Pharmacological Reviews[JOURNAL]
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200 papers
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.
Preclinical abuse potential testing using behavioral economics and drug self-administration demand-curve analysis: A strategy to improve resolution of drug stratification for regulatory control.
Banks ML, Negus SS, Varshneya NB … +6 more , Reissig CJ, Chiapperino D, Strickland JC, Reed DD, Hursh SR, Kearns DN
Pharmacol Rev · 2026 Mar · PMID 41637884 · Full text
New chemical entities (NCEs) that act on the central nervous system are synthesized in pharmaceutical drug development programs for investigational purposes or by clandestine laboratories for illicit purposes. One compon...
New chemical entities (NCEs) that act on the central nervous system are synthesized in pharmaceutical drug development programs for investigational purposes or by clandestine laboratories for illicit purposes. One component in the regulatory evaluation process of any NCE is abuse potential assessment, which involves both preclinical and human laboratory experiments to compare a NCE with an established and validated positive control that has known abuse potential in humans. Although multiple procedures are available in both preclinical and human laboratories, this review has focused on preclinical drug self-administration procedures because these results are heavily weighted in the regulatory evaluation process. Preclinical drug self-administration procedures have demonstrated high predictive validity for human abuse potential, and procedures that use simple fixed-ratio schedules of reinforcement, as recommended by the current U.S. Food and Drug Administration guidance, have good sensitivity for detecting drug reinforcement and abuse potential. However, these procedures have displayed poor resolution for ranking NCEs along an abuse-potential continuum that may inform controlled substance schedule placement. This review discusses the utility of behavioral economic/demand-curve experimental designs as a method to improve the resolution for differentiating relative reinforcing strength across drugs and ranking abuse potential for considerations of regulatory control. Theoretical benefits of demand-curve analysis are considered, and experimental parameters that optimize those benefits are reviewed. The influence of chronic drug exposure and history on demand-curve metrics of drug reinforcing strength and abuse potential is also reviewed. Future directions are highlighted toward empirically determining the utility of behavioral economic approaches for preclinical abuse potential assessment. SIGNIFICANCE STATEMENT: Simple fixed-ratio schedules of reinforcement have good sensitivity for detecting drug reinforcement and abuse potential but have poor resolution for ranking chemical entities along an abuse-potential continuum. Behavioral economic/demand-curve approaches maybe a method to increase resolution for abuse potential assessment. Accordingly, a preclinical abuse potential algorithm incorporating both simple fixed-ratio schedules and behavioral economic/demand-curve methods is described. Finally, the manuscript describes how individual subject traits and state variables, including chronic drug exposure and history, impact behavioral economic metrics of drug abuse potential.
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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From physiopathology to treatment of familial hypercholesterolemia: Existing and emerging pharmacotherapies.
Cicero AFG, Mahjoubin-Tehran M, Reiner Ž … +3 more , Eid AH, Jamialahmadi T, Sahebkar A
Pharmacol Rev · 2026 Mar · PMID 41616414 · Publisher ↗
Familial hypercholesterolemia (FH) is a hereditary disorder with a semidominant inheritance pattern, characterized by elevated levels of low-density lipoprotein cholesterol, which significantly increases the risk of earl...
