Pharmacological Reviews[JOURNAL]
Sun
200 papers
Therapeutic potential of crystal-engineered berberine cocrystals ameliorates PCOS phenotypes via AMPK-IRS1/PI3K/Akt axis: An integrative computational and preclinical study.
Kamalakannan U, Sai Durga Surampudi AV, Racha V … +3 more , Amanchy R, Jain N, Muralidharan K
J Pharmacol Exp Ther · 2026 May · PMID 42275928 · Publisher ↗
Polycystic ovary syndrome (PCOS) is a complex endocrine-metabolic disorder characterized by hyperandrogenism, chronic anovulation, and insulin resistance, with hyperinsulinemia playing a pivotal role in exacerbating ovar...
Polycystic ovary syndrome (PCOS) is a complex endocrine-metabolic disorder characterized by hyperandrogenism, chronic anovulation, and insulin resistance, with hyperinsulinemia playing a pivotal role in exacerbating ovarian dysfunction. Although berberine (BBR) exhibits insulin-sensitizing properties, its therapeutic potential is limited by poor oral bioavailability. Our previous study developed BBR cocrystals with gallic and gentisic acid, achieving a 1.8-fold increase in C to overcome bioavailability issues. The present study evaluated berberine-gallic acid (BBR-GAL) and berberine-gentisic acid (BBR-GEN) using an integrated in silico and in vivo approach in a letrozole-induced PCOS mouse model. Molecular docking simulations suggested stronger predicted binding of BBR relative to gallic acid and gentisic acid across all receptor systems, supporting its role as the dominant binder. Further, the coformers exhibited weaker but spatially proximal interactions, indicating potential indirect effects on the local binding environment. In vivo, letrozole administration induced hallmark PCOS features, including weight gain, impaired glucose tolerance, hyperandrogenism, ovarian inflammation, and disruption of hepatic insulin signaling. Treatment with BBR-GAL and BBR-GEN significantly improved metabolic parameters and restored insulin responsiveness. Notably, treatment with cocrystals was associated with increased adenosine monophosphate-activated protein kinase activation and reduced insulin receptor substrate-1 Ser307 phosphorylation, leading to enhanced phosphatidylinositol 3-kinase/protein kinase B signaling. Furthermore, treatment attenuated ovarian inflammation by downregulating interleukin 1-beta, interleukin 6, and tumor necrosis factor-alpha, and normalized luteinizing hormone receptor and androgen receptor expression. Collectively, these findings support the further investigation of BBR-GAL and BBR-GEN as multitarget agents that integrate insulin sensitization, antiinflammatory activity, and hormonal regulation for the management of PCOS. SIGNIFICANCE STATEMENT: This study demonstrates that crystal-engineered BBR cocrystals show improved efficacy against metabolic and reproductive dysfunction in an experimental model of PCOS. By restoring hepatic insulin signaling through modulation of the adenosine monophosphate-activated protein kinase-insulin receptor substrate-1/phosphatidylinositol 3-kinase/protein kinase B axis and attenuating ovarian inflammation, these formulations provide mechanistic validation for improved therapeutic efficacy. These findings indicate that crystal-engineered BBR could be a useful approach in improving the endocrine-metabolic phenotypes of preclinical PCOS.
Chimeric antigen receptor T-cell therapy in rheumatoid arthritis.
Dec P, Kubisa A, Plewa P … +1 more , Pawlik A
J Pharmacol Exp Ther · 2026 May · PMID 42275927 · Publisher ↗
Chimeric antigen receptor T-cell (CAR-T) therapy, previously used primarily in oncology, is emerging as a promising immunomodulatory strategy for rheumatoid arthritis. Its mechanism of action is based on T-cell engineeri...
