Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Investigation of dose-exposure-response relationship for adeno-associated virus-mediated delivery of antibody genes.","authors":"Aneesh Rajwade, Shufang Liu, Mokshada Kumar, Avanobe Ghobrial, Sara Hahn, Dhaval K Shah","doi":"10.1016/j.jpet.2025.103601","DOIUrl":"10.1016/j.jpet.2025.103601","url":null,"abstract":"<p><p>Adeno-associated virus (AAV)-based gene therapies have advanced significantly, yet the pharmacology of these therapies, particularly the relationship between dose and transgene expression, remains incompletely understood. Here, we investigated the dose-response dynamics of AAV8 vectors encoding an antibody (trastuzumab) gene in C57BL/6 mice to assess virus pharmacokinetics, transgene expression, liver toxicity, and immunogenicity across a broad dose range (1E8-1E13 vector genomes/mouse). Whole-body viral pharmacokinetics data revealed dose nonproportionality, with higher doses leading to less than proportional increases in AAV exposure across most tissues, except for the spleen, which exhibited a more than proportional increase. Plasma transgene concentrations demonstrated a sigmoidal dose-response relationship, with Emax of ∼ 8000 nM and EC50 of ∼8E9 vector genomes, indicating saturation at higher doses. Immune responses to AAV8 were dose-dependent, with IgM titers peaking on day 2 and IgG titers appearing by day 21, both escalating with increasing doses. Elevated aspartate aminotransferase and alanine aminotransferase levels at higher doses indicate a hepatotoxic effect. These findings suggest that the nonlinear dose-exposure relationship stems from saturable tissue distribution, nonlinear transgene production, or heightened immune activation at higher doses. Importantly, the nonlinearity in translational efficiency and an increased risk for immunogenicity and hepatotoxicity at higher dose levels underscore the critical need to optimize AAV dosing to balance efficacy and safety. These data provide valuable insights into the pharmacology of AAV gene therapies and offer a framework for determining optimal dosing strategies that maximize therapeutic benefit while minimizing toxicity and immunogenicity. SIGNIFICANCE STATEMENT: The research presented here demonstrates that there is an optimal dose for adeno-associated virus-based therapies and exceeding this dose might lead to more immunogenicity, more toxicity, and reduced transgene expression.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103601"},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting kinase target inhibition level for efficacy in rheumatoid arthritis: A translational approach based on collagen-induced arthritis rodent studies.","authors":"Rui Li, Roger Gifford, Peter Symanowicz, Cara M M Williams, Martin Hegen","doi":"10.1016/j.jpet.2025.103589","DOIUrl":"10.1016/j.jpet.2025.103589","url":null,"abstract":"<p><p>Setting a clinically efficacious dose in the preclinical stage is an important but challenging task in developing new therapies, including small-molecule kinase inhibitors for rheumatoid arthritis (RA). Besides pharmacokinetics and potency, another key component in determining the efficacious dose of a small molecule targeted therapy is the target inhibition level required for efficacy, which few established approaches can predict based on preclinical data. Using collagen-induced arthritis rodent data, we aimed to establish a translational approach in predicting the lowest efficacious target inhibition level in patients with RA, assuming that similar levels of target inhibition are required for efficacy in both patients and animal models. Target inhibition levels of tofacitinib, zimlovisertib, and 3 literature kinase inhibitors at efficacious and inefficacious doses were compared between patients and rodents using a new approach based on average inhibition level (I_AVG). For comparison purposes, classic approaches based on average, maximal, and minimal exposures and durations with exposure above IC₃₀, IC₅₀, IC₇₀, and IC₉₀ are also included in our analysis. We found that the lowest I_AVG required for efficacy was generally consistent between humans and rodents. Overall, the I_AVG-based approach led to a better alignment between rodent and human efficacy and is more universally applicable than other approaches. For future kinase inhibitors in discovery or development, I_AVG-based rodent-to-human translation can be used to identify the target inhibition level required for efficacy and corresponding efficacious dose in patients with RA. SIGNIFICANCE STATEMENT: Identifying the target inhibition level required for clinical efficacy in the preclinical stage is important in developing new therapies. However, there are few established approaches aiming to predict this level based on preclinical data. Using data from kinase inhibitors for rheumatoid arthritis, this study proposed a rodent-to-human translation approach. The established translation helps to predict the efficacious inhibition level and corresponding efficacious dose for future kinase inhibitors for rheumatoid arthritis. The approach may also be applicable to other small-molecule targeted therapies.