis. Moreover, we demonstrate that Van can be successfully incorporated into stable negatively charged liposomes, significantly enhancing its uptake by IR-HepG2 cells and improving therapeutic efficacy compared with free Van. This study presents a novel therapeutic approach for T2DM, specifically addressing IR and offering the first proof-of-concept that Van exhibits increased efficacy when it is precisely delivered to IR cells using nanotechnology.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 9","pages":"3334–3345"},"PeriodicalIF":3.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}