The Journal Of Pharmacology And Experimental Therapeutics[JOURNAL]
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200 papers
Linagliptin and/or α-pinene attenuate cisplatin nephrotoxicity in rats via modulating phosphatase and tensin homolog-induced kinase 1/Parkin/microtubule-associated proteins 1A/1B light chain 3II/SQSTM1/sequestosome-1-assisted mitophagy.
Elgendy AA, Nematalla HA, Elharoun M … +1 more , Abdel-Raheem IT
J Pharmacol Exp Ther · 2026 Jun · PMID 42258992 · Publisher ↗
Acute kidney injury is considered the most harmful and prevalent type of cisplatin-induced nephrotoxicity. In the current research, the potential prophylactic effects of linagliptin and/or α-pinene were investigated on c...
Acute kidney injury is considered the most harmful and prevalent type of cisplatin-induced nephrotoxicity. In the current research, the potential prophylactic effects of linagliptin and/or α-pinene were investigated on cisplatin-induced functional, biochemical, and structural changes in rat kidneys. Forty Sprague-Dawley male rats were separated into five groups (n = 8): (1) normal group; (2) model group (cisplatin 7.5 mg/kg, i.p., single dose); (3) linagliptin group (3 mg/kg, p.o. for 18 days); (4) α-pinene group (50 mg/kg, p.o. for 18 days); and (5) linagliptin + α-pinene group (linagliptin 3 mg/kg + α-pinene 50 mg/kg, p.o.) for 18 days. Cisplatin was administered to all groups on day 15, excluding the normal group. Possible antioxidant, anti-inflammatory, and antiapoptotic activities were evaluated. In addition, mitophagy and mitochondrial biogenesis boosting mechanisms of both drugs were examined. Cisplatin administration produced a marked elevation in serum creatinine, urea, and renal kidney injury molecule-1 levels. Oxidative stress was markedly increased in the kidney homogenate. Similarly, cisplatin elevated renal inflammatory markers, activated the inflammasome, and increased apoptotic markers. It diminished mitophagy and mitochondrial biogenesis by reducing phosphatase and tensin homolog-induced kinase 1, Parkin, and peroxisome proliferator-activated receptor γ coactivator 1α levels. Contrarily, cisplatin raised microtubule-associated proteins 1A/1B light chain 3II and SQSTM1/sequestosome-1 levels. Coadministration of linagliptin and α-pinene demonstrated a potential prophylactic strategy in this preclinical model, likely through attenuation of oxidative stress, inflammation, apoptosis, and enhancement of mitophagy. However, this combination requires further validation in additional experimental models, including optimization of dosing regimens and evaluation of potential interactions with chemotherapy outcomes. SIGNIFICANCE STATEMENT: Linagliptin and/or α-pinene attenuate cisplatin-induced nephrotoxicity in rats by modulation of mitochondrial biogenesis and mitophagy.
Circumvention of acquired resistance to topoisomerase II-targeted anticancer agents in HL-60 leukemia cells by prevention of intronic polyadenylation.
Zhao X, Cassel SR, Eaton SE … +4 more , Li J, Wang X, Elton TS, Yalowich JC
J Pharmacol Exp Ther · 2026 May · PMID 42258907 · Publisher ↗
DNA topoisomerase IIα (TOP2α; 170 kDa, TOP2α/170) is a nuclear enzyme that plays a key role in chromosomal segregation at mitosis by catalyzing transient DNA double-stranded breaks, allowing replicated DNA duplexes to se...
