The Journal Of Pharmacology And Experimental Therapeutics[JOURNAL]
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200 papers
Reprogramming oncogenic mitochondria in pancreatic adenocarcinoma through BRD4 inhibition leads to programmed cell death.
Cai C, Spinrad MW, Gattie LC … +8 more , Wang R, Afjal MA, Yang J, Yadak N, Shibata D, Li W, Bajwa A, Glazer ES
J Pharmacol Exp Ther · 2025 Nov · PMID 41232326 · Full text
Pancreatic ductal adenocarcinoma (PDA) is an almost universally fatal disease. Recent advances in the understanding of PDA bioenergetic dynamic equilibrium have illuminated a potential therapeutic target in bromodomain-r...
Pancreatic ductal adenocarcinoma (PDA) is an almost universally fatal disease. Recent advances in the understanding of PDA bioenergetic dynamic equilibrium have illuminated a potential therapeutic target in bromodomain-related protein 4 (BRD4), the most active member of the bromo- and extraterminal domain (BET) protein family of transcription factors. We previously demonstrated that BET inhibitors (BETi) decrease PDA cell proliferation and enhance chemosensitivity. We hypothesized that BETi activates mitophagy and ferroptosis in PDA. Using pharmacological and genetic BRD4 inhibition in PDA patient-derived models, we investigated the effects of BETi on mitochondrial function, mitochondrial protein complex production, ATP production, cellular respiration, autophagy/mitophagy, and murine tumor growth with BMS-986158, a BETi. We determined the role of BRD4 in PDA by evaluating mitophagy and autophagy. In PDA models, we found that BETi decreased cellular respiration (P < .01), decreased ATP production (P < .001), and increased intracellular iron uptake (P < .01) while inducing mitophagy through dysregulated mitochondria complex protein levels. Murine PDA tumors grew slower and were smaller when treated with BETi compared with the control treatment. PDA tumors from experimentally treated mice contained more lipid vacuoles than those from the vehicle control group (P < .01), consistent with ferroptosis. BETi therapy decreased isocitrate dehydrogenase-1 expression, indicating increased chemosensitivity. BETi dysregulate mitochondrial complexes inducing mitophagy. BETi is a promising therapeutic strategy for attacking oncogenic mitochondrial behavior in PDA. We demonstrated a series of mitochondrial-centered events in a temporal sequence leading to cell death. This treatment controls tumors and increases chemosensitivity, offering a novel therapeutic strategy. SIGNIFICANCE STATEMENT: Bromo- and extraterminal domain inhibition is a novel therapeutic strategy for attacking oncogenic mitochondrial behavior in pancreatic ductal adenocarcinoma. Using this strategy in patient-derived models, this study demonstrated a series of mitochondrial-centered events in a temporal sequence leading to cell death and tumor control.
Molecular mechanisms of 10-butyl ether minocycline, a novel nonantibiotic tetracycline, as a potential treatment for inflammatory and neuroimmune-related disorders.
Shaik AA, Panthagani P, Liu X … +11 more , Navarro-Turk S, Garza J, Aguilera M, Sanchez J, Gupta K, Hamood A, Reid TW, Blough B, Pauli E, Bailoo JD, Bergeson SE
J Pharmacol Exp Ther · 2025 Nov · PMID 41223834 · Full text
The pleiotropy of minocycline (MINO), including anti-inflammatory, antioxidant, antimigratory, anti-matrix metalloproteinase (MMP), and neuroprotective effects, has been extensively reported. A novel nonantibiotic MINO d...
The pleiotropy of minocycline (MINO), including anti-inflammatory, antioxidant, antimigratory, anti-matrix metalloproteinase (MMP), and neuroprotective effects, has been extensively reported. A novel nonantibiotic MINO derivative, 10-butyl ether minocycline (BEM), was synthesized to retain the pleiotropy of MINO while minimizing side effects such as antibiotic resistance and gut dysbiosis. Previously, we showed that BEM reduced alcohol consumption in dependent murine and porcine models of alcohol use disorder. In this study, we investigated the molecular mechanisms of BEM to determine its potential as a therapeutic agent for neuroimmune and inflammatory conditions such as alcohol use disorder. Here, we report that BEM showed a nearly complete loss of antimicrobial activity against Escherichia coli, Salmonella typhi, and Candida albicans. BEM showed a dose-dependent reduction in cell viability as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, similarly to MINO. BEM also suppressed lipopolysaccharide-induced microglial activation as shown by reduced Iba1 expression in immunohistochemistry and western blot analyses. Inhibition of MMP-9 by BEM (IC50 = 42.2 μM) was improved compared to MINO (IC50 = 60.3 μM), whereas MMP-8 inhibition was moderate (IC50: BEM = 69.4 μM; MINO = 45.4 μM). BEM was found to be effective in inhibiting vascular endothelial growth factor-induced endothelial cell migration and L-glutamine-induced reactive oxygen species levels. Limited inhibition of 15-lipoxygenase activity was observed (IC50: BEM = 92.6 μM; MINO = 65.6 μM). BEM was not toxic to mitochondria, even at high concentrations (200 μM). By eliminating antimicrobial properties while preserving therapeutic pleiotropy, BEM presents an advancement in the development of a promising candidate with multimodal mechanisms to treat neuroimmune-inflammatory pathologies. SIGNIFICANCE STATEMENT: We report mechanisms of action for butyl ether minocycline, a minocycline analog under evaluation for the treatment of alcohol use disorder, which may also show efficacy for other complex disease processes that involve inflammatory or neuroimmune components. We show that butyl ether minocycline had a nearly complete loss of antimicrobial action, yet retained the pleiotropy of minocycline, likely making it a better multimodal therapeutic for long-term treatment of complex diseases with neuroimmune-related components.
Inhibiting silencing information regulator 1 is conducive to the suppression of hepatitis B virus replication by entecavir.
Li X, Tang Q, Long Y … +2 more , Liu Y, Feng F
J Pharmacol Exp Ther · 2025 Nov · PMID 41223833 · Publisher ↗
Hepatitis B is a severe viral infectious disease, and there is no effective enough way to cure it completely at present. In this study, we first probed into the effect of sirtuin 1 inhibitor III (EX527) on hepatitis B vi...
