The Journal Of Pharmacology And Experimental Therapeutics[JOURNAL]
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200 papers
Effects of specialized proresolving mediators on gut epithelial barrier in early life.
Chen J, Ouahoud S, Schreurs RRCE … +8 more , Meisner S, Vermeulen JLM, Wildenberg ME, de Jonge WJ, van Goudoever JB, de Meij TGJ, Muncan V, van den Akker CHP
J Pharmacol Exp Ther · 2026 Mar · PMID 41689898 · Full text
Damage to the intestinal epithelial barrier is a hallmark of inflammatory diseases such as necrotizing enterocolitis. Specialized proresolving mediators (SPMs), such as lipoxin A4, resolvin D1, and resolvin E1, which are...
Damage to the intestinal epithelial barrier is a hallmark of inflammatory diseases such as necrotizing enterocolitis. Specialized proresolving mediators (SPMs), such as lipoxin A4, resolvin D1, and resolvin E1, which are derived from essential fatty acids, have been shown to aid in resolving inflammation and promote mucosal healing. This study aimed to explore the effects of specific SPMs on intestinal inflammatory response in an early life in vitro model. We established 3-dimensional and 3-dimensional organoid cultures from fetal and pediatric intestines and investigated the effect of an SPM cocktail (lipoxin A4, resolvin D1, and resolvin E1) on gut epithelial maturation and barrier function. An inflammatory response of the gut barrier was provoked by lipopolysaccharide and flagellin stimulations combined with proinflammatory cytokines, tumor necrosis factor-α, and interferon gamma. Additionally, repetitive mechanical wounding was developed to test the effects of the SPM cocktail on 2-dimensional organoid monolayers. Under physiological conditions, we observed no effect of SPM cocktail treatment on gut epithelial maturation. Upon cytokine challenge, there was no modulation of the inflammatory tone of the gut barrier by the SPM cocktail. However, during the repetitive wounding and recovery assay, SPM cocktail treatment accelerated barrier recovery and maintained barrier integrity for 24 hours after repeated injuries. Our findings suggest that the SPM cocktail does not affect bacterial product- or cytokine-induced epithelial inflammation, although it may accelerate epithelial barrier recovery in mechanically wounded monolayers. These results provide valuable insights into the therapeutic potential of SPMs in neonatal intestinal inflammation. SIGNIFICANCE STATEMENT: Using early life intestinal organoid models, we found that although specialized proresolving mediators did not alter cytokine- or bacterial product-induced inflammation, they significantly enhanced epithelial barrier recovery following repeated mechanical injury.
iRhom2 deletion protects against diabetic neuropathy by suppressing neuroinflammation.
Mattos Pereira V, Wasseen ID, Zhang Z … +4 more , Sun QQ, Hosur V, Roballo KCS, Nair S
J Pharmacol Exp Ther · 2026 Mar · PMID 41666516 · Full text
Diabetic peripheral neuropathy (DPN) is a major complication of diabetes, characterized by progressive nerve damage and debilitating pain. Neuroinflammation plays a critical role in its pathogenesis, but therapeutic opti...
Diabetic peripheral neuropathy (DPN) is a major complication of diabetes, characterized by progressive nerve damage and debilitating pain. Neuroinflammation plays a critical role in its pathogenesis, but therapeutic options remain limited. A disintegrin and metalloprotease 17 (ADAM17) regulates inflammatory signaling, but its ubiquitous expression makes it a difficult target. This study examined the role of inactive rhomboid protein 2 (iRhom2), a cofactor essential for ADAM17 activation, in the development of DPN. Diabetes was induced in wild-type (WT) and iRhom2 knockout (KO) mice using streptozotocin. Both groups developed hyperglycemia (>300 mg/dL); however, only WT mice exhibited significant mechanical and thermal hyposensitivity, characteristic of DPN. iRhom2 KO mice were protected from these deficits, suggesting a glucose-independent protective mechanism. In sciatic nerves of diabetic WT mice, expression of ADAM17, iRhom2, and tumor necrosis factor-α increased by 5.3-, 7.7-, and 48-fold, respectively; these changes were attenuated in KO mice. Histological analysis showed preservation of nerve fiber structure and reduced inflammatory infiltration in diabetic iRhom2 KOs. In cultured human microglial cells, high glucose triggered oxidative stress and induction of inflammatory mediators, including cyclooxygenase-2, interleukin-6, interleukin-8, tumor necrosis factor-α, and monocyte chemoattractant protein-1. Silencing of iRhom2 reduced these responses. These findings identify iRhom2 as a critical mediator of diabetic neuropathy, acting by regulating neuroinflammation. Deletion of iRhom2 confers glucose-independent protection against neuropathic pain, highlighting iRhom2 as a promising therapeutic target for preventing or treating DPN. SIGNIFICANCE STATEMENT: This study identifies iRhom2 as a key mediator of diabetic peripheral neuropathy by driving neuroinflammation and oxidative stress. Deletion of iRhom2 provided protection against neuropathic changes, without altering glucose levels, revealing a glucose-independent mechanism. These findings establish iRhom2 as a promising therapeutic target, offering new translational opportunities to prevent or treat diabetic neuropathy.
Inhalable iguratimod-loaded nanostructured lipid carriers for asthma-chronic obstructive pulmonary disease overlap management.
Khawas S, Sharma N
J Pharmacol Exp Ther · 2026 Mar · PMID 41650753 · Publisher ↗
Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is a chronic inflammatory airway condition that presents with features of both asthma and COPD, complicating its treatment and management. In this study,...
Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is a chronic inflammatory airway condition that presents with features of both asthma and COPD, complicating its treatment and management. In this study, the potential of iguratimod-loaded nanostructured lipid carriers (IGU-NLCs) as an inhalable therapy for ACO was investigated. IGU-NLCs were formulated and characterized using Fourier-transform infrared, X-ray diffraction, thermogravimetric - differential scanning calorimetry, field emission scanning electron microscopy, and particle size analysis. The formulation demonstrated favorable physicochemical stability and nanoscale particle size distribution. IGU-NLCs demonstrated good cytocompatibility and minimal reactive oxygen species induction at 10 μg/mL in vitro, supporting their suitability for safe pulmonary delivery. An in vivo ACO model was induced by papain/cigarette smoke exposure, followed by treatment with plain IGU and IGU-NLCs via inhalation, to evaluate their therapeutic effects on oxidative stress, inflammation, and lung function. X-ray and ECG analyses revealed that IGU-NLCs more effectively reversed the airway obstruction and cardiac alterations induced by papain/cigarette smoke exposure. Histopathologic analysis showed significant improvement in lung architecture. Moreover, immunohistochemistry for CD68 revealed reduced macrophage infiltration, indicating an anti-inflammatory effect. Overall, this study demonstrates that nebulized IGU-NLCs offer a noninvasive, targeted, and effective approach to mitigate ACO pathology, highlighting their potential for clinical translation in respiratory therapeutics. SIGNIFICANCE STATEMENT: Asthma-chronic obstructive pulmonary disease overlap lacks effective therapies because of its complex pathophysiology. This study repurposed iguratimod using nanostructured lipid carriers for inhalation, which reduced inflammation, oxidative stress, and lung damage in vivo, highlighting a novel, targeted strategy for this overlapped disease.
Screening of anticancer drugs against potential carcinogenic bacterial virulence proteins in colorectal cancer: An in silico approach.
Saravanan V, Gopalakrishnan V, Majula Shifani Mahendran MI … +2 more , Guliy OI, Velusamy M
J Pharmacol Exp Ther · 2026 Mar · PMID 41650752 · Publisher ↗
Anaerobic bacteria induced colorectal cancer (CRC) represents a significant clinical concern. The understanding of cancer etiology has evolved significantly, from being predominantly viewed as genetically induced cancer...
Anaerobic bacteria induced colorectal cancer (CRC) represents a significant clinical concern. The understanding of cancer etiology has evolved significantly, from being predominantly viewed as genetically induced cancer to bacterial biofilm induced cancer. Despite the growing evidence linking bacterial virulence to tumor progression, the molecular interactions between bacterial biofilm proteins and anticancer drugs remain poorly understood. We explored the interaction of clinically used anticancer drugs (bevacizumab, capecitabine, fluorouracil, fruquintinib, leucovorin calcium, regorafenib, and tucatinib) with virulence proteins of oncomicrobes including Helicobacter pylori (cytotoxin-associated gene A), Fusobacterium nucleatum (Fusobacterium adhesion A), Bacteroides fragilis (Bfragilis toxin). Leucovorin calcium exhibited the highest binding affinity toward cytotoxin-associated gene A (-7.9 kcal/mol) through 7 hydrogen bonds. Similarly, regorafenib demonstrated strong interaction with Bfragilis toxin and Fusobacterium adhesion A, with binding affinities -8.6 and -6.5 kcal/mol, respectively, supported by multiple hydrogen and covalent bonds. Subsequent molecular dynamics simulations revealed low root mean square deviation and root mean square fluctuation values, indicating stable and compact drugs-protein interaction. Therefore, contributing to functional inactivation of bacterial virulence factors, thereby weakening bacterial colonization, biofilm formation, and events that sustain pro tumorigenic microenvironment. Overall, the present study provides computational evidence over anticancer drugs that may interact with bacterial virulence mechanisms implicated in anaerobic bacteria induced CRC, offering novel insights into therapeutic avenues capable of mitigating bacterial contributions in CRC initiation and progression. SIGNIFICANCE STATEMENT: The study focuses evaluating anticancer drugs targeting carcinogenic virulence proteins associated with bacterial biofilm mediated colorectal cancer.
Alternative reinforcement reduces oxycodone self-administration in male and female monkeys: Implications for treating opioid use disorder.
Baehr C, Harris AC
J Pharmacol Exp Ther · 2026 Mar · PMID 41638111 · Publisher ↗
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Tyrosine kinase inhibitors for wet age-related macular degeneration: The current developmental landscape.
Amin R, Kaiser PK
J Pharmacol Exp Ther · 2026 Mar · PMID 41638110 · Full text
Age-related macular degeneration (AMD) is a leading cause of permanent vision loss in older patients worldwide. The neovascular (wet) AMD is characterized by abnormal choroidal neovascularization driven by vascular endot...
