Pharmacological Reviews[JOURNAL]
Sun
200 papers
Mitochondrial metabolism as a pharmacological target for cancer therapeutics.
Yu Y, Ding W, Liu S … +3 more , Glorieux C, Liu P, Huang P
Pharmacol Rev · 2026 Apr · PMID 42208129 · Publisher ↗
Mitochondria are essential cellular organelles that were first identified in the mid-19th century. Despite more than 150 years of research and the accumulation of vast wealth of knowledge on mitochondrial structure and f...
Mitochondria are essential cellular organelles that were first identified in the mid-19th century. Despite more than 150 years of research and the accumulation of vast wealth of knowledge on mitochondrial structure and functions, new breakthroughs are still being made in recent years in key areas of mitochondrial biology. In the field of cancer research, major progress includes the elucidation of the role of mitochondria in cancer metabolic reprogramming, the discovery of signaling pathways in the crosstalk between mitochondria and the nucleus, the revelation of significant mitochondrial impact on tumor microenvironment and immune cells, the realization of the intriguing interplay between gut microbiota and cancer metabolism, the identification of molecular targets in mitochondria and the related pathways, and the development of mitochondria-targeted drugs such as mitocans for cancer treatment. This new progress underscores the essential role of mitochondria as multifaceted regulators of cancer metabolism, signal transduction, and cell survival, and as key pharmacological targets. This article will provide an up-to-date review of these important areas. The implications of these new research advances in cancer pharmacology and therapeutics will be explored, and interesting concepts that provide alternative theories for bioenergetics will also be discussed. SIGNIFICANCE STATEMENT: As a central hub for cellular energy production and biomolecule metabolism, mitochondria play essential roles in regulating metabolic and redox homeostasis, significantly affecting cell proliferation, survival, and sensitivity to pharmacological agents. Dysfunction of mitochondria in cancer cells alters these vital processes and affects tumor growth and therapeutic responses. Thus, a comprehensive understanding of mitochondrial alterations, the underlying regulatory mechanisms, and their impacts on pharmacological targets is pivotal for developing more effective therapeutic agents with significant clinical implications in cancer treatment.
Mechanistic insights into postbiotic-induced myelopoiesis and immune recovery after chemotherapy.
Gutiérrez F, Vasile B, Ivir M … +2 more , Alvarez S, Salva S
J Pharmacol Exp Ther · 2026 Jun · PMID 42202702 · Publisher ↗
Many attempts have been made to identify safer immunomodulatory agents that enhance the immune response and reduce the frequency and severity of infections in at-risk populations. Our previous studies have shown that Lac...
Many attempts have been made to identify safer immunomodulatory agents that enhance the immune response and reduce the frequency and severity of infections in at-risk populations. Our previous studies have shown that Lacticaseibacillus rhamnosus CRL1505 and its postbiotics, peptidoglycan (PG1505) and cell wall (CW1505), can improve bone marrow myelopoiesis and protect mice undergoing chemotherapy against respiratory pathogens. However, the underlying mechanisms remain poorly understood. In this study, we explored both direct and indirect mechanisms using ex vivo and in vitro approaches. Oral administration of the CRL1505 strain or its cell wall significantly increased bone marrow clonogenic activity and serum G-CSF levels, as well as the percentages of myeloid progenitors (MPP and GMP) and mature cells (neutrophils and monocytes). In vitro, conditioned media from macrophages and fibroblasts stimulated with postbiotics enhanced hematopoietic activity, whereas splenocyte-conditioned media exhibited inhibitory effects on clonogenicity. Direct stimulation of bone marrow cells with the CRL1505 strain increased LSK, MPP, and GMP populations and upregulated TLR2 expression, although clonogenic activity was reduced. Interestingly, CW1505 showed a strong stimulatory effect while PG1505 elicited immune effects more closely resembling those induced by Lacticaseibacillus rhamnosus CRL1505. These findings provide new insight into the cellular and molecular mechanisms underlying the myelopoiesis-enhancing effects of novel, safe postbiotic products. They also support the therapeutic potential of these compounds for promoting immune recovery in immunocompromised patients, such as those undergoing chemotherapy. SIGNIFICANCE STATEMENT: This study demonstrates that Lacticaseibacillus rhamnosus CRL1505 and its postbiotics enhance bone marrow myelopoiesis and G-CSF production in chemotherapy-treated mice. By revealing both direct and macrophage-mediated mechanisms that regulate hematopoiesis, our findings provide new insights into how postbiotics promote immune reconstitution. The strong myelopoiesis-stimulating activity of CW1505 further supports the potential of safe, postbiotic-based immunomodulators to improve immune recovery and reduce the infection risk during chemotherapy.
An antidote in arms: A monoclonal antibody intervention to reverse fentanyl-induced respiratory apnea.
Garcia EJ, Estrella LD, McCool S … +1 more , Chivero ET
J Pharmacol Exp Ther · 2026 Jun · PMID 42190316 · Publisher ↗
Abstract loading — click title to view on PubMed.
Pseudouridine synthase 7 as a context-specific therapeutic target in cancer.
Abundiz-Yañez K, Córdova-Bahena L, Salinas-Jazmín N … +2 more , Trejo-León AJ, Velasco-Velázquez MA
J Pharmacol Exp Ther · 2026 Jun · PMID 42190315 · Publisher ↗
Human pseudouridine synthase 7 (PUS7) catalyzes the isomerization of uridine to pseudouridine in RNA substrates. Although its catalytic region has been characterized, further studies are needed to clarify the mechanisms...