Hepatitis B is a severe viral infectious disease, and there is no effective enough way to cure it completely at present. In this study, we first probed into the effect of sirtuin 1 inhibitor III (EX527) on hepatitis B virus (HBV) replication following inhibition of silencing information regulator 1 (SIRT1) and whether EX527 can enhance the efficacy of entecavir (ETV) in anti-HBV therapy. The synergistic interaction of EX527 (10 μM) with ETV (25 μg/mL) was performed in the HBV steady-state replicating cell line HepG2.2.15. The expression profiles of HBV DNA, total RNA, pregenomic RNA, hepatitis B surface antigen, hepatitis B e antigen, HBV X antigen, hepatitis B core antigen, tumor necrosis factor-α, interleukin-6, and nuclear factor-κB were examined by real-time quantitative polymerase chain reaction, ELISA, immunofluorescence, and Western blot. The results show that silenced SIRT1 expression significantly inhibited the replication of HBV. The combination of SIRT1 inhibitor and ETV further reduced HBV DNA levels (24 hours: P = .0012; 95% combination index (CI), 0.1563-0.3164; 48 hours: P = .0025; 95% CI, 0.1990-0.4746; 72 hours: P = .0009; 95% CI, 0.2011-0.3867), total RNA (24 hours: P < .0001; 95% CI, 0.3183-0.4506; 48 hours: P = .0011; 95% CI, 0.2500-0.4964; 72 hours: P = .0011; 95% CI, 0.2978-0.5937) and pregenomic RNA (24 hours: P < .0001; 95% CI, 0.2624-0.3194; 48 hours: P = .0001; 95% CI, 0.3158-0.4554; 72 hours: P = .0022; 95% CI, 0.2586-0.5975) levels compared to ETV monotherapy. Significant reduction in hepatitis B surface antigen (24 hours: P = .0002; 95% CI, 113.3526-173.7049; 48 hours: P < .0001; 95% CI, 128.9962-160.8836; 72 hours: P < .0001; 95% CI, 129.0970-164.7718), hepatitis B e antigen (24 hours: P = .0094; 95% CI, 1.2650-4.9331; 48 hours: P = .0215; 95% CI, 0.7548-5.4610; 72 hours: P = .0003, 95% CI, 4.5457-7.4308), HBV X antigen (24 hours: P = .0009; 95% CI, 0.2263-0.4302; 48 hours: P < .0001; 95% CI, 0.3094-0.3866; 72 hours: P = .0019; 95% CI, 0.2393-0.5325) and hepatitis B core antigen (24 hours: P = .0010; 95% CI, 0.3161-0.6200; 48 hours: P = .0022; 95% CI, 0.2847-0.6571; 72 hours: P = .0012; 95% CI, 0.2571-0.5188) levels were observed in the SIRT1 inhibitor and ETV combination groups. Cotreatment with EX527 and ETV had a more conspicuous effect on the inflammatory factors: tumor necrosis factor-α (mRNA: P < .0001; 95% CI, 0.2207-0.2961; protein: P = .0226; 95% CI, 5.3050-40.7000), interleukin-6 (mRNA: P < .0001; 95% CI, 0.2413-0.3220; protein: P = .0134; 95% CI, 0.5065-1.6998), and nuclear factor-κB (P = .0057; 95% CI, 0.1808-0.4268). These in vitro results indicated that the combination of SIRT1 inhibitor EX527 and ETV can effectively inhibit the replication of HBV. SIGNIFICANCE STATEMENT: This study has important theoretical and practical significance. It explores the factors influencing the replication of the hepatitis B virus from a new perspective and provides new ideas for follow-up research.
Acid ceramidase as a novel target for adiponectin receptor agonist to abrogate podocyte NLRP3 inflammasome activation and glomerular inflammation during obesity.
Li G, Huang D, Kidd JM … +6 more , Zou Y, Wu X, Zhang Y, Gehr TWB, Li N, Li PL
J Pharmacol Exp Ther · 2025 Dec · PMID 41223812 · Full text
Adiponectin receptor (AdipoR) agonists protect against glomerular inflammation and injury in obesity-related glomerulopathy (ORG), but their molecular mechanisms remain unclear. Given the implication of the ceramide sign...
Adiponectin receptor (AdipoR) agonists protect against glomerular inflammation and injury in obesity-related glomerulopathy (ORG), but their molecular mechanisms remain unclear. Given the implication of the ceramide signaling pathway in the pathogenesis of ORG, the present study tested whether AdipoR agonists target acid ceramidase (AC) to inhibit NLRP3 inflammasome activation in podocytes, thereby blocking glomerular inflammation and injury during obesity. Confocal microscopy showed that adiponectin attenuated visfatin-induced NLRP3 inflammasome activation and IL-1β-containing multivesicular body (MVB) formation in podocytes. Nanoparticle tracking analysis revealed that adiponectin suppressed visfatin-induced extracellular vesicle release, an effect dependent on AC activity. Structured illumination microscopy demonstrated that visfatin reduced lysosome-MVB interaction in podocytes, which was restored by adiponectin via enhancement of TRPML1 channel-mediated Ca release. The rescue of lysosome-MVB interaction and TRPML1 channel activity by adiponectin was mimicked by the AC enhancer but interfered with by the AC inhibitor. In vivo, high-fat diet (HFD) treatment induced NLRP3 inflammasome activation and T cell infiltration in glomeruli and increased urinary extracellular vesicle excretion in mice, which were exaggerated by podocyte-specific Smpd1 gene (gene code of acid sphingomyelinase) overexpression in Smpd1/Podo mice compared with WT/WT mice. AdipoRon, a synthetic AdipoR agonist, reduced HFD-induced glomerular inflammation in both WT/WT and Smpd1/Podo mice, but its effect was blocked by AC inhibition. Moreover, podocyte-specific Smpd1 gene overexpression aggravated HFD-induced podocyte injury, proteinuria, and glomerular sclerosis, which were mitigated by AdipoRon in an AC-dependent manner. Additionally, we found that the protective actions of AdipoRon may be mainly attributed to the activation of AdipoR1, but not AdipoR2. Taken together, our findings suggest that AC activation mediates the protective effects of AdipoR agonists against glomerular inflammation and injury in ORG, highlighting AC as a potential therapeutic target. SIGNIFICANCE STATEMENT: This study identifies acid ceramidase as a key mediator of adiponectin receptor agonist action in podocytes, linking its activation to suppression of NLRP3 inflammasome and extracellular vesicle release, and highlighting a novel therapeutic target in obesity-related kidney disease.