Age-related macular degeneration (AMD) is a leading cause of permanent vision loss in older patients worldwide. The neovascular (wet) AMD is characterized by abnormal choroidal neovascularization driven by vascular endothelial growth factor (VEGF), platelet-derived growth factor, and Tie2 signaling pathways, leading to retinal damage and progressive vision decline. Current standard-of-care anti-VEGF therapies aim to limit choroidal neovascularization through extracellular targeting of cytokines involved in the VEGF signaling pathway implicated in angiogenesis. Although these existing therapies can be effective, many patients face a high treatment burden of multiple intraocular injections, which can negatively impact compliance, safety, and long-term efficacy. Tyrosine kinase inhibitors (TKIs) aim to address these limitations by offering longer durability, broad-spectrum targeting of angiogenic pathways, and a reduction in treatment burden through intracellular targeting of angiogenic pathways. With multiple pharmaceutical TKI candidates advancing through clinical trials and showing promising data, this class of drugs could lead to a shift in future treatment options for patients with wet AMD. Despite the progress TKIs have made, there have yet to be any candidates approved for wet AMD treatment. Much of the existing evidence is from early-phase and short-term studies, and questions remain about long-term efficacy and safety compared to current standard-of-care anti-VEGF therapies. Nevertheless, with multiple candidates advancing through phase III clinical trials, TKIs have the potential to emerge as a next-generation treatment class that may transform the wet AMD therapeutic landscape. SIGNIFICANCE STATEMENT: Given the chronic nature of wet age-related macular degeneration and the limitations of current anti-vascular endothelial growth factor therapies, tyrosine kinase inhibitors have emerged as a promising class of anti-angiogenic agents. This review highlights the recent clinical developments in this evolving therapeutic landscape.
Structural modifications of the tumor necrosis factor-α inhibitor Enbrel affect its therapeutic efficacy in a mouse model of rheumatoid arthritis.
Birnboim-Perach R, Aharon A, Amir A … +6 more , Grotto O, Palgi-Shloosh M, Diesendruck Y, Beltran N, Nahary L, Benhar I
J Pharmacol Exp Ther · 2026 Mar · PMID 41633063 · Publisher ↗
Therapeutic blockade of proinflammatory cytokines has revolutionized the treatment of rheumatoid arthritis (RA), leading to the approval of several therapeutic biologics for RA. A prominent target in RA is tumor necrosis...
Therapeutic blockade of proinflammatory cytokines has revolutionized the treatment of rheumatoid arthritis (RA), leading to the approval of several therapeutic biologics for RA. A prominent target in RA is tumor necrosis factor-α (TNF-α), a proinflammatory cytokine. Etanercept (Enbrel), a fusion protein comprising the soluble portion of the p75-TNF receptor and the Fc fragment of human IgG1 (hinge, CH2, and CH3 domains) was the first TNF-α specific biologic to make a substantial impact for the treatment of RA. Enbrel (etanercept) differs structurally and functionally from other anti-TNF-α biologics (monoclonal antibodies), primarily because of its unique structure. This study aimed to explore whether structural modifications of Enbrel with specific focus on isotype variation and the incorporation of the CH1 domain to the Fc constant region, can potentiate its therapeutic efficacy. We developed 4 murine versions of Enbrel: mEnbrel2a and mEnbrel1, with and without the CH1 domain. These versions were assessed for their ability to bind and neutralize TNF-α in vitro, as well as their therapeutic effects in vivo using an experimental RA mouse model. We found that all mEnbrel variants bound TNF-α with comparable affinities. However, the mEnbrel2a derivatives, particularly with the CH1 domain, exhibited superior TNF-α neutralization in vitro. In vivo, mEnbrel2a with a CH1 domain provided the most significant reduction in disease severity. These findings underscore the critical role of isotype and domain selection in optimizing the therapeutic potential of Fc-fusion proteins and provide valuable insights applicable to other Fc-fusion proteins and a broader range of pathologies. SIGNIFICANCE STATEMENT: This study reveals that isotype and Fc domain engineering of tumor necrosis factor-α-targeting biologics enhances therapeutic efficacy against rheumatoid arthritis in a mouse model. Specifically, incorporation of the CH1 domain into an Enbrel-based Fc-fusion protein of the mouse IgG2a isotype significantly improved disease outcomes (delay of onset, arthritis severity, reduction in inflammatory white blood cells), highlighting the importance of Fc configuration for optimizing mEnbrel. These findings provide a foundation for the rational design of next-generation Fc-fusion therapeutics for autoimmune diseases.
NS-229, a novel Janus kinase 1 inhibitor, ameliorates eosinophilic vasculitis in an ovalbumin-induced mouse model by modulating multiple cytokine signaling pathways.
Kageyama K, Kikuchi E, Hoshino N … +3 more , Ito M, Akiyama S, Shiba Y
J Pharmacol Exp Ther · 2026 Feb · PMID 41633022 · Publisher ↗
Methyl (1-{[6-{[(1S)-1-cyclopropylethyl]amino}-2-(pyrazolo[5,1-b][1,3]thiazol-7-yl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)carbamate mono(4-methylbenzenesulfonate) monohydrate (NS-229) is a novel Janus kinase 1 inhibitor...
