Pharmacological Reviews[JOURNAL]
Sun
200 papers
Striatal remodeling in Parkinson disease.
Emerson SD, Sugimoto C, Honeycutt SC … +1 more , Calipari ES
J Pharmacol Exp Ther · 2026 Jul · PMID 42401195 · Publisher ↗
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Loaded and coated: Outer membrane vesicles get a critical boost from a lipopolysaccharide adjuvant payload in a rationally designed anti-Helicobacter pylori nanoparticle.
Jones JA, Simberg D
J Pharmacol Exp Ther · 2026 Jul · PMID 42401194 · Publisher ↗
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Comparative analysis of ligand binding affinities and functional profiles at recombinant human β-adrenergic receptor subtypes 1, 2, and 3.
Bindel LJ, Seifert R
J Pharmacol Exp Ther · 2026 Jun · PMID 42401193 · Publisher ↗
β-Adrenergic receptors (βAR) are G protein-coupled receptors with major physiological and therapeutic relevance in cardiovascular and respiratory conditions. Although numerous ligands have been investigated, binding affi...
β-Adrenergic receptors (βAR) are G protein-coupled receptors with major physiological and therapeutic relevance in cardiovascular and respiratory conditions. Although numerous ligands have been investigated, binding affinities and functional annotations remain incomplete and fragmented across databases. This review systematically integrates ligand binding affinities and functional profiles at recombinant human βAR from the Psychoactive Drug Screening Program K database and the International Union of Basic and Clinical Pharmacology/British Pharmacological Society (IUPHAR/BPS), with a focus on clinically important ligands, receptor selectivity, and characteristic patterns. Database agreement, affinity patterns, stereoisomer-specific information and concordance with primary literature are evaluated. In total, 156 ligands with pK ≥ 5 were collected. Median pK values were 6.6 for hβAR, 6.15 for hβAR, and 5.8 for hβAR. A pronounced overlap between hβAR and hβAR was observed, reflected in similar median affinities and shared ligand profiles, whereas hβAR showed narrower data coverage and a more distinct affinity distribution. Most ligands were listed for more than 1 hβAR, and 37 ligands had binding data for all 3 hβAR. Functional characterization was available for 90 ligands, whereas 61 lacked annotations. Database comparison revealed low overlap in ligand listings (28.8%). Stereoisomer data were highly incomplete, and in several cases, affinity-based stereoisomer comparisons differed from literature-reported stereoisomeric superiority. Summarized, substantial similarity between hβAR and hβAR ligand binding patterns is observed, whereas hβAR appears less extensively characterized. Considerable fragmentation, incomplete receptor profiling and methodological heterogeneity limit the evaluation of receptor and ligand characteristics. Binding affinity and functional behavior must be interpreted as context-dependent parameters influenced by experimental systems, G protein coupling conditions and stereochemical specification. SIGNIFICANCE STATEMENT: This analysis systematically integrates ligand binding affinities and functional labels at recombinant human βAR from the Psychoactive Drug Screening Program (PDSP) K database and the International Union of Basic and Clinical Pharmacology/British Pharmacological Society (IUPHAR/BPS) Guide to Pharmacology, providing a structured and comprehensive overview of ligand profiles. It identifies substantial data fragmentation, incomplete receptor and stereoisomer characterization, and limited concordance between databases. For clinically relevant ligands, it was demonstrated that therapeutic subtype classification does not always correspond to strict affinity-based receptor selectivity.
Decoding the oncogenic functions and translational potential of Twinfilin-1.
Chong ZX
J Pharmacol Exp Ther · 2026 Jun · PMID 42398162 · Publisher ↗
Twinfilin-1 (TWF1) is a cellular protein that binds actin, phosphoinositides, and capping protein. Although multiple studies have reported the tumor-regulatory role of TWF1, a comprehensive and critical review of these f...
Twinfilin-1 (TWF1) is a cellular protein that binds actin, phosphoinositides, and capping protein. Although multiple studies have reported the tumor-regulatory role of TWF1, a comprehensive and critical review of these findings remains unavailable. This review addresses this gap by consolidating current evidence on the tumor-modulatory functions of TWF1. The literature indicates that dysregulation of TWF1 or its actin-binding activity can promote carcinogenesis by influencing interleukin-11/signal transducer and activator of transcription 3, protein kinase B, epithelial-to-mesenchymal transition, or autophagy. The mechanisms by which TWF1 regulates tumorigenesis are tissue-dependent and vary across different tissues. At least 10 microRNAs, 2 long noncoding RNAs, and 1 circular RNA have been identified as interacting with TWF1, either directly or indirectly, to regulate its expression and tumor-controlling function. High TWF1 expression has been observed in at least 8 types of solid tumors, but not in liquid cancers, highlighting its potential as a diagnostic biomarker for solid tumors. Furthermore, its increased expression in solid tumors can help predict cancer patient prognosis. However, despite these findings, the translational potential of TWF1 requires further validation through in-depth mechanistic studies and large-scale clinical trials, as current evidence is primarily derived from bioinformatics analyses, preclinical studies, or small prospective cohorts. Once the tumor-promoting role of TWF1 is confirmed, future research should then evaluate its sensitivity and suitability as a biomarker or therapeutic target. SIGNIFICANCE STATEMENTS: Twinfilin-1 (TWF1) regulates various cellular processes that contribute to solid cancer cell proliferation, metastasis, and resistance to treatment. These functions suggest that TWF1 has translational potential as both a biomarker and a therapeutic target in cancer management.
Antiproliferative effects of HIV integrase strand transfer inhibitors in experimental models for cancer research: A narrative review.