Factors that influence the conditioned reinforcing effects of a cocaine-associated stimulus.
Robertson SH, Rysztak LG, Jutkiewicz EM
J Pharmacol Exp Ther · 2025 Dec · PMID 41218230 · Full text
Cocaine-associated stimuli acquire conditioned reinforcing effects and can precipitate relapse. We used the New Response Acquisition procedure to examine factors that influenced the conditioned reinforcing effects of coc...
Cocaine-associated stimuli acquire conditioned reinforcing effects and can precipitate relapse. We used the New Response Acquisition procedure to examine factors that influenced the conditioned reinforcing effects of cocaine-associated stimuli in rats. According to this procedure, rats first experienced Pavlovian conditioning, during which they were exposed to intravenous cocaine deliveries and stimulus (light + white noise) presentations. After Pavlovian conditioning, animals learned to respond to the cocaine-paired stimulus alone. The number of responses made for that stimulus reflected the conditioned reinforcing effects of the cocaine-associated stimulus. Across 3 experiments, the extent to which the dose of cocaine during Pavlovian conditioning (experiment 1), food restriction (experiment 2), and the number of cocaine-stimulus pairings and the number of days of Pavlovian conditioning (experiment 3) led to different conditioned reinforcing effects of the cocaine-associated stimulus. Taken together, we found that cocaine-associated cues took on conditioned reinforcing effects dose-dependently, were augmented by food restriction, and were most robust following 10 days of Pavlovian conditioning relative to 5 days of conditioning. These findings advance our understanding of the conditions under which cocaine-associated stimuli can act as a conditioned reinforcer. SIGNIFICANCE STATEMENT: Cocaine-associated stimuli acquire conditioned reinforcing effects via Pavlovian conditioning that drive drug-seeking and relapse. Understanding the conditions under which cocaine-associated stimuli take on conditioned reinforcing effects can be used to inform efforts to curtail cocaine use disorder.
Delta opioid receptor activation influences responding to earn cocaine-associated cues in the New Response Acquisition procedure.
Rysztak LG, Hoying L, Rice KC … +2 more , Robertson SH, Jutkiewicz EM
J Pharmacol Exp Ther · 2025 Dec · PMID 41218229 · Full text
Environmental cues that have been associated with drug-taking can evoke drug-craving and drug-seeking and drive relapse. Using the New Response Acquisition procedure, we evaluated the extent to which activation of delta...
Environmental cues that have been associated with drug-taking can evoke drug-craving and drug-seeking and drive relapse. Using the New Response Acquisition procedure, we evaluated the extent to which activation of delta opioid receptors (DORs) changes responding for cocaine-associated stimuli. We hypothesized that activation of DORs, either directly via agonists or indirectly via protected concentrations of endogenous enkephalin peptides, would increase the conditioned reinforcing effects of cues. First, animals undergo Pavlovian conditioning during which rats received 5 infusions of cocaine (0.32 mg/kg/inf) and either paired or unpaired presentations of a stimulus (light + tone) per day for 10 days. Next, nosepokes were added to the operant chamber and rats were allowed to respond for presentations of cocaine-associated stimuli (acquisition). Consistent with previous findings, animals assigned to paired Pavlovian conditioning emitted more responses for cue presentations than animals assigned to the unpaired control. Interestingly, acute administration of SNC80 (DOR agonist; 3.2 mg/kg s.c.) on acquisition session 4 led to robust increases in responding for the cocaine-paired cues in the paired, but also increased responding for cues in rats assigned to unpaired and saline control groups. Further, the enkephalinase inhibitor RB101 (10 mg/kg intravenous), which maintains extracellular concentrations of enkephalins, increased active responding in a DOR-dependent manner. These data suggest that activation at DORs influences behaviors maintained by cues and sheds light on the neurobiology underlying the conditioned reinforcing effects of drug-associated stimuli. SIGNIFICANCE STATEMENT: We used a more rigorous test of conditioned reinforcement to show that activation of delta opioid receptors increases the reinforcing effects of cocaine-paired cues, depending on conditioning history, which implicates the delta opioid receptor system as a target to reduce relapse.
Proteolysis targeting chimeras as senolytics: An emerging senotherapy for combating aging.
Cruickshank-Taylor AB, Kozora JS, Carew JS … +2 more , Nawrocki ST, Wang W
J Pharmacol Exp Ther · 2025 Nov · PMID 41206997 · Publisher ↗
Cellular senescence, a persistent state of cell cycle arrest, accumulates in aged organisms, contributes to tissue dysfunction, and drives aging-related phenotypes. Clearance of senescent cells decreases chronic, low-gra...