Methyl (1-{[6-{[(1S)-1-cyclopropylethyl]amino}-2-(pyrazolo[5,1-b][1,3]thiazol-7-yl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)carbamate mono(4-methylbenzenesulfonate) monohydrate (NS-229) is a novel Janus kinase 1 inhibitor currently being evaluated in a phase 2 global study (NCT06046222) for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA). We investigated the nonclinical efficacy of NS-229 to support its therapeutic use in treating EGPA. Its effects were investigated in human peripheral blood eosinophils, human peripheral blood mononuclear cells, and a mouse model of eosinophilic vasculitis induced by ovalbumin. In human peripheral blood eosinophils, NS-229 and an anti-interleukin (IL)-5 antibody, but not prednisolone, significantly decreased the expression of CD69 induced by IL-5. In human peripheral blood mononuclear cells, NS-229 and prednisolone, but not the anti-IL-5 antibody, significantly decreased the production of cytokines such as interferon gamma, IL-5, and IL-13, induced by anti-CD3/CD28 antibody. NS-229 inhibited the development of vascular lesions, decreased eosinophil counts in the blood and bronchoalveolar lavage fluid, and lowered bronchoalveolar lavage fluid lymphocyte counts in the ovalbumin-induced eosinophilic vasculitis mouse model. The effects of NS-229 in the mouse model were comparable to those of prednisolone and tofacitinib, a pan-Janus kinase inhibitor. Regarding safety, NS-229 did not influence the platelet or red blood cell counts, which were significantly elevated with tofacitinib and prednisolone, respectively. NS-229 did not affect body weight, which was significantly increased with tofacitinib and significantly decreased with prednisolone. Collectively, the nonclinical investigation of NS-229 showed a suppression of multiple cytokine signals and inhibition of vascular lesion formation without impacting the relevant side-effect parameters, suggesting its potential as an additional treatment option for EGPA. SIGNIFICANCE STATEMENT: NS-229 inhibited the formation of vascular lesions in a mouse model of ovalbumin-induced eosinophilic vasculitis without affecting certain side-effect parameters. The underlying mechanism of action is suggested to be the selective inhibition of multiple cytokine signals via JAK1.
Retraction Notice to "The Protective Effect of Superoxide Dismutase Mimetic M40401 on Balloon Injury-Related Neointima Formation: Role of the Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1" J Pharmacol Exp Ther 311 (2004) 44-50.
Muscoli C, Sacco I, Alecce W … +9 more , Palma E, Nistico R, Costa N, Clementi F, Rotiroti D, Romeo F, Salvemini D, Mehta JL, Mollace V
J Pharmacol Exp Ther · 2026 Jan · PMID 41620270 · Publisher ↗
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Corrigendum to "Potassium 2-(1-hydroxypentyl)-benzoate improves memory deficits and attenuates amyloid and τ pathologies in a mouse model of Alzheimer's disease" The Journal of Pharmacology and Experimental Therapeutics 350 (2014) 361-374.
Peng Y, Hu Y, Xu S … +6 more , Rong X, Li J, Li P, Wang L, Yang J, Wang X
J Pharmacol Exp Ther · 2026 Jan · PMID 41620269 · Publisher ↗
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Cholesterol-dependent control of endosomal escape regulates intracellular trafficking of small interfering RNA therapeutics and interactions with small molecule drugs.
Tawfik SM, Giang Nguyen LT, Jin J … +2 more , Armanios B, Zhong XB
J Pharmacol Exp Ther · 2026 Feb · PMID 41564596 · Full text
Small interfering RNA (siRNA) therapeutics are an emerging modality for treating genetic and metabolic diseases, with 8 approved drugs now in clinical use. Despite substantial advances in delivery technologies, including...
Small interfering RNA (siRNA) therapeutics are an emerging modality for treating genetic and metabolic diseases, with 8 approved drugs now in clinical use. Despite substantial advances in delivery technologies, including lipid nanoparticles and N-acetylgalactosamine conjugates, inefficient intracellular trafficking, particularly endosomal escape, remains a critical limitation. Here, we identify cellular cholesterol as a key regulator of siRNA intracellular trafficking, endosomal escape, and pharmacologic efficacy. Using a 2D hepatocyte cell culture model and cationic-lipid-mediated delivery, we show that pharmacologic cholesterol reduction via statin treatment significantly impairs siRNA-mediated gene silencing with minimal effects on cellular uptake, indicating a post-internalization trafficking defect. Cholesterol supplementation restores silencing, confirming its essential role in functional siRNA activity. Confocal imaging reveals increased siRNA entrapment in late endosomes following statin treatment, consistent with impaired endosomal escape. Notably, chloroquine, an endosomal escape enhancer, rescues gene silencing under cholesterol-reduced conditions. Mechanistically, we identify annexin A2 (ANXA2) as a critical mediator of this cholesterol-sensitive trafficking pathway, as ANXA2 knockdown abrogates the restorative effect of cholesterol supplementation. Together, these findings uncover a previously unrecognized cholesterol- and ANXA2-dependent mechanism regulating siRNA efficacy. While these mechanistic insights are specific to cationic-lipid-based delivery, they highlight intracellular cholesterol as an important determinant of siRNA endosomal escape. Future studies using microphysiological systems or in vivo models will be essential to validate and extend these findings beyond this 2D cell culture model. SIGNIFICANCE STATEMENT: This study uncovers cholesterol as an essential and previously unrecognized determinant of small interfering RNA therapeutic efficacy, acting through annexin A2 to enable endosomal escape, a critical bottleneck in RNA drug delivery. The findings position cholesterol modulation as a viable approach to improve the intracellular delivery and therapeutic effectiveness of RNA-based drugs.
Beyond exercise and appetite: The expanding biology and therapeutic potential of N-lactoyl-phenylalanine.
Oni OP, Scott B, Schwartz LC … +3 more , MacCormack TJ, Hankir M, Rourke JL
J Pharmacol Exp Ther · 2026 Feb · PMID 41547294 · Full text
N-lactoyl-phenylalanine (Lac-Phe) has emerged as a signaling metabolite connecting cellular metabolism to systemic physiology. Synthesized through carnosine dipeptidase 2-mediated conjugation of lactate and phenylalanine...