Human pseudouridine synthase 7 (PUS7) catalyzes the isomerization of uridine to pseudouridine in RNA substrates. Although its catalytic region has been characterized, further studies are needed to clarify the mechanisms underlying its substrate recognition and specificity. PUS7 promotes tumor progression in glioblastoma, pancreatic adenocarcinoma, neuroblastoma, hepatocellular carcinoma, and colorectal cancer by altering RNA stability, translational fidelity, and splicing, ultimately regulating key oncogenic processes such as cell proliferation, self-renewal, metabolic reprogramming, and stress responses. Additionally, PUS7 can promote tumor progression through noncatalytic mechanisms, as observed in colorectal cancer, where it forms protein-protein complexes that activate oncogenic signaling pathways. Conversely, PUS7 exhibits tumor-suppressive functions in gastric carcinoma and papillary thyroid carcinoma by targeting mRNAs and miRNAs that regulate gene expression linked to reduced tumor aggressiveness. These findings indicate that PUS7 may represent a context-dependent therapeutic target and underscore the need for further research to clarify the molecular basis of its effects in cancer. Such knowledge may guide the development of new therapeutic strategies for PUS7-driven tumors. SIGNIFICANCE STATEMENT: Recent studies reveal that dysregulated pseudouridine synthase activity contributes to the progression of malignancies such as glioblastoma, pancreatic adenocarcinoma, neuroblastoma, colorectal cancer, and hepatocellular carcinoma. Here, we review the pseudouridine synthase's structure-function relationships and context-specific activities. The evidence discussed will help the development of selective therapeutic strategies targeting RNA modification pathways.
Synergistic immunomodulatory combinations induce robust human tolerogenic dendritic cells for antigen-specific regulatory T cell generation.
Jia S, Mell J, Deak P
J Pharmacol Exp Ther · 2026 Jun · PMID 42184694 · Publisher ↗
Restoring antigen-specific immune tolerance remains a central challenge in the treatment of autoimmune diseases, as conventional immunosuppressive therapies lack specificity and can compromise protective immunity. Tolero...
Restoring antigen-specific immune tolerance remains a central challenge in the treatment of autoimmune diseases, as conventional immunosuppressive therapies lack specificity and can compromise protective immunity. Tolerogenic dendritic cell (tolDC) therapies offer a promising strategy for inducing durable, antigen-specific regulatory T cell (Treg) responses, but current methods for generating tolDCs are limited by poor longevity and Treg generative capacity. This study evaluates the clinical potential of Push/Pull Immunomodulation (PPI), a novel combinatorial approach identified through high-throughput molecular screening, in human monocyte-derived dendritic cells (moDCs). The phenotype, cytokine profile, and longevity of PPI-treated moDCs were benchmarked against conventional tolDC induction agents. Functional assays assessed the capacity of PPI-tolDCs to induce antigen-specific Tregs. PPI-treated moDCs exhibited increased expression of tolerogenic markers (interleukin-10, programmed cell death receptor ligand 1, and B- and T-lymphocyte attenuator), enhanced in vitro longevity, and a unique transcriptomic signature characterized by upregulation of IDO1, IDO2, and T cell-sustaining cytokines. Notably, PPI9 induced robust, antigen-specific Treg responses, suggesting the potential for long-term tolerance induction. Although transient tumor necrosis factor-α release and moderate upregulation of CD40 and CD86 were observed, these did not impair Treg generation, indicating that PPI-tolDCs overcome key barriers associated with conventional tolDC therapies. PPI enables the generation of stable, long-lived human tolDCs with superior capacity to induce antigen-specific Tregs. Ongoing studies will further explore the translational potential of PPI-tolDCs for clinical applications in autoimmunity and transplantation. SIGNIFICANCE STATEMENT: This study validates a novel molecular combination to generate tolerogenic dendritic cells with primary human cells. These tolerogenic dendritic cells have potential use as a cell therapy for autoimmune diseases and transplantation.
Integrated network pharmacology and Mendelian randomization analysis to elucidate potential mechanisms of curcumin and resveratrol in myocardial infarction treatment.
Zha C, Weng M, Xu C … +5 more , Yuan Y, He Y, Qi Y, Shi P, Shen X
J Pharmacol Exp Ther · 2026 Jun · PMID 42173079 · Publisher ↗
Myocardial infarction (MI) is a major global health burden with limited restorative therapies. Natural compounds such as curcumin and resveratrol offer potential as adjunctive treatments. To elucidate their molecular tar...
Myocardial infarction (MI) is a major global health burden with limited restorative therapies. Natural compounds such as curcumin and resveratrol offer potential as adjunctive treatments. To elucidate their molecular targets and mechanisms in MI using integrated network pharmacology and summary-data-based Mendelian randomization (SMR). Potential targets of curcumin, resveratrol, and MI-related genes were retrieved from multiple databases. SMR and colocalization analyses using genome-wide association study (FinnGen R12, Million Veteran Program) and expression/protein quantitative trait loci (eQTLGen, Fenland, UK Biobank Pharma Proteomics Project, and deCODE), inferred causal links between target gene/protein expression and MI risk. Protein-protein interaction networks were analyzed for hub genes and drug-target-disease networks were constructed. Gene Ontology/Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed. Molecular docking assessed compound-target binding. SMR analyses with subsequent validation in Million Veteran Program cohort identified 47 core targets associated with MI and potentially modulated by curcumin and/or resveratrol, exhibiting robust, genetically supported causal associations with MI risk. Further SMR, colocalization, and validation pinpointed key genes such as fibronectin 1 (FN1) and RELA (nuclear factor-κB p65 subunit) with strong MI risk associations and modulation by both compounds. Protein-protein interaction analysis identified FN1, RELA, poly(ADP-ribose) polymerase 1, Sirtuin 1, and tumor protein p53 as hub genes. Gene Ontology/Kyoto Encyclopedia of Genes and Genomes enrichment revealed involvement in inflammation, apoptosis, oxidative stress, and key signaling pathways such as phosphatidylinositol 3-kinase/Akt signaling pathway and adenosine monophosphate-activated protein kinase. Molecular docking confirmed strong curcumin/resveratrol binding to FN1 and RELA. Curcumin and resveratrol demonstrate therapeutic potential in MI by modulating a network of targets, prominently FN1 and RELA. These actions converge on crucial protective mechanisms such as reducing inflammation and oxidative stress, providing a basis for developing novel adjunctive MI therapies. SIGNIFICANCE STATEMENT: This study identifies 47 genetically supported targets linking curcumin and resveratrol to reduced myocardial infarction risk, with fibronectin 1 and RELA emerging as key modulators. By integrating network pharmacology, summary-data-based Mendelian randomization, colocalization, and molecular docking, it reveals how these natural compounds may attenuate inflammation, oxidative stress, and cell survival pathways (eg, PI3K-Akt, AMPK), supporting their potential as adjunctive therapies to improve myocardial infarction outcomes.
