Journal of Pharmacology and Experimental Therapeutics最新文献

Estrogen receptor-related receptors (ERRα, ERRβ, and ERRγ) are orphan nuclear receptors that regulate genes involved in mitochondrial biogenesis, oxidative phosphorylation, fatty acid oxidation, and the Krebs cycle. ERRs are essential for skeletal muscle adaptation to aerobic exercise and represent promising targets for exercise mimetic therapeutics. We previously developed an ERR pan-agonist, SLU-PP-332 (332), which improves aerobic performance in mice but lacks oral bioavailability. Here, we characterize SLU-PP-915 (915), a chemically distinct ERR pan-agonist that is orally bioavailable and exhibits potent in vivo exercise mimetic activity. Compound 915 enhances aerobic exercise performance (distance and duration) to a similar extent as 332 when administered intraperitoneally and maintains comparable efficacy when administered orally, adjusted for systemic exposure. Both compounds robustly induce the expression of DNA damage-inducible transcript 4 (Ddit4), a gene induced by acute aerobic exercise, with levels matching or exceeding levels induced by treadmill running, depending on the muscle examined. Notably, 915 synergizes with exercise training to further enhance Ddit4 and mitochondrial gene expression. These findings position orally active ERR agonists such as 915 as promising agents for the treatment of metabolic disorders (eg, obesity, type 2 diabetes, and metabolic disease-associated steatohepatitis), cardiovascular disease (heart failure), and muscle-related pathologies, including sarcopenia and muscular dystrophies. SLU-PP-915 offers a valuable chemical tool for exploring the chronic therapeutic potential of ERR activation. SIGNIFICANCE STATEMENT: The nuclear receptor estrogen receptor-related receptor plays an important role in driving the physiological adaptations to exercise. The article describes the ability of a pan-estrogen receptor-related receptor agonist SLU-PP-915, which also displays oral bioavailability, to enhance exercise capacity.

Loss of dopamine neurons in Parkinson disease (PD) leads to motor deficits. Dopamine D2 receptor (D2R) agonists treat PD-associated motor deficits by acting on postsynaptic receptors located within the striatum that have been upregulated due dopamine loss. However, mechanisms that contribute to increased D2R activity in PD to enhance D2R function are poorly described. Spinophilin is a protein phosphatase 1 targeting protein that is expressed in postsynaptic dendritic spines and interacts with postsynaptic D2Rs. However, how spinophilin regulates D2R function is unknown. In the current study, we found that loss of spinophilin, specifically in indirect pathway medium spiny neurons and cholinergic interneurons limited the suppression of locomotion caused by the D2R agonist, quinpirole. Mechanistically, using proximity labeling in neuro2A cells and coimmunoprecipitaitons in striatal lysates from wildtype and spinophilin knockout mice, we found that spinophilin promotes the interaction of the D2R with intracellular proteins, suggesting spinophilin mediates agonist-induced D2R internalization. Therefore, our data support future studies targeting the spinophilin/D2R interaction to enhance D2R agonist activity, which may promote the efficacy of current PD therapeutics. SIGNIFICANCE STATEMENT: This manuscript demonstrates that spinophilin mediates agonist-induced D2R protein interactions with intracellular proteins and locomotor suppression. The study delineates spinophilin as a potential target to enhance the efficacy of D2R agonists, a mainstay treatment for Parkinson disease.