Zanella I, Manenti M, Cesanelli F … +4 more , Codenotti S, Fanzani A, Castelli F, Quiros-Roldan E
J Pharmacol Exp Ther · 2026 Jun · PMID 42398161 · Publisher ↗
A growing body of literature suggests that integrase strand transfer inhibitors (INSTIs), a cornerstone of antiretroviral therapy for the treatment of HIV infection, seem to possess antiproliferative properties against s...
A growing body of literature suggests that integrase strand transfer inhibitors (INSTIs), a cornerstone of antiretroviral therapy for the treatment of HIV infection, seem to possess antiproliferative properties against some types of cancer and/or anti-invasion effects. Preclinical studies describe as INSTIs, including dolutegravir, raltegravir, cabotegravir, and elvitegravir and some 1,2,3-triazole derivatives, can inhibit the growth of various cancer cell lines and some of them seem to also have direct inhibitory effects on human endogenous retrovirus reactivation. This review comprehensively synthesizes and analyzes this evidence, detailing the proposed multimechanistic actions behind these effects, such as induction of DNA damage, inhibition of key oncogenic pathways, triggering of oxidative stress and diverse cell death modalities. All described compounds seem to have potential effects on cancerous cells, and these effects may be also independent from their antiretroviral activity, that is, may be separated from the mere effect on suppression of human endogenous retrovirus reactivation in cancerous cells. Although the type of target cancer, the mechanisms of action (ie, enzyme or protein inhibition, oxidative stress, DNA methylation, and DNA damage) or the ultimate effects (ie, cell proliferation, migration, or invasion) were different in most of the studies and sometimes inconsistent, all these studies suggest several potential targets of INSTIs that deserve further investigations. Although the incidence of many cancers is higher in people with HIV infection compared with the general population, the relative risk has been decreasing over time for many cancers. Further studies are then needed to assess the effects of INSTI therapies on malignancies in people living with HIV. SIGNIFICANCE STATEMENT: Currently, the effects of using integrase strand transfer inhibitors (INSTIs) on cancer development in people living with HIV are difficult to determine because of the multifactorial cause of cancer in these patients and the long period in which cancer manifests. This review examines the antiproliferative properties of INSTIs, describing the proposed mechanisms through which they may exert this effect in preclinical studies.
Modulation of morphine tolerance and dependence by pyrroloquinoline quinone in mice: Insights into mechanistic bridge from N-methyl-D-aspartate receptors-calcium/calmodulin-dependent protein kinase II signaling to oxidative neuroinflammation.
Nicola MA, Hefny FH, Morsy RMI … +3 more , Abdel-Maksoud FM, Gamea MG, Hamdy MM
J Pharmacol Exp Ther · 2026 Jun · PMID 42391961 · Publisher ↗
Morphine remains a cornerstone for managing nociceptive pain, yet its clinical utility is severely limited by the development of tolerance and physical dependence. This study investigated the potential of pyrroloquinolin...
Morphine remains a cornerstone for managing nociceptive pain, yet its clinical utility is severely limited by the development of tolerance and physical dependence. This study investigated the potential of pyrroloquinoline quinone (PQQ), a natural redox-active cofactor with antioxidant and anti-inflammatory properties, to mitigate these adverse effects in mice. Animals received morphine (5 mg/kg, i.p.) twice daily for 9 days. PQQ (5 mg/kg, i.p.) was administered either concurrently with morphine for 9 days or as a single dose on the final day. Results demonstrated that PQQ treatment significantly reduced the development of morphine tolerance, as measured by the hot plate test, and dependence through reduction of naloxone-precipitated withdrawal signs. Biochemically, PQQ decreased levels of key mediators involved in neuroplasticity and oxidative stress, including calcium/calmodulin-dependent protein kinase II, glutamate, tumor necrosis factor-α, and malondialdehyde, while increasing the antioxidant glutathione. Immunohistochemical analysis showed that PQQ reduced c-Fos protein expression in the brain. Furthermore, the docking analysis supported these findings and uncovered novel underexplored molecular targets, with alternative distinct binding modes and modulatory effects. PQQ displayed strong binding affinities for N-methyl-D-aspartate receptors at a previously unrecognized site, as well as for calcium/calmodulin-dependent protein kinase II, IκB kinase, and Kelch-like ECH-associated protein 1 proteins. These interactions suggest distinct modulatory effects on critical pathways involved in tolerance and dependence. In conclusion, PQQ effectively reduces morphine-induced tolerance and dependence through multifaceted mechanisms. Its efficacy, combined with its high safety profile as a natural compound, positions it as a promising therapeutic candidate for overcoming the significant challenges associated with long-term morphine use. SIGNIFICANCE STATEMENT: This study identifies the neuroprotective effect of PQQ against morphine tolerance and dependence, where PQQ affected many targets, with unique interaction sites and binding modes to N-methyl-D-aspartate receptors and calcium/calmodulin-dependent protein kinase II. By targeting relevant pathways, PQQ can be considered as a novel effective suppressor of morphine tolerance and dependence, and a safe natural compound that offers a multifaceted promising approach for this problem.
Aryl hydrocarbon receptor pharmacology-mechanisms, ligands, and therapeutic potential.
Bobrovs R, Olafsen NE, Åhrling SS … +1 more , Matthews J
Pharmacol Rev · 2026 Jun · PMID 42385421 · Publisher ↗
The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that has emerged as a key modulator of several physiological and pathological processes. Historically, AHR has been studied for its role as a...
