Journal of Pharmacology and Experimental Therapeutics最新文献

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.

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.

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.

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.

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.

The mechanisms underlying L-DOPA-induced dyskinesia (LID) largely arise from maladaptive plasticity in striatal circuits leading to altered neuronal responses to dopamine (DA) signaling. Cyclic nucleotides play a major role in the molecular cascades of DA signaling, and particularly cAMP is known to be associated with LID mechanisms. Cyclic nucleotide levels in striatal neurons are regulated by phosphodiesterases (PDEs), and 1 isoenzyme with selective affinity for cAMP and high expression in the striatum is PDE7. Here, the PDE7 inhibitor OMS-401 was evaluated for antidyskinetic effects in a nonhuman primate (NHP) model of advanced Parkinson's disease. A series of systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration followed by chronic L-DOPA treatment were used to induce advanced parkinsonism and reproducible LID in a group of 3 macaques. The effects of the PDE7 inhibitor OMS-401 were analyzed with a dose-response curve design in coadministration trials for 2 doses of L-DOPA (optimal and suboptimal). Motor disability, LID, and drug adverse reactions were assessed using standardized scales for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated NHPs. OMS-401 significantly reduced LIDs in a dose-dependent fashion without interacting with the antiparkinsonian action of L-DOPA or inducing side effects in parkinsonian NHPs. Results confirm that cAMP levels in striatal neurons play a critical role in LID mechanisms, and that PDE7 inhibition may be a strategy to control LID over the long-term DA replacement therapy in Parkinson's disease. SIGNIFICANCE STATEMENT: This study shows that selective phosphodiesterase 7 inhibition with OMS-401 reduces dyskinesia in a Parkinson's primate model without affecting L-DOPA's benefits. Phosphodiesterase 7 inhibition may offer a promising approach for L-DOPA-induced dyskinesia management, providing an alternative to treatments with dose-limiting side effects.

Despite advances in therapies that target low-density lipoprotein (LDL), atherosclerotic cardiovascular disease (ASCVD) remains a major cause of morbidity and mortality. This has led to the investigation of other biomarkers, including lipoprotein(a) [Lp(a)]. Lp(a) is a variant of LDL that is genetically determined, has proatherogenic, proinflammatory, and prothrombotic effects, and has a linear correlation with ASCVD risk. Approximately 20%-30% of the global population has elevated serum Lp(a). Recommendations for increased Lp(a) testing has heightened the need for effective medications to target this biomarker. Although traditional antilipemic agents have demonstrated negligible effects on Lp(a), multiple targeted therapies are emerging, including antisense oligonucleotides, small interfering RNA agents, and small molecules. The efficacy of these novel agents observed in early clinical trials and the development of alternate treatment modalities, including gene editing and RNA-based innovations, signal a promising new era of ASCVD prevention via non-LDL pathways. SIGNIFICANCE STATEMENT: Lipoprotein(a) is a genetically determined biomarker that significantly impacts atherosclerotic risk. The development of novel therapies that lower lipoprotein(a) warrants a broad understanding to increase comfortability and optimize utilization upon market approval.

Targeted protein degradation is an emerging strategy for experimental and therapeutic ablation of biologically important proteins. To elicit the degradation of their cellular targets, targeted protein degraders act by co-opting the endogenous cellular degradation machineries through chemically-induced proximity. While targeted protein degradation was serendipitously discovered as the mode of action of approved anticancer drugs including fulvestrant and thalidomide, recent years have witnessed systematic endeavors for the rational design of targeted protein degraders for diverse biological targets. Such endeavors have led to 3 major classes of targeted protein degraders including molecular glue degraders, proteolysis targeting chimeras, and hydrophobic tag-based degraders. Of these, several agents are clinically approved or currently evaluated in clinical trials for use in diseases such as cancer, neurodegenerative disorders, autoimmune and dermatologic conditions. The novel chemical and pharmacologic nature of targeted protein degraders heralds an emerging paradigm of pharmacology, known as event-driven pharmacology, which is different in many aspects from the occupancy-based pharmacology of conventional small-molecule inhibitors. In this review, we discuss the emerging pharmacology of different classes of targeted protein degraders including the molecular basis of their drug action and key pharmacologic properties pertinent to efficacy, selectivity, safety, and dosing considerations. SIGNIFICANCE STATEMENT: Targeted protein degradation is a novel strategy that establishes induced-proximity pharmacology as a promising next-generation therapeutic modality. This review provides insights into the common organizing principles of this emerging approach and the prospects for this rapidly evolving field.