Chimeric antigen receptor T-cell (CAR-T) therapy, previously used primarily in oncology, is emerging as a promising immunomodulatory strategy for rheumatoid arthritis. Its mechanism of action is based on T-cell engineering, enabling the selective elimination of autoreactive B cells, long-lived plasma cells, and other effector populations that sustain chronic inflammation. The most advanced constructs (including CD19-directed CAR-T therapy, B-cell maturation antigen-directed CAR-T therapy, and modular anti-fluorescein isothiocyanate CAR-T therapy) demonstrate the ability to achieve profound and sustained depletion of pathogenic immune cells, reduce proinflammatory cytokine levels, and induce remission in patients refractory to biological therapies. Advances in the design of subsequent generations of CARs, together with safety-enhancing technologies such as inducible caspase-9, herpes simplex virus thymidine kinase, and monoclonal antibody-based safety switches, have significantly improved control of adoptive lymphocyte activity and reduced the risk of cytokine release syndrome and persistent immunosuppression. However, therapeutic efficacy depends on multiple immunological factors, including the anticitrullinated protein antibody status, cytokine profile, and the functional reserve of T cells used for genetic modification. Preclinical evidence and early clinical observations suggest that CAR-T therapy may represent a new class of disease-modifying treatment for rheumatoid arthritis, with the potential to achieve durable remission and inhibit joint destruction. Nevertheless, further well controlled studies are required to optimize target selection, establish long-term safety, and define how this technology can be effectively integrated with existing therapeutic strategies. SIGNIFICANCE STATEMENT: This article discusses the possibility of a new application of chimeric antigen receptor T-cell (CAR-T) therapy in the treatment of patients with rheumatoid arthritis (RA). CAR-T therapy represents a novel approach for treatment of autoimmune diseases, including RA. Originally developed for hematological malignancies, this technology involves genetic modification of T cells to enable specific recognition and elimination of autoreactive B cells. Recently, increasing research into CAR-T therapy for RA has highlighted both substantial therapeutic potential and important safety concerns.
Reframing SGLT2 inhibition: Anti-inflammatory mechanisms and drug target insights emerging from EMPA-TROPISM.
El-Yazbi AF, Fayed R, El-Nikhely N … +1 more , Mechref YS
J Pharmacol Exp Ther · 2026 Jun · PMID 42275926 · Publisher ↗
Abstract loading — click title to view on PubMed.
Potential regulation of kynurenine pathway metabolism by the galantamine-memantine combination in rheumatologic diseases: A hypothesis-driven review.
Mathew N, George S, Rejimon P … +13 more , Orofino C, Shaikh A, Mistry D, Mazahreh L, Jose A, Imran H, Gupta SJ, Sen R, Ferraro TN, Lovejoy DB, Rahman S, Stone TW, Koola MM
J Pharmacol Exp Ther · 2026 Jun · PMID 42269448 · Publisher ↗
Recent studies have highlighted the pivotal role of the kynurenine pathway (KP) in systemic inflammatory disorders. Although KP modulation has been explored in diseases such as dementia and schizophrenia, its therapeutic...
Recent studies have highlighted the pivotal role of the kynurenine pathway (KP) in systemic inflammatory disorders. Although KP modulation has been explored in diseases such as dementia and schizophrenia, its therapeutic potential in rheumatologic diseases remains largely unexplored. The objective of this article is to explore the potential role of the galantamine-memantine combination, with or without N-acetylcysteine (NAC), in regulating KP metabolism and its possible relevance to the pathophysiology of rheumatologic diseases. This article proposes a novel therapeutic strategy involving a combination of galantamine, a modulator of nicotinic receptor, and memantine, a N-methyl-D-aspartate receptor antagonist, with or without NAC, to target KP dysfunction in rheumatologic diseases. Galantamine and memantine may exert synergistic neuroimmune effects by reducing the production of neurotoxic KP metabolites, such as quinolinic acid, while promoting protective branches of the pathway. NAC, through its antioxidant properties, may further support this approach by mitigating oxidative stress and restoring immune balance. This combined therapy seeks to address key mechanisms of inflammatory rheumatologic diseases such as rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, osteoarthritis, and psoriatic arthritis. This multifaceted approach may represent a potential direction for the treatment of rheumatologic diseases by integrating metabolic, neuroimmune, and antioxidant pathways. If future studies support the proposed mechanistic interactions, galantamine-memantine combination could potentially be explored as an adjunctive strategy alongside existing therapies. However, its clinical impact on treatment requirements or health care costs remains unknown and requires investigation in well designed randomized controlled trials. SIGNIFICANCE STATEMENT: A growing body of evidence in rheumatologic diseases implicates the kynurenine pathway (KP) metabolism. The galantamine-memantine combination, with or without N-acetylcysteine, through its regulatory action in KP could potentially be explored as an adjunctive strategy alongside existing therapies. Future randomized controlled trials are essential to establish efficacy, safety, and optimal patient selection.