The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that has emerged as a key modulator of several physiological and pathological processes. Historically, AHR has been studied for its role as a mediator of the toxic responses of environmental pollutants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin. Because of this, its potential as a therapeutic target was overlooked. AHR is now regarded as a multifunctional regulator of inflammation, immunity, barrier tissue integrity, metabolism, and cancer biology. AHR signaling is modulated by an array of structurally diverse endogenous, microbial, dietary, pharmaceutical, and xenobiotic ligands. AHR exhibits extensive crosstalk with many signaling pathways, which contributes to highly context-specific biological outcomes. Recent advances and enhanced interest in AHR pharmacology have accelerated the development of therapeutically relevant AHR ligands, including the clinically approved AHR agonist, tapinarof, for the treatment of psoriasis and atopic dermatitis, as well as emerging AHR antagonist strategies in cancer immunotherapy. Structural efforts have succeeded in providing valuable insight into ligand-AHR interactions that will further contribute to improved and rational design of AHR ligands. However, significant challenges remain, including AHR ligand promiscuity, complex negative feedback regulation, extensive signaling crosstalk, and long-term safety concerns. Here, we review the molecular mechanisms of AHR activation, its physiological and pathological functions, and the current advances of its therapeutic targeting. SIGNIFICANCE STATEMENT: The aryl hydrocarbon receptor (AHR) has emerged from its origins in toxicology to become a promising clinically relevant target for the treatment of dermatological, gastroenterological, and autoimmune diseases as well as cancer. This review summarizes the current knowledge of AHR pharmacology, including molecular signaling, endogenous and exogenous ligands, physiological and pathological functions, present and emerging therapeutic targeting strategies, as well as challenges that remain for translation into safe clinical therapies.
Improving drug delivery to mitigate cisplatin nephrotoxicity.
Cleveland KH
J Pharmacol Exp Ther · 2026 Jun · PMID 42385420 · Publisher ↗
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Sublethal stress from polypharmacy modulates scavenging function and fenestrations in mouse liver sinusoidal endothelial cells.
Gnanachandran K, Hovland DS, Pospíšil J … +4 more , Szafranska K, Mach J, Hilmer SN, McCourt PAG
J Pharmacol Exp Ther · 2026 Jun · PMID 42385419 · Publisher ↗
Polypharmacy, the concurrent use of multiple medications, is increasingly prevalent in older people and is associated with adverse outcomes such as falls, frailty, functional, and cognitive decline, and increased hospita...
Polypharmacy, the concurrent use of multiple medications, is increasingly prevalent in older people and is associated with adverse outcomes such as falls, frailty, functional, and cognitive decline, and increased hospitalization and mortality. The liver, as the primary site of metabolism, is exposed to varying drug concentrations during first pass metabolism, hepatic clearance and perfusion, potentially causing alterations in liver sinusoidal endothelial cells (LSEC). LSEC are specialized endothelial cells responsible for maintaining fenestrations-dynamic, transcellular pores that facilitate the exchange of substances between the blood and liver parenchyma. Disruption of fenestrations can compromise liver function, contributing to a variety of hepatic disorders. This study investigated the effects of 4 commonly prescribed drugs-metoprolol, citalopram, oxybutynin, and oxycodone-on LSEC function. We examined their impact on LSEC viability, endocytosis, and fenestration morphology at both systemic steady-state and first-pass concentrations, separately and in a polypharmacy cocktail to model clinical exposure. All treatments induced sublethal metabolic changes, but effects on LSEC functions were drug- and concentration-dependent. Citalopram and oxybutynin caused dose-dependent defenestration, whereas metoprolol and oxycodone produced mild, nondose-dependent effects. Endocytic activity was increased with oxybutynin, metoprolol, oxycodone, and the polypharmacy cocktail, whereas citalopram had no effect. The polypharmacy cocktail triggered synergistic defenestration at first-pass concentrations, but not at steady-state levels. These results highlight the concentration-dependent and combinatorial effects of polypharmacy on LSECs, emphasizing the need to consider endothelial responses in drug safety and pharmacokinetic assessments, particularly in patients exposed to multiple medications. SIGNIFICANCE STATEMENT: Polypharmacy is increasingly common, however, its effects on liver sinusoidal endothelial cells remain poorly understood. Using in vitro models, this study shows that drug combinations can induce sublethal functional and structural alterations in these cells, highlighting endothelial dysfunction as a potential early mechanism contributing to drug-induced liver impairment.
Purmorphamine mitigates 3-nitropropionic acid-induced neurodegeneration via enhancing the brain-derived neurotrophic factor/protein kinase B/glycogen synthase kinase-3β signaling and attenuation of oxidative/nitrosative stress, neuroinflammation, and apoptosis.
Habib MZ, Kamar SA, Mostafa MO … +10 more , Aboul-Ela YM, Rabei MR, Kamel MM, Abdelrahman SE, Salama AA, Elshaer MMA, Olama NK, Moussa N, Hadhoud RM, Elnahas EM
J Pharmacol Exp Ther · 2026 Jun · PMID 42385418 · Publisher ↗
Huntington disease (HD) is a progressive neurodegenerative condition marked by characteristic motor deficits, cognitive decline, and psychiatric disturbances. The mitochondrial toxin 3-nitropropionic acid (3-NP) reliably...