Immunomodulatory and anticancer effects of phytochemicals: A comprehensive analysis.
Eltokhy MA, Curcic M, Modaresahmadi S … +3 more , Gaikwad S, La-Beck NM, Srivastava SK
Pharmacol Rev · 2026 Apr · PMID 42172715 · Publisher ↗
Natural compounds have been a part of traditional medicine for generations, and recent studies are now recognizing their potential to influence the immune system in cancer treatment. This review focuses on how specific p...
Natural compounds have been a part of traditional medicine for generations, and recent studies are now recognizing their potential to influence the immune system in cancer treatment. This review focuses on how specific plant-derived chemicals can modulate immune checkpoints such as PD-1, PD-L1, and CTLA-4, which play a central role in cancer immunotherapy, mainly in preclinical and early translational studies. Compounds including curcumin, isothiocyanates, apigenin, luteolin, and berberine demonstrate mechanisms that inhibit immune evasion, are associated with enhanced cytotoxic T-cell responses, and modulate the tumor microenvironment, primarily in the in vitro and in vivo models. Several other phytochemicals such as anthocyanins, triptolide, and epigallocatechin gallate, have shown promise in preclinical models by disrupting oncogenic signaling pathways and promoting antitumor immunity. Although many of these agents face challenges such as low bioavailability, advances in drug delivery systems, and synergistic combinations with current therapies offer a compelling direction for potential cancer treatments. Understanding the molecular interactions of these natural agents can provide hypothesis generation and novel insights into potential effective and less toxic immunotherapeutic approaches. This comprehensive review further provides a thorough understanding of phytochemicals' translational and mechanistic relevance, highlights knowledge gaps, and guides future research directions that could improve integrative cancer immunotherapy techniques, noting that most of the available evidences are derived from preclinical studies. SIGNIFICANCE STATEMENT: Accumulating evidence suggests that phytochemicals modulate immune responses within the tumor microenvironment. These compounds have diverse mechanisms, ranging from cytokine modulation to effects on macrophages, T-cells, and pathways such as STAT3, NF-κB, and PD-L1. This review clarifies how phytochemicals influence immunotherapy outcomes and how they might be used more deliberately in cancer care. Unlike prior reviews, this work explicitly classifies phytochemicals according to whether they enhance antitumor immunity, suppress immune activation, or exert context-dependent dual effects relevant to immune checkpoint therapy.
4-Hydroxybenzyl isothiocyanate as a novel hydrogen sulfide-releasing antihypertensive agent.
Yusuf M, Benkli AB
J Pharmacol Exp Ther · 2026 Jun · PMID 42167126 · Publisher ↗
Naturally occurring isothiocyanates can release hydrogen sulfide (HS), a cardioprotective gasotransmitter involved in vascular tone regulation; however, the vascular actions of 4-hydroxybenzyl isothiocyanate (HBITC), der...
Naturally occurring isothiocyanates can release hydrogen sulfide (HS), a cardioprotective gasotransmitter involved in vascular tone regulation; however, the vascular actions of 4-hydroxybenzyl isothiocyanate (HBITC), derived from benzyl glucosinolates, have not been functionally characterized. We investigated whether HBITC exerts vasorelaxant, coronary vasodilatory, and antihypertensive effects through HS-dependent signaling mechanisms, including Kv7 channel activation, transient receptor potential ankyrin 1 stimulation, and modulation of endogenous HS-producing enzymes (cystathionine γ-lyase, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase). HS release was quantified fluorometrically in human aortic smooth muscle cells using Washington State Probe-1, membrane hyperpolarization was assessed with bis (1,3-dibutylbarbituric acid) trimethine oxonol, and vasorelaxation was examined in isolated rat aortic rings under intact, endothelium-denuded, and Nω-nitro-L-arginine methyl ester-treated conditions. Coronary flow was measured in Langendorff-perfused hearts, and the effects of blood pressure were evaluated in normotensive and spontaneously hypertensive rats. HBITC induced concentration-dependent intracellular HS release and robust membrane hyperpolarization, comparable to the large-conductance Ca-activated K channel (Kv) opener. It produced direct, endothelium-independent vasorelaxation, potentiated by intact endothelium and attenuated by nitric oxide synthase inhibition, reversibly suppressed noradrenaline-evoked vasoconstriction, restored angiotensin II-impaired coronary flow, and selectively reduced systolic blood pressure in spontaneously hypertensive rats. Collectively, these findings identify HBITC as a novel HS-releasing vasorelaxant with antihypertensive potential and support its development as a dietary-derived scaffold for vasoprotective therapeutics. SIGNIFICANCE STATEMENT: This study identifies 4-hydroxybenzyl isothiocyanate as a previously uncharacterized dietary hydrogen sulfide donor that produces potent vasorelaxation, restores coronary flow under vasospastic conditions, and selectively lowers blood pressure in hypertensive animals. By engaging Kv7 channels, transient receptor potential ankyrin 1 signaling, and endothelial nitric oxide-hydrogen sulfide crosstalk, 4-hydroxybenzyl isothiocyanate highlights a promising natural scaffold for next-generation antihypertensive and vasoprotective therapies.
Nanomedicine to enhance melanoma radiotherapy: Mechanisms and translational prospects.
