Molecular Pharmacology最新文献

{"title":"Cannabinoid receptor 2 activating antibodies: A promising therapeutic strategy for macrophage-driven fibro-inflammatory diseases.","authors":"Raghavender Reddy Gopireddy, Dipankar Bhattacharya, Swastik Sen, Monica A Schwartz, Scott L Friedman, Richard C Yu, Toshi Takeuchi, Lauren J Schwimmer","doi":"10.1016/j.molpha.2026.100102","DOIUrl":"10.1016/j.molpha.2026.100102","url":null,"abstract":"<p><p>Fibrotic diseases, often fueled by chronic inflammation, represent a major unmet medical need. A critical driver of this process is the activation of macrophages, which secrete pro-inflammatory cytokines and chemokines, leading to immune cell recruitment and collagen deposition by myofibroblasts. Agonizing the cannabinoid receptor 2 (CB2), expressed on macrophages, offers a potential therapeutic avenue to suppress this activation. Despite widespread interest in CB2 modulation, challenges remain in the development of small-molecule agonists, including insufficient specificity and poor drug-like properties. Antibodies are highly specific with favorable pharmacokinetics and bioavailability, but G-protein coupled receptor (GPCR) agonist antibodies have been difficult to discover. Herein, the first-in-class CB2 agonist antibodies, AB120 and AB150, are presented. These antibodies are CB2 specific, G-α biased, and effectively decrease the expression of macrophage activation markers and key pro-inflammatory cytokines, including IL-6, IL-1β and TNF-α. Furthermore, treatment of ex vivo human precision-cut liver slice with CB2 agonist antibodies both reduces inflammatory markers and decreases collagen expression reinforcing their potential as antifibrotic agents. Thus, these novel CB2-specific agonist antibodies may be effective for a range of fibrotic and inflammatory conditions driven by chronic macrophage activation and demonstrating the potential of GPCR antibody agonists to drug this challenging class of targets. SIGNIFICANCE STATEMENT: Fibrotic diseases, which are typically driven by chronic inflammation lack effective treatments. CB2 agonism modulates macrophage activation to reduce pro-inflammatory cytokines suggesting a novel therapeutic avenue, but small-molecule CB2 agonists have faced substantial limitations due to off-target effects. Herein, two novel CB2-specific agonist antibodies with potent anti-inflammatory and antifibrotic effects in vitro and in a human ex vivo liver fibrosis model are presented. These antibodies provide a promising new therapeutic strategy and highlight the advantages of antibodies as GPCR agonist drugs.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 3","pages":"100102"},"PeriodicalIF":3.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147290488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"UCM-A86 is a selective positive allosteric modulator of GluN1/GluN3 NMDA receptors.","authors":"Avery J Benton, Mia R Johns, Emil Diamant, Nirvan Rouzbeh, Valdemar P Sørensen, Carly M Anderson, Davide Secci, Zhucheng Zhang, Andrew R Rau, Rasmus P Clausen, Kasper B Hansen","doi":"10.1016/j.molpha.2026.100103","DOIUrl":"10.1016/j.molpha.2026.100103","url":null,"abstract":"<p><p>NMDA receptors are ionotropic glutamate receptors that mediate excitatory neurotransmission in the central nervous system where they play critical roles in normal and pathological brain functions and neurodevelopment. Glutamate/glycine-activated GluN2-containing NMDA receptors (GluN1/GluN2) have been extensively studied, whereas the physiological roles and pharmacology of glycine-activated GluN3-containing receptors (GluN1/GluN3) remain less understood. Although GluN1/GluN3 receptors exhibit unique functional properties and play distinct roles in neuronal development and synapse maturation, studies of their precise roles in neurophysiology and circuit function are impeded by limited availability of GluN3-selective pharmacological tools. This study explores UCM-A86, a novel GluN3-selective positive allosteric modulator, with EC₅₀ values of 21 μM and 19 μM at GluN1/GluN3A and GluN1/GluN3B receptors, respectively. UCM-A86 selectively potentiates GluN1/GluN3A and GluN1/GluN3B receptors by 436% and 174%, respectively, relative to activation by glycine, with no activity at GluN1/GluN2A-D receptors. Furthermore, UCM-A86 selectively potentiates responses from native GluN1/GluN3A receptors expressed in somatostatin-expressing interneurons of the somatosensory cortex with