Huntington disease (HD) is a progressive neurodegenerative condition marked by characteristic motor deficits, cognitive decline, and psychiatric disturbances. The mitochondrial toxin 3-nitropropionic acid (3-NP) reliably replicates the HD pathological features by inducing selective striatal and cortical neurodegeneration. Increasing evidence indicates that activation of the Sonic Hedgehog (Shh) signaling could enhance neurotrophic and prosurvival signaling, particularly through modulation of the brain-derived neurotrophic factor (BDNF)/protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β) cascade. Via activation of the Shh pathway, purmorphamine (PUR)-the smoothened agonist-may offer a therapeutic benefit against HD-like pathology. However, its in vivo efficacy in 3-NP neurotoxicity remains unexplored. To examine this possibility, 48 male Wistar rats were assigned to control, PUR, 3-NP, and 3-NP/PUR groups and treated daily for 21 days. Behavioral performance was assessed using the open field, rotarod, novel object recognition, and Morris water maze (MWM) tests, whereas hippocampal, prefrontal, and striatal tissues were evaluated for Shh pathway gene expression, BDNF/Akt/GSK-3β signaling, oxidative/nitrosative stress markers, and histopathological alterations. PUR markedly improved 3-NP induced motor and cognitive deficits, alleviated the BDNF/Akt/GSK-3β signaling, and attenuated oxidative/nitrosative stress, neuroinflammation, and apoptosis. In conclusion, to the best of our knowledge, these findings provide the first evidence that purmorphamine affords significant neuroprotection against 3-NP induced neurodegeneration by activating Shh-dependent BDNF/Akt/GSK-3β signaling and mitigating the key pathological processes, highlighting its promise as a potential therapeutic agent for HD-related neuropathology. SIGNIFICANCE STATEMENT: This study provides the first in vivo evidence that purmorphamine, a Sonic Hedgehog pathway agonist, effectively mitigates 3-nitropropionic acid-induced neurodegeneration by restoring the brain-derived neurotrophic factor/protein kinase B/glycogen synthase kinase-3β signaling cascade. By addressing core pathological features such as motor deficits, cognitive decline, and neuroinflammation, these findings highlight the therapeutic potential of targeting the Sonic Hedgehog pathway as a multitarget strategy for managing Huntington disease-like neurodegenerative conditions.
Nanomedicine strategies targeting STAT3 in cancer: From tumor suppression to microenvironment modulation.
Chama Z, Yousif AY, Patel PN … +7 more , Singh G, Arora V, Baig MR, Abohassan M, Nayak PP, Iqbal MS, Basunduwah TS
J Pharmacol Exp Ther · 2026 May · PMID 42361451 · Publisher ↗
Signal transducer and activator of transcription 3 (STAT3) is a central oncogenic signaling hub that regulates tumor proliferation, survival, metastasis, angiogenesis, immune evasion, and therapeutic resistance across mu...
Signal transducer and activator of transcription 3 (STAT3) is a central oncogenic signaling hub that regulates tumor proliferation, survival, metastasis, angiogenesis, immune evasion, and therapeutic resistance across multiple cancer types. Persistent STAT3 activation, driven by aberrant cytokine signaling, growth factor receptors, and oncogenic kinases, promotes transcriptional programs that support malignant progression and suppress antitumor immunity. Despite its recognized role as an attractive therapeutic target, direct pharmacological inhibition of STAT3 has been challenging because of poor bioavailability, off-target toxicity, and limited tumor specificity of conventional inhibitors. In recent years, nanocarrier-based drug delivery systems have emerged as promising platforms to overcome these limitations by enabling targeted, protected, and sustained STAT3 inhibition. Diverse nanocarrier modalities, including polymeric nanoparticles, lipid-based systems, inorganic nanomaterials, and hybrid or covalent-organic frameworks, have been developed to deliver STAT3 inhibitors, small interfering RNA, short hairpin RNA, and plasmid DNA with improved therapeutic indices. These platforms not only enhance intracellular delivery and tumor accumulation but also enable combination strategies that simultaneously modulate STAT3 and complementary oncogenic pathways. This review provides a comprehensive mechanistic overview of STAT3 signaling in cancer and critically evaluates recent advances in nanocarrier-mediated STAT3 inhibition. Furthermore, it discusses key challenges, including immune context dependency, adaptive resistance, safety concerns, and translational barriers, while highlighting future directions for precision nanomedicine. Collectively, this work underscores the potential of nanotechnology-enabled STAT3 targeting as a next-generation anticancer strategy. SIGNIFICANCE STATEMENT: Persistent activation of signal transducer and activator of transcription 3 represents a critical driver of tumor progression and therapeutic resistance across diverse malignancies, yet its direct pharmacological targeting has remained limited by suboptimal drug properties and systemic toxicity. This review highlights how nanocarrier-based delivery platforms redefine signal transducer and activator of transcription 3 inhibition by improving tumor specificity, intracellular bioavailability, and combinatorial therapeutic potential.
Mast cell proteases and their significance in physiology, pathology, and therapeutic approaches.
Derakhshani A, Mahajan L, Lesack K … +7 more , Saranjam N, Khazaie K, Pejler G, Krawetz R, Edgington-Mitchell LE, Maun HR, Dufour A
Pharmacol Rev · 2026 May · PMID 42361439 · Publisher ↗
Mast cells (MCs) are versatile, multifunctional immune cells with broad roles in physiological homeostasis and pathogenic processes. MCs are found in most tissues, including skin, lungs, intestines, and peritoneum, and t...