Proteolysis-targeting chimeras (PROTACs) are gathering considerable interest due to their ability to address previously undruggable targets. We were keen to understand the potential for these very large molecules to interact with transporters that may influence absorption, distribution, metabolism, and excretion or toxicity properties and to what extent this may be predictable using machine learning models. Consequently, we tested a set of PROTACs against several human drug transporters, namely the equilibrative nucleoside (ENT) family transporters ENT1 and ENT2, which have been directly implicated in the uptake of anticancer or antiviral drugs into target cells. We describe the dramatic inhibition observed for ENT1 and ENT2 but not for the unrelated transporter organic anion transporter 4. In addition, we report dose-response relationships for ENT1 to show some PROTACs are nanomolar inhibitors. We also explored the chemistry space of small molecules tested against ENT1 and ENT2 and compared them with PROTACs to illustrate that they are found on the periphery and close to other larger small molecules. While PROTACs are thought of as a dissimilar class to small molecules, it may be possible to bring them closer to those Food and Drug Administration-approved orally available large molecules, and in turn, increase their oral bioavailability. The outcomes of these combined in vitro and computational assessments could influence PROTAC development, be useful for their repurposing as ENT1 inhibitors for several disease indications beyond their primary one, and be used for transporter machine learning model generation and evaluation. SIGNIFICANCE STATEMENT: Proteolysis-targeting chimeras are an increasingly popular class of molecules for which we do not have a complete picture of their absorption, distribution, metabolism, and excretion or toxicity properties. For example, their interactions with uptake and efflux transporters are unknown. Here, we provide evidence that many proteolysis-targeting chimeras act as inhibitors of equilibrative nucleoside transporters 1 and 2. We hope to stimulate further study of their potential for inhibition of other transporters.

The opioid antagonists, naloxone and nalmefene, are used clinically to rapidly reverse opioid overdose, but often precipitate withdrawal symptoms in opioid-dependent individuals. This study compared 2 medications used for opioid use disorder, buprenorphine and methadone, to naloxone for reversing fentanyl-induced effects in rats. Buprenorphine alone did not produce significant respiratory depression at 0.5-5.0 mg/kg. Rats were challenged with 0.1 mg/kg fentanyl, which resulted in a significant reduction in oxygen saturation (SpO₂), and naloxone 0.1 mg/kg, buprenorphine 3.0 mg/kg, methadone 2.25 mg/kg, or saline control was given to reverse fentanyl effects. Antinociception and SpO₂ were restored to baseline by 15 minutes after administration of naloxone and buprenorphine. The saline group showed a slow return to baseline SpO₂ within 30 minutes, whereas methadone extended the duration of, but did not enhance, the effects of fentanyl. To determine whether buprenorphine could rapidly (within minutes) reverse fentanyl-induced respiratory depression, rats were given a dose of fentanyl 0.1 mg/kg s.c., followed by saline, naloxone 0.1 mg/kg, or buprenorphine 3.0 mg/kg, and SpO₂ was monitored continuously for 10 minutes. Both naloxone and buprenorphine reversed fentanyl effects within 3.5 minutes, whereas the saline group did not return to baseline levels during the monitoring period. Buprenorphine at 0.3 and 1.0 mg/kg also reversed fentanyl effects, with a slower onset of reversal. In a follow-up study, rats received fentanyl followed by saline, buprenorphine, or methadone for reversal, and blood and brain levels were measured. Fentanyl concentration in the brain was not significantly affected by methadone and buprenorphine treatment, suggesting that differences in SpO₂ were not attributable to pharmacokinetic interactions. These data support repurposing buprenorphine for the treatment of opioid overdose. SIGNIFICANCE STATEMENT: Opioid overdoses cause ∼80,000 annual deaths in the United States. Buprenorphine is an opioid partial agonist used for opioid use disorder. This study used a rat model to compare buprenorphine to naloxone for efficacy in reversing fentanyl-induced respiratory depression.