Cellular senescence, a persistent state of cell cycle arrest, accumulates in aged organisms, contributes to tissue dysfunction, and drives aging-related phenotypes. Clearance of senescent cells decreases chronic, low-grade inflammation and restores tissue repair capacity, thus improving human health and lifespan. Senolytics that selectively eliminate senescent cells have become a promising antiaging strategy. To date, current senolytics are largely developed by repurposing anticancer agents. Therefore, senolytics usually possess various on- and off-target toxicities. These toxicities could preclude their clinical use as antiaging agents, as elderly people are more susceptible to adverse drug effects than young individuals. Proteolysis targeting chimeras as senolytics, termed "SenoTACs," are attractive for more effective treatment of aging-related diseases. In comparison to small molecule inhibitors, SenoTACs can eliminate senescent cells by degrading targeted proteins in a substoichiometric manner, providing better target ability, longer-lasting therapeutic effect, broadened target capability, and decreased drug resistance. Recent efforts have led to the development of several senescence-targeting proteolysis targeting chimeras, including ARV825, PZ15227, 753B, Gal-ARV-771, and Gal-MS99, which exhibit selective senolytic activity and improved safety and efficacy profiles when compared with small molecule inhibitors. In this minireview, we summarize the development of the emerging field. SIGNIFICANCE STATEMENT: The severe toxicities associated with current senolytics may limit their clinical utility as antiaging agents, as older populations are more susceptible to adverse drug effects. PROteolysis TArgeting Chimeras (PROTACs) that induce selective degradation of target proteins, are emerging as a promising therapeutic strategy to address this unmet medical need. Recently, PROTACs have been explored as novel senolytics-termed "SenoTACs," which display improved safety and efficacy in targeting senescent cells for fighting aging-related diseases.
Endothelin-converting enzyme 2 regulates κ opioid receptor trafficking and function.
Gupta A, Gomes I, Sierra S … +2 more , Osman A, Devi LA
J Pharmacol Exp Ther · 2025 Dec · PMID 41205376 · Full text
Previous studies show that endothelin-converting enzyme 2 (ECE2), an enzyme involved in nonclassical processing of neuropeptide precursors, regulates the rate and extent of μ and δ opioid receptor recycling, but not inte...
Previous studies show that endothelin-converting enzyme 2 (ECE2), an enzyme involved in nonclassical processing of neuropeptide precursors, regulates the rate and extent of μ and δ opioid receptor recycling, but not internalization following activation by select synthetic and endogenous peptidic agonists. This study focuses on κ opioid receptors (KORs) and examines how prodynorphin and proenkephalin-derived peptides that are substrates of ECE2 modulate the internalization and recycling of both KOR and ECE2; as controls we use peptides that are not ECE2 substrates. First, we use a proximity-based ligation assay to show that KOR and ECE2 are in close proximity to directly interact and cointernalize. Treatment with the peptides induces internalization and recycling of ECE2 at a rate and extent comparable to that of KOR with longer opioid peptides inducing fast and robust internalization and recycling of both ECE2 and KOR compared with shorter peptides. We find that in recombinant cell lines and naïve cells expressing endogenous receptors, a small molecule ECE2 inhibitor attenuates KOR recycling as well as signaling by only peptides that are ECE2 substrates. Taken with the differential expression of ECE2 in the brain (relatively high expression in midbrain and dentate gyrus of the hippocampus and low expression in the striatum), these results highlight a pivotal role for ECE2 in differentially modulating KOR function. SIGNIFICANCE STATEMENT: This study highlights a role for endothelin-converting enzyme 2 in agonist mediated regulation of κ opioid receptor function by select prodynorphin and proenkephalin-derived peptides. Collectively, studies by authors suggest that endothelin-converting enzyme 2 inhibitors could be developed as therapeutics for pathologies involving dysregulations in κ opioid receptor signaling.
An antifentanyl monoclonal antibody reverses fentanyl-induced apnea in pigs.
Baehr C, Hatschbach E, Vigliaturo J … +13 more , Hicks D, Pandit S, Hollingsworth M, Green H, Hau D, Gay E, Decker AM, Hoppe B, Khaimraj A, Aucoin D, Runyon SP, Guedes AGP, Pravetoni M
J Pharmacol Exp Ther · 2025 Nov · PMID 41197228 · Publisher ↗
The incidence of fatal drug overdoses has increased dramatically over the past decade due to the widespread availability of fentanyl and its analogs. As a complementary strategy to current overdose reversal agents, monoc...
The incidence of fatal drug overdoses has increased dramatically over the past decade due to the widespread availability of fentanyl and its analogs. As a complementary strategy to current overdose reversal agents, monoclonal antibodies (mAbs) are in development as therapeutics for prevention and reversal of fentanyl overdose. In the present study, the anti-fentanyl mAb HY6-F9 was tested for reversal of fentanyl-induced respiratory arrest (apnea) in a porcine model. In a first study, following fentanyl-induced apnea, chimeric HY6-F9 and naloxone control were administered as an intravenous bolus. Both chimeric HY6-F9 and naloxone restored spontaneous breathing within 90 seconds. Treatment with mAb increased the concentration of fentanyl in serum by 10-fold within the first minute after mAb bolus administration. In a second study, after induction of apnea, humanized HY6-F9 and naloxone control were administered as a slow intravenous infusion over 10 minutes to determine the ED to restore baseline breathing. In this study, the mean ± SEM ED of humanized HY6-F9 and naloxone to restore baseline respiratory rate were 16.0 ± 1.3 mg/kg and 6.9 ± 1.8 μg/kg, respectively. During mAb infusion, the concentration of fentanyl in serum increased proportionally to the concentration of infused mAb. The anti-fentanyl mAb ablated fentanyl-dependent opioid receptor activation in an in vitro system with concentrations of fentanyl similar to those observed in pigs after mAb treatment. These results demonstrate the efficacy of an anti-fentanyl mAb as a treatment to reverse fentanyl overdose. SIGNIFICANCE STATEMENT: Treatments for opioid use disorder and overdose are urgently needed. Here, we show that an anti-fentanyl monoclonal antibody reversed fentanyl-induced apnea in pigs, and caused rapid (<1 minute) redistribution of fentanyl into serum. Fentanyl was 99% bound by monoclonal antibodies and showed no activity at the opioid receptor.
Mitigation of thromboinflammation by rivaroxaban ameliorates metabolic and structural manifestations of metabolic dysfunction-associated steatohepatitis in rats: Comparison to other antithrombotic drugs.
Rageh B, Shamaa M, Agami M … +2 more , El-Yazbi AF, Wahid A
J Pharmacol Exp Ther · 2025 Nov · PMID 41187529 · Publisher ↗
Metabolic dysfunction-associated steatohepatitis (MASH) poses a significant public health challenge, characterized by liver fat accumulation accompanied with inflammation and cell damage. Patients with MASH commonly exhi...