no modulation of hippocampal AMPA receptor-mediated and GluN1/2 NMDA receptor-mediated excitatory postsynaptic currents. Mechanistic studies suggest that UCM-A86 modulation is facilitated by agonist binding (or channel gating) and that UCM-A86 primarily potentiates GluN1/GluN3A by increasing open probability with no effect on mean channel conductance. These findings advance the synthetic pharmacology of GluN1/GluN3 receptors and provide a novel tool for modulation of native GluN3-containing NMDA receptors. Significance Statement: This study introduces UCM-A86 as the first positive allosteric modulator selective for GluN3-containing NMDA receptors, addressing a critical gap in the pharmacological toolbox for investigating these understudied receptor subtypes. Using electrophysiological approaches in both recombinant and native systems, UCM-A86 demonstrates specific modulation of GluN3-containing NMDA receptors without affecting GluN2-containing NMDA receptors or AMPA receptors. UCM-A86 therefore provides new avenues to investigate the physiological roles of GluN3 subunits in normal and pathological brain function.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 3","pages":"100103"},"PeriodicalIF":3.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13095639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147290538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A subunit-selective negative allosteric modulator of GluN1/GluN3A glycine-activated receptor.","authors":"Leon Jacobs, TrangKimberly T Nguyen, Adam McCallum, Matt P Epplin, Riley E Perszyk, Scott J Myers, Ken Liu, Yanli Yang, Aletta E Van der Westhuyzen, Kelsey A Nocilla, James Allen, Elijah Z Ullman, Ding Liu, Yufei Du, Hongjie Yuan, Dennis C Liotta, Stephen F Traynelis","doi":"10.1016/j.molpha.2026.100104","DOIUrl":"10.1016/j.molpha.2026.100104","url":null,"abstract":"<p><p>The ionotropic glutamate N-methyl-d-aspartate (NMDA) receptor gene family includes 7 homologous subunits (GluN1, GluN2A-D, and GluN3A-B). The coassembly of GluN1 and GluN2 form the well-studied NMDA receptor, which requires binding of both glutamate and glycine to be activated. However, glycine alone can activate receptors assembled from the GluN1/GluN3 subunits, though the role of these glycine-activated receptors in the central nervous system remains poorly understood. We have previously identified a negative allosteric modulator (EU1180-438) that was a selective inhibitor of GluN3-containing receptors over NMDA, AMPA, kainate, GABA, inhibitory glycine, and other receptors. This compound was equally potent for both GluN3A- and GluN3B-containing receptors. Here we describe 2 novel negative allosteric modulators, EU1180-560 and EU1180-590, that are selective for GluN1/GluN3A over GluN1/GluN3B receptors. EU1180-560 and EU1180-590 inhibit GluN1/GluN3A receptors with an IC₅₀ value of approximately 2.6 μM and 3.7 μM, respectively, with no detectable effect on GluN1/GluN3B receptors. Both compounds produce noncompetitive, voltage-independent inhibition, consistent with a negative allosteric modulation mechanism. These compounds also have little to no effect on GluN1/GluN2-containing NMDA, AMPA, GABA, glycine, P2X, and kainate receptors. EU1180-590 additionally shows promising brain penetration. These results emphasize the potential utility of a GluN1/GluN3A subunit-selective allosteric modulator for use as experimental tool compounds to advance our understanding of the physiological role of GluN1/GluN3A receptors in the brain. These data also demonstrate the feasibility for development of GluN3A-selective therapeutic agents for potential treatment of neurological and neuropsychiatric diseases. SIGNIFICANCE STATEMENT: A novel negative allosteric modulator that acts specifically at GluN1/GluN3A receptors was identified. This compound should serve as a useful tool in future studies designed to elucidate the functional role of GluN1/GluN3A receptors in the central nervous system.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 3","pages":"100104"},"PeriodicalIF":3.