Frontiers In Pharmacology[JOURNAL]
Sun
200 papers
Comparative post-marketing reporting signals of elagolix and myfembree in endometriosis: a FAERS pharmacovigilance study.
Bai M, Shen S, Chen JY
Front Pharmacol · 2026 · PMID 42328640 · Full text
BACKGROUND: Elagolix and Myfembree are gonadotropin-releasing hormone (GnRH)-pathway therapies used for endometriosis, but their post-marketing safety reporting patterns remain incompletely characterized. Because spontan...
BACKGROUND: Elagolix and Myfembree are gonadotropin-releasing hormone (GnRH)-pathway therapies used for endometriosis, but their post-marketing safety reporting patterns remain incompletely characterized. Because spontaneous reporting databases are susceptible to reporting bias and differential market exposure, comparative analyses require cautious interpretation. METHODS: We analyzed quarterly data from the FDA Adverse Event Reporting System (FAERS) from 2015Q3 to 2026Q1. Deduplicated female reports with endometriosis-related indications were identified and classified as elagolix, Myfembree, or other endometriosis-related reports. The primary analysis consisted of drug-specific case-noncase disproportionality analyses for elagolix and Myfembree separately within the female endometriosis reporting background. A direct elagolix-versus-Myfembree head-to-head analysis was performed as a secondary analysis. Reporting odds ratios (RORs), proportional reporting ratios (PRRs), and information components (ICs) were calculated at the preferred term (PT) level. Sensitivity analyses included serious-report-only, healthcare-professional-only, physician-only, complete-age, reporter-type-stratified, overlapping-market-period, and bootstrap analyses. RESULTS: A total of 4,428 deduplicated female endometriosis-related reports were included, comprising 1,744 elagolix reports, 280 Myfembree reports, and 2,404 other endometriosis-related reports. Serious reports accounted for 31.2% of elagolix reports and 26.8% of Myfembree reports. In drug-specific case-noncase analyses, elagolix showed robust disproportionality signals for hot flush, night sweats, and suicidal ideation. Myfembree showed distinct reporting signals for reproductive and bleeding-related PTs, including heavy menstrual bleeding and intermenstrual bleeding. In the secondary head-to-head analysis, selected PTs including hot flush, nausea, headache, depression, arthralgia, and suicidal ideation showed higher reporting signals for elagolix, whereas alopecia showed a lower reporting signal for elagolix. Sensitivity analyses using alternative algorithms, reporter-type restrictions, overlapping-market-period restriction, complete-age restriction, and bootstrap validation generally supported the direction of the main selected reporting patterns, although some estimates were limited by small cell counts. CONCLUSIONS: Elagolix and Myfembree showed distinct post-marketing reporting signal profiles among female endometriosis-related FAERS reports. Elagolix was characterized mainly by vasomotor and selected neuropsychiatric reporting signals, whereas Myfembree was characterized mainly by reproductive and bleeding-related reporting signals. These findings represent hypothesis-generating reporting differences rather than clinical incidence rates or causal risk estimates. Further pharmacoepidemiologic studies with denominator data and adjustment for patient-level confounding are needed to clarify comparative safety profiles.
Post-marketing safety evaluation of mirogabalin using the JADER database.
Sun X, Li L, Li G … +6 more , Wang L, Zhang H, Lu C, Zhao Y, Chen J, Wang A
Front Pharmacol · 2026 · PMID 42328639 · Full text
BACKGROUND: Mirogabalin, a novel third-generation α2-δ calcium channel ligand, is approved for diabetic peripheral neuropathic pain (DPNP). However, its post-marketing safety profile remains insufficiently characterized,...
BACKGROUND: Mirogabalin, a novel third-generation α2-δ calcium channel ligand, is approved for diabetic peripheral neuropathic pain (DPNP). However, its post-marketing safety profile remains insufficiently characterized, particularly regarding novel signals and comparative safety profiles with established therapies. OBJECTIVES: This study aimed to identify and characterize adverse event (AE) signals associated with mirogabalin, evaluate demographic differences, and compare signal strength with pregabalin and gabapentin. METHODS: We conducted a pharmacovigilance analysis using the Japanese Adverse Drug Event Report (JADER) database (January 2019-June 2025). Disproportionality analysis was performed using the Reporting Odds Ratio (ROR) and Information Component (IC) methods. Subgroup analyses by sex and age, sensitivity analyses restricted to monotherapy reports, and time-to-onset (TTO) analysis using Weibull modeling were conducted. RESULTS: Among 463 healthcare professional-reported AE reports, 33 positive signals were identified. Beyond known AEs (e.g., dizziness, somnolence), six novel potential signals were detected: pleural effusion (n = 6), contusion (n = 4), toxic encephalopathy (n = 4), Cardiac failure congestive (n = 4), deafness (n = 3), and angioedema (n = 3). Head-to-head comparisons revealed that mirogabalin exhibited significantly higher reporting odds ratios (RORs) than pregabalin for pleural effusion (ROR = 2.39, 95%CI: 1.01-5.65), toxic encephalopathy (ROR = 6.37, 95%CI: 1.99-20.36), contusion (ROR = 3.35, 95%CI: 1.14-9.87), and deafness (ROR = 3.67, 95%CI: 1.04-12.91), and significantly higher RORs than gabapentin for cardiac failure congestive (ROR = 6.05, 95%CI: 1.78-20.54). Subgroup analysis revealed sex- and age-related differences: male patients showed higher reporting proportions of muscle weakness, myoclonus, erythema multiforme, urinary retention, and elevated liver enzymes, whereas females exhibited higher proportions of renal impairment and falls; elderly patients (≥65 years) showed higher reporting frequencies of dizziness and rhabdomyolysis, whereas the 18-65 age group showed higher proportions of hepatic and cardiovascular events. Sensitivity analysis partially supported the stability of some signals, with rhabdomyolysis identified exclusively in monotherapy reports. The median TTO was 6 days (IQR: 2-42), indicating an early-clustering pattern (β = 0.55, 95% CI: 0.50-0.60). Sensitivity analysis after excluding outliers yielded a median TTO of 5 days (IQR: 2-28) with β = 0.72 (95% CI: 0.65-0.80). CONCLUSION: This study extends the understanding of mirogabalin's post-marketing safety profile by identifying six novel signals and revealing distinct safety signal profiles compared with established α2-δ ligands. Demographic-stratified monitoring strategies are warranted to optimize patient safety.
