Pharmacological Reviews[JOURNAL]
Sun
200 papers
Gut microbiome and bile acid metabolism in liver disease: Mechanisms, clinical implications, and therapeutic opportunities.
Zhou H, Huang Y, Chen C … +2 more , Song M, Hylemon PB
Pharmacol Rev · 2026 Mar · PMID 41759374 · Full text
The intricate interplay between the gut microbiome and bile acid metabolism via the gut-liver axis is fundamental to hepatic homeostasis. Perturbations in this axis are increasingly implicated in the pathogenesis of dive...
The intricate interplay between the gut microbiome and bile acid metabolism via the gut-liver axis is fundamental to hepatic homeostasis. Perturbations in this axis are increasingly implicated in the pathogenesis of diverse liver diseases, including metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, cholestatic liver diseases, and hepatocellular carcinoma. This review integrates current understanding of hepatic bile acid synthesis, enterohepatic circulation, and gut microbial bile acid transformations, detailing how bile acids function as signaling molecules through nuclear receptors including farnesoid X receptor, pregnane X receptor, vitamin D receptor, constitutive androstane receptor, and G-protein-coupled receptors; G protein-coupled bile acid receptor 1 (also known as Takeda G protein-coupled receptor 5), and sphingosine-1-phosphate receptor 2. We explore disease-specific alterations in gut microbiota composition and bile acid profiles in metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, cholestatic liver diseases, and liver cancers, focusing on mechanisms linking gut dysbiosis, impaired intestinal barrier function, altered bile acid signaling, inflammation, and immune modulation to liver injury and progression. Furthermore, we discuss the clinical implications, highlighting the potential of microbiome signatures and bile acid profiles as diagnostic and prognostic biomarkers. Therapeutic strategies targeting the gut-liver axis, including probiotics, fecal microbiota transplantation, farnesoid X receptor agonists, and fibroblast growth factor 19 analogs, are reviewed. Finally, we address current challenges and future directions, emphasizing the need for multiomics integration, functional studies, and personalized medicine approaches to leverage the gut-liver axis for improved liver disease management. SIGNIFICANCE STATEMENT: Disruption of the gut microbiome-bile acid-liver axis is now recognized as a unifying mechanism driving multiple liver diseases, including metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, cholestatic liver diseases, and hepatocellular carcinoma. Unraveling the molecular and microbial interactions within this axis offers fundamental insights into disease pathogenesis and reveals novel therapeutic opportunities. Integrating multiomics technologies with artificial intelligence-based analytics will accelerate the discovery of predictive biomarkers and personalized interventions, advancing the field toward precision-based liver disease treatment protocols.
Discovery of a pyridine-piperazine-based small molecule that enhances the activity of peptidase neurolysin.
ElSayed ElZorkany H, Kandil H, Jayaraman S … +16 more , Aly A, Esfahani SH, Patel D, Dannecker D, Maciag M, Paul A, Lowran K, Kumari S, Bose S, Ostrov DA, Wu CG, Dickson A, Abbruscato TJ, Trippier PC, Orlando BJ, Karamyan VT
J Pharmacol Exp Ther · 2026 Mar · PMID 41759240 · Full text
Neurolysin (Nln) is a peptidase recognized for its cerebroprotective function in acute ischemic stroke. This study aimed to identify small molecule activators of Nln as research tools to further explore the role of this...
Neurolysin (Nln) is a peptidase recognized for its cerebroprotective function in acute ischemic stroke. This study aimed to identify small molecule activators of Nln as research tools to further explore the role of this enzyme in stroke and other neurological disorders. Building on our previous computational screen of ∼140,000 compounds from the National Cancer Institute Developmental Therapeutics Program database, we extended experimental testing to the top 100 candidates using an Nln enzymatic assay. A pyridine-piperazine derivative (Py-Pip) was identified as a hit molecule and was characterized in detail. Py-Pip concentration-dependently enhanced the hydrolysis of both synthetic and natural substrates (neurotensin, angiotensin I, and bradykinin) by rat Nln, and displayed comparable activating effects on human and mouse orthologs. Importantly, Py-Pip exhibited a favorable selectivity profile, showing no potentiation of homologous metallopeptidases or unrelated enzymes. Kinetic analysis revealed that Py-Pip increases the catalytic efficiency (V/K) of Nln via a nonessential activation mechanism, whereas competition assays with inhibitor dynorphin A(1-13) confirmed that Py-Pip acts at a distinct, nonoverlapping site. Direct binding was further validated by orthogonal biophysical techniques, including differential scanning fluorimetry, microscale thermophoresis, and biolayer interferometry, whereas circular dichroism spectroscopy indicated activator-induced secondary structural changes. These findings validate that Nln activity can be enhanced by small molecules and establish Py-Pip as a novel, nonpeptide scaffold for developing potent, "drug-like" activators to investigate Nln biology and therapeutic potential. SIGNIFICANCE STATEMENT: This study reports the discovery of a novel nonpeptide small molecule that selectively enhances the activity of neurolysin (Nln), a peptidase implicated in cerebroprotection. Unlike previous peptide-based activators, this molecule provides a stable, "drug-like" scaffold and a structural foundation for the development of potent Nln activators to probe Nln biology and therapeutic potential in ischemic stroke.
