Journal of Pharmacology and Experimental Therapeutics最新文献

PD-1 and PD-L1 are programmed cell death proteins and ligands that form a key axis of immune checkpoints that tumors use to escape immune surveillance. Although immune checkpoint inhibitors that activate this pathway have revolutionized the treatment of cancer, resistance and unpredictable responses to a patient are still significant issues. There is growing evidence that noncoding RNAs (ncRNAs) such as microRNAs, long noncoding RNAs, and circular RNAs are key regulators of PD-1/PD-L1 signaling. These ncRNAs control the PD-L1 expression by directing its mRNA and indirectly maintaining the upstream signaling processes, consequently influencing tumor progression, immune cell activity, and drug responses. This review, based on existing research on the mechanistic functions of ncRNAs in PD-1/PD-L1-based immune suppression, discusses the possibility of using ncRNAs as biomarkers to predict immunotherapy response and as new therapies. We also address opportunities in the field of translation, such as ncRNA-based interventions and combinations with checkpoint blockade, and the challenges, which require resolution to move to the clinical practice. The combination of ncRNA biology and tumor immunology has potential applications in the area of precision immunotherapy and the creation of more meaningful treatment tools against malignancies that are resistant to treatment. SIGNIFICANCE STATEMENT: The current review outlines the regulatory functions of noncoding RNAs in the programmed cell death protein 1/programmed cell death ligand 1 immune checkpoint and highlights their role in tumor immune evasion and therapeutic responses regulation. With an interwoven method of mechanistic understanding and translational approaches, this study outlines noncoding RNAs as potential biomarkers and therapeutic targets and provide new approaches to increment the activity of checkpoint blocks and improve precision cancer immunotherapy.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by joint inflammation and systemic symptoms. This study evaluates the efficacy of liraglutide (LIRA), a glucagon-like peptide-1 receptor agonist, in RA management, particularly in conjunction with methotrexate (MTX), a standard RA therapy on complete Freund's adjuvant (CFA)-induced arthritis. Rats were injected with 0.12 mL of CFA (10 mg/1 mL) intradermally on day 1. Rats were divided into 6 groups, Normal group, Model group, MTX group (methotrexate 1 mg/kg/wk/i.p.), LIRA protection group (liraglutide 75 μg/kg/day/i.p. from day 1 to day 56), LIRA group (liraglutide 75 μg/kg/day/i.p. from day 15 to day 56), LIRA + MTX group (liraglutide 75 μg/kg/day/i.p. + methotrexate 1 mg/kg/wk/i.p. from day 15 to day 56). The arthritic rats developed significant joint destruction accompanied by alterations in metabolic parameters, elevated inflammatory cytokines, and enhanced apoptosis and autophagy. Liraglutide treatment and protection significantly showed metabolic hexokinase 2-succinate-hypoxia-inducible factor 1α axis modulation, inflammasome NOD-like receptor family, pyrin domain containing 3 suppression, apoptosis and autophagy flux normalization and joint pathology improvement. Liraglutide produced more pronounced effects when administered in combination with methotrexate. In conclusion, liraglutide demonstrated significant therapeutic and protective efficacy in a CFA-induced rat model of RA. The mechanism involves metabolic reprogramming where liraglutide downregulated the hexokinase 2-succinate-hypoxia-inducible factor 1αaxis, correcting disease-associated metabolic dysregulation. Similarly, liraglutide inhibited key proinflammatory signaling cascades, specifically the nuclear factor κB/NOD-like receptor family, pyrin domain containing 3/interleukin-1β and tumor necrosis factor-α/P38 mitogen-activated protein kinase pathways. SIGNIFICANCE STATEMENT: Rheumatoid arthritis is a chronic immuno-inflammatory disorder causing joint damage. Liraglutide presents opportunities for repurposing metabolic agents in the treatment of autoimmune illnesses. Liraglutide modulates metabolic dysfunction, normalizes autophagy markers, inflammatory pathways, and lower apoptotic signals in complete Freund's adjuvant-induced arthritis in rats.

Naltrexone-precipitated withdrawal in animals that receive morphine daily can include decreases in operant responding. However, naltrexone also can decrease operant responding in untreated animals, depending on prior naltrexone exposure and reinforcer contingencies. The present study was conducted to further evaluate changes in the behavioral effects of naltrexone consequent to morphine exposure and changes in behavioral context. Tolerance to the effects of both μ- (morphine, heroin, buprenorphine, methadone) and κ-opioid (U50,488) agonists during daily chronic morphine also was evaluated. Squirrel monkeys (n = 4) responded under a multiple schedule consisting of 4 18-minute cycles, each comprising a 10-minute timeout period followed by 3-minutes during which fixed-ratio responding was maintained by food presentation, a 2-minute timeout period, and 3-minutes during which fixed-ratio responding was maintained by stimulus-shock termination (SST). Control response rates were comparable under both schedule conditions. All drugs decreased food-maintained responding and, albeit requiring 0.5-1 log unit higher doses, morphine, heroin, methadone, and U50,488 also decreased SST-maintained responding. Daily morphine (3.2 mg/kg/day) produced tolerance to the rate-decreasing effects of μ-opioid agonists in the absence of sensitization to naltrexone's rate-decreasing effects. Doubling the daily dose of morphine and eliminating components of SST-maintained responding resulted in a 1.5-log unit leftward shift of the naltrexone dose-effect function. Full sensitization to naltrexone's ability to decrease food-maintained responding (3-log unit leftward shift) emerged after reintroducing SST-maintained performance into daily sessions. These results indicate that naltrexone's effects on operant responding during morphine maintenance can be influenced by behavioral context as well as the level of dependence. SIGNIFICANCE STATEMENT: Repeated administration of high naltrexone doses in nonopioid dependent individuals may result in behaviorally disruptive effects of low doses (naltrexone supersensitivity). Low doses of naltrexone also have disruptive effects during opioid dependence. These studies show that the expression of naltrexone effects during opioid dependence is a product of both pharmacological and behavioral factors.