International Union of Basic and Clinical Pharmacology. CXXII. Applying an objective evaluation to the status of class A orphan G protein-coupled receptors.
Alexander SPH, Bennett KA, Brown AJ … +16 more , Glass M, Gloriam DE, Hanson J, Insel PA, Kelly E, Langmead CJ, Martemyanov KA, Neubig RR, Offermanns S, Rosenkilde MM, Schulte G, Smith NJ, Wu H, Faccenda E, Harding SD, Davenport AP
Pharmacol Rev · 2026 May · PMID 42269381 · Publisher ↗
In this review, we, on behalf of the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology, describe criteria for assessing the evidence for pairing receptors with endogenous/...
In this review, we, on behalf of the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology, describe criteria for assessing the evidence for pairing receptors with endogenous/physiological ligands for formal receptor deorphanization. This process is illustrated through consideration of the class A G protein-coupled receptors (GPCRs) not yet formally paired with an endogenous/physiological ligand by the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology. Of the 67 orphan class A GPCRs considered, 25 class A GPCRs have no identified endogenous agonists, although 5 (GPR21, GPR27, GPR52, GPR85, and GPR88) have synthetic ligands that have the potential to be used as tools for uncovering physiological roles and further pharmacological properties of these receptors. Surprisingly, 6 orphan GPCRs (GPR135, GPR152, GPR153, MRGPRF, MRGPRG, and MRGPRX3) have no clear pharmacology or phenotype reported following genetic disruption. Thirty-two orphan GPCRs have been paired with at least 1 endogenous agonist (mainly lipids and their derivatives, peptides, and other metabolites), but further characterization is required from the scientific community to validate these results. We identify 10 orphan class A GPCRs for which there are plausible grounds for considering deorphanization: GPR4 (protons), GPR15 (GPR15L), GPR31 (12S-hydroxyeicosatetraenoic acid), GPR39 (zinc divalent ions, Zn), GPR65 (protons), GPR68 (protons), GPR132 (9-hydroxyoctadecadienoic acid), GPR183 (7α,25-dihydroxycholesterol), MRGPRD (β-alanine), and MRGPRX1 (bovine adrenal medulla peptide 8-22). The issue of nomenclature for these 10 GPCRs will be considered by further subcommittees of the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology. We hope this review will prompt further investigations into these members of the currently most widely clinically exploited protein superfamily. SIGNIFICANCE STATEMENT: The use of systematic, rational nomenclature for drug targets provides a framework to ensure consistent identification and rapid recognition. Given that G protein-coupled receptors have fundamental physiological roles and are widespread targets of drugs in current clinical use, we hope the target summary and deorphanization criteria provided here will prompt renewed efforts to investigate these orphan receptors as regulators of physiology and as opportunities for future therapeutic exploitation.
Pharmacokinetic and pharmacological characterization of novel agmatine-based antihyperalgesic compounds.
Clements BM, Peterson CD, Jones P … +8 more , Kitto KF, Caye LD, Barajas C, Jakkaraj SR, Akgün E, Georg GI, Wilcox GL, Fairbanks CA
J Pharmacol Exp Ther · 2026 Jun · PMID 42263435 · Publisher ↗
Chronic pain remains a major burden to patients globally. The use of current established analgesics can be limited because of side effects. Agmatine, a nonopioid endogenous amine, reduces hyperalgesia in chronic pain. Ho...