DNA topoisomerase IIα (TOP2α; 170 kDa, TOP2α/170) is a nuclear enzyme that plays a key role in chromosomal segregation at mitosis by catalyzing transient DNA double-stranded breaks, allowing replicated DNA duplexes to separate. Given its importance during mitosis and high expression level in proliferating cells, TOP2α/170 is a prominent target for anticancer therapy. However, the effectiveness of TOP2-targeted agents is often compromised by acquired drug resistance, which in patients is most associated with decreased TOP2α/170 protein expression, thereby diminishing drug-induced TOP2α-DNA complexes and cytotoxic DNA damage. Mimicking this clinical chemoresistance phenotype, reduced TOP2α/170 mRNA/protein was previously reported in an acquired HL-60 cell line associated with production of a C-terminal truncated 160 kDa protein (TOP2α/160). In this report, intronic polyadenylation (IPA) within intron 33 (I33) of the TOP2α/170 gene, responsible for production of TOP2α/160, was recapitulated by quantitative real-time polymerase chain reaction, 3'-rapid amplification of cDNA ends, and Sanger sequencing. HL-60/MX2 cells are crossresistant to multiple TOP2-targeted agents. To circumvent drug resistance, CRISPR/Cas9 gene editing with homology-directed repair was used to mutate/enhance the weak 5' splice site at the exon 33/I33 junction of the TOP2α gene to improve splicing out of I33 and to suppress IPA. The resulting splice site gene-edited clone, designated MX2/SS-Edit, expressed reduced TOP2α/160 mRNA/protein, increased TOP2α/170 mRNA/protein, and exhibited partial restoration of sensitivity to mitoxantrone, etoposide, and amsacrine. Together, results indicated that strengthening the weak TOP2α exon 33/I33 splice site by knock-in gene editing attenuated IPA offering a strategy to circumvent resistance to TOP2-targeted therapies. SIGNIFICANCE STATEMENT: Results presented here validated drug resistance in the HL-60/MX2 leukemia cell line driven by intronic polyadenylation (IPA) within intron 33 of the DNA topoisomerase IIα (TOP2α) gene, which produced a truncated and predominantly cytoplasmic TOP2α protein isoform (TOP2α/160). Using CRISPR/Cas9/homology-directed repair gene editing, the weak exon 33/intron 33 5' splice site was enhanced to suppress IPA, which restored expression of full-length protein (TOP2α/170) and led to a gain-of-function in drug sensitivity, offering a potential strategy to overcome drug resistance.
Lumateperone as an alternative to clozapine in treatment-resistant schizophrenia: Insights from a quantitative systems pharmacology model.
Mishra A, Mishra BR, Maiti R … +1 more , Hota D
J Pharmacol Exp Ther · 2026 May · PMID 42250291 · Publisher ↗
Clozapine remains the only drug with superior efficacy in treatment-resistant schizophrenia (TRS) but is limited by underutilization and significant adverse effects, motivating mechanistic approaches to identify clozapin...
Clozapine remains the only drug with superior efficacy in treatment-resistant schizophrenia (TRS) but is limited by underutilization and significant adverse effects, motivating mechanistic approaches to identify clozapine-like alternatives. We developed a 2-layer quantitative systems pharmacology model for TRS. Layer 1 integrates binding affinities at 12 receptor mechanisms with theory-driven mechanistic weights derived from contemporary clozapine pharmacology frameworks. Layer 2 extends predictions with positron emission tomography-calibrated effective brain concentrations back-calculated from published [C]raclopride observations, active metabolite modeling and dose-dependent benefit-risk integration. Eight treatments were scored on a 0-1 efficacy scale using weighted mechanism components, transformed to predicted TRS response rates via a Hill-type transformation function calibrated to clozapine. Bayesian Monte Carlo with Dirichlet priors (5000 iterations) propagated uncertainty, and model performance was externally validated against TRS trial data for 5 drugs (root mean square error 3.5%, r = 0.964). Predicted response rates formed hierarchical tiers: clozapine-lumateperone and clozapine-aripiprazole combinations ≈33%; clozapine (400 mg) 30% (95% CI, 25-34%); lumateperone (42 mg) 28% (24-31%); aripiprazole 24% (19-29%); risperidone (4 mg) 12%; olanzapine (15 mg) 10%; and haloperidol (10 mg) 2%. The positron emission tomography-calibrated dose-response extension (root mean square error 7.25%, mean absolute error 2.88% for D occupancy prediction) revealed that lumateperone possesses the widest therapeutic window (14-84 mg) with an optimal benefit-risk dose of 55 mg (predicted 30.3% response, response rate-extrapyramidal symptoms ratio = 25), compared with response rate-EPS ratio = 11.5 for clozapine 400 mg. Haloperidol, olanzapine, and risperidone did not exhibit a therapeutic window that met benefit-risk criteria. Model simulations identify lumateperone as a promising alternative TRS candidate with a favorable benefit-risk profile, warranting prospective dose-finding clinical trials. SIGNIFICANCE STATEMENT: This study develops and validates a 2-layer quantitative systems pharmacology model integrating receptor-level mechanisms with positron emission tomography-calibrated dose-response to predict treatment outcomes in treatment-resistant schizophrenia. It identifies lumateperone as a clozapine-like candidate with near-comparable efficacy but a superior therapeutic window, generating clinically testable hypotheses for optimized dosing and combination strategies.