N-lactoyl-phenylalanine (Lac-Phe) has emerged as a signaling metabolite connecting cellular metabolism to systemic physiology. Synthesized through carnosine dipeptidase 2-mediated conjugation of lactate and phenylalanine, Lac-Phe increases acutely in response to exercise and feeding, the primary drivers of its elevation under physiologic conditions. In preclinical models, Lac-Phe acts as a potent regulator of energy balance. Its administration suppresses appetite and reduces body weight in obesity, whereas pharmacologic interventions such as metformin elevate circulating Lac-Phe to produce similar anorexigenic effects. Converging evidence implicates central mechanisms, including inhibition of orexigenic agouti-related peptide neurons, positioning Lac-Phe as a mediator linking peripheral metabolic signals to appetite control. The first human Lac-Phe clinical trial in individuals with obesity began dosing in 2025, evaluating appetite suppression and glucose-lowering effects. Beyond metabolism, Lac-Phe promotes anti-inflammatory macrophage polarization, conferring protection in murine models of colitis and spinal cord injury. Circulating Lac-Phe also rises in conditions such as mitochondrial dysfunction, sepsis, and phenylketonuria, suggesting broader associations with perturbed energy metabolism and systemic stress responses. This review integrates current knowledge spanning molecular mechanisms, physiological regulation, and clinical translation. We examine Lac-Phe biosynthesis, tissue distribution, and regulatory patterns across physiological and disease states, and highlight emerging mechanisms of action in metabolic and inflammatory signaling. Finally, we discuss key knowledge gaps, highlighting the need to define targets, transporters, and tissue sources to shape the next phase of discovery. Collectively, these advances position Lac-Phe at the forefront of exerkine biology and as a promising molecular link between metabolism, immunity, and therapeutic innovation. SIGNIFICANCE STATEMENT: Evidence across molecular, physiological, and translational domains positions Lac-Phe as a promising therapeutic target. This review frames our understanding of Lac-Phe biology-from its biosynthesis to its roles in energy balance and outlines the key questions that will define ongoing discovery.
Naringenin-functionalized polyester nanoparticles improve oral urolithin A delivery and protect against cisplatin-induced kidney injury via heme oxygenase-1 activation and mitochondrial quality control.
Wahab AT, Ganugula R, Sheikh-Hamad D … +3 more , Bolisetty S, Arora M, Kumar MNVR
J Pharmacol Exp Ther · 2026 Feb · PMID 41534475 · Publisher ↗
Cisplatin remains a cornerstone of chemotherapy, but its clinical use is often limited by cisplatin-induced acute kidney injury, a condition driven by oxidative stress, inflammation, and mitochondrial dysfunction. Here,...
Cisplatin remains a cornerstone of chemotherapy, but its clinical use is often limited by cisplatin-induced acute kidney injury, a condition driven by oxidative stress, inflammation, and mitochondrial dysfunction. Here, we developed naringenin-functionalized polyester nanoparticles (P2Ns-NAR) to enhance the oral delivery and therapeutic efficacy of urolithin A (UA), a mitochondrial-targeting metabolite with cytoprotective properties. The resulting formulation, P2Ns-NAR-UA, conferred kidney protection in vitro and in vivo, outperforming the nontargeted nanoparticle formulation (P2Ns-UA). Notably, in vivo efficacy was achieved at a 50% lower dose. Molecular docking studies suggest UA exhibits a favorable heme oxygenase-1 binding energy of -7.43 kcal/mol, supporting its potential as a promising drug candidate. Mechanistic studies demonstrated that P2Ns-NAR-UA upregulate heme oxygenase-1 and activate PTEN-induced putative kinase 1/Parkin-mediated mitophagy, promoting mitochondrial quality control and preserving dynamics by increasing mitofusin-1/2 and reducing dynamin-related protein 1 and mitochondrial fission protein 1 expression. Treatment also attenuated inflammatory cytokines (interleukin 6, interleukin 8, and tumor necrosis factor-α), immune activation markers (cluster of differentiation 80 and 45), and kidney injury biomarkers (neutrophil gelatinase-associated lipocalin, cystatin C, and osteopontin). Histological analysis confirmed reduced tubular damage and fibrosis. These findings establish P2Ns-NAR-UA as a promising oral therapeutic platform to mitigate cisplatin-induced acute kidney injury through coordinated modulation of inflammation, oxidative stress, and mitochondrial homeostasis. Further investigation in cisplatin-resistant cancer models is warranted to establish this platform's dual therapeutic potential and translational value. SIGNIFICANCE STATEMENT: This study shows that naringenin-functionalized polyester nanoparticles improves intestinal uptake of encapsulated agents through intestinal folate receptors. Naringenin-functionalized polyester nanoparticles loaded with urolithin A (P2Ns-NAR-UA) doubles the efficacy of polyester nanoparticles loaded with urolithin A, achieving comparable results at half the dose. The formulation enhances cell health, reduces inflammation, and restores kidney function, making it a promising adjuvant to cisplatin therapy by improving outcomes while minimizing toxicity.
Salusin α counteracts salusin β to attenuate artery medial calcification through the inhibition of oxidative stress and extracellular signal-regulated protein kinases signaling pathway in rats with chronic kidney disease.
Gao Q, Wang M, Cao WJ … +5 more , Xia CX, Zhu HX, Tang RJ, Zhou YB, Chen LL
J Pharmacol Exp Ther · 2026 Jan · PMID 41534472 · Publisher ↗
BACKGROUND: Arterial medial calcification (AMC) is closely associated with morbidity and mortality in people with chronic kidney disease (CKD). Endogenous bioactive peptides, salusin α and salusin β, are alternative spli...