Integrating CRISPR functional genomics with admixture-aware psychotropic pharmacogenetics in Brazil.
Rodrigues BB, Bittencourt JC, Dos Santos VGM … +2 more , Costamilan CADVL, Herkenhoff ME
Front Pharmacol · 2026 · PMID 42328638 · Full text
Variability in the clinical response to psychotropic drugs remains a major barrier to effective psychiatric care. Pharmacogenetics offers a powerful framework for individualizing antidepressant and antipsychotic therapy,...
Variability in the clinical response to psychotropic drugs remains a major barrier to effective psychiatric care. Pharmacogenetics offers a powerful framework for individualizing antidepressant and antipsychotic therapy, yet its implementation is complicated in genetically diverse populations. In Brazil, centuries of admixture among European, African, and Indigenous peoples have created a highly heterogeneous genomic landscape that limits the direct applicability of international pharmacogenetic guidelines. This review synthesizes evidence on ancestry-dependent allele frequencies, regional genetic gradients, and their clinical implications for psychotropic prescribing. It further discusses how integrating CRISPR functional genomics with admixture-aware psychiatry can experimentally validate population-specific variants, refine metabolizer phenotype classification, and support the development of ancestry-informed therapeutic guidelines. By combining genome editing, pharmacogenomic profiling, and regional admixture data, this integrative approach can improve dose prediction, reduce adverse drug reactions, and promote health equity. Ultimately, the convergence of pharmacogenetics, functional genomics, and precision medicine initiatives positions Brazil as a global model for equitable, ancestry-aware psychopharmacology.
Research progress of artificial intelligence in high-throughput drug screening.
Liu X, Ren X, Li P … +6 more , Li X, Ren X, Sui C, Zhou H, Luo F, Tao L
Front Pharmacol · 2026 · PMID 42328637 · Full text
High-throughput screening (HTS) is widely used in modern drug discovery. It enables batch activity testing of compounds and provides important support for the identification of active compounds. However, its screening ef...
High-throughput screening (HTS) is widely used in modern drug discovery. It enables batch activity testing of compounds and provides important support for the identification of active compounds. However, its screening efficiency and accuracy need to be improved. To address this issue, artificial intelligence (AI) has been gradually integrated into the HTS workflow. Leveraging the advantages of machine learning (ML) and deep learning (DL), AI optimizes applications in structure-based and ligand-based virtual screening, combination drug screening, image analysis, and post-screening data analysis and interpretation, driving the intelligent development of drug discovery. This paper reviews recent research progress in the application of AI in HTS, discusses the implementation of machine learning models, and summarizes key AI applications in HTS-related compound screening, image recognition, and hit identification from complex screening data, aiming to accelerate the development of innovative drugs.
Revisiting low-molecular-weight heparin for venous thromboembolism: from pharmacology to precision dosing and implementation.
Zhu S, Ni Q, He J
Front Pharmacol · 2026 · PMID 42328636 · Full text
BACKGROUND: Despite the increasing use of direct oral anticoagulants, low-molecular-weight heparin (LMWH) remains important in venous thromboembolism (VTE) care when oral therapy is unsuitable, temporarily unsafe, or dif...
BACKGROUND: Despite the increasing use of direct oral anticoagulants, low-molecular-weight heparin (LMWH) remains important in venous thromboembolism (VTE) care when oral therapy is unsuitable, temporarily unsafe, or difficult to manage, particularly during pregnancy, cancer-associated thrombosis, renal impairment, and peri-procedural care. Objective: To review how LMWH pharmacology informs practical decisions about dosing, anti-factor Xa monitoring, treatment interruption and restart, and switching between anticoagulants. METHODS: We performed a narrative review of contemporary guidelines, randomized trials, systematic reviews, pharmacokinetic/pharmacodynamic studies, drug labels, and laboratory medicine evidence, focusing on literature published from 1 January 2015 to 18 December 2025, with selected earlier sources retained for foundational pharmacologic principles. RESULTS: LMWH can be used with standard fixed or weight-based dosing in many stable patients, but reassessment is needed when renal function, body weight, pregnancy physiology, cancer-related bleeding risk, critical illness, or procedural timing changes the relationship between dose and exposure. Anti-factor Xa testing should not be used routinely; it is most useful when sampling is standardized and the result can guide a specific action, such as dose adjustment, interval extension, treatment interruption, or switching to unfractionated heparin. CONCLUSION: LMWH remains useful when oral anticoagulants are difficult to use safely. Its clinical value depends on clear dose selection, renal-function reassessment, selective monitoring, planned interruption and restart, and timely switching when patient risk or treatment feasibility changes.
Efficacy and safety of combining commercial Chinese polyherbal preparation with conventional medicine in the treatment of coronary microvascular disease: a systematic review and network meta-analysis.