Positive allosteric modulation of the delta opioid receptor attenuates depression-like and pain-like behaviors but does not promote convulsions.
Jutkiewicz EM, Palleiko BA, Dripps IJ … +4 more , Livingston KE, Roques BP, Clements BM, Traynor JR
J Pharmacol Exp Ther · 2026 May · PMID 42250290 · Publisher ↗
The delta opioid receptor (DOR) has been a focus of research for the treatment of depression and certain pain disorders. Unfortunately, clinical translation of delta opioid agonists to humans has proved challenging partl...
The delta opioid receptor (DOR) has been a focus of research for the treatment of depression and certain pain disorders. Unfortunately, clinical translation of delta opioid agonists to humans has proved challenging partly because of their propensity to cause convulsions at higher doses. The discovery that the DOR can be allosterically modulated has opened the possibility of developing compounds that may be able to produce some of the positive therapeutic effects, either as standalone treatments to enhance the action of endogenous opioid peptides or as sparing agents allowing the use of lower doses of DOR agonists, which could reduce the chance of inducing convulsions. BMS-986187 is a positive allosteric modulator of DOR. The behavioral effects of BMS-986187 related to depression and pain have not been investigated. In this study, we examined the impact of BMS-986187 on DOR-mediated antidepressant-like effects in the forced swim test, antinociceptive and antiallodynic actions and propensity to cause convulsions. BMS-986187 (1 mg/kg) showed antidepressant-like effects when administered alone, but did not produce convulsions. BMS-986187 (10 mg/kg) also enhanced the antinociceptive and antiallodynic effects of the standard DOR agonist SNC80, with only a very minor effect on SNC80-mediated convulsions. The results suggest the development of positive modulators of DOR for the management of pain and/or depression. SIGNIFICANCE STATEMENT: The delta opioid receptor (DOR) has been suggested as a target to treat depression and pain. However, agonists at this receptor can cause convulsions. This study demonstrates that a positive allosteric modulator of DOR administered alone reduces depression-like behaviors and, in combination with a DOR agonist, shows robust pain-relieving actions, without convulsive effects. This suggests a novel and safe treatment for depression and/or pain.
Integrating CYP2D6 and MATE1 activities in drug-drug interaction assessment: Insights from newly developed antidepressant drug ammoxetine.
Chen R, Ferri N
J Pharmacol Exp Ther · 2026 Jun · PMID 42242161 · Publisher ↗
Abstract loading — click title to view on PubMed.
The intelectin 1-bestrophin-2-glutamate axis regulates glutamate homeostasis and suppresses colorectal cancer progression.