Familial hypercholesterolemia (FH) is a hereditary disorder with a semidominant inheritance pattern, characterized by elevated levels of low-density lipoprotein cholesterol, which significantly increases the risk of early atherosclerosis-related cardiovascular disease. This review discusses the genetics, epidemiology, diagnosis, and novel therapeutic approaches for FH. Mutations in the LDL receptor gene are the primary cause of FH. Less common causes include mutations in proprotein convertase subtilisin/kexin type 9 and apolipoprotein B-100. In extremely rare cases, LDLR adaptor protein 1 mutations can also cause FH. Epidemiological data indicate that FH is frequently underdiagnosed, particularly within certain ethnic populations. Diagnostic criteria often rely on clinical manifestations and family history, although genetic testing is increasingly advocated for confirmation. Recent advancements in pharmacotherapy offer substantial opportunities for effective low-density lipoprotein cholesterol control and management of FH, providing new hope for affected patients. This includes established drugs such as proprotein convertase subtilisin/kexin type 9 inhibitors, inclisiran, lomitapide, and bempedoic acid. Emerging therapies include evinacumab, lerodalcibep, antisense oligonucleotide-based drugs, certain cholesteryl ester transfer protein inhibitors like obicetrapib, AZD8233, gemcabene, diacylglycerol O-acyltransferase-2 inhibitors, acyl-CoA:cholesterol acyltransferase-2 inhibitors, vupanorsen, volanesorsen, olezarsen, pelacarsen (TQJ230), olpasiran (AMG890), zerlasiran (SLN360), lepodisiran (LY3819469), and muvalaplin. However, some of these newer agents are specifically designed to lower elevated Lp(a), which often occurs in patients with FH, and triglycerides. Furthermore, gene-editing approaches, such as clustered regularly interspaced short palindromic repeats -Cas9 and meganuclease, as well as vaccines targeting key components of cholesterol metabolism, represent promising future directions for FH treatment. SIGNIFICANCE STATEMENT: Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein cholesterol levels, which increase the risk of atherosclerotic cardiovascular disease. Conventional therapies, such as statins, often have limited efficacy in patients with FH. Recent pharmacological advancements provide significant opportunities for successful low-density lipoprotein cholesterol management and control of FH. Although some of these agents are already used, several highly effective compounds are in development, heralding a promising future for FH treatment.
Platelet activation, aspirin, and cancer: From basic science to clinical trials.
Patrono C, Burn J, Patrignani P … +1 more , Langley RE
Pharmacol Rev · 2026 Jan · PMID 41592353 · Full text
There is extensive evidence that aspirin prevents cancer, but the mechanism of action is uncertain. Once-daily low-dose aspirin (75-100 mg) completely and permanently inactivates the cyclooxygenase (COX) activity of pros...
There is extensive evidence that aspirin prevents cancer, but the mechanism of action is uncertain. Once-daily low-dose aspirin (75-100 mg) completely and permanently inactivates the cyclooxygenase (COX) activity of prostaglandin G/H synthase-1 (COX-1) in platelets, suppressing thromboxane (TX)A-dependent platelet activation. In this article, we review the mechanistic links between platelet activation, inflammation, cancer development, and progression and summarize recent clinical trial results and associated biomarker studies. We hypothesize that persistently enhanced platelet activation has 2 distinct tumorigenic consequences mediated by the release of TXA: (1) at sites of gastrointestinal mucosal lesions, it promotes a local inflammatory response with COX-2 induction and enhanced prostaglandin E biosynthesis, contributing to early events in carcinogenesis; (2) it inhibits T-cell immunity to cancer by the activation of TXA receptors in lymphocytes, promoting cancer progression and metastasis dissemination. Supporting these hypotheses, abnormal and persistent platelet activation has been demonstrated in patients recently diagnosed with cancer and in those with adenomatous colonic polyps. To date, most clinical trials evaluating aspirin have focused on either primary cancer prevention, metastasis prevention (adjuvant treatment), or cardiovascular prevention. For an individual, benefits may accrue from one (or all) of these areas, and they collectively need to be balanced against bleeding risk. Collating large clinical datasets for meta-analysis alongside mechanistic studies will inform the interpretation of clinical trials, with the aim of identifying individuals most likely to benefit from aspirin. SIGNIFICANCE STATEMENT: We reviewed the experimental and clinical evidence supporting a previously unrecognized role of platelet activation in both the early stage of colorectal carcinogenesis and in cancer progression and metastasis. The findings support the use of low-dose aspirin in cancer prevention and treatment. Data from large randomized clinical trials support the use of aspirin for the prevention of Lynch syndrome cancers and in the adjuvant setting for patients with colorectal cancer whose tumors have a mutation in the phosphatidylinositol 3-kinase pathway genes. Although thromboxane A-dependent platelet activation is the most thoroughly investigated mechanism and the established drug target of the antiplatelet effect of low-dose aspirin, it seems biologically plausible that other pathways of platelet activation, such as the ADP-P2Y pathway, may play a similar and possibly complementary role.