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146227360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amantadine derivative Amt-1 enhances antiviral defense against influenza A virus via Nrf2/HO-1 pathway.","authors":"Shixin Li, Jingyan Wei, Shaofen Zhou, Shuaiqi Ma, Peihang Jiang, Jian He","doi":"10.1016/j.molpha.2025.100099","DOIUrl":"10.1016/j.molpha.2025.100099","url":null,"abstract":"<p><p>The rise of drug-resistant influenza A virus (IAV) strains and severe lung injury caused by excessive inflammation highlight the need for new antivirals that combine antiviral and immunomodulatory effects. Adamantane, an established anti-IAV agent, targets the viral M2 matrix protein, but widespread mutations have limited its clinical utility. Previously, we identified that 2,5-dihydroxybenzylalcohol and its derivatives possess anti-IAV activity. In this study, we synthesized a series of adamantane-2,5-dihydroxy-benzylalcohol derivatives via reductive amination. Among these, Amt-1 demonstrated strong antiviral activity against both amantadine-sensitive (H1N1 PR8) and clinical isolates IAV strains (-log IC₅₀ = 6.12-6.51 M). Mechanistic analyses, including immunofluorescence, isothermal titration calorimetry, quantitative polymerase chain reaction, ELISA, luciferase assays, and western blotting, revealed that Amt-1 not only interacts with the peptide segment of M2 ion channel protein (-log Kd = 5.08 M) but also activates nuclear factor erythroid 2-related factor 2, leading to increased heme oxygenase-1 expression and reduced production of proinflammatory cytokines interleukin-6, interleukin-1β, and tumor necrosis factor-α. Additionally, Amt-1 inhibited IAV-induced nuclear factor kappa-B activation, thereby suppressing viral replication. In vivo, Amt-1 reduced lung viral titers and mitigated histopathological damage in mice, surpassing amantadine in controlling inflammation and increased survival to 33%. In summary, Amt-1 is the first adamantane derivative shown to exert anti-IAV effects by modulating nuclear factor erythroid 2-related factor 2/heme oxygenase-1-mediated anti-inflammatory pathways and nuclear factor kappa-B-driven antiviral responses, while retaining M2 ion channel inhibition. This host-directed mechanism addresses drug resistance and limits immunopathology, making Amt-1 a promising therapeutic candidate for resistant influenza infections. SIGNIFICANCE STATEMENT: Amt-1 exhibits a dual mechanism of action, including direct antiviral effects through residual M2 affinity and host-directed anti-inflammatory activity mediated by the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 and nuclear factor kappa-B pathways. This balanced immunomodulatory and antiviral profile presents a distinct approach in adamantane-based drug development.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 2","pages":"100099"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oligomerization of transmembrane adenylyl cyclase isoforms.","authors":"Sadikshya Aryal, John J G Tesmer, Carmen W Dessauer, Val J Watts","doi":"10.1016/j.molpha.2026.100101","DOIUrl":"10.1016/j.molpha.2026.100101","url":null,"abstract":"<p><p>Membrane-bound adenylyl cyclases (ACs) function as vital enzymes that convert external signals into intracellular responses through the second messenger cAMP. Traditionally viewed as monomers, ACs are now recognized to form oligomers, introducing new regulatory mechanisms. This minireview synthesizes emerging structural and biochemical evidence for AC oligomerization and explores its functional significance. Oligomerization plays a critical role in the localization of ACs by regulating retention in the endoplasmic reticulum, membrane targeting, and distribution within signaling microdomains. Functional data suggest that dimer/oligomer interfaces act as regulatory nodes, although isoform-specific differences in oligomer architecture and functional consequences remain poorly understood. Defining the mechanisms underlying these differences is a critical area for future investigation. Importantly, the structural variability of oligomer interfaces, relative to conserved catalytic domains, offers new therapeutic potential that may enable isoform-selective modulation of AC activity. By integrating past and current research, this review frames oligomerization as a fundamental, yet underexplored, determinant of cAMP signaling. Advancing our understanding of the assembly, regulation, and dynamics of AC oligomers may open new avenues for precise control of cAMP signaling in both physiological and pathological contexts. SIGNIFICANCE STATEMENT: Oligomerization of membrane adenylyl cyclases adds regulatory complexity to cAMP signaling by modulating catalytic activity, localization, and compartmentalization. Distinct homo- and hetero-oligomers may underlie isoform-specific functions and offer new therapeutic opportunities.