Metabolic dysfunction-associated steatohepatitis (MASH) poses a significant public health challenge, characterized by liver fat accumulation accompanied with inflammation and cell damage. Patients with MASH commonly exhibit hypercoagulability. Our previous work showed that direct oral anticoagulants exert anti-inflammatory effects in early stages of metabolic dysfunction. Mitigation of thromboinflammation ameliorated the manifestations of cardiometabolic complications. Here, we examine the protective effects of rivaroxaban in a rat model of MASH and compare it to representatives of 2 other antithrombotic drug classes, enoxaparin and clopidogrel, as well as silymarin, a bona fide hepatoprotective agent. Rats were divided into 6 groups: control, MASH (induced by an atherogenic diet), and treatment groups receiving either silymarin (50 mg/kg by mouth), rivaroxaban (20 mg/kg by mouth), enoxaparin (2 mg/kg subcutaneously), or clopidogrel (6.75 mg/kg by mouth) for 8 weeks, starting in the third week of induction. MASH rats showed elevated markers of visceral adipose thromboinflammation, along with liver injury markers (aspartate aminotransferase, alanine aminotransferase, and serum albumin), heightened hepatic levels of inflammatory cytokines (interleukin [IL]-1β and IL-6), reduced antioxidant capacity, and an imbalance in coagulation factors (elevated activated coagulation Factor X and Factor VIII/Protein C) compared with the control group. Anticoagulants and silymarin treatment led to varying degrees of amelioration of these MASH-associated abnormalities. Rivaroxaban demonstrated the most substantial improvement in thromboinflammatory markers, reaching levels comparable to the control group, with percentage improvements of approximately 52%, 49%, and 42% in activated coagulation Factor X, IL-1β, and IL-6, respectively. These findings suggest that direct oral anticoagulants hold promise as therapeutic agents for MASH by targeting the underlying thromboinflammatory state. SIGNIFICANCE STATEMENT: Metabolic dysfunction-associated steatohepatitis is a global health issue. In a rat model of the disease, rivaroxaban improves liver injury markers, outperforming bona fide hepatoprotective substances. This study emphasizes the role of thromboinflammation in metabolic dysfunction-associated steatohepatitis and highlights direct anticoagulants as a potential novel treatment approach.
Ibudilast perpetuates stress-induced anxiety-like behavior and fear memory expression in adult Sprague-Dawley rats.
Enga RM, Naderi AO, Scott EM … +9 more , Coachman KD, Silva GM, Bergman EM, May MD, Batuure AB, Fenlon NS, DeMar JC, Matson LM, Lowery-Gionta EG
J Pharmacol Exp Ther · 2025 Nov · PMID 41176883 · Publisher ↗
The relationship between neuroinflammatory processes and stress-related disorders is complex with neuroinflammation both resulting from, and contributing to, the stress response. Findings from both preclinical studies an...
The relationship between neuroinflammatory processes and stress-related disorders is complex with neuroinflammation both resulting from, and contributing to, the stress response. Findings from both preclinical studies and clinical trials suggest that ibudilast (IBUD), a glial cell activation attenuator and phosphodiesterase inhibitor, has shown promise for mitigating the adverse behavioral effects of stress exposure and stress-related neuropsychiatric disorders. The objective of the present study was to determine the effect of IBUD administration on anxiety-like behavioral performance and fear memory expression in rats following stressor exposure. Here, adult male Sprague-Dawley rats were behaviorally tested in the elevated plus maze (EPM) and acoustic startle response tests 2 days before (day 1) and 2 days after (day 5) exposure to a stressor (inescapable footshock). Five days after stressor exposure, IBUD (0-10 mg/kg, i.p.) was administered 1 hour prior to a daily fear expression test session (days 8-11). Behavioral performance in the EPM and acoustic startle test was measured again on the following day (day 12). Following this, multiplex immunoassays were used to determine neuroinflammatory cytokine/chemokine levels in various brain regions. In a separate experiment, the effects of IBUD on locomotor activity and anxiety-like behavior were characterized in an open field test in rats with no history of stressor exposure. Stress exposure significantly (P < .05) reduced open arm exploration in the EPM-effects that were prolonged following IBUD treatment in a dose-dependent manner. Pretest administration of IBUD resulted in significantly (P < .05) greater freezing behavior during the fear expression tests with no evidence of fear extinction, whereas fear extinction was evident in vehicle-treated control rats. In nonstressed rats, IBUD reduced total locomotor activity and center exploration in the open field in a dose-dependent manner. Neuroinflammatory marker levels in the prefrontal cortex and amygdala were positively correlated with anxiety-like behavioral performance outcomes. Together, results suggest IBUD perpetuates stress-induced anxiety-like behavior and stress-associated fear memory expression (ie, hinders fear memory extinction). Further investigations into the interactions between IBUD administration and stressor exposure are needed to understand the implications of administering this drug in the context of stress exposure. SIGNIFICANCE STATEMENT: Ibudilast, a glial cell inhibitor and promising treatment candidate for various psychiatric disorders, was found to prolong fear expression and anxiety-like behavior in stress-exposed rats. Results suggest added characterization and consideration of its interactions with traumatic stress is needed.
Anti-IGF-1R antisense oligonucleotide CT102: A promising therapeutic agent for graves' ophthalmopathy.
Zhou Y, Wang W, Song G
J Pharmacol Exp Ther · 2025 Nov · PMID 41175836 · Publisher ↗
Graves' ophthalmopathy (GO) is an orbital inflammatory autoimmune disease with limited treatment options. Advances in understanding of disease pathogenesis, particularly the dysregulated insulin-like growth factor-1 rece...