The neuropharmacological basis of placebo analgesia: Mechanisms and clinical applications in the context of chronic pain.
Boorman DC, Crawford LS, Siddiqi Z … +3 more , Martin LJ, Henderson LA, Keay KA
Pharmacol Rev · 2026 Mar · PMID 41579472 · Publisher ↗
The therapeutic value of placebo analgesia to treat conditions of chronic pain is both underappreciated and understudied. It is now abundantly clear that chronic pain is caused by a complex array of biological adaptation...
The therapeutic value of placebo analgesia to treat conditions of chronic pain is both underappreciated and understudied. It is now abundantly clear that chronic pain is caused by a complex array of biological adaptations, including changes to neural, endocrine, and immune function, which undoubtedly explains why it is so difficult to treat. Paradoxically, however, this also presents a unique opportunity for placebo interventions by offering several biological targets that could lead to analgesic relief for chronic pain patients. In this review, we first outline the problem of chronic pain, highlighting the similarities and differences between acute and chronic pain mechanisms. Next, we comprehensively review studies investigating the neurobiological and neuropharmacological mechanisms underlying placebo analgesia in acute and chronic pain contexts. We conclude that the neural mechanisms and neuropharmacology of placebo analgesia in the context of chronic pain are currently poorly understood and deserve specific focus for future research. Finally, we discuss the range of therapeutic possibilities for placebo interventions to provide clinically relevant and meaningful pain relief to chronic pain patients, many of which could be quickly, easily, and ethically implemented into clinical practice today. SIGNIFICANCE STATEMENT: Chronic pain remains a significant global health challenge as it is often resistant to conventional treatments. This review synthesizes our current knowledge of the neurobiology of acute and chronic pain and highlights key overlaps in the mechanisms of placebo analgesia. We highlight how placebo-based strategies, including expectancy modulation, pharmacological conditioning, and open-label placebos, could be ethically integrated into clinical practice to enhance pain management. These approaches offer a promising avenue to activate endogenous pain relief systems, reduce opioid reliance, and personalize treatment for both placebo responders and nonresponders. Harnessing placebo mechanisms presents a largely underused yet promising approach to chronic pain management, with the potential to refine existing treatment strategies and address the global burden of chronic pain.
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.
Animal models of attention-deficit/hyperactivity disorder: Diversity and validity.
Sarah BSN, Sandra SS, Mari-Carmen M … +9 more , Otmane B, Tania B, Abbas A, Laurent G, Paul B, Nóra K, Ana-Maria SP, Walid H, Marc L
Pharmacol Rev · 2026 Jan · PMID 41529545 · Publisher ↗
Attention-deficit/hyperactivity disorder (ADHD) is one of the most widespread neurodevelopmental disorders globally, marked by chronic symptoms of inattention and/or hyperactivity-impulsivity. Its multifactorial origin a...