Chronic pain remains a major burden to patients globally. The use of current established analgesics can be limited because of side effects. Agmatine, a nonopioid endogenous amine, reduces hyperalgesia in chronic pain. However, a relatively short plasma half-life and potentially moderate distribution across biological barriers may limit use. We developed a line of agmatine-based novel antihyperalgesic compounds with increased lipophilicity to improve biodistribution to the central nervous system (CNS). Through the present study, we compared 4 agmatine-based compounds for their initial pharmacological outcomes in vivo in models of thermal and tactile hypersensitivity, and we characterized their pharmacokinetic profiles and distribution to the CNS. To determine pharmacokinetic parameters, strategically substituted agmatines (SSAs) SSA1-4 were administered intravenously or orally, and plasma concentrations were assessed using high-performance liquid chromatography-mass spectrometry/mass spectrometry. To determine the in vivo pharmacological effects, agmatine or SSA1-4 were administered intrathecally, systemically, or orally, and the inhibition of N-methyl-d-aspartate-evoked nociceptive responses or complete Freund adjuvant-induced tactile hypersensitivity was determined. Agmatine and SSA1-4 inhibited N-methyl-d-aspartate-evoked nociceptive behaviors and thermal hyperalgesia following intrathecal administration. Distribution and elimination half-life were comparable to or increased relative to the parent compound, although oral bioavailability (SSA3 and SSA4) became limited by solubility. Both SSA3 and SSA4 effectively crossed the CNS barriers, and SSA4 resulted in increased CNS agmatine concentrations. These results suggest that the SSAs induce similar pharmacological outcomes compared with agmatine, with improved CNS distribution and plasma exposure. Agmatine-based compounds may be effective alternative antihyperalgesic agents for the treatment of pain. SIGNIFICANCE STATEMENT: Four new chemical entities, based on the agmatine structure, demonstrate comparable or improved pharmacokinetic parameters and pharmacological responses relative to agmatine. Agmatine-based new therapeutics may meet an urgent need for new, nonopioid analgesic therapeutics to treat chronic pain.
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.
Are we underestimating the benefits of lipid-lowering therapies?
Pirillo A, Casula M, Olmastroni E … +3 more , Scotti S, Corsini A, Catapano AL
Pharmacol Rev · 2026 May · PMID 42247802 · Publisher ↗
Cardiovascular disease remains the leading cause of morbidity and mortality worldwide, with elevated low-density lipoprotein cholesterol (LDL-C) recognized as a causal factor and the primary target for the prevention of...
Cardiovascular disease remains the leading cause of morbidity and mortality worldwide, with elevated low-density lipoprotein cholesterol (LDL-C) recognized as a causal factor and the primary target for the prevention of atherosclerotic cardiovascular disease (ASCVD). Currently available lipid-lowering agents, including statins, ezetimibe, bempedoic acid, and proprotein convertase subtilisin/kexin type 9 inhibitors, can significantly reduce the risk of cardiovascular events across a broad range of patient populations. New oral therapies with novel mechanisms of action and potentially lower costs compared with biologics (including oral proprotein convertase subtilisin/kexin type 9 inhibitors and a new cholesteryl ester transfer protein inhibitor) are under investigation to expand the armamentarium of lipid-lowering drugs and increase the number of patients who can be treated if they prove clinically beneficial. To fully understand the potential health benefits of lipid-lowering therapies, it is essential to consider the concept of cumulative LDL-C exposure and its lifelong impact on ASCVD risk. Genetic studies, Mendelian randomization, and clinical trials consistently demonstrate the cardiovascular benefits of early reduction in LDL-C. However, despite this evidence, treatment gaps, inadequate prescribing, and suboptimal treatment adherence are widespread. The cost-benefit ratio and public health impact emphasize the potential of LDL-C lowering to prevent cardiovascular events and reduce the health care burden. In addition to LDL-C, other risk factors such as lipoprotein(a), triglyceride-rich lipoproteins, and apolipoprotein B must be considered, whereas nonlipid-based mechanisms of atheroprotection, such as inflammation modulation and thrombogenic risk reduction, are also being explored. The future of lipid-lowering and ASCVD prevention requires a more individualized lipid management strategy to optimize cardiovascular outcomes across the lifespan. SIGNIFICANCE STATEMENT: Early and sustained low-density lipoprotein cholesterol reduction dramatically reduces lifelong cardiovascular risk; however, the adoption of lipid-lowering strategies in clinical practice remains suboptimal. Bridging this gap by understanding the true potential of lipid-lowering therapies could significantly reduce the global burden of atherosclerotic disease.
Vein graft failure: Pathophysiology, detection, prevention and emerging therapeutic strategies.