Hsu CY, Rizaev J, AlAbdulhadi SAS … +5 more , Abbas Al-Khafaji ZK, Gupta PK, Samikan KR, Sahoo S, Bainsal N
J Pharmacol Exp Ther · 2026 Jun · PMID 42167125 · Publisher ↗
Melanoma is an aggressive and highly malignant skin cancer characterized by rapid proliferation, early metastatic dissemination, and pronounced resistance to conventional therapies, including radiotherapy. This intrinsic...
Melanoma is an aggressive and highly malignant skin cancer characterized by rapid proliferation, early metastatic dissemination, and pronounced resistance to conventional therapies, including radiotherapy. This intrinsic radioresistance is largely attributed to melanoma's high mutational burden, efficient DNA damage repair capacity, elevated antioxidant defenses, and a uniquely immunosuppressive tumor microenvironment. Consequently, improving the therapeutic efficacy of radiotherapy in melanoma remains a major clinical challenge. Recent advances in nanomedicine have introduced innovative strategies to enhance radiotherapeutic outcomes by integrating physical, chemical, and biological mechanisms of tumor sensitization. Diverse nanoplatforms, including lipid-based, polymeric, and inorganic nanoparticles, enable precise tumor targeting through passive and active mechanisms and support multifunctional therapeutic modalities. High atomic number (high-Z) nanoparticles such as gold, bismuth, and platinum amplify radiation dose deposition and reactive oxygen species generation, thereby promoting DNA damage and apoptosis. In parallel, nanoparticle-mediated photothermal and photodynamic therapies further augment radiosensitivity, whereas immune-modulatory nanocarriers enhance antitumor immune responses and synergize with immunotherapy. Importantly, beyond drug delivery, the intrinsic physicochemical properties of nanomaterials, such as catalytic activity, surface reactivity, magnetic responsiveness, and electronic features, play critical roles in modulating tumor metabolism, redox balance, and the tumor microenvironment. By highlighting preclinical and emerging clinical evidence, we outline current challenges, translational opportunities, and future directions for precision radiotherapy strategies aimed at overcoming melanoma radioresistance and improving therapeutic outcomes. SIGNIFICANCE STATEMENT: Melanoma's intrinsic radioresistance arises from rapid DNA double-strand break repair, elevated glutathione-mediated antioxidant defenses, and immune evasion. This review delineates how high-Z nanoparticles, catalytic nanozymes, and multifunctional nanocarriers enhance radiotherapy by amplifying dose deposition, generating reactive oxygen species, inhibiting DNA repair pathways, and promoting immunogenic cell death. These insights define rational design principles for nanoparticle-assisted, precision radiotherapy strategies in melanoma.
Erratum to "Links between COVID-19, long COVID, and neurodegeneration: The role of glycosphingolipids" [Pharmacological Reviews 78 (2026) 100113].
Spedding M, Aerts J, Alexander S … +17 more , Bellozzi Woestelandt AG, Chiricozzi E, Henriques A, Lledo PM, Loeffler JP, Perera R, Platt FM, Pradat PF, Rene F, Schapira A, St Clair L, Talbot K, Taquet M, Toborek M, Turner B, Zandi M, Gressens P
Pharmacol Rev · 2026 May · PMID 42160940 · Publisher ↗
Abstract loading — click title to view on PubMed.
Enhanced antinociception of mixed efficacy opioid peptidomimetics through P-glycoprotein modulation.
Anand JP, Kochan KE, Montgomery D … +3 more , Nastase AF, Mosberg HI, Jutkiewicz EM
J Pharmacol Exp Ther · 2026 Jun · PMID 42150457 · Publisher ↗
μ-Opioid receptor agonists are widely used in the treatment of pain, but produce many adverse effects. Studies suggest that co-administration of a μ-opioid receptor agonist with a δ-opioid receptor antagonist relieves pa...
μ-Opioid receptor agonists are widely used in the treatment of pain, but produce many adverse effects. Studies suggest that co-administration of a μ-opioid receptor agonist with a δ-opioid receptor antagonist relieves pain with reduced adverse effects. We evaluated the antinociceptive effects of previously reported μ-opioid receptor agonist/δ-opioid receptor antagonist peptidomimetics in the acetic acid stretch assay and the warm water tail withdrawal (tail-flick) assay. All compounds produced anticonception in the ASSA; however, only 2 compounds, AAH8 and AMB47, produced antinociception in the tail-flick assay. the structurally similar analogs, AAH9 and AMB39, were ineffective. We hypothesized that this was due to pharmacokinetic differences. To test this hypothesis, we examined these compounds in the tail-flick assay after both intravenous and intracerebroventricular administration. Neither AAH9 nor AMB39 had any effect when given intravenously but both compounds produced antinociception after intracerebroventricular administration. AAH8 and AMB47 produced antinociceptive effects via all routes of administration. We hypothesized that crossing the blood-brain barrier was the limiting factor and tested the effects of AAH9 and AMB39 in combination with a P-glycoprotein inhibitor, Elacridar. After pretreatment with Elacridar, peripheral administration of AAH9 and AMB39 produced antinociception in the tail-flick assay. The dose-response curves for AAH8 and AMB47 were unaffected by pretreatment with Elacridar. These data suggest that even structurally similar peptidomimetics may have different pharmacokinetic properties that limit their antinociceptive effects. Understanding these pharmacokinetic properties may aid in the rational design of mixed efficacy peptidomimetic opioid ligands for the treatment of pain. SIGNIFICANCE STATEMENT: Many compounds fail out of drug development campaigns because of a lack of efficacy. One reason for this is the inability to reach the site of action. In this report, we describe 2 pairs of compounds with significantly different pharmacokinetic profiles and describe strategies for determining central nervous system penetration of opioid ligands.
Reinventing amlodipine.
Grzymala B, Halldórsdóttir DÞ, Þorsteinsson H … +5 more , Þorfinnsdóttir K, Sveinsdóttir HS, Parker MO, Foulquier S, Karlsson KÆ
J Pharmacol Exp Ther · 2026 Jun · PMID 42139800 · Publisher ↗
Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder, and pharmacological treatments have limited mechanistic specificity. Most nonstimulants target noradrenergic tone but show modes...
Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder, and pharmacological treatments have limited mechanistic specificity. Most nonstimulants target noradrenergic tone but show modest efficacy. l-Type calcium channels (LTCCs) modulate neuronal excitability, catecholaminergic transmission, cortical plasticity, and neuroinflammation, processes central to ADHD pathophysiology. This review evaluates the evidence for repurposing the LTCC blocker amlodipine as a novel ADHD therapeutic. We propose a mechanistic framework where amlodipine acts within attention/arousal circuits to stabilize dopaminergic and noradrenergic tone, restore D2-autoreceptor feedback, enhance plasticity, and reduce neuroinflammation. This systems-level model provides explanatory links between drug action and ADHD pathophysiology, highlighting therapeutic avenues not addressed by current treatments. Contrary to historical assumptions, recent evidence confirms that amlodipine penetrates the blood-brain barrier. Convergent preclinical findings show phenotype rescue in zebrafish and rat models of ADHD, accompanied by normalization of ADHD-relevant metabolic pathways. Complementary biobank analyses suggest reduced traits associated with ADHD among genetically at-risk individuals taking amlodipine. Given enantiomeric pharmacology, S-amlodipine, with higher LTCC affinity and fewer off-target liabilities than R-amlodipine, emerges as a preferred candidate. Together, these findings warrant a reappraisal of LTCC modulation in ADHD. By providing mechanistic explanations of how amlodipine engages ADHD-relevant circuits, this review clarifies its therapeutic potential and reshapes our understanding of the drug itself, with implications for repurposing, enantiomer-specific development, and broader clinical translation. We outline next steps, including comparative S- versus R-amlodipine studies, mechanistic dissection of LTCC subtypes in attentional networks, and controlled clinical testing to evaluate amlodipine's viability as a nonstimulant therapeutic. SIGNIFICANCE STATEMENT: Genetic, preclinical, and translational evidence implicates dysregulated l-type calcium channel signaling in attention-deficit/hyperactivity disorder, providing a mechanistic rationale for evaluating amlodipine as a therapeutic candidate. S-amlodipine is the rational development form, as it mediates the principal l-type calcium channel activity, whereas R-amlodipine may contribute to nonbeneficial brain or tolerability effects. This review defines a clear translational path focused on S-amlodipine, warranting prospective, dose-optimized clinical trials to determine efficacy on attentional and executive dysfunction with acceptable safety.
Minor cannabinoids CBD, CBG, CBN, and CBC differentially modulate sensory neuron activation.
Rabl K, Gruenke L, Banfal A … +3 more , Eilers H, Hellman J, Schumacher MA
J Pharmacol Exp Ther · 2026 Jun · PMID 42139799 · Publisher ↗
The use of minor cannabinoids has been advanced, in part, by the idea of providing relief from pain and inflammation without the unwanted psychogenic effects associated with delta-9-tetrahydro-cannabinol (ΔTHC). With a f...
The use of minor cannabinoids has been advanced, in part, by the idea of providing relief from pain and inflammation without the unwanted psychogenic effects associated with delta-9-tetrahydro-cannabinol (ΔTHC). With a focus on peripheral nociception, 4 common minor cannabinoids: cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN), and cannabichromene (CBC) were studied in primary cultures of mouse dorsal root ganglion (DRG) neurons. We queried whether calcium responses induced by the 4 cannabinoids differed in potency of activation, neuronal size preference, and dose-response relationships. Additionally, we determined the dependence of CBD and CBN on key channel receptors that are known to mediate pain and/or antinociception. Individually, CBD, CBG, and CBC directed greater response magnitudes when compared with CBN. All 4 minor cannabinoids activated overlapping size populations of sensory neurons. CBD and CBG activated the widest range of DRG neuron sizes (smaller-larger), overlapping with smaller capsaicin-sensitive neurons. In contrast, CBN and CBC activated predominantly larger sensory neurons. CBD diverged from other minor cannabinoids in directing a linear dose-response profile, whereas CBG and CBC directed sigmoidal profiles and CBN activated DRG neurons with an inverted U-shaped dose-response relationship. CBD-induced activation of DRG neurons was dependent on coexpression of the nociceptive channel transient receptor potential cation channel subfamily Vanilloid member 1 (TRPV1) plus cannabinoid receptor 1 (CBR), whereas CBN-induced activation was independent of TRPV1 and CBR. Overall, we observed that minor cannabinoids CBD, CBG, CBN, and CBC directed unique activation properties across a diverse population of sensory neurons. Such differences underlie the hypothesis that a combination of minor cannabinoids can direct complementary antinociceptive activity. SIGNIFICANCE STATEMENT: Minor cannabinoids CBD, CBG, CBN, and CBC differ in their dose-dependent properties of sensory neuronal activation. CBD-induced activation of small to large sensory neurons was dependent on coexpression of the nociceptive channel TRPV1 plus CBR and directed a linear dose-response profile. In contrast, CBN activated predominantly larger sensory neurons in an inverted U-shaped dose-response profile and was independent of TRPV1 and CBR. A combination of minor cannabinoids is hypothesized to direct complementary antinociceptive activity.
Mechanisms by which chromobox homolog 4 regulates angiogenic mimicry and angiogenic activity in osteosarcoma.
Gui H, Li B
J Pharmacol Exp Ther · 2026 Jun · PMID 42139798 · Publisher ↗
Osteosarcoma (OS) is a very aggressive malignant neoplasm characterized by significant metastases and a deficiency of treatment targets. Therefore, it is urgent to find new therapeutic mechanisms and targets for OS. We a...