Graves' ophthalmopathy (GO) is an orbital inflammatory autoimmune disease with limited treatment options. Advances in understanding of disease pathogenesis, particularly the dysregulated insulin-like growth factor-1 receptor (IGF-1R) signaling network in the orbital fibroblasts, have led to the development of targeted therapies against IGF-1R for GO. In this study, we aimed to evaluate the preclinical therapeutic potential of CT102, an IGF-1R-targeting antisense oligonucleotide. Antisense oligonucleotides represent a promising class of therapeutics due to their direct regulation of disease-causing genes and their variants, providing a compelling alternative to traditional "protein-specific" therapies. A GO-related rat model was established via intraperitoneal injection of bovine thyroglobulin and validated via the elevated serum thyroid peroxidase antibodies and suppressed serum thyroid-stimulating hormone levels. The GO-related rat model exhibited stable and consistent pathologic alterations of the extraocular muscles. Ocular administration of CT102 is well tolerated, and high-dose CT102 treatment showed therapeutic benefits as illustrated by the downregulation of IGF-1R level in ocular muscle tissue and reduction in pathologic abnormalities. Restoration of GO-associated biomarkers, including serum thyroid peroxidase antibody and serum thyroid-stimulating hormone levels, was observed in the high-dose CT102 group compared with normal controls. Furthermore, CT102 demonstrates superior modulation of GO-associated biomarkers relative to 2 positive controls: teprotumumab, the only anti-IGF-1R antibody approved by the US Food and Drug Administration, and miR-143, an RNA therapeutic targeting IGF-1R. To our knowledge, this study provides, for the first time, a rationale for clinical trials of CT102 in patients with GO and highlights the potential of anti-IGF-1R antisense oligonucleotides as a therapeutic strategy for GO. SIGNIFICANCE STATEMENT: To our knowledge, this study is the first to describe the therapeutic potential of anti- insulin-like growth factor-1 receptor antisense oligonucleotides in Graves' ophthalmopathy (GO), providing the rationale for future clinical trials in patients with GO and highlighting the potential of anti-insulin-like growth factor-1 receptor antisense oligonucleotide as a therapeutic strategy for GO.
Novel AMP-activated protein kinase activators and their potential for mitigating renal injury and fibrosis.
Harley G, Mount PF
J Pharmacol Exp Ther · 2025 Nov · PMID 41175835 · Publisher ↗
Disordered energy regulation within the kidney represents an important therapeutic target to reduce the severity of acute kidney injury and subsequent fibrosis. AMP-activated protein kinase (AMPK) is stimulated in situat...
Disordered energy regulation within the kidney represents an important therapeutic target to reduce the severity of acute kidney injury and subsequent fibrosis. AMP-activated protein kinase (AMPK) is stimulated in situations of cellular energy deprivation to act as a key regulator of cellular and systemic energy metabolism. AMPK activation has been shown to be protective against renal injury and fibrosis in numerous experimental studies using metformin and aminoimidazole-4-carboxamide ribonucleotide. However, studies with these traditional AMPK activators are limited by these agents being indirect activators of AMPK, with unwanted off-target effects that may limit their use. Novel AMPK activators represent a promising new therapy in kidney protection, as well as in a range of other chronic diseases. AMPK phosphorylates multiple targets to regulate numerous pathways, thereby enabling multiple mechanisms to reduce kidney injury. This review outlines important mechanisms of renal injury and fibrosis as well as the current landscape of novel AMPK activators. It outlines experimental evidence for mechanisms of novel AMPK activators and how these relate to injury and fibrosis within the kidney. Finally, it discusses the potential of these agents, as well as current challenges in their development. SIGNIFICANCE STATEMENT: Multiple studies have identified dysregulated energy metabolism as a treatment target for kidney disease, revealing novel AMP-activated protein kinase (AMPK) activators as a promising new therapy to address this opportunity for protection against kidney injury and fibrosis. Despite this promise, novel AMPK activators are yet to find a clinical role for kidney disease or other conditions. Barriers to be considered in future studies include concerns about cardiac hypertrophy and oncogenesis as well as elucidation of precise pharmacokinetic properties. Nonetheless, the large volume of beneficial preclinical data for kidney health provides motivation for future studies to address these needs.
Essential roles of mechanistic target of rapamycin in the induction of steroid resistance in group 2 innate lymphoid cells and severe asthma.
Matsuda M, Shimora H, Nakayama Y … +5 more , Matsumura M, Kitao A, Ariyoshi Y, Sannomiya Y, Nabe T
J Pharmacol Exp Ther · 2025 Nov · PMID 41172625 · Publisher ↗
Approximately 5% to 10% of asthma patients are resistant to glucocorticoid therapy; however, the mechanisms by which this resistance develops remain unclear. The present study investigated whether and how mechanistic tar...
Approximately 5% to 10% of asthma patients are resistant to glucocorticoid therapy; however, the mechanisms by which this resistance develops remain unclear. The present study investigated whether and how mechanistic target of rapamycin (mTOR) is involved in the development of steroid resistance using in vitro and in vivo murine models. The interleukin (IL)-33/thymic stromal lymphopoietin (TSLP)/IL-7-induced growth of group 2 innate lymphoid cells (ILC2) in vitro was resistant to dexamethasone (DEX), but suppressed by everolimus, an mTOR inhibitor, in a concentration-dependent manner. The inhibition of ILC2 growth by the combination of DEX and everolimus was significantly stronger than that by everolimus monotherapy. The combination of the pan-class I phosphatidylinositide-3 kinase inhibitor, buparlisib and the pan-Akt inhibitor, capivasertib also attenuated the resistance of IL-33/TSLP/IL-7-exposed ILC2s to DEX. The expression of the antiapoptotic factor, B-cell lymphoma-extra large, induced by IL-33/TSLP/IL-7 in ILC2s was significantly reduced by everolimus. Additionally, everolimus effectively suppressed the IL-33/TSLP/IL-7-induced phosphorylation of glucocorticoid receptors (GR) at the Ser234 residue, which has been reported to cause GR dysfunction. In the steroid-resistant asthma mouse model in vivo, under treatment with everolimus, DEX inhibited the development of airway remodeling and increased the number of ILC2s in the lungs. The present results suggest that the phosphoinositide 3-kinase/protein kinase B/mTOR pathway plays an essential role in the development of steroid resistance in ILC2s and asthma pathogenesis through both the expression of B-cell lymphoma-extra large and phosphorylation of GR. Therefore, mTOR inhibitors have the potential to restore glucocorticoid sensitivity and, thus, exert steroid-sparing effects in severe asthma patients. SIGNIFICANCE STATEMENT: Approximately 5% to 10% of asthma patients exhibit resistance to steroid therapy, posing a major clinical challenge due to limited treatment options. This study demonstrates that activation of the phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (mTOR) pathway induces steroid resistance in group 2 innate lymphoid cells. Targeting mTOR with everolimus restores steroid sensitivity, highlighting mTOR inhibition as a promising pharmacotherapy for steroid-resistant asthma.