Pharmacogenetic influence on bupropion bioactivation and clinical outcomes in major depressive disorder.
Kharasch ED, Lenze EJ
J Pharmacol Exp Ther · 2026 Mar · PMID 41759239 · Publisher ↗
This investigation addressed influences of CYP2B6 and CYP2C19 genetic polymorphisms on steady-state bupropion disposition, antidepressant outcomes and side effects, and evaluated influences of pharmacokinetic variability...
This investigation addressed influences of CYP2B6 and CYP2C19 genetic polymorphisms on steady-state bupropion disposition, antidepressant outcomes and side effects, and evaluated influences of pharmacokinetic variability on pharmacogenetic results. This was a preplanned secondary analysis of a prospective, 24-week, randomized, double-blind, crossover trial which compared pharmacokinetics and antidepressant effects across brand and 3 generic bupropion XL 300 mg drug products in 70 participants with major depressive disorder in remission, who were genotyped for CYP2B6 and CYP2C19 polymorphisms. We measured steady-state enantiomeric plasma and urine bupropion and primary (hydroxybupropion, a bioactivation pathway), reduced, and secondary metabolites, clinical depression (Montgomery-Asberg depression rating scale), side effects, and influence of CYP2B6 and CYP2C19 polymorphisms on bupropion disposition and drug effects across all 4 drug products (pooled analysis). Results showed that CYP2B6 polymorphisms (CYP2B6∗6 allele and the 516G>T variant alone) had a significant influence on bupropion disposition, including apparent oral clearance and enantiomers hydroxylation. Since bioactivation via bupropion hydroxylation has therapeutic importance, CYP2B6 polymorphisms could be clinically relevant. However, there were no significant differences between CYP2B6∗6 or 516G>T gene groups in either depression or side effect scores, at baseline on patients' own bupropion, or during the crossover phase of 4 bupropion products. CYP2C19 polymorphisms had a small and clinically unimportant influence on bupropion minor metabolites and secondary metabolism, and no effect on depression or side effect scores. Results show that CYP2B6 polymorphisms significantly influenced bupropion enantiomers steady-state disposition, but not long-term antidepressant or side effects. These findings may have relevance for clinical pharmacogenetic testing in depression. SIGNIFICANCE STATEMENT: This pharmacogenetic study in major depressive disorder evaluated both pharmacokinetics and clinical effects. CYP2B6 polymorphisms (CYP2B6∗6 allele, 516G>T variant) had significant influence on steady-state bupropion enantiomers apparent oral clearance and hydroxylation, but there was no association between CYP2B6∗6 or 516G>T gene groups and either depression or drug side effects. CYP2C19 polymorphisms had a small and clinically unimportant influence on bupropion minor metabolites and secondary metabolism and no effect on depression or side effect scores. These results may have implications for genetic testing in bupropion pharmacotherapy of major depressive disorder.
Links between COVID-19, long COVID, and neurodegeneration: The role of glycosphingolipids.
Spedding M, Aerts J, Alexander S … +17 more , Bellozzi Woestelandt AG, Chiricozzi E, Henriques A, Lledo PM, Loeffler JP, Perera R, Platt FM, Pradat PF, Rene F, Schapira A, St Clair L, Talbot K, Taquet M, Toborek M, Turner B, Zandi M, Gressens P
Pharmacol Rev · 2026 Mar · PMID 41740316 · Publisher ↗
Glycosphingolipids (GSLs) play major roles in viral infections by mediating viral entry and egress from cells in lipid rafts; however, GSLs are also important in neurodegenerative diseases. The role of GSLs in acute COVI...
Glycosphingolipids (GSLs) play major roles in viral infections by mediating viral entry and egress from cells in lipid rafts; however, GSLs are also important in neurodegenerative diseases. The role of GSLs in acute COVID-19 infection is critical but remains less-studied in the sequelae of long COVID (post-COVID condition); because the same enzymes that regulate GSL metabolism are critical for viral entry and exit, neuromuscular junctions, neurological function, and cellular metabolism, it is important to determine whether long COVID may increase the risk of subsequent neurodegeneration. SARS-CoV-2 infection alters lipid metabolism and oxygen use and can bind to and modify the expression of neurotrophic GSLs such as GM1 ganglioside. GM1 (N-acetylneuraminic acid) is human-specific and probably evolved as a result of a pandemic 3-2.5 million years ago that drove its selection. GM1 functions as a coreceptor with angiotensin-converting enzyme 2 for SARS-CoV-2 while also being a neurotrophin. Viral multiplication takes place in the endoplasmic reticulum/Golgi apparatus, where GSLs are synthesized. This review defines the complex interaction between viruses, GSLs, and neurodegeneration, which provides new perspectives on the interlinked metabolic changes. A European working group has been set up to assess the risks of neurodegeneration with long COVID, based on potential GSL-mediated mechanisms. SIGNIFICANCE STATEMENT: The SARS-CoV-2 pandemic has resulted in a large number of subjects living with long-term consequences (long COVID). Glycosphingolipids and gangliosides are involved in both viral infections and neurodegeneration; hence, it is important to evaluate whether long COVID may increase the risk of neurodegeneration via this route. This study is the result of a European consortium formed to evaluate this possibility.