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103589"},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Difamilast topically ameliorates pruritus, dermatitis, and barrier dysfunction in atopic dermatitis model mice by inhibiting phosphodiesterase 4, especially the 4B subtype.","authors":"Kazuyoshi Kirima, Yuya Hoshino, Naoya Arichika, Takashi Wadatsu, Yusuke Kakumoto, Masafumi Shibamori, Hidetaka Hiyama","doi":"10.1016/j.jpet.2025.103582","DOIUrl":"10.1016/j.jpet.2025.103582","url":null,"abstract":"<p><p>Atopic dermatitis (AD) is a common chronic inflammatory skin disorder, characterized by itchy eczema. The complex interplay among pruritus, skin inflammation, and barrier dysfunction contributes to the development, progression, and chronicity of AD. Phosphodiesterase 4 (PDE4), an enzyme that specifically degrades cAMP, is expressed in a variety of cell types, including immune cells, fibroblasts, and keratinocytes. PDE4 is involved in the persistence and exacerbation of chronic inflammatory diseases such as chronic obstructive pulmonary disease, asthma, psoriasis, and AD. One of the topical PDE4 inhibitors, difamilast, has been shown to be effective in the clinical treatment of AD. However, its pharmacological effects and mechanisms of action are not completely understood. Therefore, we evaluated the effects of difamilast on pruritus, dermatitis, and skin barrier dysfunction in MC903-induced AD model mice. The results revealed that a single application of difamilast dramatically reduced the number of scratching events, an indicator of pruritus, and repeated application of difamilast reduced the increase in ear thickness, an indicator of dermatitis, and transepidermal water loss, an indicator of barrier dysfunction. In addition, these symptoms were milder in PDE4B-deficient mice than in wild-type mice, and difamilast treatment had little or no further therapeutic effects on attenuating AD symptoms. In summary, our study demonstrated that difamilast effectively alleviates the primary symptoms of AD through the inhibition of PDE4B, as one of its mechanisms. SIGNIFICANCE STATEMENT: This study characterized the therapeutic effects of difamilast on the major symptoms of atopic dermatitis, including pruritus, dermatitis, and skin barrier dysfunction. The study also revealed a detailed mechanism of action of difamilast, in which its therapeutic effect is mediated mainly by PDE4B inhibition. This study may provide new insights into the use of difamilast for the treatment of atopic dermatitis.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103582"},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated assessment of continuous uroflow cystometry and visceromotor responses to bladder distension in urethane-anesthetized mice.","authors":"Eric Woon, Shaopeng Zhang, Longtu Chen, George Kuchel, Jenna Bartley, Bin Feng","doi":"10.1016/j.jpet.2025.103587","DOIUrl":"10.1016/j.jpet.2025.103587","url":null,"abstract":"<p><p>Bladder-related disorders, such as underactive or overactive bladder and chronic pelvic pain syndromes, are typically studied by recording cystometrogram and visceromotor responses (VMRs) to urinary bladder distension (UBD) in anesthetized rats. Recently, similar studies have been conducted in mice due to their suitability for genetic manipulation. However, assessing bladder physiology and pain in aged mice remains challenging due to inconsistencies in anesthesia. Here, we optimized a urethane anesthesia protocol to enable robust cystometrogram (CMG) recordings and VMR in female mice of 2 different age groups: mature (10-12 months) and aged (18-22 months). Mice were first anesthetized with 1.75% isoflurane inhalation for the surgical implantation of a bladder catheter and stainless-steel wire electrodes to the external oblique musculature for delivering bladder distension and recording muscular response respectively. Another catheter was placed intraperitoneally for continuous delivery of urethane (0.15-0.23 g/kg per hour for 2 hours). CMG was measured by delivering slow bladder filling (1.5 mL/h) through the catheter while recording intravesical pressure, VMR responses from external oblique musculature, and micturition volume. Afterwards, VMR response to UBD was recorded. In another cohort, both CMG and VMR response to UBD were assessed before and after intravesical infusion of 0.5% acetic acid and 0.1% lidocaine. Intravesical infusion of acetic acid significantly enhanced the VMR to grader bladder distension and disrupted the regular micturition cycles, which were normalized by intravesical lidocaine. This anesthesia protocol produced robust CMG and VMR recordings for 2 hours in mice of both age groups, enabling focused studies to advance mechanistic understanding of bladder-related disorders. SIGNIFICANCE STATEMENT: A urethane anesthesia protocol was optimized for robust cystometrogram and visceromotor response recordings in mature and aged mice. This model allows assessment of bladder physiology and pain, demonstrating that acetic acid disrupts micturition and enhances pain responses, which lidocaine normalizes.