Mast cells (MCs) are versatile, multifunctional immune cells with broad roles in physiological homeostasis and pathogenic processes. MCs are found in most tissues, including skin, lungs, intestines, and peritoneum, and they vary in numbers, types, and biological functions. MCs are implicated in host defense against various pathogens, including bacteria, viruses, and fungi. Additionally, MCs are crucial in protecting against toxins, including those present in venoms from multiple species, such as honeybees, snakes, scorpions, and lizards. Although MCs play an essential role in host defense, they are mostly known for their detrimental actions in allergic reactions, such as asthma, food allergy, anaphylaxis, mastocytosis, and various inflammatory skin conditions. Under such conditions, MCs are activated (via IgE-mediated or other mechanisms) and release a range of potent proinflammatory mediators, including tumor necrosis factor α. In addition to cytokines, they are major producers of histamine and various proteases, including chymase, tryptase, and carboxypeptidase A3. As a result, these mediators contribute to the pathological manifestations associated with inflammatory conditions and other disorders. This review focuses mainly on the biological role of MCs and their proteases, with a focus on chymase and tryptase, as well as their inhibitors as candidate therapies for MC-driven diseases. SIGNIFICANCE STATEMENT: Mast cells (MCs) and their proteases are central regulators of tissue homeostasis, barrier defense, and inflammation across multiple organs, but are also associated with numerous diseases. Ongoing research has shown that the function of MCs is highly dependent on their tissue location, where the local tissue environment shapes their phenotype, protease expression, and, consequently, their biological functions. However, further investigation is required to more precisely understand the physiological conditions governing the transition of MCs from maintaining tissue homeostasis to acquiring pathogenic functions, particularly with respect to their protease-dependent activities. By profiling MC heterogeneity using multiomics approaches to map protease-driven signaling networks, it will be possible to gain deeper insight into their functional roles and establish a conceptual framework to guide the development of next-generation, mechanism-based therapeutics that selectively modulate MC activity in human diseases.
Inflammasome formation and interleukin-1β secretion are reduced in peripheral blood monocytes from HIV+ cannabis users.
Finn BM, Sermet S, Crawford RB … +2 more , Gulick P, Kaminski NE
J Pharmacol Exp Ther · 2026 May · PMID 42320431 · Publisher ↗
Chronic systemic inflammation remains a defining feature of human immunodeficiency virus (HIV) infection, partly driven by the translocation of microbial-derived products, including toll-like receptor 4 agonist lipopolys...
Chronic systemic inflammation remains a defining feature of human immunodeficiency virus (HIV) infection, partly driven by the translocation of microbial-derived products, including toll-like receptor 4 agonist lipopolysaccharide, from the gut, which is a well established HIV reservoir. These products activate peripheral blood monocytes, leading to the secretion of proinflammatory cytokines, particularly interleukin-1β (IL-1β), which exacerbates systemic inflammation. Cannabis and its bioactive constituents, Δ-tetrahydrocannabinol (THC) and cannabidiol, exhibit immune-modulating properties, yet their effects on innate immune pathways in HIV remain poorly defined. Here, we investigated the impact of cannabis use and individual cannabinoids, THC and cannabidiol, on toll-like receptor 4-induced ASC-incorporating inflammasome activation, IL-1β secretion, and caspase-1 activity in monocytes derived from HIV-negative and HIV-positive individuals. We hypothesized that cannabis use and cannabinoid treatment impair inflammasome-mediated inflammation in HIV+ individuals, potentially mitigating IL-1β-driven immune activation. Our results show that inflammasome formation was reduced in both HIV+ marijuana (cannabis use status, MJ)- and HIV+MJ+ (MJ: cannabis use) derived monocytes compared with HIV- derived monocytes. Despite this, HIV+MJ- monocytes secreted more IL-1β than HIV- monocytes, whereas HIV+MJ+ monocytes secreted IL-1β at levels comparable to those of HIV- cells. Both THC and cannabidiol suppressed inflammasome formation and IL-1β secretion in a concentration-dependent manner, with THC producing a greater magnitude of reduction in caspase-1 activity in HIV- monocytes. Cannabis use by HIV+ individuals lowered IL-1β secretion by peripheral blood monocytes compared with that of non-cannabis-using HIV+ donors, implicating an inhibitory role in immune activation. These findings support the therapeutic potential of cannabinoids in reducing HIV-associated systemic inflammation. SIGNIFICANCE STATEMENT: Cannabis use reduced inflammasome activation and interleukin-1β (IL-1β) release in human immunodeficiency virus (HIV)+ monocytes. HIV+ cannabis users showed IL-1β levels comparable to HIV- individuals, whereas HIV+ cannabis nonusers displayed elevated levels of IL-1β secretion. The combination of reduced ASC-incorporating inflammasome formation but elevated IL-1β in HIV+ nonusers suggests involvement of noncanonical IL-1β maturation pathways.
Translational medications development for methamphetamine use disorder: A systematic review of preclinical, human laboratory, and clinical research.
Johansen AN, Smith MA, Stoops WW
Pharmacol Rev · 2026 May · PMID 42314583 · Publisher ↗
The prevalence of methamphetamine use disorder (MUD) remains discouragingly high. Relatively few clinical trials have focused on identifying new pharmacotherapies for MUD, and no medications have received US Food and Dru...