Glioblastoma (GBM) represents one of the most lethal and therapy-resistant forms of brain tumors, characterized by high heterogeneity, metabolic reprogramming, and recurrence. In the current study, we aimed to identify novel small molecule inhibitors targeting mutant isocitrate dehydrogenase 1 (IDH1), a crucial enzyme involved in GBM tumor metabolism. For this aim, machine learning-based quantitative structure-activity relationships modeling was combined with structure-based e-Pharmacophore screening to virtually screen ultralarge chemical libraries containing around 157 million compounds. The best hits were selected based on docking score, predicted pIC₅₀ value, and molecular mechanics/generalized Born surface area binding energy calculations. Furthermore, molecular dynamics (MD) simulations were conducted to validate the selected hit compounds. In total, 36 compounds were subjected to short MD simulations (10 ns), and 16 molecules showing low binding free energies (below -90 kcal/mol) were further analyzed through long MD simulations (100 ns). Among these, 11 synthetically available hits were ordered and experimentally tested on human glioblastoma U87 and U251 cell lines. Our experimental results showed that 5 of the tested compounds (hits 1, 4, 5, 6, and 7) reduced spheroid formation by nearly 80%-90% and inhibited cell proliferation. Moreover, these hits decreased the oxygen consumption rate and extracellular acidification rate (ECAR), by up to 62% and 55%, respectively, indicating inhibition of both mitochondrial respiration and glycolysis. Furthermore, Western blot and quantitative real-time polymerase chain reaction analyses revealed downregulation of glycolytic enzymes and stemness markers. Moreover, steered MD and free energy perturbation analyses confirmed the stable interactions of these compounds at the IDH1 mutant active site. This multistage in silico-in vitro approach allowed the identification of metabolically disruptive novel mutant IDH1 inhibitors that suppress glycolysis, mitochondrial respiration, and cancer stemness in glioblastoma cells. These compounds represent promising scaffolds for the development of next-generation GBM therapeutics. SIGNIFICANCE STATEMENT: This study integrate machine learning-guided quantitative structure-activity relationships modeling with structure-based pharmacophore screening to discover small molecule inhibitors of mutant IDH1, a central mediator of metabolic reprogramming in glioblastoma. Lead compounds identified through this pipeline inhibit mutant IDH1 activity, disrupt metabolic pathways required for glioblastoma cell viability, and concomitantly reduce stem-like phenotypes in vitro, consistent with a dual mechanism of action that targets both bulk tumor cells and cancer stem-like populations.

Alzheimer disease (AD) and aging have similar molecular mechanisms that are affected by genetic as well as environmental variables. Based on current research, gut microbiomes contribute to age-specific biological processes and play an essential role in maintaining host homeostasis. Several molecular processes, including the host DNA methylation mechanism, are affected by microbially derived metabolites such as short-chain fatty acids, folate, and choline. This interaction establishes a mechanistic causal relationship that further shapes gene expression, inflammatory balance, and neuronal function in aging and related diseases. In this review, we looked at recent research showing how gut dysbiosis and its associated metabolites impact DNA methylation, which consequently contributes to disease progression in AD and aging. We also talked about how the DNA clock and age-associated methylation drifts can be used for forecasting biological aging. In addition, we discussed recent findings on how microbial and diet-based interventions may restore the methylation patterns that might be involved in aging and neurodegenerative processes. We also implicated the possible use of methylation-based biomarkers in the diagnosis of AD. Additionally, we have also explored the potential therapeutic benefits of using microbiome modulators, dietary modifications, and pharmacological interventions. Next, we highlighted the importance of multiomics and longitudinal studies to build the causal connection underlying methylation dynamics and microbial changes in neurodegeneration. Altogether, this review highlights the potential of the microbiome-methylation axis as an approach to understanding aging and establishing precision strategies to maintain cognitive health. SIGNIFICANCE STATEMENT: This review explores the interplay between DNA methylation and gut microbiota in aging and Alzheimer's disease. It highlights the gut-brain axis and summarizes recent findings on microbiome-driven epigenetic changes and metabolites influencing cognitive decline. The review also emphasizes microbiome-targeted therapeutic strategies for age-related disorders. Overall, it integrates current molecular insights with emerging approaches for the detection, prevention, and management of Alzheimer's disease and associated cognitive challenges.