Lu D, Zhou Y, Zhang H … +5 more , Wang J, Lu K, Li Y, Guo C, Zhu Y
J Pharmacol Exp Ther · 2026 May · PMID 42242160 · Publisher ↗
Colorectal cancer (CRC) is a highly prevalent malignancy with a poor prognosis, and metabolic reprogramming (eg, glutamic acid metabolism) drives its progression. However, the key regulators of glutamic acid homeostasis...
Colorectal cancer (CRC) is a highly prevalent malignancy with a poor prognosis, and metabolic reprogramming (eg, glutamic acid metabolism) drives its progression. However, the key regulators of glutamic acid homeostasis in CRC remain undefined. We analyzed the expression and prognostic significance of bestrophin-2 (BEST2) and intelectin 1 (ITLN1) using The Cancer Genome Atlas and Genotype-Tissue Expression datasets. Stable cell lines with BEST2/ITLN1/glutamine synthetase (GS) overexpression or knockdown were constructed, and functional assays including Cell Counting Kit-8, flow cytometry, and ELISA were performed to explore their roles in cell proliferation, apoptosis, and glutamic acid metabolism. Coimmunoprecipitation/immunofluorescence were used to validated BEST2-GS interaction. A nude mouse xenograft model was used to confirm the in vivo effects of the ITLN1-BEST2-GS axis. BEST2 and ITLN1 were downregulated in CRC tissues, and their expression correlated with a favorable prognosis in patients with CRC. BEST2 suppressed CRC cell proliferation and promoted apoptosis by reducing intracellular glutamic acid levels, which was mediated by its membrane-localized interaction with GS to modulate GS activity. ITLN1 acted as an upstream positive regulator of BEST2 by enhancing its promoter activity and exerted tumor-suppressive effects in a BEST2-dependent manner. The ITLN1-BEST2-GS axis orchestrated glutamic acid homeostasis, and ITLN1 overexpression significantly inhibited xenograft tumor growth in nude mice. The ITLN1-BEST2-GS axis regulates glutamic acid metabolism to suppress CRC progression, thus identifying novel potential therapeutic targets for this malignancy. SIGNIFICANCE STATEMENT: The intelectin 1-bestrophin-2-glutamine synthetase axis modulates glutamic acid metabolism and exerts a tumor-suppressive effect in colorectal cancer.
Exosomal miR-376c-3p derived from cardiac fibroblasts triggers cardiac hypertrophy by targeting ERP44.
Zhang Y, Hu X, Li J … +4 more , Jiang L, Huang J, Zhang B, Ye J
J Pharmacol Exp Ther · 2026 May · PMID 42242159 · Publisher ↗
Recent studies have revealed that exosomes, important regulators of intercellular communication, participate in various cardiac abnormalities, including hypertrophy. Cardiac fibroblasts (CFs) are one of the most abundant...
Recent studies have revealed that exosomes, important regulators of intercellular communication, participate in various cardiac abnormalities, including hypertrophy. Cardiac fibroblasts (CFs) are one of the most abundant cell types of the heart. Exosomes secreted by CFs (CFs-Exo) have been proven to participate in myocardial ischemia and atrial fibrillation. However, the roles of CFs-Exo in cardiac hypertrophy and the underlying mechanism remain to be elucidated. Our study revealed that exosomes from isoproterenol (ISO)-stimulated CFs induced hypertrophic responses and activated the calcium signaling pathway in neonatal rat cardiomyocytes (CMs). The expression of microRNA-376c-3p (miR-376c-3p) was significantly increased in CFs following ISO stimulation; concomitantly, the contents of miR-376c-3p were also increased in their exosomes. The pro-hypertrophic effects of ISO-stimulated CFs could be attributed to the exosomal delivery of miR-376c-3p, which was subsequently absorbed by neonatal rat CMs and resulted in elevated cellular miR-376c-3p content. Furthermore, endoplasmic reticulum protein 44 was identified as a direct target of miR-376c-3p. MiR-376c-3p suppressed endoplasmic reticulum protein 44 in CMs to promote Ca release from the sarcoplasmic reticulum, leading to the activation