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103587"},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Compounds with dual glutaminase inhibition and Nrf2 activation activities enhance morphine analgesia and reduce pain sensitization in chemotherapy-induced peripheral neuropathy mouse model.","authors":"Brandon K Foster, Valentin Kliebe, Hilal F Elnaham, Michael K Thompson, Sid L Sagna, James S Patton, Shaina C Brown, Xin Chen, Tuoen Liu, Jessica Bowden, John Streicher, Wei Lei","doi":"10.1016/j.jpet.2025.103583","DOIUrl":"10.1016/j.jpet.2025.103583","url":null,"abstract":"<p><p>Chemotherapy-induced peripheral neuropathy (CIPN) affects millions of patients, substantially impacting their quality of life. However, there are limited effective treatments available for alleviating CIPN. Therefore, discovering new approaches to manage neuropathic pain is in high clinical demand. Compound 968 (C968) and CU1015, both identified as glutaminase inhibitors with applications in cancer therapy, have shown promise in enhancing the anticancer activities of chemotherapy drugs in previous studies. However, their potential impact on CIPN has not been fully elucidated. This study aims to determine effects of C968 and CU1015 on pain and morphine-mediated analgesia in the CIPN mouse model. The CD-1 male and female mice received 4 doses of paclitaxel (intraperitoneal injection) to induce CIPN. Following CIPN development, mice were treated with C968 or CU1015 (intrathecal injection) 24 hours prior to morphine administration. To assess the impact of C968 or CU1015 on CIPN development, mice were treated with these compounds while concurrently receiving paclitaxel injections. The mechanical threshold was measured using the von Frey filaments. We found that C968 or CU1015 enhanced morphine analgesia in CIPN mice. C968 or CU1015 also attenuated the development of CIPN in male, but not in female mice, at the dose tested. This potential sex difference may be linked to the activation of pain-related signal transduction pathways involving ERK and AKT in the spinal cord. These findings suggest that compounds with dual glutaminase inhibition and Nrf2 activation activities could be a novel approach for treating CIPN. SIGNIFICANCE STATEMENT: This study demonstrates that compounds with dual glutaminase inhibition and Nrf2 activation activities could be a promising therapeutic target for managing neuropathic pain.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103583"},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144120046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced negative modulation of urotensin II on cardiac function and [Ca²⁺]_i regulation in a diabetic rat model: Insights into molecular and cellular mechanisms.","authors":"Xiaowei Zhang, Zhe Chen, Jing Cao, Peng Zhou, Zhi Zhang, Xiaoqiang Sun, Yixi Liu, Tiankai Li, Heng-Jie Cheng, Che Ping Cheng","doi":"10.1016/j.jpet.2025.103594","DOIUrl":"10.1016/j.jpet.2025.103594","url":null,"abstract":"<p><p>The direct cardiac effects of urotensin II (UII) in normal and diabetic subjects remain controversial. The alteration and functional significance of cardiac UII/UII receptor (UT) in diabetes are still unclear. We assessed the hypothesis that in diabetes, the cardiomyocyte UII/UT system is increased. This augmentation is proposed to exacerbate the dysfunctional [Ca²⁺]_i regulation, enhance inhibitions of left ventricle (LV) and myocyte contraction and relaxation, leading to worsening cardiac dysfunction. We compared LV myocyte UII and UT expression, LV and myocyte contractile, [Ca²⁺]_i transient ([Ca²⁺]_iT) and calcium current (I_Ca,L) responses to UII stimulation in male Sprague-Dawley rats (12/group) with streptozotocin-induced diabetes mellitus and controls. We found that UII and UT protein levels were significantly greater in diabetic myocytes than in control myocytes. Compared with control rats, UII (400 pmol/kg, i.p.) administration produced greater decreases in LV contractility of E_ES (diabetes mellitus: 32% vs C: 13%) and M_SW with significantly increased LV time constant relaxation in diabetes. In response to UII (10^-5 M) superfusion, diabetic myocytes had much greater decreases in the velocity of shortening and relengthening accompanied by significantly larger decreases in the peak systolic [Ca²⁺]_iT and I_Ca,L (29% vs 15%). These responses were abolished by pretreatment of diabetic myocytes with urantide, pertussis toxin, or dibutyryl-cAMP, respectively. We conclude that UII has direct negative inotropic and lusitropic cardiac effects in both normal and diabetic rats. In diabetes, cardiac UII/UT is upregulated, enhancing UII-caused negative modulation on cardiac function and [Ca²⁺]_i regulation. This may contribute to the progression of cardiac dysfunction in diabetes and diabetic cardiomyopathy. SIGNIFICANCE STATEMENT: Urotensin II (UII) has direct negative inotropic and lusitropic cardiac effects in both normal and diabetic rats. Compared with normal rats, cardiac UII/UII receptors (UT) were upregulated in diabetic rats, resulting in significantly greater decreases in [Ca²⁺]_iT and I_Ca,L and increased inhibitions of left ventricle and myocyte contraction and relaxation. These effects are coupled with UT and mediated by G_i proteins. These data provide new insights and evidence that upregulation of cardiomyocyte UII/UT may promote the progressive cardiac dysfunction in diabetes and diabetic cardiomyopathy.