Osteosarcoma (OS) is a very aggressive malignant neoplasm characterized by significant metastases and a deficiency of treatment targets. Therefore, it is urgent to find new therapeutic mechanisms and targets for OS. We assessed the capability of chromobox homolog 4 (CBX4) to modulate OS growth using in vivo and in vitro dual tests utilizing short hairpin RNA technology, 3-dimensional tumor sphere building, immunofluorescence co-localization, and other biotechnological methods. Our findings indicated that CBX4 was overexpressed in OS tissues, and the silencing of CBX4 markedly reduced OS cell proliferation, migration, and invasion. CBX4 modulates vasculogenic mimicry through its influence on yes1 associated transcriptional regulator (YAP1) and neuropilin-2/vascular endothelial growth factor A (NRP2/VEGFA) pathway, hence promoting angiogenic activity, a mechanism perhaps linked to CBX4's role in regulating mitochondrial autophagy. CBX4 affects vasculogenic mimicry by regulating the YAP1 and NRP2/VEGFA pathways and promotes the OS process. CBX4 may serve as a novel biomarker for OS, potentially offering innovative approaches for early diagnosis and tailored therapy of OS. SIGNIFICANCE STATEMENT: Osteosarcoma (OS) is a very aggressive malignant neoplasm characterized by significant metastases and a deficiency of treatment targets. Therefore, it is urgent to find new therapeutic mechanisms and targets for OS. Chromobox homolog 4 may serve as a novel biomarker for OS, potentially offering innovative approaches for early diagnosis and tailored therapy of OS.
Agomelatine restores apoptotic and glial homeostasis in methotrexate-induced cortical neurotoxicity.
Usta Z, Çavdarlı K, Türkoglu Ö … +2 more , Milletsever A, Kılınçkaya S
J Pharmacol Exp Ther · 2026 Jun · PMID 42127633 · Publisher ↗
Methotrexate (MTX), a commonly used chemotherapeutic and immunosuppressive agent, induces dose-dependent neurotoxicity characterized by oxidative stress, glial reactivity, and dysregulation of apoptotic signaling, contri...
Methotrexate (MTX), a commonly used chemotherapeutic and immunosuppressive agent, induces dose-dependent neurotoxicity characterized by oxidative stress, glial reactivity, and dysregulation of apoptotic signaling, contributing to chemotherapy-related cognitive impairment. Agomelatine (AGO), a melatonergic melatonin receptor type 1/melatonin receptor type 2 receptor agonist and 5-hydroxytryptamine receptor 2C antagonist, exhibits antioxidant, anti-inflammatory, and antiapoptotic properties, suggesting potential neuroprotection. Twenty-four female Wistar rats were randomly divided into control, MTX, MTX + AGO, and AGO groups (n = 6 each). AGO (20 mg/kg/d, by mouth) was administered for 7 days, with a single MTX injection (20 mg/kg, i.p.) on day 2. Cortical tissues were examined histopathologically (Hematoxylin and Eosin), immunohistochemically (glial fibrillary acidic protein and oligodendrocyte transcription factor 2), and molecularly via RT-quantitative polymerase chain reaction (qPCR) (Bcl-2-associated X protein and B-cell lymphoma 2 [BCL2]). MTX-induced marked cortical neurodegeneration, vascular hyperemia, gliosis, and parenchymal hemorrhage, accompanied by elevated glial fibrillary acidic protein and oligodendrocyte transcription factor 2 expression. MTX also increased proapoptotic Bcl-2-associated X protein and decreased antiapoptotic BCL2 expression, shifting the Bcl-2-associated X protein/BCL2 ratio toward apoptosis. AGO cotreatment significantly mitigated these alterations, preserving cortical cytoarchitecture, reducing glial activation, and restoring apoptotic balance. AGO alone upregulated BCL2 expression without histopathological abnormalities. AGO confers significant neuroprotection against MTX-induced cortical toxicity by attenuating glial reactivity and re-establishing apoptosis survival equilibrium. These findings highlight AGO as a promising adjunct therapeutic strategy for reducing chemotherapy-related neurotoxicity and improving neurological outcomes in MTX-treated patients. SIGNIFICANCE STATEMENT: Agomelatine, a clinically available melatonergic antidepressant, mitigated methotrexate-induced cortical neurotoxicity in rats by dampening astrocytic/oligodendrocytic reactivity and restoring the Bcl-2-associated X protein/B-cell lymphoma 2 apoptotic balance. These findings identify glial apoptotic homeostasis as a tractable target and support repurposing agomelatine as an adjunct to reduce chemotherapy-related neurotoxicity and potentially improve cognitive outcomes in methotrexate-treated patients.
Anti-inflammatory effect of deoxylapachol by regulating interleukin 17/Toll-like receptor/tumor necrosis factor signaling pathways.
Wang Y, Xu L, Feng L … +6 more , Zhao H, Li F, Sik AG, Chen X, Liu K, Wang R
J Pharmacol Exp Ther · 2026 Jun · PMID 42127632 · Publisher ↗
Deoxylapachol (DLP), a natural product of marine origin, firstly isolated from the New Zealand brown algae, was firstly found has potent anti-inflammatory activities both in vitro and in vivo experiments. The study's obj...
Deoxylapachol (DLP), a natural product of marine origin, firstly isolated from the New Zealand brown algae, was firstly found has potent anti-inflammatory activities both in vitro and in vivo experiments. The study's objective is aimed at its prospective molecular mechanisms. Firstly, the anti-inflammatory effect of DLP was assessed in zebrafish models induced by copper sulfate, tail-cutting and lipopolysaccharide exposure, respectively. The results showed that DLP effectively alleviated the acute inflammatory response by inhibiting the migration of immune cells, and the elevation of reactive oxygen species and nitric oxide. Moreover, DLP regulated the mRNA expression of tumor necrosis factor-α, matrix metalloproteinase 9, signal transducer and activator of transcription 3, nuclear factor of kappa light polypeptide gene enhancer in B-cells, cyclooxygenase-2, caspase-3, myeloperoxidase, glycogen synthase kinase 3 beta, mitogen-activated protein kinase 14a, mitogen-activated protein kinase 1, and hypoxia-inducible factor 1 alpha genes related to the interleukin (IL)-17/Toll-like receptor/TNF signaling pathway, and inflammatory cytokines (transforming growth factor beta, nucleotide-binding domain, leucine-rich repeat containing family, pyrin domain containing 3, IL-1β, IL-4, IL-6, IL-8, IL-10, Toll-like receptor 2 [TLR2], TLR3, TLR4, IL-17a, and IL-17b). DLP also regulates the expressions of proteins such as Tumor Necrosis Factor-α, nuclear factor of kappa light polypeptide gene enhancer in B-cells, matrix metalloproteinase 9, cyclooxygenase-2, p-P38, signal transducer and activator of transcription 3, GSK3α/β, caspase-3, inducible nitric oxide synthase, IL-18, nucleotide-binding domain, leucine-rich repeat containing family, pyrin domain containing 3, peroxisome proliferator-activated receptor and nuclear factor (erythroid-derived 2)-like 2. In conclusion, our finding indicated that DLP has the potential to be a candidate drug for the effective treatment of inflammation. SIGNIFICANCE STATEMENT: This study has shown that deoxylapachol exerts a potent anti-inflammatory effect in zebrafish inflammatory models. Deoxylapachol, a natural product of marine origin, has the potential to be an effective agent for anti-inflammatory treatment.