Guo X, Li Q, Jiang H … +4 more , Ren C, Shu C, Zhao X, Li Y
Front Pharmacol · 2026 · PMID 42328635 · Full text
OBJECTIVE: To systematically assess and compare the efficacy and safety of 19 commercial Chinese polyherbal preparation for coronary microvascular disease (CMVD) through a frequentist network meta-analysis (NMA) of rando...
OBJECTIVE: To systematically assess and compare the efficacy and safety of 19 commercial Chinese polyherbal preparation for coronary microvascular disease (CMVD) through a frequentist network meta-analysis (NMA) of randomized controlled trials. METHODS: A comprehensive search was performed across multiple databases through November 2025 to identify studies evaluating the effectiveness of CCPPs in treating CMVD. Two independent reviewers screened studies, extracted data, and assessed risk of bias. The NMA was conducted using a frequentist random-effects model, and statistical analyses were performed in Stata 18.0. Network diagrams, league tables, and SUCRA (surface under the cumulative ranking curve) plots were generated to compare and rank the treatments. RESULTS: Sixty-seven randomized controlled trials (RCTs) involving 6,139 patients were included. All CCPPs combined with conventional medicine (CM) demonstrated potential advantages in efficacy compared to CM alone, but the optimal agent is highly outcome-specific. Yixinshu Tablets may be more favorable for improving microvascular function by reducing the index of microcirculatory resistance (IMR) and increasing coronary flow reserve (CFR). Tongxinluo Capsule showed a relatively greater reduction in corrected thrombolysis in myocardial infarction frame count (cTFC) and a higher total effective rate in the included studies. Shexiang Tongxin Dripping Pills was associated with a more pronounced elevation in left ventricular ejection fraction (LVEF). Danshen Dripping Pills ranked highest for reducing endothelin-1 (ET-1) and increasing nitric oxide (NO) levels. Yindan Xinnao Tong Capsules exhibited a relatively greater decrease in high-sensitivity C-reactive protein (hs-CRP). Additionally, Shexiang Baoxin Pills was associated with the lowest risk of adverse events. CONCLUSION: The combination of CCPPs with CM for CMVD may be associated with improved clinical outcomes compared to CM alone. However, these initial results require confirmation through high-quality, rigorously designed clinical trials. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251245224, identifier CRD420251245224.
What leads to medication errors in polish hospitals from the perspectives of nurses? a multicenter cross-sectional survey.
Kwiecień-Jaguś K, Kopeć M, Małecka-Dubiela A … +1 more , Guzak B
Front Pharmacol · 2026 · PMID 42328634 · Full text
BACKGROUND: Patient safety in pharmacotherapy is a critical element of proper medical care, and when properly implemented, it delivers real therapeutic benefits. The project aimed to analyse the causes of medication admi...
BACKGROUND: Patient safety in pharmacotherapy is a critical element of proper medical care, and when properly implemented, it delivers real therapeutic benefits. The project aimed to analyse the causes of medication administration errors in hospitals with varying referral levels. The study was part of a larger research project. METHODS: From the 585 hospitals in Poland, 50 were randomly selected. The 488 nurses agreed to participate in the study. Four hundred sixty-eight completed questionnaires were finally included in the statistical analysis. Research data collection began in 2023, and the entire process took a year. A descriptive analysis for socio-demographic data was used. Factor analysis and varimax rotation were used to transform large amounts of raw, complex data into a clear, interpretable structural model. RESULTS: The Polish version of the Medication Administration Error scale was validated and rechecked with the alpha-Cronbach index. A part A of the questionnaire, which consists 29 statements about the reason of Medication Administration Errors, achieved 0.93 - with is considered as a very good. The main results showed that the most common reasons for medication error in the administration process in intensive and internal units are: appearance of drug, drug similarity, and illegible orders. On an equal footing in terms of the number of points obtained (AVG > 4), other identified factors are: Pharmacists are not available 24 h a day" (item 12) and "Brand-name drugs are replaced by other generics (item 13). A huge problem is the lack of training on new drugs used in the hospital, and the frequent use of abbreviations. The second, no less important issue, especially in the more conservative units, is interruption in the preparation process and staff shortages. CONCLUSION: Most of the factors that lead to MAE, as identified by nursing personnel in internal and intensive care units, can be modified through management processes using prepared tools, scientific recommendations, and technologies. Some areas, such as the shortage of medical personnel in conservative general wards, require further work and up-to-date legislation.
Evaluation of free radical scavenging and anxiolytic activities of (Boiss.) B. Fedtsch. bioactive metabolites through multi-method experimental and computational approaches.
Gani R, Yousuf U, Siddiquee NH … +9 more , Mir MA, Yaseen A, Bashir N, Varadharajan V, Hossain MI, Dar PA, Dar MY, Bhat ZA, Bhat BA
Front Pharmacol · 2026 · PMID 42328633 · Full text
ETHNOPHARMACOLOGICAL RELEVANCE: is a valued traditional Persian medicinal spice used as a calming and anxiolytic agent. However, the bioactive metabolites responsible for its antioxidant and anxiolytic effects, and thei...