Inhibitors of sodium-glucose cotransporter: When wasting fuel is sought and beneficial to health.
Alhenc-Gelas F
J Pharmacol Exp Ther · 2025 Nov · PMID 41172624 · Publisher ↗
Abstract loading — click title to view on PubMed.
Endothelial-to-mesenchymal transition in the central nervous system: A potential therapeutic target to combat age-related vascular fragility.
Vance ML, Nagy D, Brunner E … +5 more , Morkotinis V, Black JL, Refai LH, Csiszar A, Conley SM
J Pharmacol Exp Ther · 2025 Nov · PMID 41172623 · Full text
Age-related dysfunction of the central nervous system, including cognitive impairment and visual disorders, is a major concern for the aging population, affecting health span and quality of life. Age-related vascular dys...
Age-related dysfunction of the central nervous system, including cognitive impairment and visual disorders, is a major concern for the aging population, affecting health span and quality of life. Age-related vascular dysfunction in the central nervous system includes an increase in blood-brain or blood-retina barrier permeability, an increase in vascular fragility, and impaired neurovascular coupling, contributing to cognitive impairment and vision loss. While these pathologies occur in the brain and eye with age, gaps remain in our understanding of the underlying cellular mechanisms. During the process of endothelial-to-mesenchymal transition (EndMT), endothelial cells lose their characteristic endothelial phenotypes, which are critical for vascular function, such as barrier integrity, and transition to a mesenchymal-like phenotype. EndMT is triggered by many age-related stimuli and is involved in the progression of many age-related diseases (eg, atherosclerosis, cardiovascular disease, etc). Here, we review what is known about the role of EndMT in vascular fragility in the aging brain and eye, explore the mechanistic links between endothelial cell transdifferentiation and age-associated vascular pathologies of the central nervous system, and identify potential therapeutic targets ripe for future exploration with the goal of preserving vascular function with aging by regulating EndMT. SIGNIFICANCE STATEMENT: Endothelial-to-mesenchymal transition is a key form of cellular plasticity that leads to disrupted barrier function and vascular disorders. Here, we evaluate what is known about this process in the brain, highlight potential targetable mechanisms to block it, and identify areas where further research is needed.
Prevention of fatty acid-induced maladaptation in secretin tumor cell-1 enteroendocrine cells by allicin, a transient receptor potential ankyrin 1 agonist.
Mahajan N, Lal R, Kumar V … +9 more , Khare P, Baboota RK, Rana P, Dhingra N, Lewiński A, Karbownik-Lewińska M, Gesing A, Kondepudi KK, Bishnoi M
J Pharmacol Exp Ther · 2025 Nov · PMID 41160938 · Publisher ↗
Enteroendocrine cells (EECs) in the gastrointestinal tract play a critical role in sensing dietary fat and regulating the secretion of gut hormone. However, chronic high-fat diet (HFD) intake can lead to maladaptive chan...
Enteroendocrine cells (EECs) in the gastrointestinal tract play a critical role in sensing dietary fat and regulating the secretion of gut hormone. However, chronic high-fat diet (HFD) intake can lead to maladaptive changes in these cells, impairing hormone regulation. Transient receptor potential ankyrin 1 (TRPA1), an ion channel endogenously expressed in EECs, is known to promote gut hormone secretion when activated. Previous studies have shown that gut TRPA1 expression is reduced in HFD-fed mice, but the underlying molecular mechanisms remained unclear. In this study, we used the secretin tumor cell-1 (STC-1) enteroendocrine cell line treated with a fatty acid (FA) mixture (oleic acid: stearic acid in a 2:3 ratio) to mimic chronic HFD exposure in vitro. Our data from label-free proteomics, flow cytometry, and western blotting revealed that FA treatment causes TRPA1 downregulation through AMP-activated protein kinase and Ca signaling pathways. This downregulation was accompanied by altered expression of genes and proteins involved in gut hormone synthesis and secretion. We further investigated the protective effect of allicin, a natural TRPA1 agonist found in garlic. Allicin treatment prevented TRPA1 downregulation both in FA-treated STC-1 cells and in HFD-fed C57BL/6J mice. In conclusion, this study elucidates the AMP-activated protein kinase-dependent mechanisms behind FA-induced TRPA1 downregulation in EECs and highlights how this contributes to gut hormone dysregulation. Importantly, dietary TRPA1 agonists such as allicin can counteract these effects, suggesting potential for development of functional foods (eg, allicin, thiocyanates, cuminaldehyde, cinnamaldehyde) to mitigate HFD-related gut hormone disturbances. SIGNIFICANCE STATEMENT: The results of this study showed that fatty acids downregulate transient receptor potential ankyrin 1, a key ion channel involved in regulating the secretion of gut hormones. Furthermore, this study investigated the potential protective effects of allicin, a dietary transient receptor potential ankyrin 1 agonist, using both an in vitro secretin tumor cell-1 model and an in vivo high-fat diet-fed C57Bl/6 mouse model.
Targeting neutral sphingomyelinase 2 by cambinol decreases cell proliferation and migration of metastatic castration-resistant prostate cancer cells.
Dawud D, Kartamyshev M, Kumar T … +3 more , Bilal UM, Kang L, Abd Elmageed ZY
J Pharmacol Exp Ther · 2025 Nov · PMID 41151229 · Publisher ↗
Metastatic castration-resistant prostate cancer (mCRPC) remains a major clinical challenge in the treatment of advanced-stage prostate cancer, particularly among American men. Despite current therapeutic options, disease...