BACKGROUND: Arterial medial calcification (AMC) is closely associated with morbidity and mortality in people with chronic kidney disease (CKD). Endogenous bioactive peptides, salusin α and salusin β, are alternative splicing products from preprosalusin encoded by the torsion dystonia-related gene. The present study was designed to explore their roles and mechanisms in AMC under CKD condition. CKD rats with AMC were induced by feeding an adenine (0.75%) with high phosphorus (1.5%) diet for 4 weeks. Calcification in A7r5 cells (rat thoracic aorta smooth muscle cells) was induced with calcifying media. The results showed that in rats with CKD and in the calcifying media-treated A7r5 cells, salusin α protein level was reduced, whereas salusin β was elevated in plasma, in aorta and in A7r5 cells, respectively. Calcification, osteogenic transition, oxidative stress, and extracellular signal-regulated protein kinases (ERK) activation were significantly induced, and these changes were effectively reversed by salusin α application, but notably promoted by salusin β administration. More importantly, salusin α or the ERK activation inhibitor U0126 pretreatment in vitro attenuated the promoting effects of salusin β on calcification, osteogenic transition and oxidative stress and ERK activation which also were alleviated by U0126 treatment in vivo. This study indicates that salusin α can attenuate AMC and counteract the promoting effect of salusin β on AMC by inhibiting oxidative stress and the activation of ERK signaling pathway, suggesting that upregulating the expression of salusin α, but downregulating the expression of salusin β in aorta, may be a good strategy for the treatment of vascular calcification under CKD condition. SIGNIFICANCE STATEMENT: The current study found that bioactive peptides, salusin α and salusin β, were important mediators in arterial medial calcification (AMC) under CKD conditions. Salusin α could attenuate AMC and counteract the promoting effect of salusin β on AMC by inhibiting ERK activation and oxidative stress, and the inhibition of ERK activation effectively relieved AMC in CKD. Our findings provide new insights for preventing AMC under CKD condition.
Efficacy and safety of fibroblast growth factor 21 analogs in metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis: A systematic review and network meta-analysis.
Abdeljawad MM, Hasan MT, Fareed A … +7 more , Abouelmagd K, Abdelkader Saed SA, Ali S, Keshk M, Khan M, Taha NA, Taha AM
J Pharmacol Exp Ther · 2026 Jan · PMID 41529428 · Publisher ↗
Metabolic dysfunction-associated steatotic liver disease has emerged as a global public health concern. Fibroblast growth factor 21, a liver hormone, is gaining interest because of its ability to regulate metabolism and...
Metabolic dysfunction-associated steatotic liver disease has emerged as a global public health concern. Fibroblast growth factor 21, a liver hormone, is gaining interest because of its ability to regulate metabolism and improve metabolic dysfunction-associated steatotic liver disease. In this network meta-analysis, we investigated the efficacy of these treatments in treating metabolic dysfunction-associated steatotic liver disease. A comprehensive search was conducted across electronic databases, including PubMed, Scopus, the Cochrane Library, and Web of Science, till August 2025. We used R software to analyze data using a random effects model. Heatmaps were used to visualize the included interventions' ranking. We included 9 clinical trials comprising 1277 patients. Among them, 284 received efruxifermin, 263 received pegbelfermin, 151 received pegozafermin, 65 received efimosfermin, 139 received MK-3655, and 375 received a placebo. Pegozafermin and efruxifermin were effective in improving liver fibrosis (RR, 3.89-3.93, P < .05; RR, 2.23-1.91, P < .05, respectively), whereas the other interventions did not yield statistical significance. Efimosfermin α, efruxifermin, and pegozafermin improved different metabolic parameters, including adiponectin, hemoglobin A1c, and non-high-density lipoprotein. However, no significant differences were observed in body weight and low-density lipoprotein. For liver enzymes, efimosfermin α had the greatest reduction of alanine aminotransferase and aspartate aminotransferase, whereas efruxifermin was most effective in reducing γ-glutamyl transferase levels. The odds of adverse events were higher in pegozafermin, efimosfermin, and efruxifermin groups, mainly attributed to mild to moderate gastrointestinal adverse events. In conclusion, efruxifermin and pegozafermin are promising therapeutic options with a tolerable adverse event profile; meanwhile, efimosfermin α showed promising results in improving metabolic parameters, with histologic results yet to be published. SIGNIFICANCE STATEMENT: This meta-analysis evaluates the efficacy of fibroblast growth factor 21 analogs in improving metabolic dysfunction-associated steatotic liver disease. Efruxifermin and pegozafermin were the most significant in improving liver fibrosis; moreover; significant improvements in some metabolic parameters were observed with efimosfermin α, efruxifermin, and pegozafermin.
Inhibition of CYP2A6-mediated nicotine metabolism: A potential strategy for smoking cessation therapy.
Olawale ME, Lazarus P
J Pharmacol Exp Ther · 2026 Feb · PMID 41529330 · Publisher ↗
Despite the availability of US Food and Drug Administration-approved pharmacotherapies, smoking continues to be a significant public health problem, with long-term cessation rates often falling below 20%. The cytochrome...