ETHNOPHARMACOLOGICAL RELEVANCE: is a valued traditional Persian medicinal spice used as a calming and anxiolytic agent. However, the bioactive metabolites responsible for its antioxidant and anxiolytic effects, and their underlying mechanisms, remain largely unexplored. AIM OF THE STUDY: This study evaluated the antioxidant and anxiolytic potential of hydroalcoholic extracts and solvent fractions of fruits through bioactivity-guided isolation, supported by and validation to mechanistically confirm its traditional use in anxiety disorders. MATERIALS AND METHODS: Fruits were extracted with 70% hydroalcoholic solvent and successively fractionated with solvents of increasing polarity. Antioxidant activity was assessed via total phenolic content (TPC), total flavonoid content (TFC), DPPH radical scavenging, and reducing power assays. The most active ethyl acetate fraction underwent bioactivity-guided isolation, yielding three fatty acids (myristic, palmitic, and stearic acid) characterized by spectroscopic methods. Anxiolytic effects of the isolates were tested in Swiss albino mice using elevated plus maze (EPM) and light-dark arena (LDA) tests. Acute oral toxicity was evaluated per OECD guidelines (2000 mg/kg). In-silico studies included molecular docking against MAO, GABA(A) β3 subunit, COMT, and SERT, followed by 200 ns MD simulations to assess binding stability. RESULTS: The ethyl acetate fraction showed the highest antioxidant activity (TPC: 337.408 ± mg GAE/g; TFC: 286.665 ± mg RU/g) with superior DPPH scavenging and reducing power. Stearic acid exhibited significant anxiolytic-like effects in both EPM and LDA tests (P < 0.01-0.001 vs. control), comparable to diazepam, without sedation or motor impairment. No acute toxicity was observed at 2000 mg/kg. Docking revealed strong binding affinities (ΔG = -5.3 to -7.6 kcal/mol) driven by hydrogen bonds and hydrophobic interactions. MD simulations confirmed complex stability over 200 ns with favourable RMSD, RMSF, and persistent interactions. CONCLUSION: This study provides the first mechanistic evidence supporting the traditional Persian use of as a natural anxiolytic. Stearic acid, isolated via bioactivity-guided fractionation, emerges as a promising multi-target antioxidant and anxiolytic scaffold, validating its ethnomedicinal relevance and potential for safer plant-derived therapeutics against anxiety disorders.
Modulatory effect of porous silicon water-formulated catechin on gut microbiome in chronic unpredictable mild stress-induced dementia in a rat model.
Alnasser SM, Ravikumar S, Jayaraman S … +2 more , Selvaraj D, Gunasekaran V
Front Pharmacol · 2026 · PMID 42328632 · Full text
Stress-induced dysbiosis exacerbates mental health by modulating the nervous system and gut permeability. In this study, we investigate the therapeutic potential of porous silicon water-mixed catechin in alleviating chro...
Stress-induced dysbiosis exacerbates mental health by modulating the nervous system and gut permeability. In this study, we investigate the therapeutic potential of porous silicon water-mixed catechin in alleviating chronic stress-induced dementia in rats. In a 28-day study, chronic unpredictable mild stress (CUMS)-induced rats were treated with (2.5 × 10^9 CFU, p.o), porous silicon water (7 mg/kg, p.o), catechin (30 mg/kg, p.o), and porous silicon water-mixed catechin (PSC) (7 mg and 30 mg/kg, p.o). The effect of porous silicon water-mixed catechin was evaluated through behavioral studies, plasma acetylcholinesterase activity, plasma glutamate, brain reactive oxygen species (ROS), brain endogenous anti-oxidant enzymes, metagenomics analysis, and histological examination of the prefrontal cortex and hippocampus. Administration of PSC significantly improved spatial learning and memory by reducing escape latency time and increased exploratory behavior in the open platform. PSC significantly inhibited acetylcholinesterase enzyme activity and restored endogenous antioxidants such as superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GSH) while reducing lipid peroxidation (LPO) compared to the CUMS group. In addition, PSC decreased the brain ROS levels, as determined by a fluorescence assay, and reduced plasma glutamate levels. 16S rRNA V3-V4 metagenomic analysis revealed a significant increase in microbial diversity (Shannon index: 7.52), microbial richness (Chao1 index: 1059.41), β-diversity index, and overall taxonomic abundance in treated rats. CUMS-induced morphological alterations in the hippocampus and prefrontal cortex were significantly improved following PSC administration. In the present study, Pearson correlation coefficient (r) demonstrates an association between gut microbial abundance and AChE activity. Hence, it has been concluded that PSC treatment may significantly modulate the gut microbiome and improve cognition in chronic unpredictable mild stress-induced dementia.
Integrated transcriptomics identifies ER stress-associated apoptosis in post-resuscitation AKI and supports early Dl-3-n-butylphthalide-associated renoprotection in a porcine TCA model.
Zhou K, Du W, Chen Y … +2 more , Hu Y, Lan P
Front Pharmacol · 2026 · PMID 42328631 · Full text
BACKGROUND: Dl-3-n-butylphthalide (NBP) is a small-molecule compound derived from celery seeds with anti-inflammatory, antioxidant, and anti-apoptotic properties. Although NBP has shown protective effects in various kidn...