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 2","pages":"100101"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13095467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Constitutive activity among orphan G protein-coupled receptors: Molecular mechanisms and pharmacological perspectives.","authors":"Ryan E Murphy, Hudson R Smith, John A Allen","doi":"10.1016/j.molpha.2025.100100","DOIUrl":"10.1016/j.molpha.2025.100100","url":null,"abstract":"<p><p>Recent advancements in the study of orphan G protein-coupled receptors (oGPCRs) have revealed a large number with high levels of constitutive G protein signaling. Structural studies have suggested a new paradigm in which many constitutively active oGPCRs are auto-activated by their own intrinsic protein motifs, which act as auto-agonists. This includes extracellular loop 2 acting as auto-agonist to promote active-state conformations and G protein signaling. In some cases, the oGPCRs lack inhibitory microswitches that may drive a high level of constitutive activity. In this brief review, we discuss oGPCR constitutive activity, highlighting the auto-activating orphan receptors and overview structural underpinnings of constitutive activity. A discussion into the pharmacological and cell signaling implications of oGPCR constitutive activity is provided. We also propose a new concept in which orphan GPCR constitutive activity sets the baseline tone for cellular signaling and allows for dynamic regulation of cAMP signaling. Taken together, recent mechanistic studies with many oGPCRs indicate high constitutive activity is a common phenomenon that modulates cellular signaling and that can be tuned with pharmacology. SIGNIFICANCE STATEMENT: Recent literature describes a subset of orphan Class A G protein-coupled receptors with high constitutive signaling that auto-activate by their own intrinsic protein motifs. Herein, a new concept is proposed in which oGPCR constitutive activity allows dynamic regulation of cAMP signaling. Recently solved structures and functional studies of constitutively active oGPCRs provide fresh insights into oGPCR signaling with relevance for both health and disease.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 2","pages":"100100"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13003736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146113558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transient receptor potential ankyrin 1 promotes the expression of interferon-stimulated antiviral genes in human A549 lung epithelial cells.","authors":"Samu Luostarinen, Antti Pemmari, Julia Vistbacka, Amirbabak Sioofy-Khojine, Mari Hämäläinen, Heikki Hyöty, Eeva Moilanen","doi":"10.1016/j.molpha.2025.100098","DOIUrl":"10.1016/j.molpha.2025.100098","url":null,"abstract":"<p><p>Transient receptor potential ankyrin 1 (TRPA1) is an ion channel known for its chemosensory function in neurons, causing pain and neurogenic inflammation. TRPA1 is activated by many noxious compounds including some inflammatory mediators. We and others have shown that TRPA1 is also expressed in epithelial cells, but its function in the epithelial barrier remains unclear. Here, we discovered in RNA-seq studies that inhibition of TRPA1 reduced the expression of a large number of antiviral and inflammatory genes under the influence of the key antiviral cytokine interferon beta in human A549 lung epithelial cells. In the gene ontology analysis, the terms most strongly affected by TRPA1 antagonists included many associated with antiviral defense such as \"defense response to virus\" and \"antiviral innate immune response.\" To validate the RNA-seq results, selected antiviral genes such as myxovirus resistance protein 1 were further studied and found to be upregulated by TRPA1 by using reverse transcription quantitative polymerase chain reaction and western blotting, pharmacological TRPA1 inhibitors, TRPA1-targeting small interfering RNA, and ex vivo lung tissue cultures from TRPA1-deficient mice. Mechanistically, TRPA1 inhibitors partially reduced interferon beta-induced Ca²⁺ influx, phosphorylation of the transcription factor signal transducer and activator 1, and the interferon-sensitive response element-dependent transcription. These data suggest that TRPA1 mediates cellular signaling and biologically relevant changes in gene expression induced by type I interferons. The results offer TRPA1 as a novel treatment target for inflammatory conditions characterized by enhanced type I interferon activity such as hyperinflammatory states associated with viral infections and some autoimmune diseases, but TRPA1 inhibition may also influence interferon-induced antiviral immunity. SIGNIFICANCE STATEMENT: We found that the transient receptor potential ankyrin 1 channel can promote gene expression changes induced by type I interferons in human lung epithelial cells. Inhibiting transient receptor potential ankyrin 1 could decrease interferon-induced inflammation but could also influence the antiviral state.