The prevalence of methamphetamine use disorder (MUD) remains discouragingly high. Relatively few clinical trials have focused on identifying new pharmacotherapies for MUD, and no medications have received US Food and Drug Administration approval. The lack of available pharmacotherapies may be due to failure to follow a rational, translational medications development pipeline progressing from preclinical work to the human laboratory to clinical trials. Our review thus has 2 primary goals: to (1) assess the scope of the literature evaluating candidate medications for MUD and (2) identify drugs screened to treat MUD across research domains, analyzing concordance across contexts. We identified 36 randomized, double-blind, placebo-controlled clinical trials that evaluated 25 candidate medications for MUD. Only 5 of these putative treatments (aripiprazole, bupropion, d-amphetamine, modafinil, and naltrexone) had also been evaluated in human laboratory and preclinical laboratory contexts. Overall, most studies showed no change in methamphetamine use (ie, no effects of treatment) across contexts. Although literature from these contexts imply a high degree of negative predictive validity, we encountered limitations at each level of analysis that prevented us from fully confirming concordance (eg, lack of positive predictive validity). These trends and limitations highlight the extent to which methamphetamine treatments are under-researched relative to other substance use disorders, such as cocaine use disorder. To address this gap in the literature, we advocate for future work that identifies therapeutic targets and, by consequence, classes of medications (repurposed or novel) to treat MUD. We conclude this review with additional comments about future research directions and treatment considerations. SIGNIFICANCE STATEMENT: Investment in methamphetamine use disorder (MUD) medications development remains poor. To date, no pharmacotherapies have received US Food and Drug Administration (FDA) approval to treat MUD, and few candidate medications have been systematically evaluated using a translational medications development pipeline (eg, beginning with preclinical research and progressing to human laboratory research and clinical trials). Adhering to the translational pipeline while incorporating new FDA guidance, such as evaluating nonabstinence outcomes, may be useful in facilitating MUD medications development.
Arginine vasopressin: A promising therapeutic target for metabolic syndrome.
Elsamad G, Alotaibi MI, Echtay KS … +2 more , Murphy D, Greenwood MP
J Pharmacol Exp Ther · 2026 May · PMID 42314465 · Publisher ↗
Globally, the prevalence of metabolic syndrome (MetS) among adults is around 20%-25%. MetS is associated with an increased risk of cardiovascular morbidity and mortality. The pathogenesis of MetS is multifactorial, with...
Globally, the prevalence of metabolic syndrome (MetS) among adults is around 20%-25%. MetS is associated with an increased risk of cardiovascular morbidity and mortality. The pathogenesis of MetS is multifactorial, with no single factor being an obvious target for treatment. Rather, complex genetic and environmental factors result in visceral obesity, insulin resistance, hyperglycemia, dyslipidemia, and hypertension. A growing body of epidemiological evidence is indicative of an association between arginine vasopressin (AVP) and MetS and its components. Indeed, the clinical marker of AVP, copeptin, has been proposed as a biomarker of MetS. Moreover, experimental studies support a causal relationship between AVP and MetS. This suggests that AVP should be considered in the management of MetS. However, there is lack of clinical trials. This review summarizes the accumulating literature describing the roles of AVP in the pathophysiology of MetS and discusses its role as a possible therapeutic target. SIGNIFICANCE STATEMENT: This review highlights the emerging role of arginine vasopressin (AVP) as a central regulator linking hydration, energy balance, and cardiometabolic risk in metabolic syndrome. By integrating mechanistic, epidemiological, and therapeutic evidence, AVP signaling was identified as a promising yet complex target in the prevention and management of metabolic syndrome.
Structure-based prediction of muscarinic M1/M3 receptor antagonist activity: Curated dataset and scaffold-aware evaluation.
Enokiya T, Yamaguchi T
J Pharmacol Exp Ther · 2026 May · PMID 42308581 · Publisher ↗
Aspiration pneumonia and delirium are clinically relevant adverse outcomes that can be influenced by anticholinergic drug effects, but existing burden scales do not explicitly capture receptor-subtype differences or prov...
Aspiration pneumonia and delirium are clinically relevant adverse outcomes that can be influenced by anticholinergic drug effects, but existing burden scales do not explicitly capture receptor-subtype differences or provide continuous compound-level estimates from chemical structure. We developed structure-based models to predict muscarinic M1/M3 receptor antagonist activity using curated data from the ChEMBL bioactivity database. Activity records for human cholinergic receptor muscarinic subtypes 1-5 (CHRM1-CHRM5) were retrieved, assay-level curation was performed, and a functional antagonist core dataset was constructed for CHRM1 and CHRM3. After removal of compounds without observed M1 or M3 labels, the resulting dataset comprised 553 compounds and was divided by Bemis-Murcko scaffolds into training, validation, and test sets (442, 56, and 55). Candidate models included extended-connectivity fingerprint with radius 2 and 2048 bits-based machine learning models, single-task graph isomorphism networks, auxiliary pretraining using CHRM1/CHRM3 binding data, and late-fusion models combining extended-connectivity fingerprint with radius 2 and 2048 bits with graph neural network embeddings. Within the fixed scaffold-split exploratory model-comparison analysis, candidate models were compared by considering the overall pattern of validation-set performance together with consistency of fixed scaffold-split test-set behavior. In the fixed scaffold-split exploratory model-comparison analysis, different retained model configurations were identified for M1 and M3 within the common set of evaluated candidate model families. For M1, the retained late-fusion LightGBM model, a gradient boosting machine (GBM) implementation, showed a fixed scaffold-split test area under the receiver operating characteristic curve of 0.809, area under the precision-recall curve of 0.910, Matthews correlation coefficient of 0.426, and balanced accuracy of 0.708. For M3, the retained extended-connectivity fingerprint with radius 2 and 2048 bits + LightGBM model showed a fixed scaffold-split test area under the receiver operating characteristic curve of 0.944, area under the precision-recall curve of 0.976, Matthews correlation coefficient of 0.766, and balanced accuracy of 0.833. These findings indicate that structure-based models can capture subtype-dependent prediction patterns for curated in vitro M1/M3 antagonist labels under scaffold-aware internal evaluation. The representative compound analyses should be interpreted as illustrative demonstrations of model behavior rather than external validation. Further validation using independent functional antagonist datasets will be required to establish generalizability to broader chemical space or translational applicability. SIGNIFICANCE STATEMENT: Using a curated CHRM1/CHRM3 functional antagonist dataset and scaffold-aware internal evaluation, this study modeled binary in vitro muscarinic M1/M3 antagonist labels from chemical structure. Within this exploratory framework, different retained model configurations were identified for M1 and M3. The representative compound analyses provide illustrative, hypothesis-generating subtype-level profiling, but external validation will be required before generalizability or translational applicability can be established.