BACKGROUND: Dl-3-n-butylphthalide (NBP) is a small-molecule compound derived from celery seeds with anti-inflammatory, antioxidant, and anti-apoptotic properties. Although NBP has shown protective effects in various kidney diseases, its role in traumatic cardiac arrest (TCA)-induced acute kidney injury (AKI) remains unclear. This study aimed to investigate the effects of NBP on AKI following TCA in pigs and to determine whether these effects were associated with modulation of ERS/UPR-associated apoptotic readouts. METHODS: We integrated ischemia-reperfusion injury (IRI)-related bulk transcriptomic/microarray datasets with single-cell RNA sequencing (scRNA-seq) data. Differential expression analysis, Hallmark GSEA, and GSVA/ssGSEA were performed to quantify unfolded protein response (UPR) and apoptosis, focusing on proximal tubule (PT) cells via PT-state stratification, pseudo-bulk differential analysis, and pseudotime inference. For validation, healthy male Bama minipigs were randomized to Sham, TCA, or TCA+NBP groups. NBP (2.5 mg/kg, i.v.) was administered within 120 min after return of spontaneous circulation (ROSC). Serum creatinine (Cr) and blood urea nitrogen (BUN) were measured at 1, 2, 4, and 24 h; kidneys harvested at 24 h underwent H&E and TUNEL staining, immunohistochemistry (KIM-1, NGAL), and Western blotting (PERK, CHOP, caspase-12, caspase-3). RESULTS: Integrated bulk, single-cell, PT-state, pseudotime, and PT pseudo-bulk analyses prioritized a PT-enriched PERK-ATF4-CHOP-associated stress-apoptosis module, predominantly within injury-associated PT states. Along PT injury-state progression, HSPA5/GRP78, PERK/EIF2AK3, ATF4, CHOP/DDIT3, and apoptosis-related effectors showed coordinated transcript-level remodeling, suggesting engagement of an ERS/UPR-associated stress-apoptosis program rather than establishing pathway causality. Compared with TCA, NBP significantly reduced Cr and BUN, alleviated histopathologic injury, decreased KIM-1/NGAL expression, reduced TUNEL-positive cells and caspase-3 abundance, and was associated with lower PERK, CHOP, and caspase-12 protein expression. CONCLUSION: A PT-enriched PERK-ATF4-CHOP-associated ERS/UPR stress-apoptosis module was prioritized in injury-associated proximal tubule states during IRI-related AKI. In a porcine TCA model, NBP was associated with reduced early AKI severity within a 24 h observation window, accompanied by lower PERK/CHOP/caspase-related ERS/UPR-associated and apoptosis-related readouts.
Efficacy of hyaluronic acid and butyroyl glutathione in the management of glaucoma-related ocular surface disease: a prospective, interventional, double-blind, cross-over post market study.
Gallo Afflitto G, Fanelli M, Petrone V … +8 more , Chirico R, Ceccarelli F, Martucci A, Minutolo A, Aiello F, Garaci E, Matteucci C, Nucci C
Front Pharmacol · 2026 · PMID 42328630 · Full text
INTRODUCTION: To evaluate the efficacy of a novel eye drop formulation containing hyaluronic acid (0.2%) and butyroyl-glutathione (GSHC4, 0.4%) in glaucoma-associated ocular surface disease (G-OSD), and to explore putati...
INTRODUCTION: To evaluate the efficacy of a novel eye drop formulation containing hyaluronic acid (0.2%) and butyroyl-glutathione (GSHC4, 0.4%) in glaucoma-associated ocular surface disease (G-OSD), and to explore putative mechanisms of action through in vitro assays of corneal epithelial wound healing and cytokine modulation under basal, inflammatory, and oxidative stress conditions. METHODS: In this preliminary, hypothesis-generating, prospective, double-blind, cross-over study, 16 patients with glaucoma or ocular hypertension and coexisting dry eye symptoms were randomized to receive either HA alone or HA + GSH-C4 for 4 weeks, separated by a 1-week washout. Clinical endpoints included the Ocular Surface Disease Index (OSDI), FACES scale, tear film break-up time (TFBUT), Schirmer test, and NEI fluorescein staining. Tear cytokines were quantified at multiple timepoints. In vitro, human corneal epithelial cells underwent scratch-wound assays and cytokine profiling. RESULTS: Fifteen of sixteen patients completed the study. HA + GSH-C4 significantly improved OSDI (p < 0.001), FACES scores (p = 0.012), TFBUT (p < 0.001), and NEI-SS (p < 0.001) compared with HA alone. No treatment-related adverse events were observed. Tear cytokine analysis revealed a reversible treatment-specific elevation of selected mediators (e.g., IFN-γ, IL-12p70) consistent with a controlled pro-repair response. The HA + GSH-C4 accelerated epithelial wound closure and selectively suppressed MCP-1 across all tested conditions. DISCUSSION: The HA + GSH-C4 formulation improved G-OSD symptoms and ocular surface stability, accompanied by a dynamic cytokine response in tears. These findings support its clinical utility and suggest a dual mechanism involving barrier restoration and modulation of ocular surface immune responses.
Beyond resorption: targeting osteoclast fusion and polarization to restore balanced bone remodeling.
Uehara S, Nakamura M, Kobayashi Y … +1 more , Udagawa N
Front Pharmacol · 2026 · PMID 42328629 · Full text
The prevalence of osteoporosis is increasing worldwide as populations age, creating a growing clinical burden of fragility fractures and highlighting limitations of current antiresorptive therapies. Conventional agents s...