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 2","pages":"100098"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12975360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amiodarone irrecoverably impairs the function of human ether-a-go-go-related gene potassium channels.","authors":"Illia Gelman, Wentao Li, Jun Guo, Reese Bogart-Cherry, Nicole Tomei, Neelakshi Sharma, Angelia Pan, Tonghua Yang, Adrian Baranchuk, Mohammad El-Diasty, Shetuan Zhang","doi":"10.1016/j.molpha.2025.100094","DOIUrl":"10.1016/j.molpha.2025.100094","url":null,"abstract":"<p><p>The class III antiarrhythmic drug amiodarone (AMIO) inhibits the rapidly activating delayed rectifier K⁺ current that is conducted by the human ether-a-go-go-related gene (hERG) encoded channel. Like other class III antiarrhythmic drugs, AMIO can cause long QT syndrome. In the present study, we investigated the effects of AMIO and its major metabolite, desethylamiodarone, on hERG channels expressed in human embryonic kidney (HEK)293 (hERG-HEK) as well as in cardiomyocyte-derived H9c2 cells. Our results show that after acute inhibition of hERG current (I_hERG) by AMIO (IC₅₀ of 0.2 μM) or desethylamiodarone (IC₅₀ of 0.5 μM), continuous washout of the drug for 20 to 25 minutes during whole-cell patch clamp recordings did not lead to any current recovery. Furthermore, when hERG-HEK cells were cultured with AMIO overnight, and I_hERG was recorded in a drug-free bath solution, AMIO treatment resulted in a concentration-dependent inhibition of I_hERG with an IC₅₀ of 0.3 μM. In contrast, such overnight treatments did not affect the expression of hERG channels shown by Western blot analyses. However, the mature hERG protein of AMIO-pretreated cells cultured in a drug-free medium degraded faster than that of control cells, indicating that AMIO treatment modified the property of mature hERG channels, making them permanently nonconductive and less stable. Consistently, our results showed that following AMIO-mediated inhibition, recovery of I_hERG during cell culture in drug-free conditions resulted from newly made channels, and a full recovery took up to 20 hours. Thus, AMIO-mediated hERG inhibition may persist for tens of hours after drug discontinuation, which has clinical importance. SIGNIFICANCE STATEMENT: Amiodarone (AMIO) is a frequently used antiarrhythmic drug that blocks human ether-a-go-go-related gene (hERG) potassium channels. The present study revealed that, unlike other hERG-interacting drugs, AMIO irrecoverably inhibits hERG channel currents. Upon removal of AMIO after hERG inhibition, recovery of hERG currents relies on newly made channels in a process of up to 20 hours. Thus, lingering effects on hERG channels after AMIO discontinuation are anticipated, which have important clinical implications.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 1","pages":"100094"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12881259/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elucidating molecular mechanisms governing tumor necrosis factor-alpha-mediated regulation of amyloid beta 42 uptake in blood-brain barrier endothelial cells.","authors":"Vrishali S Salian, Geoffry L Curan, Val J Lowe, Xiaojia Tang, Krishna R Kalari, Karunya K Kandimalla","doi":"10.1016/j.molpha.2025.100088","DOIUrl":"10.1016/j.molpha.2025.100088","url":null,"abstract":"<p><p>Cerebrovascular inflammation is prevalent in a majority of patients with Alzheimer disease. Elevated levels of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), circulating in the plasma have been shown to cause the inflammation of blood-brain barrier (BBB) endothelium lining the cerebral microvasculature in Alzheimer disease. The BBB inflammation triggered by exposure of TNF-α in the peripheral circulation can aggravate the accumulation of Aβ peptides in Alzheimer disease brain. In the current