DSP-2342, a novel 5-hydroxytryptamine 2A/7 receptor antagonist, has therapeutic potential for behavioral and psychological symptoms of dementia.
Hatakama H, Sugao K, Kassai M … +10 more , Miyauchi M, Baba S, Takeda Y, Miyazaki K, Yamada K, Niu M, Natsutani I, Saito K, Nishikawa H, Kato T
J Pharmacol Exp Ther · 2026 May · PMID 42302487 · Publisher ↗
In an aging society, behavioral and psychological symptoms of dementia (BPSD) have emerged as a major public health concern. BPSD includes diverse symptoms such as psychosis, anxiety, and agitation/aggression. Although a...
In an aging society, behavioral and psychological symptoms of dementia (BPSD) have emerged as a major public health concern. BPSD includes diverse symptoms such as psychosis, anxiety, and agitation/aggression. Although antipsychotics are widely used to manage BPSD, their use is limited because of safety concerns, particularly extrapyramidal symptoms associated with dopamine D receptor antagonism. Therefore, there is a need for antipsychotic drugs that are effective without relying heavily on D receptor blockade. Here, we report DSP-2342, a novel selective 5-hydroxytryptamine 2A/7 (5-HT/5-HT) receptor antagonist, which exhibits very low affinity for D receptors. A mouse-behavior phenotyping platform predicted that DSP-2342 possesses antipsychotic, anxiolytic, mood-stabilizing, and antidepressant signatures. Consistent with these predictions, DSP-2342 suppressed phencyclidine-induced hyperlocomotion in mice, reduced freezing in rat contextual fear conditioning test. DSP-2342 also attenuated aggressive behavior in resident-intruder test in Alzheimer disease model mice. Furthermore, DSP-2342 restored cognitive performance in another Alzheimer disease model mice, as assessed by the novel object recognition test. To explore the underlying mechanism, a rat microdialysis study showed that DSP-2342 increased extracellular levels of noradrenaline, dopamine, and glutamate in the medial prefrontal cortex. The whole-brain c-Fos mapping revealed that DSP-2342 activated multiple brain regions and demonstrated a synergistic integration of 5-HT and 5-HT receptor antagonism, potentially underlying its distinctive pharmacological profile. Collectively, these findings suggest that the broad pharmacological effects of DSP-2342 through dual antagonism of 5-HT and 5-HT receptors may enable the management of diverse BPSD while maintaining a favorable safety profile. SIGNIFICANCE STATEMENT: DSP-2342, a novel 5-hydroxytryptamine 2A/7 antagonist, shows preclinical efficacy across behavioral and psychological symptoms of dementia (BPSD)-including psychosis, anxiety, and agitation-while improving cognition. Unlike typical antipsychotics, it has very low dopamine D2 affinity, suggesting lower motor side-effect risk and a safer profile for BPSD.
Reharnessing the therapeutic potential of gallium-based compounds in oncology: From the laboratory to the clinic.
Chitambar CR, Zoss CJ, Al-Gizawiy MM … +2 more , Schmainda KM, Connelly JM
Pharmacol Rev · 2026 May · PMID 42302450 · Publisher ↗
Despite advances in the treatment of certain malignancies, it is anticipated that there will be 626,140 cancer deaths in the United States in 2026. Thus, there remains a great need to develop new antineoplastic drugs wit...
Despite advances in the treatment of certain malignancies, it is anticipated that there will be 626,140 cancer deaths in the United States in 2026. Thus, there remains a great need to develop new antineoplastic drugs with unique mechanisms of action distinct from those of existing drugs. Also relevant is revisiting agents that showed promise in early research. Some of these agents struggled to advance for reasons including an incomplete understanding of their molecular targets and insufficient commitment to pursuing their development. Gallium compounds initially gained attention as radiogallium Ga complexes for tumor imaging in cancer patients, but were later found in clinical trials of nonradioactive gallium nitrate to have antineoplastic activity against lymphoma and urothelial malignancies. Coincident with this, tris(8-quinolinolato)gallium(III) has been shown to be active against solid tumors and has now re-emerged in clinical trials as oral AP-002. Subsequent investigations showed that gallium exerts its antineoplastic activity by disrupting iron-dependent processes essential to cancer development and growth. Recent preclinical studies of oral gallium maltolate demonstrated its activity against glioblastoma, an aggressive brain tumor, leading to a Food and Drug Administration-approved phase 1 clinical trial for patients with relapsed glioblastoma. This review will focus on the evolution of gallium compounds in malignancy; advances in our knowledge of their mechanisms of action and tumor resistance; their interactions with cellular iron homeostasis and other targets; the past and present preclinical and clinical experience with gallium compounds; and the development of promising gallium-based agents on the horizon. SIGNIFICANCE STATEMENT: Gallium compounds showed anticancer activity in early clinical studies; however, an incomplete understanding of their mechanisms of action and resistance hindered the selection of patients most likely to benefit from treatment. Herein, we review the development of gallium compounds from early preclinical research to clinical trials for cancer. Recent insights into gallium's molecular targets have advanced the translation of gallium from the laboratory to a clinical trial of oral gallium maltolate in glioblastoma. Newer gallium compounds are being developed; their advancement is eagerly anticipated.