The prevalence of osteoporosis is increasing worldwide as populations age, creating a growing clinical burden of fragility fractures and highlighting limitations of current antiresorptive therapies. Conventional agents such as bisphosphonates and denosumab effectively reduce fracture risk but suppress osteoclast number and activity indiscriminately, potentially impairing bone remodeling dynamics and silencing osteoclast-derived anabolic and angiogenic coupling signals. Recent advances have redefined osteoclasts as multifunctional cells that not only resorb bone but also orchestrate osteoblast differentiation and type H angiogenesis through factors such as PDGF-BB, S1P, Wnt10b, BMP6, and CTHRC1. These insights underscore the need for therapeutic strategies that temper pathological resorption while preserving beneficial coupling. This review integrates emerging molecular mechanisms regulating two key functions of osteoclasts, progenitor cell fusion and functional polarization, and evaluates their translational potential as selective antiresorptive targets. Fusion is driven by fusogen (DC-STAMP, OC-STAMP, Atp6v0d2, CD9, integrins), recognition systems (DC-STAMP, Siglec-15-sialylated TLR2), and alterations in membrane-cortical adhesion mediated by phosphatidylserine exposure, annexin A5, ERM, and BAR proteins. Osteoclast polarization relies on integrin αvβ3-Src-Pyk2 signaling, Rho-family GTPases. Recently, leucine-rich repeat kinase (LRRK1) has attracted attention as a factor that integrates both c-Src signaling and Rho-family GTPase signaling. Therapeutically, multiple modalities such as neutralizing antibodies against DC-STAMP/OC-STAMP, Siglec-15 inhibitors, small molecules such as E8431 (DC-STAMP antagonist) and C21 (Dock5 inhibitor), and LRRK1 inhibitors demonstrate the feasibility of selectively modulating fusion or polarization while maintaining osteoblast-coupling pathways. These strategies may complement conventional antiresorptives to provide safer, more physiologically balanced osteoporosis treatments. Collectively, emerging evidence positions osteoclast fusion and polarization as highly selective and clinically promising targets. A future therapeutic framework may integrate: (i) modest suppression of osteoclast number, (ii) targeted fusion inhibition to preserve preosteoclast-derived blood vessel formation, and (iii) polarization-directed modulation to reduce resorption while sustaining bone formation.
The GPR17 agonist galinex restores oligodendrocyte maturation under inflammatory conditions.
Castro E Silva JH, Marangon D, Boccazzi M … +7 more , Raffaele S, Cignitti N, Bavetta M, Arisi I, Fumagalli M, Abbracchio MP, Lecca D
Front Pharmacol · 2026 · PMID 42328628 · Full text
INTRODUCTION: Chronic neuroinflammation disrupts oligodendrocyte differentiation and limits effective remyelination across multiple neurological disorders. Among the molecular regulators integrating inflammatory cues wit...
INTRODUCTION: Chronic neuroinflammation disrupts oligodendrocyte differentiation and limits effective remyelination across multiple neurological disorders. Among the molecular regulators integrating inflammatory cues with oligodendrocyte maturation, G protein-coupled receptor 17 (GPR17) has emerged as a critical checkpoint. Physiologically, GPR17 expression is low in early oligodendrocyte precursor cells (OPCs), peaks in immature oligodendrocytes, and is subsequently downregulated to allow terminal maturation. Under neuroinflammatory conditions, GPR17 expression persists, suggesting a possible role in impaired oligodendrocyte maturation and defective myelination. Here, we tested whether receptor modulation by the selective GPR17 agonist Galinex (GAL) can support oligodendrocyte maturation under inflammatory conditions. METHODS: Differentiating oligodendroglial cultures were exposed to a pro-inflammatory cytokine cocktail composed of TNFα, IL-1β, and IFNγ. We first identified a subtoxic inflammatory condition, defined as cytokine exposure that did not cause overt loss of cell viability, and assessed oligodendrocyte maturation, myelin-associated marker expression, GPR17 expression, and transcriptional remodelling. Publicly available transcriptomic signatures from neuroinflammatory mouse models and human Alzheimer's disease and multiple sclerosis brains were used for cross-comparison. The effect of GAL was then evaluated by molecular, morphological, and functional readouts, including a synthetic nanofiber myelination assay. RESULTS: Subtoxic cytokine exposure consistently impaired oligodendrocyte morphological maturation, reduced the expression of myelin-associated markers, and was accompanied by increased GPR17 expression. Transcriptomic analysis revealed coordinated remodelling of pathways related to protein synthesis and proteostasis, mitochondrial metabolism, lipid homeostasis, and inflammatory/immunogenic-like responses, together with senescence- and DNA damage-associated features. Cross-comparison with disease-associated transcriptomic signatures showed significant overlap with neuroinflammatory modules, supporting the relevance of the inflammatory pathways engaged in our model. GAL treatment partially restored terminal maturation-associated features and oligodendrocyte morphology. Moreover, in the nanofiber assay, GAL significantly increased the length of MBP-positive segments compared with CTK-treated cells, suggesting improved wrapping/myelination-like capacity after inflammatory challenge. DISCUSSION: Together, this study establishes a controlled in vitro model linking inflammatory cytokine exposure, disease-associated transcriptional alterations, and impaired oligodendrocyte differentiation. Our findings indicate that pharmacological modulation of GPR17 can promote oligodendrocyte maturation and wrapping features under non-permissive inflammatory conditions. This strategy should be considered as an oligodendroglial-directed approach that may complement anti-inflammatory or immunomodulatory interventions.
Surface modification strategies of oral liposomes: functional design and barrier enhancement.
Jin P, Wu S, Wang Y … +5 more , Ni Y, Ruan Q, Yuan Z, Yao H, Li J
Front Pharmacol · 2026 · PMID 42328627 · Full text
Oral administration is the most prevalent and preferred clinical route due to its non-invasiveness, high patient compliance, and convenience. However, the oral delivery of many therapeutic drugs is hindered by low bioava...