study, we have shown that infusion of wild-type mice with TNF-α led to an increase in permeability and influx of Aβ42 into the mice brain using dynamic single-photon emission computed tomography/computed tomography imaging. To corroborate these findings, we demonstrated that TNF-α increases Aβ42 accumulation in vitro in human cerebral microvascular endothelial cells /D3 and primary porcine brain endothelial cells. In addition, our results in human cerebral microvascular endothelial cells/D3 polarized monolayers show that TNF-α alters the expression of cofilin, actin, and dynamin, which are critical components for Aβ endocytosis by BBB endothelial cells. These results suggest a mechanistic pathway by which TNF-α may promote Aβ accumulation at the BBB and the underlying interactions between inflammation and Aβ exposure that drives BBB dysfunction. Hence, a therapeutic intervention aimed at addressing elevated TNF-α levels in Alzheimer disease may potentially reduce Aβ-related cerebrovascular dysfunction in Alzheimer disease brain. SIGNIFICANCE STATEMENT: Elevated plasma tumor necrosis factor-α drives Aβ pathology in Alzheimer disease, promoting cerebrovascular inflammation, but its role in endothelial Aβ uptake in the brain is unclear. This study shows tumor necrosis factor-α increases Aβ42 accumulation in the blood-brain barrier endothelium by altering the expression of blood-brain barrier endocytic proteins cofilin, actin, and dynamin.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 1","pages":"100088"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13095448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145912436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging roles of ubiquitin-specific proteases in the cardiovascular system.","authors":"Bipradas Roy, Preston C Nibley, Richard Jiang, Sudha K Shenoy","doi":"10.1016/j.molpha.2025.100091","DOIUrl":"10.1016/j.molpha.2025.100091","url":null,"abstract":"<p><p>The universal posttranslational modification ubiquitination was originally discovered in the 1980s as a tag appended to cellular proteins to mark them for degradation by the 26S proteasomal complex. Subsequent discoveries have established ubiquitination as a process that directs spatial and temporal activities of proteins that are integral to all biochemical pathways in cells, in addition to its canonical role in facilitating life-death decisions of proteins. Protein ubiquitination is counterbalanced by ∼100 enzymes called deubiquitinases (DUBs) expressed in human cells. Although ubiquitination affects a plethora of cellular functions, the role of DUBs was initially linked to neuronal development, and later to cancer, where deregulation of protein degradation coincided with both increased expression of DUBs and worsening of disease pathology. As such, inhibition of DUBs has been regarded as a therapeutic approach for various cancers, and major investments of time and resources have been dedicated for developing DUB inhibitors for cancer therapy. The important roles of DUBs in the cardiovascular system have only recently been appreciated. DUBs play a protective anti-inflammatory role in the vascular smooth muscle, endothelium, as well as macrophages, and also serve to mitigate pathological remodeling of the myocardium in mice. Activation or positive allosteric modulation of DUBs could provide therapeutic benefit in the 2 major cardiovascular diseases, atherosclerosis and heart failure. In this review, we highlight the roles of select DUBs that have been characterized for their critical functions in the heart and vasculature. SIGNIFICANCE STATEMENT: Cardiovascular diseases represent a major global health burden and remain the leading cause of morbidity and mortality, accounting for approximately 18 million deaths annually worldwide. Among these, atherosclerosis and heart failure are 2 interrelated conditions with multifactorial, chronic, and complex etiologies, necessitating the development of more effective therapeutic strategies to reduce mortality and improve quality of life. Emerging evidence suggests that several deubiquitinases exert protective effects by attenuating atherosclerosis and cardiac dysfunction in murine models, highlighting the potential of deubiquitinase modulators to serve as novel therapeutic agents for cardiovascular diseases.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 1","pages":"100091"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}