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103594"},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic stress-mediated cell death and autophagy in human lung cancer cells.","authors":"Himani Joshi, Ying Huang, M Saeed Sheikh","doi":"10.1016/j.jpet.2025.103598","DOIUrl":"10.1016/j.jpet.2025.103598","url":null,"abstract":"<p><p>Lung cancer remains one of the major causes of cancer-related mortality. Thus, newer therapeutic approaches are urgently needed. Because cancer is a metabolic disease, lung cancer cells have also rewired their metabolism to gain growth advantage and support survival. Therefore, the use of metabolic stress-inducing agents as a therapeutic strategy for lung cancer is an attractive idea. In this study, we have investigated the anticancer potential of CB-839 and metformin. CB-839, a selective glutaminase-1 inhibitor, creates glutamine-deficient conditions, and metformin is an antidiabetic drug. We report that CB-839 and metformin induce metabolic stress and inhibit growth of human lung cancer cells. Of note, lung cancer cells that harbor mutant K-Ras are more sensitive to these agents compared to cells with wild-type K-Ras status. In the K-Ras mutant cells, these agents induce cell death partly, via death receptor 5 (DR5)-dependent extrinsic pathway. However, in the lung cancer cells harboring wild-type K-Ras, these agents activate autophagy without significant effect on DR5 regulation. Pretreatment of K-Ras wild-type cells with autophagy inhibitor improves the anticancer potential of these agents coupled with activation of DR5-dependent pathway. Our results further show that the growth inhibitory effects of these agents appear to be linked to the mutant K-Ras status because pan-K-Ras inhibitor that inhibits the mutant K-Ras proteins blunted the growth inhibitory effects of these agents in cells harboring mutant K-Ras. Collectively, our results provide valuable new insights into exploiting the metabolic rewiring of lung cancer cells by using metabolic stress-inducing drugs as an important therapeutic approach. SIGNIFICANCE STATEMENT: Anticancer potential of CB-839 and metformin is investigated in lung cancer. These agents induce cell death partly, via death receptor 5-dependent pathway, and a relationship with K-Ras status of lung cancer cells is noted. Lung cancer cells with mutant K-Ras are more sensitive compared to cells with wild-type K-Ras. Autophagy inhibition of K-Ras wild-type cells improves the anticancer potential. This study provides new insights into exploiting the metabolic rewiring of lung cancer cells as an important therapeutic strategy.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103598"},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioactive phytoconstituent millettone as a potential inhibitor of catechol O-methyltransferase: Implications for neuroprotective therapy in Parkinson's disease.","authors":"Mohammad Khalid, Mohammed H Alqarni, Ahmed I Foudah","doi":"10.1016/j.jpet.2025.103592","DOIUrl":"10.1016/j.jpet.2025.103592","url":null,"abstract":"<p><p>Catechol O-methyltransferase (COMT) is a cation-dependent enzyme essential for the metabolism of catechols, including dopamine, norepinephrine, caffeine, and estrogens. COMT is highly expressed in tissues such as the brain, liver, and erythrocytes, and its elevated levels in dopaminergic neurons are implicated in Parkinson's disease. Considering it as a promising target for drug development against Parkinson's disease, this study employed in silico screening of plant-derived compounds from the IMPPAT 2.0 data base to identify potential COMT inhibitors. Compounds were initially filtered out based on their pharmacokinetic properties and binding affinities. Further screening included ligand-receptor interaction calculations, pan-assay interface compounds filtering, ADMET analysis, and biological activity prediction, followed by stability assessments to select the most promising phytochemicals. Millettone emerged as a top candidate, demonstrating high affinity and specific binding interactions with COMT. Comprehensive evaluations, including all-atom molecular dynamics simulations and essential dynamics analysis, further supported millettone's stability and effectiveness as a potential COMT inhibitor. These findings suggest that millettone is a strong candidate for further experimental studies, with potential application as an anti-Parkinson's therapeutic targeting COMT. SIGNIFICANCE STATEMENT: This study identified a plant-based natural compound, millettone, as a potential catechol O-methyltransferase inhibitor through in silico screening and molecular dynamics simulations. Its strong binding and stability suggest therapeutic potential for Parkinson's disease, warranting further experimental validation.