Moving beyond shock: Rich-lean transition procedures as a modern approach to anxiolytic screening.
Rough MI, Kratzenberg JL
J Pharmacol Exp Ther · 2026 Mar · PMID 41740199 · Full text
Abstract loading — click title to view on PubMed.
Selective serotonin reuptake inhibitor fluoxetine, reduces solid tumor burden and metastasis through activation of host antitumor immune response and modulation of tumor microenvironment.
Mahanti K, Saha J, Mondal P … +5 more , Sarkar D, Pramanik A, Das D, Mahato M, Bhattacharyya S
J Pharmacol Exp Ther · 2026 Mar · PMID 41734401 · Publisher ↗
The tumor microenvironment (TME) plays a pivotal role in tumorigenesis, metastasis, and resistance to therapy. Although immunotherapeutic approaches such as CAR-T cells, immune checkpoint inhibitors, and tumor vaccines h...
The tumor microenvironment (TME) plays a pivotal role in tumorigenesis, metastasis, and resistance to therapy. Although immunotherapeutic approaches such as CAR-T cells, immune checkpoint inhibitors, and tumor vaccines have demonstrated promising therapeutic effectiveness, tumor heterogeneity and immunosuppression continue to limit their efficacy in solid tumors, therefore, development of effective low-cost TME targeted therapy is necessary. Recent studies indicate, selective serotonin reuptake inhibitors display immune modulatory effects. Fluoxetine is an US Food and Drug Administration-approved selective serotonin reuptake inhibitor widely used in treatments of depression in patients with cancer, its effects toward immune responses in TME and effectiveness in management of solid tumor has not been explored previously. In this study, we investigated the immunoregulatory and antitumor effects of fluoxetine on solid tumor using syngeneic orthotropic B16-F10 melanoma and 4T1 breast carcinoma models in mice. Fluoxetine oral application significantly decreased the primary tumor burden and development of metastatic nodules. Histopathology, flowcytometry and confocal imaging revealed that fluoxetine significantly activates host antitumor immune system through increased cytotoxic interferon gamma secreting T cells and M1-macrophages accumulation at both primary and metastatic sites that results in elevated activated caspase-8 in cancer cells leading to immune mediated tumor cell death. Fluoxetine treatment led to decrease in immunosuppressive cells populations such as myeloid derived suppressor cells, M2-macrophages, regulatory T cells, while also reducing the level of cancer stemness markers and proteins associated with epithelia to mesenchymal transition and metastasis. Collectively, our study indicates the multifaceted role of fluoxetine in modulating the solid TME and highlight its potential in designing of novel anticancer treatment regimen. SIGNIFICANCE STATEMENT: Fluoxetine, an US Food and Drug Administration-approved selective serotonin reuptake inhibitor reduces solid tumor (breast and melanoma) load through immune mediated tumor cell death and restore antitumor immunity. It remodels tumor microenvironment, activates T cells, reduces cancer stemness and metastasis via regulation of epithelial mesenchymal transition factors, hypoxia Inducible factor 1α, and β-catenin.
Role of solute carrier transporters in the biodistribution and toxicity of chemotherapeutic drugs.
Boeckman M, Drabison T, Germakovski A … +7 more , Warmuth A, Ahmed B, Chowdhury AT, Hu S, Sprowl JA, Sparreboom A, Huang KM
Pharmacol Rev · 2026 Mar · PMID 41722177 · Full text
Our understanding of the solute carrier (SLC) family of transporters has greatly increased in recent years, especially in oncology, and a wealth of information is now available, indicating that certain SLC family members...
Our understanding of the solute carrier (SLC) family of transporters has greatly increased in recent years, especially in oncology, and a wealth of information is now available, indicating that certain SLC family members contribute to the cellular accumulation of small-molecule cancer drugs at sites of injury and to unwanted toxicity in normal tissues. The present review aimed to provide an overview of the toxic effects of commonly used chemotherapy drugs that are associated with SLC-mediated transport, how these associations have been derived, what ensuing intervention strategies have been explored, and how the investigation of these phenomena might change in the near future with the availability of increasingly sophisticated and innovative models and techniques. It is expected that this rapidly emerging field continues to contribute to filling our gaps in knowledge and will aid in the development of interventions aimed at preventing debilitating side effects of cancer drugs and improving the quality of life. SIGNIFICANCE STATEMENT: Toxicities associated with small-molecule chemotherapeutics can be debilitating or even life-threatening and pose a burden on the healthcare system. Improving our understanding of the initiating transporter-mediated mechanisms of these side effects is crucial to the development of preventative or treatment strategies.