Attention-deficit/hyperactivity disorder (ADHD) is one of the most widespread neurodevelopmental disorders globally, marked by chronic symptoms of inattention and/or hyperactivity-impulsivity. Its multifactorial origin and phenotypic heterogeneity make it a complex condition, and despite substantial research, the precise causes of ADHD remain poorly understood. A significant challenge in advancing ADHD research is the lack of a unified resource that consolidates animal models across different species and considers the diversity of ADHD subtypes and associated coexisting conditions. This lack of standardization of the models delays progress in developing a deeper understanding of the neuronal and molecular mechanisms behind the disorder, which is essential to advance its treatment. This review aims to bridge this gap by offering a comprehensive compilation of available animal models used in ADHD research, accompanied by an evaluation of their validity. It is essential for researchers to have access to a range of models, each selected based on the specific scientific objectives and hypotheses of their studies. The review highlights that an extensive approach to studying ADHD, including its various dimensions and associated conditions, requires the use of multiple animal models. Moreover, it emphasizes the importance of assessing the mechanisms and broader effects of current pharmacological treatments while also exploring novel therapeutic possibilities. By providing a clearer and more structured resource, this work pursues to assist researchers in selecting the most appropriate models for their investigations. Additionally, it aims to contribute to the broader understanding of ADHD neurobiology, offering new perspectives for new models and the potential for more targeted therapeutic strategies. SIGNIFICANT STATEMENT: Attention-deficit/hyperactivity disorder (ADHD), one of the most prevalent neurodevelopmental disorders globally, is marked by inattention and/or hyperactivity-impulsivity. This review evaluates animal models for ADHD and its coexisting conditions, emphasizing the need for diverse models to reflect its complexity. It underscores the importance of selecting appropriate models to address specific research goals and investigates current and potential pharmacological treatments, providing a vital resource for advancing ADHD research and improving therapeutic approaches.
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.
Targeting fatty acid synthase for cancer drug discovery: Retrospective analyses and outlook.
Cui Q, Josephraj S, Gu B … +2 more , Liu JY, Zhang JT
Pharmacol Rev · 2026 Jan · PMID 41519050 · Full text
Enhanced de novo lipogenesis is a hallmark of cancer cells, enabling their proliferation, metastasis, and resistance to therapy. Among key lipogenic enzymes, fatty acid synthase (FASN) is frequently overexpressed in canc...
Enhanced de novo lipogenesis is a hallmark of cancer cells, enabling their proliferation, metastasis, and resistance to therapy. Among key lipogenic enzymes, fatty acid synthase (FASN) is frequently overexpressed in cancer but minimally expressed in most normal adult tissues, making it an appealing drug target. Human FASN is the sole cytosolic type I enzyme responsible for the de novo synthesis of palmitate. It is a homodimer of 270 kDa multidomain protein, functioning like an automatic assembly line. Its acyl carrier protein domain serves as a flexible arm, transporting the elongating acyl chain through other enzymatic domains responsible for chain elongation and modification, including malonyl/acetyltransferase, β-ketoacyl synthase, enoyl reductase, β-ketoacyl reductase, dehydrase, and thioesterase. The process begins at the malonyl/acetyltransferase domain, where the acetyl and malonyl groups from acetyl-CoA and malonyl-CoA, respectively, are transferred to the acyl carrier protein. FASN has been validated to play vital roles in promoting cancer progression, supporting cancer cell survival, reprogramming lipid metabolism, modulating oncogenic signaling pathways, and inducing drug resistance. Over the past 2 decades, significant progress has been made in developing inhibitors targeting different domains of FASN, including structure-based drug design, repurposing existing drugs, and nature-derived compounds with FASN-inhibitory properties. Despite these efforts, only a handful of inhibitors have entered clinical trials, such as 3-V Biosciences-2640 (denifanstat) and repurposed omeprazole, and none have received regulatory approval to date. In this review, we critically evaluate FASN-targeting strategies, highlight domain-specific targeting challenges, and discuss emerging insights that may help overcome current limitations, aiming to guide future discovery and optimization of FASN-targeted therapeutics. SIGNIFICANCE STATEMENT: Enhanced lipogenesis and fatty acid synthase overexpression in cancer make this multidomain enzyme an attractive target for therapy and overcoming drug resistance. Despite progress with novel and repurposed inhibitors, none have gained approval. This review critically examines past efforts, current challenges, and offers insights to guide future development of effective fatty acid synthase-targeting cancer therapeutics.
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.
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