Brown SD, Sanchez-Esteban S, Clark L … +9 more , Miteva K, Krilis G, Forsythe RO, Nicklin SA, Carmichael S, Berry C, Al-Attar N, Newby DE, Baker AH
Pharmacol Rev · 2026 May · PMID 42242173 · Publisher ↗
Coronary and peripheral artery bypass graft surgery remain cornerstones of cardiac and vascular surgery, respectively. They utilize the saphenous vein as the preferred conduit, although it suffers from poor midterm and l...
Coronary and peripheral artery bypass graft surgery remain cornerstones of cardiac and vascular surgery, respectively. They utilize the saphenous vein as the preferred conduit, although it suffers from poor midterm and long-term outcomes, with the grafted vein often becoming occluded. Current therapeutic approaches aim to manage complications rather than prevent graft failure directly, and despite progress, failure rates have remained unchanged in decades, meaning there remains an unmet clinical need for novel therapeutic approaches. As access to the grafted tissue is available at the time of surgery, coronary and peripheral artery bypass graft are particularly suited to perioperative therapeutic manipulation and intervention that can be delivered locally and directly to the tissue immediately before grafting. Ongoing research attempts to uncover novel genes driving bypass graft failure that can be targeted for such therapies. In addition to protein-coding genes, multiple examples of noncoding genes driving graft failure are now described, including microRNAs and long noncoding RNAs with cell type-specific roles. The increasing wealth of single cell, single nuclei and spatial transcriptomic data related to cardiovascular pathologies are revealing novel target loci that could facilitate greater specificity for target manipulation in specific pathogenic cell types. In parallel, extensive research continues to develop advanced imaging techniques that can be used to monitor the patency of grafts over time, and guide the effective design of advanced therapies. Here, we discuss the progress in these areas and highlight how harmony among these will accelerate therapeutic progress toward vein graft disease. SIGNIFICANCE STATEMENT: Coronary or peripheral artery bypass surgery using saphenous vein grafts are among the most commonly performed cardiovascular surgeries for advanced vascular occlusions. However, both suffer from poor long-term graft patency. The continued development of next-generation multiomics technologies and advanced therapies are illuminating new therapeutic targets that offer hope toward novel precision medicines for peripheral and coronary artery bypass graft failure.
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.
Friend or foe? Glial-vascular interactions in health and neurodegenerative disease.
McQuaid C, Sewell M, Montagne A
Pharmacol Rev · 2026 May · PMID 42229063 · Publisher ↗
Dysfunction of glial and vascular cells is increasingly recognized as a central feature of neurodegenerative diseases. Growing evidence points to disruptions in glial-vascular interactions, which are critical for maintai...
Dysfunction of glial and vascular cells is increasingly recognized as a central feature of neurodegenerative diseases. Growing evidence points to disruptions in glial-vascular interactions, which are critical for maintaining the functions of the neurogliovascular unit throughout the lifespan, as key contributors to disease initiation and progression. However, the mechanisms governing this complex intercellular crosstalk and its potential role in disease pathogenesis remain incompletely understood. In this review, we summarize the current understanding of glial-vascular communication across health and disease, with a particular focus on Alzheimer disease, stroke, cerebral small vessel disease, Parkinson disease, Huntington disease, and multiple sclerosis. We highlight emerging cellular and molecular interactions of interest, outline major gaps in our understanding, and discuss innovative tools, including transcriptomics, which are reshaping the study of neurogliovascular dynamics. A central unresolved question is whether glial and/or vascular dysfunction represents the primary initiating event across neurodegenerative diseases, or whether these processes emerge in parallel through shared upstream drivers. Unraveling these interactions may ultimately reveal novel therapeutic opportunities for a broad range of neurodegenerative conditions. SIGNIFICANCE STATEMENT: Neurogliovascular unit interactions are fundamental to brain homeostasis, yet the molecular basis of this crosstalk and its disruption in neurodegeneration remains poorly understood. This review provides the first comprehensive synthesis of molecular mechanisms governing the Neurogliovascular unit interface across physiological and pathological conditions, integrating evidence from related disorders. By consolidating key signaling pathways, disease-associated alterations, and emerging experimental approaches, this review offers a unifying framework to guide biomarker development and therapeutic targeting.
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.
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