Flavorants enhance nicotine vapor self-administration in diet-induced obese female mice.
Tetteh-Quarshie S, Mensah EN, Booker DM … +1 more , Henderson BJ
J Pharmacol Exp Ther · 2026 Mar · PMID 41719691 · Publisher ↗
Nicotine dependence and obesity are global health issues. Emerging studies suggest that obese individuals are more likely to develop nicotine dependence. Despite this knowledge, there have been few investigations into wh...
Nicotine dependence and obesity are global health issues. Emerging studies suggest that obese individuals are more likely to develop nicotine dependence. Despite this knowledge, there have been few investigations into whether nicotine dose and/or chemical flavorants commonly found in nicotine-containing products modulate nicotine dependence in obese models. Therefore, our objective was to examine whether low (6 mg/mL) or high (60 mg/mL) dose nicotine, with or without flavor impact vaping-related behaviors in a diet-induced obesity (DIO) mouse model. Briefly, adult male and female DIO mice were trained to self-administer 6 or 60 mg/mL nicotine, with or without menthol and green apple (GA) flavors using an e-Vape self-administration assay. Overall, DIO female mice assigned to flavored e-liquids self-administered more nicotine than their male counterparts. Additionally, DIO female mice assigned to 6 mg/mL nicotine + menthol exhibited higher nicotine reinforcement-related behavior than female mice assigned 6 mg/mL nicotine (unflavored). Reinforcement-related behavior was not changed in DIO male mice assigned to e-liquids containing 60 mg/mL nicotine. However, DIO female mice exhibited menthol- and GA-induced enhancements in reinforcement-related behavior with 60 mg/mL nicotine. By combining a noncontingent vapor exposure assay with fast-scan cyclic voltammetry, we observed that menthol and GA flavorants, when combined with 6 or 60 mg/mL nicotine, increased tonic- and phasic-stimulated dopamine signaling in the nucleus accumbens core. Together, these preclinical findings provide additional evidence that nicotine plus popular chemical flavorants such as menthol and GA could alter dopamine signaling in the reward pathway and promote vaping-related behaviors in a DIO mouse model. SIGNIFICANCE STATEMENT: This study highlights the effects of flavorants on vaping-related behaviors in a diet-induced obese mouse model. Collectively, this study revealed that flavorants commonly found in vaping products alter dopamine release in the nucleus accumbens core-a phenomenon linked with nicotine addiction.
Empagliflozin mitigates doxorubicin-induced nephrotoxicity by modulating sirtuin 1, nuclear factor-κB/tumor necrosis factor-α, and cleaved caspase-3 pathways without compromising its cytotoxic efficacy.
Tawfik AG, Habib HA, Zeidan EM … +1 more , Heeba GH
J Pharmacol Exp Ther · 2026 Mar · PMID 41702351 · Publisher ↗
Doxorubicin (DOX), an anthracycline antibiotic, is a first-line chemotherapy drug for managing various tumors. Its hazards, particularly nephrotoxicity, complicate its clinical application. Empagliflozin (EMPA), an antid...
Doxorubicin (DOX), an anthracycline antibiotic, is a first-line chemotherapy drug for managing various tumors. Its hazards, particularly nephrotoxicity, complicate its clinical application. Empagliflozin (EMPA), an antidiabetic drug inhibiting sodium-glucose cotransporter 2, exhibits multiple benefits in different illnesses based on its ability to mitigate oxidative injury, inflammation, and apoptosis. Therefore, this work was conducted to evaluate EMPA's therapeutic efficacy in abrogating DOX-elicited renal impairment and to elucidate the underlying mechanisms mediating this proposed ameliorative effect. Thirty-four male Wistar rats randomly divided into control, EMPA (10 mg/kg/d, intragastric (i.g.), DOX (20 mg/kg, single intraperitoneal injection on day 10), and DOX + EMPA (10 mg/kg/d of EMPA, i.g. administration for 12 days and 20 mg/kg, single intraperitoneal injection of DOX on day 10) were involved. In vitro cytotoxicity assay was also performed using KMH2, MG63, and MCF7 cancer cell lines. Counteraction of DOX-impaired renal function by EMPA was proved by a decline in levels of serum urea, creatinine, and cystatin C levels, as well as preserved renal architecture. EMPA mitigated oxidative stress in renal tissues, as presented by a reduction in malondialdehyde and an increase in both reduced glutathione and superoxide dismutase. Moreover, EMPA alleviated DOX-induced downregulation of sirtuin 1 and upregulation of nuclear factor-κB, tumor necrosis factor-α, and cleaved caspase-3. Additionally, the cytotoxic activity of DOX in KMH2 and MG63 cancer cell lines was significantly (P < .05) promoted by EMPA. Collectively, antioxidant, anti-inflammatory, and antiapoptotic influences contributed to the preservative potential of EMPA against DOX-induced kidney toxicity. Moreover, EMPA enhanced the DOX cytotoxic impact in different cancer cell lines. SIGNIFICANCE STATEMENT: This study demonstrates that empagliflozin attenuates doxorubicin (DOX)-induced renal impairment in rats and promotes DOX's cytotoxic effects via its antioxidant and anti-inflammatory potentials. These preclinical findings highlight empagliflozin as a hopeful therapeutic tool to preserve the kidney during DOX treatment.