of calcineurin/nuclear factors of activated T cells signaling and the subsequent onset of hypertrophy. Additionally, transfection of CFs with miR-376c-3p mimic upregulated miR-376c-3p in the derived exosomes. Administration of mimic upregulated miR-376c-3p in the derived exosomes provoked cardiac hypertrophy and impaired heart function in mice. In contrast, downregulation of miR-376c-3p in exosomes of CFs ameliorated the detrimental effects of exosomes on CMs. These results uncovered a new role of CFs-Exo in the pathogenesis of cardiac hypertrophy, suggesting a potential therapeutic strategy by counteracting exosomal miR-376c-3p. SIGNIFICANCE STATEMENT: Our data showed that the microRNA-376c-3p (miR-376c-3p) level was increased in isoproterenol-activated fibroblasts and secreted exosomes, which subsequently provoked hypertrophic responses via promoting Ca release from the sarcoplasmic reticulum in cardiomyocytes. The detrimental effects of miR-376c-3p could be attributed to the inhibition of the downstream target endoplasmic reticulum protein 44. These findings highlighted a novel mechanism of exosome-mediated pathological cardiac hypertrophy and suggested a promising therapeutic strategy by intervening in exosomal miR-376c-3p.
Pharmacology and nonclinical development of teplizumab, a first-in-class immunotherapy for delaying the onset of type 1 diabetes.
Mamidi RNVS, Peakman M, Schmider W … +6 more , Benstein K, Knecht LA, Miller D, Glascott P, Sundermann E, Bluestone JA
J Pharmacol Exp Ther · 2026 Jun · PMID 42224885 · Publisher ↗
Teplizumab is a nonmitogenic anti-CD3 monoclonal antibody approved to delay the onset of clinical type 1 diabetes. To address the challenge of the absence of crossreactivity of teplizumab with CD3 of different preclinica...
Teplizumab is a nonmitogenic anti-CD3 monoclonal antibody approved to delay the onset of clinical type 1 diabetes. To address the challenge of the absence of crossreactivity of teplizumab with CD3 of different preclinical species that are typically used in preclinical development, a mouse surrogate of teplizumab (MST) that binds to mouse CD3 and was used in preclinical development to characterize pharmacology, toxicology, and toxicokinetics in mouse models. Teplizumab and MST showed similar binding affinities for human (K = 2.3 μM) and mouse CD3 (K = 3.0 μM), respectively. In crossreactivity analyses using human tissues, teplizumab reacted primarily with splenic T-cells. In prediabetic nonobese diabetic mice, administration of MST showed delayed diabetes onset and reduced incidence of diabetes by 30% compared with the control. In toxicity studies, MST-induced decreases in T-lymphocytes were observed. No effects on fertility, reproductive performance, or embryo-fetal development were seen. In the prenatal and postnatal development study reduced fertility in the F generation was noted at the highest maternal dose. Although MST-based evaluation may have some limitations, overall, MST served as a valuable scientific alternative for translational understanding of teplizumab pharmacology in mouse model and for toxicological hazard identification of teplizumab. Furthermore, the outlined surrogate-based preclinical evaluation approach may be applicable to other monoclonal antibodies that lack crossreactivity with commonly used preclinical species. SIGNIFICANCE STATEMENT: Teplizumab reacts with human CD3 but not conventional preclinical species and cannot be evaluated in standard preclinical models of biology and safety. To enable preclinical investigation, a mouse surrogate teplizumab (MST) and mouse models were used to evaluate pharmacology and toxicity in support of clinical development. MST demonstrated utility in elucidating pharmacology, biomarker readouts of disease activity, and potential hazards. A similar surrogate-based preclinical strategy may be applicable to other monoclonal antibodies that lack crossreactivity with commonly used preclinical species.