Oral administration is the most prevalent and preferred clinical route due to its non-invasiveness, high patient compliance, and convenience. However, the oral delivery of many therapeutic drugs is hindered by low bioavailability, attributed to multiple gastrointestinal (GI) barriers including acid degradation, enzymatic hydrolysis, poor epithelial permeability, and first-pass metabolism. Liposomes have emerged as promising oral nanocarriers owing to their biocompatibility, versatile drug-loading capacity, and biomimetic membrane structure. Nevertheless, their poor physicochemical stability and inadequate cargo protection in the harsh GI environment limit clinical applications. This review summarizes the latest advances in surface modification strategies for liposomes to address these challenges. Synthetic polymer modifications (e.g., PEG, TPGS, pH-responsive Eudragit, and polydopamine) significantly boost the physicochemical stability of liposomes, prevent drug efflux, and improve mucus penetration. Natural biomacromolecule modifications (e.g., natural polysaccharides, proteins, peptides, and aptamers) effectively enhance mucoadhesion, cellular internalization, and active targeting capabilities. Meanwhile, small-molecule ligand modifications (e.g., folic acid, vitamin B12, and bile acids) actively promote intestinal transcytosis and targeted absorption by hijacking specific endogenous transporters. Notably, composite or multi-layer modification strategies (e.g., layer-by-layer assembly) achieve synergistic effects in effectively overcoming successive GI barriers. Furthermore, this review addresses the critical translational hurdles from bench to bedside, emphasizing that overcoming industrial scale-up bottlenecks (e.g., microfluidic technologies) and conducting rigorous long-term biosafety evaluations are pivotal for the future clinical and commercial success of these advanced nanocarriers. Ultimately, these sophisticated surface engineering technologies remarkably enhance the physicochemical integrity, mucus penetration ability, and cellular uptake efficiency of liposomes, laying a solid foundation for translating efficient oral nanotherapeutics from bench to market.
A comprehensive review of ischemic heart disease: pathophysiology, current treatments, natural products-based therapies, and nanotherapeutics.
Saadeldeen AM, Mansour A, El-Dessouki AM … +6 more , Fahim SA, Shaheen AM, Ismail RA, Salama RM, El-Shiekh RA, Khalifa HO
Front Pharmacol · 2026 · PMID 42328626 · Full text
Ischemic heart disease (IHD) is one of the major cardiovascular disorders leading to global morbidity and mortality and represents a huge burden on individuals and the healthcare system worldwide. Classically, it is attr...
Ischemic heart disease (IHD) is one of the major cardiovascular disorders leading to global morbidity and mortality and represents a huge burden on individuals and the healthcare system worldwide. Classically, it is attributed to obstructive atherosclerotic plaques in the epicardial coronary arteries; however, it is now understood to be a heterogeneous disease that also includes microvascular dysfunction, vasospasm, and ischemia with non-obstructive coronary arteries (INOCA). IHD is triggered by modifiable and non-modifiable risk factors, and its diagnosis relies on clinical assessment, electrocardiography, cardiac biomarkers, and advanced imaging techniques. Extensive investigations and trials have established the management of IHD, including lifestyle modifications, pharmacological therapies, and revascularization, while novel interventional, regenerative, and molecularly targeted therapies are under active investigation. This review provides a comprehensive overview of IHD, integrating its epidemiology, risk factors, pathophysiology, diagnostics, and therapeutics. IHD pathogenesis is complex, involving coronary atherosclerosis, plaque disruption, thrombosis, and myocardial ischemia-reperfusion injury that are modulated by oxidative stress, inflammation, and other signaling pathways. The review also addresses the molecular mechanisms and therapeutic potential of natural bioactive compounds, including polyphenols, terpenoids, and alkaloids, which exhibit antioxidant, anti-inflammatory, and cardioprotective effects. In addition, it highlights the multifaceted nature of IHD and underscores the need for integrated, mechanism-driven approaches to improve prevention, early detection, and personalized treatment for this global health burden.
Pathological complete response to perioperative treatment with darolutamide plus ADT in locally advanced prostate cancer without PTEN or RB1 loss: a case report.
Zhang Z, Zhai J, Ma Q … +5 more , Xiang Y, Kan J, Chu J, Wei C, Wang M
Front Pharmacol · 2026 · PMID 42318353 · Full text
Locally advanced prostate cancer (LAPC) is associated with a higher risk of recurrence and metastasis. Perioperative intensified systemic therapy may contribute to tumor downstaging. However, clinical evidence supporting...
Locally advanced prostate cancer (LAPC) is associated with a higher risk of recurrence and metastasis. Perioperative intensified systemic therapy may contribute to tumor downstaging. However, clinical evidence supporting darolutamide-based treatment in LAPC remains limited, and biomarker-informed treatment in this setting is not well established. We report the case of a 70-year-old man with cT4N1M0 LAPC without PTEN or RB1 loss by immunohistochemistry (IHC). At presentation, the patient's total prostate-specific antigen (TPSA) level was 88.80 ng/mL. Prostate multiparametric magnetic resonance imaging (mpMRI) revealed the invasion of right lateral bladder wall, bladder neck and bilateral seminal vesicles, and enlarged pelvic lymph nodes. Conventional imaging, including bone scintigraphy and computed tomography showed no evidence of distant metastasis. Transperineal prostate biopsy confirmed prostatic acinar adenocarcinoma with a Gleason score of 5 + 4 = 9 (ISUP Grade Group 5). The initial intensified systemic regimen is the doublet therapy of Darolutamide (600 mg orally twice daily) and goserelin (10.8 mg administered subcutaneously every 3 months). Castration-level testosterone was achieved after 1 month, and TPSA decreased sharply from 88.80 ng/mL to 0.15 ng/mL at month 1 and 0.008 ng/mL at month 8. After 8 months of doublet therapy, follow-up mpMRI showed no residual suspicious lesion or enlarged pelvic lymph nodes. As a tailored local consolidation strategy, the patient underwent laparoscopic radical prostatectomy (LRP) and pelvic lymph node dissection after MDT discussion. A pathological complete response (pCR) was achieved, as confirmed by postoperative pathology showing no residual tumor in the prostatectomy specimen or pelvic lymph nodes (ypT0N0). The recovery of urinary incontinence was achieved after 2 months following LRP, while Darolutamide plus ADT was continued postoperatively. During 20 months of follow-up, the patient maintained an undetectable PSA, and had no radiographic evidence of disease relapse with well treatment tolerance. This case suggests that darolutamide plus ADT, administered as a tailored perioperative intensified systemic strategy, may induce a rapid and profound PSA response and may be associated with pCR in selected patients with very high-risk LAPC, while further investigation is warranted.