Preclinical characterization of pharmacokinetics, enzyme occupancy, and pharmacodynamics of soticlestat (TAK-935), a novel cholesterol 24-hydroxylase inhibitor.
Miyamoto M, Toshiya Nishi, Koike T … +15 more , Ikeda S, Sunahara E, Watanabe S, Hasegawa S, Ishii T, Kosugi Y, Yamamoto S, Fujioka Y, Igari T, Sano N, Furuta A, Amano N, Okuda T, Takahashi J, Hirabayashi H
J Pharmacol Exp Ther · 2026 Mar · PMID 41702350 · Publisher ↗
The conversion of cholesterol to 24S-hydroxycholesterol (24HC) is a brain-specific reaction catalyzed by cholesterol 24-hydroxylase (CH24H). Soticlestat, a specific inhibitor of CH24H, has the potential to reduce 24HC le...
The conversion of cholesterol to 24S-hydroxycholesterol (24HC) is a brain-specific reaction catalyzed by cholesterol 24-hydroxylase (CH24H). Soticlestat, a specific inhibitor of CH24H, has the potential to reduce 24HC levels in the brain; 24HC is a neuroactive oxysterol that modulates several receptors and ion channels involved in regulating neural excitability. Soticlestat has been investigated as an additional treatment option for seizures associated with Dravet and Lennox-Gastaut syndromes. Comprehensive preclinical evaluation of pharmacokinetics (PK), target enzyme occupancy (EO), and pharmacodynamics (PDs)-including confirmation of their interrelationships within the brain as the target tissue-is essential for elucidating the mechanism of action of soticlestat. Preclinical data on PK, EO, and PD in rodent models facilitate translational modeling, thereby informing rational human dose selection. A divergence in the temporal profiles of soticlestat concentrations between brain and plasma was observed, with prolonged brain exposure relative to plasma clearance, consistent with the compound's slow dissociation from CH24H. Herein, we characterized the PK, PD, and EO profiles of soticlestat in rodents and demonstrated the relationship between CH24H inhibition and 24HC reduction. Soticlestat demonstrated a delayed-effect model in mice, with time lags between PK and PD as well as between brain and plasma pharmacokinetics. Subsequently, the steady-state PK/PD analysis after subcutaneous infusion in CH24H wild-type [CH24H] and knockout [CH24H] mice provided comprehensive insights into the model linking the PK, EO, and PD profiles of soticlestat. SIGNIFICANCE STATEMENT: In the present study, a clear relationship between the pharmacokinetics, target enzyme occupancy, and pharmacodynamic markers of cholesterol 24-hydroxylase for soticlestat in rodents. The preclinical pharmacokinetic/enzyme occupancy/pharmacodynamic data for soticlestat provide comprehensive mechanistic and quantitative insights into clinical population models. Importantly, these data emphasize the potential of enzyme occupancy and pharmacodynamics as strategic tools for facilitating translational research in central nervous system drug development.
The role of polysubstance use in the development, maintenance, and treatment of stimulant use disorders.
Rough MI, Nader MA
Pharmacol Rev · 2026 Mar · PMID 41690137 · Full text
Stimulant use disorders represent a significant public health challenge, with no U.S. Food and Drug Administration (FDA) pharmacotherapies currently available. A growing concern is that stimulant use rarely occurs in iso...
Stimulant use disorders represent a significant public health challenge, with no U.S. Food and Drug Administration (FDA) pharmacotherapies currently available. A growing concern is that stimulant use rarely occurs in isolation. Instead, it often involves sequential or simultaneous use of multiple substances. This review explores the mechanistic, epidemiological, clinical, and preclinical dimensions of polysubstance use involving stimulants, particularly cocaine and methamphetamine. Key gaps in the existing literature are identified to underscore the critical need for polysubstance use research across epidemiological, clinical, and preclinical domains. Additionally, the review highlights the importance of fostering interdisciplinary collaborations across these domains to inform the development of more effective interventions for stimulant use disorders and to mitigate the widespread harm caused by substance use globally. SIGNIFICANCE STATEMENT: Stimulant use rarely occurs in isolation and is frequently accompanied by polysubstance use, which increases health risks and complicates prevention and treatment strategies. This review highlights critical gaps in research examining polysubstance use involving stimulants and emphasizes the urgent need for the study of the co-use of drugs and interdisciplinary collaboration. Addressing these gaps is essential to inform the development of effective interventions for stimulant use disorders.
Effects of specialized proresolving mediators on gut epithelial barrier in early life.