Piperine-loaded solid dispersions mitigate amyloid-β-mediated oxidative stress and mitochondrial dysfunction in SH-SY5Y cells: A possible therapeutic strategy for Alzheimer's disease.
Mishra J, Singh C, Bhatti JS
J Pharmacol Exp Ther · 2026 May · PMID 42119549 · Publisher ↗
Alzheimer's disease is a progressive neurodegenerative disorder defined by the presence of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles, which together drive cognitive decline and memory...
Alzheimer's disease is a progressive neurodegenerative disorder defined by the presence of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles, which together drive cognitive decline and memory impairment. Current therapies provide only symptomatic relief, highlighting the urgent need for disease-modifying strategies targeting the underlying pathology. Piperine, a plant-derived alkaloid with neuroprotective, antioxidant, and antiamyloidogenic properties, has shown preclinical efficacy against Aβ toxicity. However, its clinical translation is limited by poor aqueous solubility and low bioavailability. The present study aimed to develop and characterize spray-dried piperine-loaded solid dispersion (PIP@SDs) to overcome these pharmacokinetic barriers and enhance neuroprotective efficacy. PIP@SDs were prepared using spray drying with leucine as a carrier to improve solubility and stability. Solid-state characterization was performed using differential scanning calorimetry, Fourier-transform infrared spectroscopy, and powdered X-ray diffraction to confirm amorphization and molecular interactions. PIP@SDs demonstrated enhanced solubility, achieving 97.5% drug release in 24 hours, compared with pure drug and improved flow properties suitable for pharmaceutical manufacturing. In SH-SY5Y cells, PIP@SDs markedly increased viability after Aβ insult (from 50.2% to 80.8%, P < .0001), reduced oxidative stress, stabilized mitochondrial membrane potential, restored calcium equilibrium, and lowered apoptosis levels relative to free piperine. Notably, PIP@SDs inhibited cholinesterase activity and prevented Aβ aggregation, with all effects confirmed through quantitative and imaging analyses. In closing, by substantially enhancing solubility and bioavailability and providing superior neuroprotection against Aβ-mediated toxicity, spray-dried PIP@SDs offer a novel, multifunctional platform that supports their continued research as a promising candidate for disease-modifying interventions in Alzheimer's and related neurodegenerative disorders. SIGNIFICANCE STATEMENT: Poor aqueous solubility and limited bioavailability restrict the therapeutic potential of many neuroprotective natural compounds. This study demonstrates that spray-dried piperine-leucine solid dispersions markedly enhance piperine dissolution and significantly attenuate amyloid-β-induced oxidative stress, mitochondrial dysfunction, and apoptosis in neuronal cells. These findings highlight a pharmacologically relevant formulation strategy that improves the bioactivity of piperine and supports its development as a multifunctional therapeutic candidate targeting oxidative and mitochondrial pathways implicated in Alzheimer disease.
Betulinic acid attenuates obesity-associated hepatic steatosis by modulating hepatic lipid handling and bile acid-regulated nuclear receptor signaling in high-fat diet-fed rats.
Uddandrao VVS, Ganesan J, Roy A … +3 more , Asokan BR, Ravikkumar VR, Sengottuvelu S
J Pharmacol Exp Ther · 2026 Jun · PMID 42119325 · Publisher ↗
Obesity-associated hepatic steatosis is a major metabolic consequence of chronic dietary lipid excess and a critical precursor to progressive liver disease. In the present study, we investigated the therapeutic potential...
Obesity-associated hepatic steatosis is a major metabolic consequence of chronic dietary lipid excess and a critical precursor to progressive liver disease. In the present study, we investigated the therapeutic potential of betulinic acid (BA), a plant-derived pentacyclic triterpenoid, in high-fat diet (HFD)-induced hepatic steatosis in rats, with specific emphasis on hepatic lipid handling and bile acid-regulated nuclear receptor signaling. Male Sprague-Dawley rats were fed an HFD for 16 weeks to induce obesity and subsequently treated with BA (40 mg/kg, oral) for 6 weeks. BA treatment markedly improved systemic dyslipidemia and reduced hepatic accumulation of triglycerides, cholesterol, free fatty acids, and phospholipids. These metabolic improvements were accompanied by normalization of serum liver marker enzymes and restoration of bile acid homeostasis. Histopathological assessment demonstrated pronounced attenuation of hepatic steatosis, lobular inflammation, hepatocyte ballooning, and a significant reduction in the Nonalcoholic Fatty Liver Disease Activity Score. At the molecular level, BA suppressed HFD-induced de novo lipogenesis by downregulating sterol regulatory element-binding protein-1c, acetyl-CoA carboxylase, and fatty acid synthase while concurrently restoring the expression of apolipoprotein B and microsomal triglyceride transfer protein. In parallel, BA re-established bile acid-regulated nuclear receptor signaling by restoring farnesoid X receptor and small heterodimer partner expression and normalizing cholesterol 7α-hydroxylase levels. Molecular docking analyses further supported these findings by revealing stable interactions of BA with multiple regulators of lipid and bile acid metabolism. Taken together, these findings identify BA as a multitarget metabolic modulator that alleviates obesity-associated hepatic steatosis through coordinated regulation of lipid metabolism and bile acid signaling pathways. SIGNIFICANCE STATEMENT: Obesity-associated hepatic steatosis lacks effective pharmacological interventions that target the underlying metabolic dysregulation. This study demonstrates that betulinic acid exerts hepatoprotective effects by coordinately suppressing hepatic lipogenesis, restoring lipid export, and normalizing bile acid-regulated nuclear receptor signaling in a HFD model. These findings identify betulinic acid as a multitarget metabolic modulator with potential therapeutic relevance for obesity-driven fatty liver disease.