Formyl peptide receptors (FPRs) mediate both proinflammatory and resolution phases of the inflammatory response involved in many disease states. Harnessing their potential for pharmaceutical development requires an accurate picture of their signaling and regulation to the many test compounds developed. This study compares distinct responses of mouse and human FPR subtypes to several ligands in an attempt to clarify the dual nature of FPR signaling. Here, we expressed human and mouse variants of FPR1 and FPR2 in HEK293 cells and assessed competition binding, bioluminescence resonance energy transfer assays to measure the interaction between receptors and either Arrestin 3 or mini-Gsi, internalization, and extracellular signal-regulated kinase 1/2 phosphorylation. Concentration-response curves for 11 distinct ligands at each subtype were generated, then analyzed to determine EC50s, Emax values, and ligand bias. All compounds were less potent than WKYMVm across receptor subtypes, with the strength of signaling correlating with affinity estimates. The rank order of potency was maintained across the signaling pathways. Notably, MMK1 was specific for human FPR2, and BMS-986235 was selective for FPR2 over FPR1 in both species. Little evidence of pathway bias was detectable, with the notable exception of the recently described pepducin F2Pal10. The majority of tested ligands exhibit efficacy at each subtype, meaning conclusions of physiological receptor function based on these compounds should be treated circumspectly. It is not possible to determine distinct signaling profiles that would explain proresolution versus inflammatory physiology, and the most likely explanation for these data would be a combination of FPR1 and FPR2 responses. SIGNIFICANCE STATEMENT: No evidence of ligand bias between G-protein activation, arrestin recruitment, or internalization was found at formyl peptide receptors for 11 distinct agonists. Differences in physiological outcome are more likely to reflect efficacy at both subtypes rather than inherent signaling bias.

Because of their pivotal role in liver fibrosis, activated hepatic stellate cells (aHSCs) may serve as a promising target for innovative medical treatments. Endoplasmic reticulum stress activation through inositol-requiring enzyme1 (IRE1)-X-box-binding protein-1 (XBP1) is a significant event associated with hepatic stellate cells (HSC) activation. We evaluated the potential impact of treatment with XBP1-specific decoy oligodeoxynucleotide (ODN) on modulation of aHSC. To activate HSCs, LX-2 cells were treated with transforming growth factor β (5 ng/mL). Meanwhile, the sequence of XBP1-specific decoy ODN was designed using the JASPAR (open-access transcription factor binding profile data base) and CLC Main Workbench (Qiagen) software. The outcome of treatment with ODN on aHSC was analyzed using quantitative reverse transcription polymerase chain reaction, immunoblotting, scratch assay, and ELISA. Transfection of activated LX-2 cells with 1 μg XBP1 decoy ODN downregulated the expression level of lysyl oxidase, tissue inhibitor of matrix metalloproteinase, α-smooth muscle actin, and fibronectin genes. In addition, the immunoblotting analysis and ELISA assay showed that XBP1 decoy ODN significantly reduced protein expression of α-smooth muscle actin and collagen secretion, respectively, compared to control cells. Our research may lead to innovative treatments for liver fibrosis, providing hope for better outcomes for patients with this chronic condition. SIGNIFICANCE STATEMENT: This study applied a novel decoy oligodeoxynucleotide targeting X-box-binding protein-1 to suppress the activation of hepatic stellate cells, a key driver of liver fibrosis. By modulating endoplasmic reticulum stress and fibrogenic gene expression, this strategy offers a promising therapeutic avenue for chronic liver diseases.

Stress exposure is often a precipitating factor underlying drug-seeking behavior that can lead to the establishment of comorbid posttraumatic stress disorder and substance use disorder (SUD) in clinical populations. The vicarious witness stress (WS) model is a potent ethologically relevant stressor that imparts many of its deleterious effects through heightened neuroimmune signaling in key stress sensitive brain regions. The present set of studies were designed to determine the impact of this psychosocial stressor on oxycodone place preference and central immune activity in female rats. In this way, we aim to better understand the neural correlates of stress-induced drug seeking in an effort to establish novel treatment targets for stress-related posttraumatic stress disorder/SUD. Female Sprague-Dawley rats were exposed to WS or nonstress control conditions prior to training for conditioned place preference with 3.0 mg/kg oxycodone. Following conditioned place preference training, rats with a history of stress were either exposed to the WS cues or left undisturbed and compared to controls for oxycodone place preference. Acute exposure to the WS cues led to the highest amount of time spent in the drug-paired compartment and this stress-induced augmentation of opioid preference was accompanied by significant increases in proinflammatory cytokines in the locus coeruleus. Taken together, these experiments established a comorbid model of stress and drug preference in female rats and have begun to identify potential brain regions that could be targeted to prevent stress-related sensitization to SUDs in females. SIGNIFICANCE STATEMENT: These studies offer insights into neuroimmune targets for the prevention of stress-induced opioid seeking with the overall goal of testing translationally relevant pharmacotherapies to prevent stress-sensitized drug-seeking responses in females.

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.