Chen J, Ouahoud S, Schreurs RRCE … +8 more , Meisner S, Vermeulen JLM, Wildenberg ME, de Jonge WJ, van Goudoever JB, de Meij TGJ, Muncan V, van den Akker CHP
J Pharmacol Exp Ther · 2026 Mar · PMID 41689898 · Full text
Damage to the intestinal epithelial barrier is a hallmark of inflammatory diseases such as necrotizing enterocolitis. Specialized proresolving mediators (SPMs), such as lipoxin A4, resolvin D1, and resolvin E1, which are...
Damage to the intestinal epithelial barrier is a hallmark of inflammatory diseases such as necrotizing enterocolitis. Specialized proresolving mediators (SPMs), such as lipoxin A4, resolvin D1, and resolvin E1, which are derived from essential fatty acids, have been shown to aid in resolving inflammation and promote mucosal healing. This study aimed to explore the effects of specific SPMs on intestinal inflammatory response in an early life in vitro model. We established 3-dimensional and 3-dimensional organoid cultures from fetal and pediatric intestines and investigated the effect of an SPM cocktail (lipoxin A4, resolvin D1, and resolvin E1) on gut epithelial maturation and barrier function. An inflammatory response of the gut barrier was provoked by lipopolysaccharide and flagellin stimulations combined with proinflammatory cytokines, tumor necrosis factor-α, and interferon gamma. Additionally, repetitive mechanical wounding was developed to test the effects of the SPM cocktail on 2-dimensional organoid monolayers. Under physiological conditions, we observed no effect of SPM cocktail treatment on gut epithelial maturation. Upon cytokine challenge, there was no modulation of the inflammatory tone of the gut barrier by the SPM cocktail. However, during the repetitive wounding and recovery assay, SPM cocktail treatment accelerated barrier recovery and maintained barrier integrity for 24 hours after repeated injuries. Our findings suggest that the SPM cocktail does not affect bacterial product- or cytokine-induced epithelial inflammation, although it may accelerate epithelial barrier recovery in mechanically wounded monolayers. These results provide valuable insights into the therapeutic potential of SPMs in neonatal intestinal inflammation. SIGNIFICANCE STATEMENT: Using early life intestinal organoid models, we found that although specialized proresolving mediators did not alter cytokine- or bacterial product-induced inflammation, they significantly enhanced epithelial barrier recovery following repeated mechanical injury.
Pharmacology and therapeutics of bile acid synthesis and modification enzymes in metabolic diseases.
Ding L, Jin L, Huang W
Pharmacol Rev · 2026 Mar · PMID 41687464 · Full text
Bile acids (BAs) are mainly synthesized in the liver as end products of cholesterol catabolism through the classic (neutral) and alternative (acidic) pathways. BA synthesis requires a coordinated series of enzymes, in wh...
Bile acids (BAs) are mainly synthesized in the liver as end products of cholesterol catabolism through the classic (neutral) and alternative (acidic) pathways. BA synthesis requires a coordinated series of enzymes, in which CYP7A1 catalyzes the rate-limiting step, whereas CYP8B1 determines the proportion of the 2 primary BAs-cholic acid and chenodeoxycholic acid. Enterohepatic circulation of BAs is essential not only for nutrient absorption but also for maintaining systemic metabolic homeostasis. The expanding catalog of BA-responsive receptors throughout the gastrointestinal tract and peripheral metabolic tissues underscores the hormone-like nature of BAs in metabolic regulation. Moreover, dynamic and bidirectional interactions between BAs and the gut microbiota introduce an additional layer of complexity that shapes physiological and pathological metabolic processes. Targeting BA synthesis and microbial modification offers substantial therapeutic potential for a wide spectrum of metabolism-related diseases. SIGNIFICANCE STATEMENT: Bile acids (BAs) comprise a large family of endogenous steroid metabolites with diverse chemical structures. They can activate or inhibit a panel of BA-responsive receptors to elicit distinct cellular signaling programs integral to metabolic regulation. Their reciprocal interactions with gut microbiota further amplify the complexity of host metabolic control. Therapeutic strategies that modulate BA synthesis and microbial BA transformation, leveraging both BA synthesis enzymes and microbial partners, hold great promise for treating metabolic disorders.
Pharmacological modulation of the blood-brain barrier: Mechanisms, therapeutic strategies, and emerging technologies.
Pediaditakis I, Tsakali S, Lemieux MR … +4 more , Brennan M, Robinson WH, Papapetropoulos S, Papapetropoulos A
Pharmacol Rev · 2026 Mar · PMID 41666794 · Publisher ↗
The blood-brain barrier (BBB) is a specialized vascular interface that safeguards central nervous system homeostasis by tightly regulating molecular exchange between blood and the brain. While essential for neuroprotecti...