Despite the availability of US Food and Drug Administration-approved pharmacotherapies, smoking continues to be a significant public health problem, with long-term cessation rates often falling below 20%. The cytochrome P450 2A6 (CYP2A6) enzyme plays a critical role in nicotine metabolism, and individuals with genetically reduced CYP2A6 activity exhibit slower nicotine clearance, lower cigarette consumption, and greater cessation success. This observation has led researchers to explore pharmacological inhibition of CYP2A6 as a strategy to aid in smoking cessation. In this review, we discuss 4 CYP2A6 inhibitors, methoxsalen, tranylcypromine, 5-(4-ethylpyridin-3-yl)thiophen-2-yl)methanamine, and cannabidiol, describing their potency, translational potential, and safety considerations. Methoxsalen, a mechanism-based inactivator, inhibits nicotine metabolism in both animals and humans, but there are concerns about its phototoxicity and off-target effects. Tranylcypromine, although a competitive inhibitor of CYP2A6, may also increase nicotine consumption via monoaminergic effects, thereby limiting its practical use in cessation therapies. 5-(4-ethylpyridin-3-yl)thiophen-2-yl)methanamine is a novel synthetic inhibitor with unprecedented potency and specificity in vitro, but lacks clinical validation to support this claim. Cannabidiol is a promising dual-action candidate because it inhibits CYP2A6 in vitro and reduces nicotine intake in rodents, as well as reduces cigarette use and cue reactivity in early human trials. Although these findings emphasize the therapeutic potential of targeting CYP2A6 in smoking cessation efforts, additional validation is required for clinical translation. These include the need for robust human pharmacokinetic studies, long-term safety evaluations, and assessment across genetically diverse populations. With additional research, CYP2A6 inhibition could become a practical and personalized way to improve smoking cessation outcomes. SIGNIFICANCE STATEMENT: This study highlights the clinical significance of inhibiting CYP2A6-mediated nicotine metabolism as a novel smoking cessation strategy by reviewing in vitro, preclinical, and clinical data of agents that mimic the slow CYP2A6 metabolizer phenotype and improve smoking cessation outcomes.
Lithium, a GSK-3β inhibitor, attenuates depression and chemobrain induced by doxorubicin in rats: Emphasis on brain BDNF/TrkB/Akt/GSK-3β/mTOR/Nrf2/HO-1 axis.
Aboul-Fotouh S, Elnahas EM, Alafifi AA … +2 more , Ahmed MY, Taha AM
J Pharmacol Exp Ther · 2026 Feb · PMID 41518901 · Publisher ↗
Although chemotherapy remains a life-saving intervention for numerous cancer patients, it is often accompanied by depressive symptoms and cognitive impairments, "chemobrain." Noteworthy, multiple studies emphasize the ro...
Although chemotherapy remains a life-saving intervention for numerous cancer patients, it is often accompanied by depressive symptoms and cognitive impairments, "chemobrain." Noteworthy, multiple studies emphasize the role of glycogen synthase kinase 3β (GSK-3β) in depression and chemobrain; nevertheless, no available data relate GSK-3β inhibitors to chemobrain. Herein, this study aims to investigate the effect of the GSK-3β inhibitor, lithium, on behavioral and neurobiological abnormalities in a doxorubicin (DOX)-induced rat model of chemobrain. The chemobrain model was established through weekly intraperitoneal injections of doxorubicin (2 mg/kg/wk) for a duration of 4 weeks, whereas lithium (100 mg/kg/d, i.p.) was administered concomitantly over the same period. Behavioral, neurochemical, and histopathological evaluations were performed after the experimental protocol. DOX-induced depressive-like behaviors and cognitive impairments, with reduction in prefrontal cortex tropomyosin receptor kinase B receptors, brain-derived neurotrophic factor protein kinase B (BDNF), and phosphorylated protein kinase B, elevating the levels of the active form of GSK-3β, which lessened phosphorylated mammalian target of rapamycin/nuclear factor-erythroid 2-related factor 2/heme oxygenase-1 and BDNF/synapsin-1 pathways, while triggering overexpression of NF-κB, proinflammatory cytokines, oxidative stress, apoptosis, tau hyperphosphorylation, and neurodegeneration. Lithium ameliorated DOX-induced behavioral, neurochemical, and histological abnormalities. To the best of our knowledge, this study presents the first evidence that lithium treatment can modulate DOX-induced depression and cognitive deficits, potentially through revamping the BDNF/tropomyosin-related kinase receptor B/protein kinase B/GSK-3β/mammalian target of rapamycin/nuclear factor-erythroid 2-related factor 2/heme oxygenase-1 signaling cascade, thereby attenuating oxidative stress, neuroinflammation, apoptosis, neurofibrillary tangles, and subsequent neurodegeneration. SIGNIFICANCE STATEMENT: To the best of our knowledge, this study is the first to detect antidepressant and procognitive effects of lithium in DOX-induced chemobrain via GSK-3β inhibition. Accordingly, lithium offers a promising therapeutic target for the management of chemotherapy-induced depression and chemobrain.
Dual sigma receptor 1 and 2 modulator improves memory behavior in mouse model of age-related cognitive decline.
Loraine A, Farr SA, Niehoff ML … +7 more , Larrea IG, Ganev Y, Samanta J, Rahman K, Crider AM, Sandoval K, Witt KA
J Pharmacol Exp Ther · 2026 Feb · PMID 41518900 · Full text
Sigma-1 (S1R) and sigma-2 (S2R) receptors are promising targets for treating Alzheimer disease (AD), playing important roles in cognitive function, with potential to mitigate neuropathology. The dual S1R/S2R receptor mod...