Artesunate does not prevent cardiac hypertrophy but inhibits heart failure progression in mice.
Zhang A, Yang G, Chu G … +4 more , Hou Z, Zhang Y, Yu Y, Yi B
J Pharmacol Exp Ther · 2026 Jun · PMID 42214973 · Publisher ↗
Heart failure (HF) poses a substantial challenge to healthcare systems globally, particularly at the advanced stages of various cardiac diseases, due to its high morbidity and mortality rates. This study aimed to assess...
Heart failure (HF) poses a substantial challenge to healthcare systems globally, particularly at the advanced stages of various cardiac diseases, due to its high morbidity and mortality rates. This study aimed to assess the therapeutic potential of artesunate in a mouse model of HF induced by isoprenaline. Adult male C57BL/6J mice were subcutaneously injected with isoprenaline (50 mg/kg/day) for 14 consecutive days, with artesunate administered during the last 7 days. Strikingly, late-phase intervention with artesunate retarded the decline of cardiac function and attenuated lung congestion in HF mice. Although it did not ameliorate cardiac hypertrophy, as indicated by unchanged heart weight and myocyte cross-sectional area, artesunate markedly alleviated interstitial fibrosis and downregulated mRNA expression of Tgfb1 and Col1a1 in failing hearts. Mechanistically, artesunate suppressed myocardial infiltration of monocytes/macrophages and downregulated key inflammatory genes, including Ccl2, Il6, Nos2, Il1b, and Tnf. Furthermore, it elevated protein levels of Nrf2, glutathione peroxidase 4, and heme oxygenase-1, and suppressed ferroptosis in failing hearts. In summary, late-phase intervention with artesunate slows HF progression in mice by mitigating myocardial inflammation, fibrosis, and ferroptosis, independent of hypertrophy regression. SIGNIFICANCE STATEMENT: Although late-phase intervention with artesunate does not impact cardiac hypertrophy, it reduces myocardial inflammation and fibrosis, slowing heart failure progression. Our findings provide compelling evidence for artesunate as a promising therapeutic candidate, with its efficacy in a clinically relevant experimental context underscoring its significant translational potential.
Low-density lipoprotein receptor-related protein 1 as a therapeutic target in acute myocardial infarction: From mechanisms to clinical translation.
Marchetta M, Lopez RI, Potere N … +4 more , Ngo LL, Saucerman J, Toldo S, Abbate A
J Pharmacol Exp Ther · 2026 Jun · PMID 42214972 · Publisher ↗
Low-density lipoprotein receptor-related protein-1 (LRP1) is a ubiquitously expressed, multifunctional membrane receptor that combines scavenger and signaling functions regulating, among others, lipid metabolism, inflamm...
Low-density lipoprotein receptor-related protein-1 (LRP1) is a ubiquitously expressed, multifunctional membrane receptor that combines scavenger and signaling functions regulating, among others, lipid metabolism, inflammation and fibrosis pathways, cell survival, and extracellular matrix remodeling. In acute myocardial infarction (AMI), these integrated actions of LRP1 are highly relevant because myocardial salvage and infarct healing depend on tuned control of ischemia-reperfusion injury (IRI), innate immune activation, and reparative remodeling. Despite major advances in reperfusion strategies, additional therapies are needed to blunt excessive postischemic inflammation and improve short and long-term outcomes after AMI. In preclinical models of AMI, LRP1 agonism limits IRI by promoting cardiomyocyte survival and dampening inflammatory amplification; this is accompanied by smaller infarct size, improved systolic function, reduced leukocyte-driven tissue damage, resulting in improved infarct healing and protection from adverse ventricular remodeling. Early clinical translation studies evaluated pharmacologic activation of this pathway. Recent pilot studies in patients with ST-elevation AMI using plasma-derived α1 antitrypsin, an endogenous LRP1 agonist, and synthetic peptide 16, a synthetic LRP1-agonist peptide, indicate feasibility and short-term tolerability, with preliminary signals consistent with reduced inflammatory burden and enzymatic injury, requiring further evaluation in larger randomized controlled trials. In this review, we summarize the molecular and cellular basis of LRP1 functions in the regulation of postinfarction cardiac inflammation and repair. We also discuss emerging clinical evidence supporting LRP1 as a novel therapeutic target to reduce IRI and promote infarct healing in patients with AMI. SIGNIFICANCE STATEMENT: Despite modern reperfusion strategies, maladaptive postischemic inflammation remains a major driver of adverse remodeling and heart failure. Low-density lipoprotein receptor-related protein-1 (LRP1) is a multifunctional receptor that integrates scavenger and signaling functions to modulate ischemia-reperfusion injury (IRI), inflammatory amplification, and postinfarction repair. This review herein synthesizes emerging preclinical and clinical evidence supporting LRP1 agonism as a novel therapeutic target to limit IRI and promote infarct healing in patients with acute myocardial infarction.