Metastatic castration-resistant prostate cancer (mCRPC) remains a major clinical challenge in the treatment of advanced-stage prostate cancer, particularly among American men. Despite current therapeutic options, disease progression and resistance continue to limit patient outcomes. Therefore, the exploration of novel therapeutic strategies is urgently needed. This study investigates the anticancer potential of cambinol, a selective inhibitor of neutral sphingomyelinase 2, alone and in combination with apalutamide, in mCRPC cells. mCRPC cells were treated with different concentrations of cambinol and apalutamide. Cell viability assay was performed to determine the half-maximal inhibitory concentration for each drug. The effects of cambinol on colony formation and cell migration were assessed. Protein expression levels of neutral sphingomyelinase 2, nuclear factor κ B, extracellular signal-regulated kinase 1/2, and protein kinase B/mammalian target of the rapamycin signaling components were evaluated using immunoblotting analysis. Cambinol treatment at 0.1× and 0.5× half-maximal inhibitory concentration significantly reduced cell viability and colony formation in a dose-dependent manner, underscoring its antiproliferative potential. Combined treatment with cambinol and apalutamide led to a marked decrease in cell migration, suggesting synergistic effects in limiting metastatic behavior. Western blot analysis revealed the downregulation of neutral sphingomyelinase 2, nuclear factor κ B, extracellular signal-regulated kinase 1/2, and protein kinase B/mammalian target of the rapamycin, indicating suppression of key survival and proliferation pathways. This study provides new insights into the multifaceted anticancer effects of cambinol in mCRPC cells, including inhibition of cell viability, colony formation, and migration. The observed molecular changes support its role in modulating critical signaling pathways. These findings warrant further investigation into the therapeutic potential of cambinol, both as a monotherapy and in combination with standard therapies, for the treatment of mCRPC. SIGNIFICANCE STATEMENT: This study aimed to evaluate the antitumor effect of cambinol, a selective inhibitor of neutral sphingomyelinase 2, and its combination with apalutamide as a potential therapeutic strategy for metastatic castration-resistant prostate cancer.
Chemical, biological, radiological, and nuclear medical countermeasures: Current challenges and future directions in drug development.
Sandal N, Mahar R
J Pharmacol Exp Ther · 2025 Nov · PMID 41138390 · Publisher ↗
Chemical, biological, radiological, and nuclear (CBRN) hazards encompass CBRN materials that can have adverse effects if accidentally or deliberately released. With the increase in the use of CBRN-related agents for rese...
Chemical, biological, radiological, and nuclear (CBRN) hazards encompass CBRN materials that can have adverse effects if accidentally or deliberately released. With the increase in the use of CBRN-related agents for research, therapeutics, diagnostics, industrial use, etc., these agents have become available. Thus, the probability of occurrences of CBRN emergencies has also increased. Therefore, nations are striving hard to strengthen themselves to handle such situations. CBRN emergency preparedness is a vast area comprising devices, drugs, equipment, systems, etc. Each aspect of CBRN preparedness is humungous, and proportionately meager efforts are under progress for various reasons. The most important aspect is that it is a matter of state because the cost of CBRN preparedness is very high. Among the different aspects, drug development for the management of CBRN emergencies is extremely important wherein several efforts by the agencies have resulted in a handful of antidotes. Additionally, research toward the development of drugs and drug products for CBRN agents is an extremely important area to be encouraged. This paper highlights the challenges in CBRN drug development. Additionally, it also suggests the measures that may help to empower the researchers and manufacturers to contribute toward CBRN medical management preparedness. SIGNIFICANCE STATEMENT: This paper underscores the urgent need for focused drug development to address the unique challenges posed by chemical, biological, radiological, and nuclear threats. It highlights existing gaps and proposes strategies to strengthen medical preparedness and response.
Targeting mitochondrial RNA polymerase for triple-negative breast cancer.
Lai X, Wang D, Gong H … +9 more , Jiang R, Yao Y, Xue Q, Liu Y, Ding Y, Zhou W, Yang S, Li H, Fang X
J Pharmacol Exp Ther · 2025 Nov · PMID 41135413 · Publisher ↗
Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis and limited therapeutic options, lacking effective molecular targets. Recent studies have highlighted the critical role of mitochondrial m...
Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis and limited therapeutic options, lacking effective molecular targets. Recent studies have highlighted the critical role of mitochondrial metabolism, particularly oxidative phosphorylation, in TNBC progression. Mitochondrial RNA polymerase (POLRMT) has been implicated in maintaining mitochondrial function and stabilizing oxidative phosphorylation complexes. Targeting POLRMT offers a promising strategy to disrupt the heightened metabolic demands of tumors. Kaplan-Meier survival analysis revealed that elevated POLRMT levels were specifically associated with poor prognosis in TNBC patients. The Cancer Genome Atlas cohorts revealed that POLRMT transcripts are upregulated in TNBC tissues, and this enzyme overexpression was linked to hypomethylation of the cg23000464 site in the promoter region. We applied cell proliferation inhibition assays to investigate the potential anti-TNBC activity of targeted siRNA, an inhibitor of mitochondrial transcription (IMT) and mitochondrial protease targeting chimera (MtPTAC). Consistent with the silencing of POLRMT using siRNA both IMT and MtPTAC effectively suppress mitochondrial transcription, impacting oxidative phosphorylation, cell proliferation, and clonogenic ability in TNBC cells. In addition to eliciting comparable effects on cell phenotypes as IMT, MtPTAC selectively degrades POLRMT and inhibits the growth of IMT-resistant cells. POLRMT may represent a promising therapeutic target for TNBC, and MtPTAC could demonstrate promising application prospects. SIGNIFICANCE STATEMENT: This study shows that mitochondrial RNA polymerase (POLRMT) overexpression-linked to promoter hypomethylation-is associated with poor patient prognosis. Silencing or inhibiting POLRMT disrupts mitochondrial transcription, impairing oxidative phosphorylation, cell proliferation, and clonogenicity. Moreover, mitochondrial protease targeting chimera selectively degrades POLRMT and overcomes resistance to conventional inhibitors, underscoring its potential as an effective treatment option for aggressive triple-negative breast cancer.
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