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103592"},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mineralocorticoid and estrogen receptors as sex-dependent modulators of vascular health in aging and obesity.","authors":"Casey G Turner, Karla de Oliveira, Iris Z Jaffe, Jennifer J DuPont","doi":"10.1016/j.jpet.2025.103591","DOIUrl":"10.1016/j.jpet.2025.103591","url":null,"abstract":"<p><p>Cardiovascular disease (CVD) is the leading cause of death in both men and women, but there are sex differences in the timing and mechanisms of disease development. Sex differences particularly influence the development of CVD in the presence of aging and obesity, 2 major risk factors of CVD. The mineralocorticoid and estrogen receptors have been identified as important regulators of vascular function in healthy and disease states. Recent evidence has highlighted interactions between these receptors in the vasculature, and innovations in global and cell-specific knockout mouse models have substantially advanced our understanding of sex-dependent roles of these receptors in vascular health and disease. This review summarizes recent advances in the sex-dependent roles of the mineralocorticoid and estrogen receptors in arterial stiffness and vasomotor dysfunction, 2 early markers of CVD development. These vascular outcomes are examined in the context of aging and obesity, 2 of the most prevalent CVD risk factors. SIGNIFICANCE STATEMENT: Cardiovascular disease (CVD) is the leading cause of death globally for women and men, but there are sex differences in the timing of CVD development across the lifespan and in mechanisms driving disease. This review summarizes sex-specific roles of mineralocorticoid and estrogen receptors in arterial stiffness and vasomotor dysfunction during aging and obesity. Understanding sex-specific mechanisms of CVD is critical to developing precision medicine strategies to prevent and treat CVD in women and men.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103591"},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A gut response: Application of human enteroid monolayers to probe the mechanism of the goldenseal-mediated inhibition of metformin intestinal absorption.","authors":"Christopher M Arian, Eimear T O'Mahony, Preston K Manwill, Tyler N Graf, Nicholas H Oberlies, Nadja B Cech, John D Clarke, Jason G Smith, Mary F Paine, Edward J Kelly, Kenneth E Thummel","doi":"10.1016/j.jpet.2025.103597","DOIUrl":"10.1016/j.jpet.2025.103597","url":null,"abstract":"<p><p>Continued growth in global sales of natural products has led to an increased risk of natural product-drug interactions that can compromise drug efficacy and safety. One such natural product, goldenseal, was shown to decrease systemic exposure to a subtherapeutic dose of oral metformin in healthy adults. A follow-up study involving therapeutic metformin doses and adults with type II diabetes demonstrated a metformin dose-dependent pharmacokinetic interaction with goldenseal. These results, along with no change in metformin half-life or renal clearance in both studies, suggested that the goldenseal-metformin interaction occurred in the gut via inhibition of an unidentified saturable intestinal transport process. We used enteroid monolayers derived from the duodenum of 4 healthy human adult donors to recapitulate the goldenseal-metformin interaction in vitro and identify the transporters involved in the observed in vivo interaction. Our results implicate thiamine transporter (ThTr) 2 as the predominant transporter involved in metformin uptake through the apical membrane, accounting for approximately 45% of total metformin intracellular accumulation. Additionally, goldenseal inhibited ThTr-2, but only under subsaturating metformin dosing concentrations. The goldenseal-metformin interaction mediated under therapeutic metformin dose conditions involves a low-affinity basolateral transporter, ThTr-1, which accounts for approximately 50% of inhibitable metformin apical to basolateral flux. However, a substantial fraction of metformin flux appears to involve paracellular transport. These results further elucidate the mechanism underlying the goldenseal-metformin interaction and suggest that enteroid monolayers are a promising model to study intestinal natural product-drug interactions. SIGNIFICANCE STATEMENT: The research presented in this article demonstrates the utility of enteroid monolayers to predict and ascertain the mechanisms of drug-drug and natural product-drug interactions. Using this model, the study was able to identify the transporters (thiamine transporter-1 and thiamine transporter-2) involved in metformin absorption that are inhibited by the natural product, goldenseal, which were previously unidentified.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103597"},"PeriodicalIF":3.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}