The blood-brain barrier (BBB) is a specialized vascular interface that safeguards central nervous system homeostasis by tightly regulating molecular exchange between blood and the brain. While essential for neuroprotection, its restrictive permeability limits therapeutic access, and its dysfunction is increasingly recognized as a driver of pathology across neurodegenerative, inflammatory, cerebrovascular, traumatic, and rare genetic disorders. In this review, we provide a comprehensive overview of pharmacological strategies to modulate BBB function, linking mechanistic insights into tight junction dynamics, transporter networks, endothelial-pericyte interactions, and immune crosstalk to emerging therapeutic approaches. We discuss interventions ranging from small molecules, peptides, and biologics to nanocarriers, noninvasive technologies, gene therapy, and stem cell-based strategies, highlighting their applications in 2 key translational contexts: transient enhancement of drug delivery and restoration of barrier integrity in disease. Ongoing challenges include ensuring safety, accounting for patient heterogeneity, and addressing the limitations of current experimental models. Finally, we consider how advances in BBB-on-chip systems, patient-specific induced pluripotent stem cell-derived models, and novel molecular targets are accelerating translation. Collectively, pharmacological modulation of the BBB, whether by reversible opening to enhance delivery or by reinforcing its protective function, represents a transformative frontier in central nervous system therapy. SIGNIFICANCE STATEMENT: The blood-brain barrier (BBB) is both a vital safeguard of neural homeostasis and a central obstacle to drug development in the central nervous system. This review integrates mechanistic insights into BBB regulation with translational advances in pharmacology and biotechnology, highlighting strategies that restore barrier integrity in disease and enhance therapeutic delivery. Emerging approaches, including gene therapy, nanotechnology, stem cell-based interventions, and next-generation human-relevant BBB models, illustrate how pharmacological innovation can overcome longstanding challenges and expand therapeutic access to the brain.
iRhom2 deletion protects against diabetic neuropathy by suppressing neuroinflammation.
Mattos Pereira V, Wasseen ID, Zhang Z … +4 more , Sun QQ, Hosur V, Roballo KCS, Nair S
J Pharmacol Exp Ther · 2026 Mar · PMID 41666516 · Full text
Diabetic peripheral neuropathy (DPN) is a major complication of diabetes, characterized by progressive nerve damage and debilitating pain. Neuroinflammation plays a critical role in its pathogenesis, but therapeutic opti...
Diabetic peripheral neuropathy (DPN) is a major complication of diabetes, characterized by progressive nerve damage and debilitating pain. Neuroinflammation plays a critical role in its pathogenesis, but therapeutic options remain limited. A disintegrin and metalloprotease 17 (ADAM17) regulates inflammatory signaling, but its ubiquitous expression makes it a difficult target. This study examined the role of inactive rhomboid protein 2 (iRhom2), a cofactor essential for ADAM17 activation, in the development of DPN. Diabetes was induced in wild-type (WT) and iRhom2 knockout (KO) mice using streptozotocin. Both groups developed hyperglycemia (>300 mg/dL); however, only WT mice exhibited significant mechanical and thermal hyposensitivity, characteristic of DPN. iRhom2 KO mice were protected from these deficits, suggesting a glucose-independent protective mechanism. In sciatic nerves of diabetic WT mice, expression of ADAM17, iRhom2, and tumor necrosis factor-α increased by 5.3-, 7.7-, and 48-fold, respectively; these changes were attenuated in KO mice. Histological analysis showed preservation of nerve fiber structure and reduced inflammatory infiltration in diabetic iRhom2 KOs. In cultured human microglial cells, high glucose triggered oxidative stress and induction of inflammatory mediators, including cyclooxygenase-2, interleukin-6, interleukin-8, tumor necrosis factor-α, and monocyte chemoattractant protein-1. Silencing of iRhom2 reduced these responses. These findings identify iRhom2 as a critical mediator of diabetic neuropathy, acting by regulating neuroinflammation. Deletion of iRhom2 confers glucose-independent protection against neuropathic pain, highlighting iRhom2 as a promising therapeutic target for preventing or treating DPN. SIGNIFICANCE STATEMENT: This study identifies iRhom2 as a key mediator of diabetic peripheral neuropathy by driving neuroinflammation and oxidative stress. Deletion of iRhom2 provided protection against neuropathic changes, without altering glucose levels, revealing a glucose-independent mechanism. These findings establish iRhom2 as a promising therapeutic target, offering new translational opportunities to prevent or treat diabetic neuropathy.
Erratum to "Animal models of attention-deficit/hyperactivity disorder: Diversity and validity" [Pharmacological Reviews 78 (2026) 100108].
Bou Sader Nehme S, Sánchez-Sarasúa S, Medrano MC … +9 more , Bouchatta O, Bitar T, Alameddine A, Galineau L, Brunault P, Kerekes N, Sanchez-Perez AM, Hleihel W, Landry M
Pharmacol Rev · 2026 Mar · PMID 41653862 · Publisher ↗
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Erratum to "Edaravone: Advances on cytoprotective effects, pharmacological properties, and mechanisms of action" [Pharmacological Reviews 78 (2025) 100101].