Sigma-1 (S1R) and sigma-2 (S2R) receptors are promising targets for treating Alzheimer disease (AD), playing important roles in cognitive function, with potential to mitigate neuropathology. The dual S1R/S2R receptor modulator (+/-)-cis-1-n-Butyl-8-methoxy-1,2,3a,4,5,9b-hexahydrobenz[e]indole hydrochloride (BBZI) was evaluated in the senescence-accelerated mouse prone 8 model of cognitive decline and AD as to behavior and hippocampal expression effects. Chronic BBZI treatment (0, 0.001, 0.01, 0.1, 1.0, or 10 mg/kg, i.p. daily, 27-days) was evaluated using a behavioral battery including open field activity (day-15), elevated plus maze (day-16), Y-maze (day-22), T-maze foot-shock avoidance (days 20 and 27), and novel object recognition (days 23 and 24). No changes were observed in open field, elevated plus maze, Y-maze, or novel object recognition tests at any dose of BBZI as compared with vehicle. BBZI enhanced T-maze foot-shock memory retention at 0.1 (P < .05, Bonferroni) and 1.0 mg/kg (P < .001, Bonferroni) compared with vehicle (day-27). In a separate cohort, a single-injection of BBZI (0, 0.001, 0.01, 0.1 & 1.0 μg, i.c.v.) with testing 7-days later showed a significant effect in the T-maze foot-shock test (P = .011) and enhanced memory retention behavior at 0.01 μg compared with vehicle (P < .05, Bonferroni). Poly(A) RNA sequencing evaluation of hippocampal tissue 24-hours after intracerebroventricular administered BBZI (1.0 μg/μL) versus vehicle showed unique gene expression changes, with notable effects relevant to mitochondrial energetics and synaptic function. Gene enrichment analysis identified affiliations with pathways involved in neurodegenerative disease. This data supports dual S1R/S2R receptor modulation as a promising strategy for AD treatment and identifies potential gene pathways involved. SIGNIFICANCE STATEMENT: Dual sigma receptor 1 and 2 modulator BBZI improved memory behavior in senescence-accelerated mouse prone 8 mice. Evaluation of senescence-accelerated mouse prone 8 hippocampal tissue 24 hours after BBZI (1.0 μg/μL i.c.v.) versus vehicle administration identified gene changes related to mitochondrial energetics and synaptic function. BBZI to mitigates cognitive decline behavior, impacting hippocampal genes critical for brain function.
Repositioning lidocaine as a TMEM16A Ca-activated Cl channel blocker for the treatment of pulmonary arterial hypertension.
Suzukawa A, Hemmi R, Fujiwara M … +6 more , Motomura T, Kondo R, Suzuki Y, Ko EA, Yamamura A, Yamamura H
J Pharmacol Exp Ther · 2026 Feb · PMID 41518899 · Publisher ↗
TMEM16A forms a Ca-activated Cl (Cl) channel that plays essential roles in the cardiovascular, gastrointestinal, and central nervous systems. Dysregulation of TMEM16A expression has been implicated in the development of...
TMEM16A forms a Ca-activated Cl (Cl) channel that plays essential roles in the cardiovascular, gastrointestinal, and central nervous systems. Dysregulation of TMEM16A expression has been implicated in the development of several diseases, making selective TMEM16A modulators attractive therapeutic candidates. Here, the effects of lidocaine, a voltage-gated Na (Na) channel blocker widely used as a local anesthetic and antiarrhythmic drug, on TMEM16A-mediated Cl currents were investigated using whole-cell patch-clamp recordings in human embryonic kidney 293 cells stably expressing human TMEM16A. Lidocaine, an amide-type local anesthetic, inhibited TMEM16A Cl currents in a concentration-dependent manner (IC = 0.69 mM). Similarly, tetracaine, an ester-type local anesthetic, suppressed TMEM16A Cl currents. Lidocaine produced weaker inhibition of human TMEM16B Cl currents (IC = 1.50 mM). Among Na channel blockers, the antiarrhythmic drugs, mexiletine and quinidine, inhibited TMEM16A currents, whereas the anticonvulsants, phenytoin and carbamazepine, showed no effect. In monocrotaline-induced pulmonary arterial hypertension (PAH) rats, in which TMEM16A expression is upregulated, lidocaine exerted stronger inhibitory effects on Cl currents in pulmonary arterial smooth muscle cells compared with those in control rats. Daily administration of lidocaine (30 mg/kg for 14 days) improved in vivo PAH parameters, including right ventricular systolic pressure, Fulton index, and pulmonary vascular remodeling, in monocrotaline-induced PAH rats. In conclusion, lidocaine inhibits TMEM16A Cl channels independently of Na channel blockade and attenuates PAH progression, supporting its potential as a repositioned therapeutic candidate for PAH. SIGNIFICANCE STATEMENT: Lidocaine, a voltage-gated Na channel blocker widely used as a local anesthetic and antiarrhythmic drug, significantly inhibited TMEM16A Ca-activated Cl channels. Lidocaine also ameliorated pulmonary arterial hypertension (PAH) progression in experimental PAH rats, suggesting that it directly targets TMEM16A Cl channels and represents a promising repositioned therapeutic option for PAH.
Erratum to "Spontaneous daily sleep disruptions associated with morphine dependence and withdrawal in rats" [The Journal of Pharmacology and Experimental Therapeutics 392 (2025) 103766].
McKelvey HA, Pierce BE, Lynch JM … +7 more , Kim AL, Holter KM, Gadient RA, Sheffler DJ, Velicelebi G, Cosford NDP, Gould RW
J Pharmacol Exp Ther · 2026 Jan · PMID 41512741 · Full text
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