Thrombin generation and the pharmacodynamics of parenteral anticoagulants.
Shaw JR, Maier CL, Hardy M … +9 more , Mullier F, Douxfils J, Tanaka K, Rocca B, Cate HT, Kim PY, Carrier M, Connors JM, Levy JH
Pharmacol Rev · 2026 May · PMID 42102583 · Publisher ↗
Parenteral anticoagulants are mainstay therapies in critical care and perioperative settings because of their unique pharmacological properties, but they have a narrow therapeutic window. This emphasizes the need to thor...
Parenteral anticoagulants are mainstay therapies in critical care and perioperative settings because of their unique pharmacological properties, but they have a narrow therapeutic window. This emphasizes the need to thoroughly understand their pharmacodynamics effects on hemostasis. Thrombin generation assays provide a comprehensive measure of coagulation and can characterize class-specific anticoagulant effects. We reviewed the literature with a focus on parenteral anticoagulants to define the role of thrombin generation as a pharmacodynamic measure of anticoagulation status. We contextualize these results in light of findings from a prior review on the effects of oral anticoagulants on thrombin generation and consider our findings in view of results stemming from comparative anticoagulation-focused epidemiologic research. This review provides proof of principle that, from a pharmacodynamics perspective, not all anticoagulants are the same. They exert class-specific effects on thrombin generation, and these divergent effects reflect differing mechanisms of action on coagulation initiation, amplification, and propagation. Anticoagulants with multiple downstream effects, such as unfractionated or low-molecular-weight heparins, are better able to suppress thrombin generation than selective direct inhibitors, such as bivalirudin, argatroban, direct oral anticoagulants, or factor XI(a) inhibitors. We propose a conceptually valid theoretical framework, grounded in mechanistic rationale, supported by experimentation, and leveraging thrombin generation as a common measure to compare and examine the pharmacodynamic impact of different anticoagulants. The knowledge reviewed herein may support the future development of more personalized approaches to anticoagulation treatment. Our findings contribute a foundation upon which future anticoagulation research can be based and warrant further investigation. SIGNIFICANCE STATEMENT: From a pharmacodynamic perspective, not all anticoagulants are the same. Oral and parenteral anticoagulants exert class-specific effects on thrombin generation, and these divergent effects reflect differing mechanisms of action on coagulation initiation, amplification, and propagation. Anticoagulants with multiple downstream effects are better able to suppress thrombin generation than selective direct inhibitors. This review proposes a theoretical framework, grounded in mechanistic rationale, and leveraging thrombin generation as a common measure to compare and examine the pharmacodynamic impact of different anticoagulants.
Chronic pantoprazole administration impairs memory behavior and motor function in mice independent of serum nutrient changes.
Fawehinmi P, Rahman K, Loraine A … +2 more , Witt K, Sandoval K
J Pharmacol Exp Ther · 2026 Jun · PMID 42096899 · Publisher ↗
Long-term proton pump inhibitor use is associated with cognitive and motor impairments and nutrient deficiencies. Whether these impairments result directly from proton pump inhibitors or indirectly from nutrient deficien...
Long-term proton pump inhibitor use is associated with cognitive and motor impairments and nutrient deficiencies. Whether these impairments result directly from proton pump inhibitors or indirectly from nutrient deficiencies remains unclear. Chronic pantoprazole treatment (0 or vehicle, 1, 10, or 100 mg/kg/day, by mouth, 38 days) was evaluated across tests of anxiety-like behavior, learning and memory behavior, and motor function and coordination in 4-month-old male C57BL/6 mice. Serum levels of holotranscobalamin and magnesium, as well as poly(A) RNA sequencing of brain tissue, were subsequently evaluated. Pantoprazole (100 mg/kg) reduced the percentage of spontaneous alternations in the Y-maze (P < .05 vs 0 and 1 mg/kg) and decreased the distance traveled in Rotarod testing (P < .05 vs vehicle), suggesting that it impaired short-term working memory behavior and motor coordination, respectively. All pantoprazole doses increased anxiety-like behavior in the open field (P < .05 vs vehicle). In novel (N) object recognition testing, pantoprazole (1 mg/kg) reduced the discrimination index at 24 hours (P < .05, vs vehicle), suggesting it impaired recognition memory behavior. Magnesium levels were similar across chronic pantoprazole groups. Holotranscobalamin, the bioavailable form of vitamin B, was lower at 10 mg/kg pantoprazole (P < .05 vs vehicle). Poly(A) RNA sequencing identified 15 differentially expressed genes in hippocampus (10 upregulated and 5 downregulated) and 32 in FC (14 upregulated and 18 downregulated) with 100 mg/kg pantoprazole treatment compared to vehicle. There was no correspondence between behavioral changes and alterations in serum nutrient levels with the respective doses of pantoprazole. SIGNIFICANCE STATEMENT: Long-term proton pump inhibitor use may affect cognition, motor function, and nutrient status. This study examined the behavioral impact of chronic pantoprazole treatment in young male mice and whether declines in serum magnesium or holotranscobalamin levels could explain behavioral changes. Doses of chronic pantoprazole that altered behavior were not associated with declines in either nutrient.
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