Dakroub F, Awada B, Abdelhady S … +11 more , Shaito AA, Eid AH, Walker J, Mondello S, Bondi CO, Moro F, Elgendy B, Wang KK, Zanier ER, Mechref Y, Kobeissy F
Pharmacol Rev · 2026 Mar · PMID 41653861 · Publisher ↗
Abstract loading — click title to view on PubMed.
Inhalable iguratimod-loaded nanostructured lipid carriers for asthma-chronic obstructive pulmonary disease overlap management.
Khawas S, Sharma N
J Pharmacol Exp Ther · 2026 Mar · PMID 41650753 · Publisher ↗
Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is a chronic inflammatory airway condition that presents with features of both asthma and COPD, complicating its treatment and management. In this study,...
Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is a chronic inflammatory airway condition that presents with features of both asthma and COPD, complicating its treatment and management. In this study, the potential of iguratimod-loaded nanostructured lipid carriers (IGU-NLCs) as an inhalable therapy for ACO was investigated. IGU-NLCs were formulated and characterized using Fourier-transform infrared, X-ray diffraction, thermogravimetric - differential scanning calorimetry, field emission scanning electron microscopy, and particle size analysis. The formulation demonstrated favorable physicochemical stability and nanoscale particle size distribution. IGU-NLCs demonstrated good cytocompatibility and minimal reactive oxygen species induction at 10 μg/mL in vitro, supporting their suitability for safe pulmonary delivery. An in vivo ACO model was induced by papain/cigarette smoke exposure, followed by treatment with plain IGU and IGU-NLCs via inhalation, to evaluate their therapeutic effects on oxidative stress, inflammation, and lung function. X-ray and ECG analyses revealed that IGU-NLCs more effectively reversed the airway obstruction and cardiac alterations induced by papain/cigarette smoke exposure. Histopathologic analysis showed significant improvement in lung architecture. Moreover, immunohistochemistry for CD68 revealed reduced macrophage infiltration, indicating an anti-inflammatory effect. Overall, this study demonstrates that nebulized IGU-NLCs offer a noninvasive, targeted, and effective approach to mitigate ACO pathology, highlighting their potential for clinical translation in respiratory therapeutics. SIGNIFICANCE STATEMENT: Asthma-chronic obstructive pulmonary disease overlap lacks effective therapies because of its complex pathophysiology. This study repurposed iguratimod using nanostructured lipid carriers for inhalation, which reduced inflammation, oxidative stress, and lung damage in vivo, highlighting a novel, targeted strategy for this overlapped disease.
Screening of anticancer drugs against potential carcinogenic bacterial virulence proteins in colorectal cancer: An in silico approach.
Saravanan V, Gopalakrishnan V, Majula Shifani Mahendran MI … +2 more , Guliy OI, Velusamy M
J Pharmacol Exp Ther · 2026 Mar · PMID 41650752 · Publisher ↗
Anaerobic bacteria induced colorectal cancer (CRC) represents a significant clinical concern. The understanding of cancer etiology has evolved significantly, from being predominantly viewed as genetically induced cancer...
Anaerobic bacteria induced colorectal cancer (CRC) represents a significant clinical concern. The understanding of cancer etiology has evolved significantly, from being predominantly viewed as genetically induced cancer to bacterial biofilm induced cancer. Despite the growing evidence linking bacterial virulence to tumor progression, the molecular interactions between bacterial biofilm proteins and anticancer drugs remain poorly understood. We explored the interaction of clinically used anticancer drugs (bevacizumab, capecitabine, fluorouracil, fruquintinib, leucovorin calcium, regorafenib, and tucatinib) with virulence proteins of oncomicrobes including Helicobacter pylori (cytotoxin-associated gene A), Fusobacterium nucleatum (Fusobacterium adhesion A), Bacteroides fragilis (Bfragilis toxin). Leucovorin calcium exhibited the highest binding affinity toward cytotoxin-associated gene A (-7.9 kcal/mol) through 7 hydrogen bonds. Similarly, regorafenib demonstrated strong interaction with Bfragilis toxin and Fusobacterium adhesion A, with binding affinities -8.6 and -6.5 kcal/mol, respectively, supported by multiple hydrogen and covalent bonds. Subsequent molecular dynamics simulations revealed low root mean square deviation and root mean square fluctuation values, indicating stable and compact drugs-protein interaction. Therefore, contributing to functional inactivation of bacterial virulence factors, thereby weakening bacterial colonization, biofilm formation, and events that sustain pro tumorigenic microenvironment. Overall, the present study provides computational evidence over anticancer drugs that may interact with bacterial virulence mechanisms implicated in anaerobic bacteria induced CRC, offering novel insights into therapeutic avenues capable of mitigating bacterial contributions in CRC initiation and progression. SIGNIFICANCE STATEMENT: The study focuses evaluating anticancer drugs targeting carcinogenic virulence proteins associated with bacterial biofilm mediated colorectal cancer.
Alternative reinforcement reduces oxycodone self-administration in male and female monkeys: Implications for treating opioid use disorder.
Baehr C, Harris AC
J Pharmacol Exp Ther · 2026 Mar · PMID 41638111 · Publisher ↗
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