Pharmacogenomics of antibacterial and antiviral therapies: Clinical actionability, evidence gaps, and future directions.
Smatti MK, Jan Z, Yassine HM
Pharmacol Rev · 2026 Apr · PMID 42296571 · Publisher ↗
Anti-infective drugs have profoundly transformed the history of medicine. Yet, with the presence of approximately 4.1-5 million interindividual genomic variants in human genome, patients are expected not to respond equal...
Anti-infective drugs have profoundly transformed the history of medicine. Yet, with the presence of approximately 4.1-5 million interindividual genomic variants in human genome, patients are expected not to respond equally to the same anti-infective drug. This genetic variability, together with nongenetic factors, influences therapeutic outcomes and contributes to drug-induced adverse events in predisposed individuals. Historically, the identification of HLA-B∗57:01 as a predictor of abacavir hypersensitivity in patients with HIV represented the first successful clinical application of pharmacogenomics (PGx) in infectious diseases. Since then, the field has continued to evolve, as evidenced by the discovery of multiple clinically relevant gene-drug pairs, primarily related to immune responses, drug metabolism, and drug transport pathways. The evidence accumulated to date has established a number of mandatory (HLA-B∗57:01-abacavir) and actionable (MT-RNR1-aminoglycosides, CYP2B6-efavirenz, G6PD-nitrofurantoin, G6PD-nalidixic acid, and G6PD-dapsone) gene-drug pairs, whereas most other associations remain informative or exploratory without current guideline-based prescribing recommendations. Despite this progress, robust PGx evidence remains predominantly focused on antiretrovirals, anti-hepatitis C virus, and selected antimicrobial drug classes, such as β-lactams, aminoglycosides, sulfonamides, and antituberculosis drugs. For many other anti-infective agents, current evidence suggests that host genetic variation may have a limited impact on drug efficacy or safety, or that existing studies remain insufficiently powered or replicated to support clinical translation. The narrow ancestral diversity in PGx studies and clinical trials has also restricted the breadth of the knowledge gained and, consequently, the development of inclusive guidelines. This review summarizes the current PGx landscape of antibacterial and antiviral drugs and highlights key challenges and opportunities to improve clinical actionability. Greater inclusion of previously underrepresented populations, coupled with integrative multiomics approaches powered by artificial intelligence and machine learning, could accelerate PGx biomarker identification, validation, and integration into personalized patient care. SIGNIFICANCE STATEMENT: Rapid and effective deployment of anti-infective drugs requires incorporating knowledge of host genetic determinants of drug effectiveness or adverse events, the latter of which is a leading cause of death. The evolution of data science, driven by available genomic data, represents an unprecedented opportunity to accelerate pharmacogenomics discovery in infectious diseases. If acquired at a population level and integrated into medical records, pharmacogenomics data can guide the prescription and/or dosing of anti-infective drugs, shifting infectious disease management toward personalized care.
Destabilization of TIP60-PXR complex by rifampicin impairs wound-induced cell migration.
Gupta E, Gupta A
J Pharmacol Exp Ther · 2026 May · PMID 42287767 · Publisher ↗
The Tat interactive protein 60 (TIP60)-pregnane and xenobiotic receptor (PXR) complex plays a pivotal role in regulating cell migration during wound healing, and disruption of this complex can impair this function. Becau...
The Tat interactive protein 60 (TIP60)-pregnane and xenobiotic receptor (PXR) complex plays a pivotal role in regulating cell migration during wound healing, and disruption of this complex can impair this function. Because PXR is a ligand-activated transcription factor responsive to structurally diverse compounds, we investigated how different ligands can influence the structural and functional integrity of the TIP60-PXR complex. Using an integrated computational approach, we assessed how various PXR ligands affect complex stability and among them, rifampicin, an established PXR activator, emerged as a notable disruptor. Although most ligands exhibited comparable docking energies in both PXR alone and the TIP60-PXR complex, rifampicin showed a significantly higher binding energy when docked with the complex, suggesting destabilization. Molecular dynamics simulations revealed that rifampicin disrupts key interface residues, with significant root mean square deviation fluctuations and a failure to stabilize the complex. Molecular mechanics Poisson-Boltzmann surface area binding free energy calculations further confirmed rifampicin's destabilizing effect. To validate these findings in a cellular context, we conducted live-cell imaging and coimmunoprecipitation assays. Rifampicin treatment drastically reduced the intracellular colocalization and physical interaction between TIP60 and PXR, thereby significantly compromising their ability to support wound-induced cell migration. This was evident across multiple cell lines, correlating with PXR expression levels. Our findings establish a direct mechanistic link between ligand-induced structural changes in PXR and the functional impairment of the TIP60-PXR complex. This study provides a critical platform for understanding how small molecules modulate coregulator interactions and offers new insights for designing targeted therapeutics aimed at enhancing tissue repair. SIGNIFICANCE STATEMENT: This study identifies ligand-dependent disruption of the TIP60-pregnane and xenobiotic receptor (PXR) complex as a critical regulatory mechanism controlling wound-induced cell migration. By combining computational modeling with cellular validation, it reveals that rifampicin uniquely destabilizes the TIP60-PXR interaction despite being a known PXR activator. These findings uncover how small molecules can selectively modulate coregulator complexes, linking ligand-induced structural changes to impaired tissue repair. The work provides mechanistic insight with important implications for drug safety and regenerative therapeutic design.
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