Nonclinical Characterization of ACP-204, a Novel Selective 5-HT2A Receptor Inverse Agonist.
Burstein ES, Olsson R, Skold N … +8 more , Jansen KE, Azar M, Sandiego C, Ridler K, Rabiner EA, Rhodes G, Dey PM, Pathak S
J Pharmacol Exp Ther · 2026 Jun · PMID 42208178 · Publisher ↗
Pimavanserin was the first US Food and Drug Administration approved antipsychotic drug that does not block D dopamine receptors at therapeutic doses. Pimavanserin is a selective 5-HT receptor inverse agonist that reduces...
Pimavanserin was the first US Food and Drug Administration approved antipsychotic drug that does not block D dopamine receptors at therapeutic doses. Pimavanserin is a selective 5-HT receptor inverse agonist that reduces the frequency of hallucinations and delusions associated with Parkinson disease. Despite these attributes, pimavanserin prolongs the QT interval at therapeutic doses, limiting the dose to 34 mg. In addition, pimavanserin has a 57-hour half-life, and reaches steady state in approximately 12 days. ACP-204 was identified as a compound with subnanomolar affinity in radioligand binding assays, and subnanomolar inverse agonist and antagonist potency at 5-HT receptors in cell-based functional assays. ACP-204 had 13-fold less affinity for 5-HT receptors in radioligand binding, and 30- to 100-fold less potency at 5-HT in the functional assays, and was over 1000-fold selective against over 70 other targets. ACP-204 had 9-fold lower potency inhibiting human ether-à-go-go-related gene than pimavanserin, and lower potency at Cav1.2 L-type calcium and Nav1.5 sodium channels, all channels associated with cardiovascular function. ACP-204 was active in 3 rodent models of schizophrenia, was orally active, and potently engaged with central 5-HT receptors in nonhuman primates. Long-term toxicity studies demonstrated wide safety margins, and pharmacokinetic modeling predicted a 14.7 to 21.7 hours half-life in humans. It is anticipated that reducing the potential for QT prolongation will allow greater dosing flexibility with ACP-204 compared with pimavanserin; additionally, a shorter half-life may provide faster onset of action because of plasma concentrations reaching steady state sooner. ACP-204 is currently being evaluated for efficacy and safety in Alzheimer disease psychosis and Lewy body dementia psychosis. SIGNIFICANCE STATEMENT: Psychotic disorders remain a major source of burden and disability worldwide, with current treatments limited by inadequate efficacy or significant side effects. ACP-204 is a novel 5-HT receptor inverse agonist/antagonist being evaluated clinically for its potential to treat Alzheimer disease psychosis and Lewy body dementia psychosis. Comprehensive nonclinical evaluations shown herein demonstrate that ACP-204 has optimized pharmacodynamic properties resulting in a favorable safety/tolerability profile, a broad therapeutic index, and promising effectiveness.
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 ↗
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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.
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.
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.
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