Genetic insights revealed ADRB1 as potential target for clear cell renal cell carcinoma.
Zhu H, Lin Q, Yu Z … +1 more , Huang X
Front Pharmacol · 2026 · PMID 42318352 · Full text
BACKGROUND: Antihypertensive drug targets are associated with various cancers, but their relationship with clear cell renal cell carcinoma (CCRCC) risk remains unclear. METHODS: Summary-data-based Mendelian randomization...
BACKGROUND: Antihypertensive drug targets are associated with various cancers, but their relationship with clear cell renal cell carcinoma (CCRCC) risk remains unclear. METHODS: Summary-data-based Mendelian randomization (SMR) and colocalization analyses were performed. Four antihypertensive drug targets (ACE, ADRB1, ADRB2, and SLC12A3) and CCRCC were included. Patients with CCRCC were identified from two large GWAS databases, including 752,817 and 315,137 individuals (Finnish cohorts), for the discovery and external validation analyses, respectively. Meta-analysis was conducted to integrate the results from both cohorts. Western blotting and prognostic analyses of tumor survival revealed the relationship between ADRB1 and CCRCC. RESULTS: ADRB1 was associated with CCRCC risk in both the discovery and validation cohorts (odds ratio (OR): 1.097, per standard deviation unit (SD) change in antihypertensive drug target perturbation equivalent to 1 SD unit of decreased blood pressure; 95% confidence interval (95% CI): 1.063-1.132; P-value = 0.016) vs. OR: 1.284; 95% CI: 1.014-1.627; P-value = 0.013). ADRB2 was associated with CCRCC risk in discovery cohort (OR: 1.224; 95% CI: 1.045-1.433; P-value = 0.019). Integrated outcomes demonstrated that both ADRB1 (OR: 1.100; 95% CI: 1.066-1.135; P-value<0.0001) and ADRB2 (OR: 1.313; 95% CI: 1.137-1.517; P-value = 0.0002) were associated with CCRCC risk. Colocalization analyses indicated that ADRB1 (PP4 = 0.996) and ADRB2 (PP4 = 0.895) shared the same region of genetic variation with CCRCC. Furthermore, ADRB1 was highly expressed in CCRCC tumor tissues and was associated with poor tumor survival and prognosis. CONCLUSION: ADRB1 was associated with the risk of CCRCC, providing additional perspectives into potential treatment strategies for CCRCC.
Empagliflozin-pirfenidone dual therapy improves cardiac function and structure in a preclinical two-hit HFpEF model.
Yu Y, Xu Y, Chen J … +9 more , Yao Y, Liu Y, Huang T, Yang S, Ling KH, Guyette JP, Shaharuddin B, Guo Z, Tan JJ
Front Pharmacol · 2026 · PMID 42318351 · Full text
BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) accounts for more than half of heart failure cases and is associated with substantial morbidity and mortality. Although sodium-glucose cotransporter-2 in...
BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) accounts for more than half of heart failure cases and is associated with substantial morbidity and mortality. Although sodium-glucose cotransporter-2 inhibitors (SGLT2is) have shown efficacy in reducing HFpEF hospitalizations, the disease's multi-pathway pathogenesis often limits the effectiveness of single-target interventions. This study examines whether the cardiovascular benefits of empagliflozin (EMPA) can be synergistically enhanced by co-administration with the targeted anti-fibrotic agent pirfenidone (PFD). AIMS: We hypothesized that simultaneous modulation of metabolic stress and pro-fibrotic signaling would lead to synergistic structural and functional recovery in a severe HFpEF phenotype. METHODS: HFpEF was induced in Sprague-Dawley rats (n = 16/group) using a two-hit model [NG-nitro-L-arginine methyl ester (L-NAME) and a high-fat diet (HFD)] over 5 weeks. The rats subsequently received daily oral EMPA (0.35 g/kg/d), PFD (0.3 g/kg/d), or combination therapy (EMPA + PFD) for 4 weeks. Treatment efficacy was evaluated via echocardiography, histopathology, and exercise tolerance testing. Further insights into the underlying transcriptional mechanisms were gained through RNA sequencing and semi-quantitative Western blotting. Bliss independence analysis was used to analyze pharmacological synergy. RESULTS: Co-treatment with EMPA + PFD significantly enhanced diastolic indices, left ventricular ejection fraction (LVEF), fractional shortening (FS), and cardiac output (CO) compared with controls and monotherapy groups (p < 0.05). Histological analysis revealed reduced cardiomyocyte hypertrophy and lower collagen deposition, particularly in the endocardium. Although additive improvement in systemic hemodynamics was observed, EMPA + PFD co-treatment exerted compartmentalized synergy within the myocardium. The combination reversed cellular hypertrophy and deep fibrosis, restoring diastolic and systolic function (p < 0.05). Transcriptomic profiling revealed that local myocardial rescue was mediated by gene networks linked to protein kinase C-activating G-protein-coupled receptor signaling, which blocked the downstream PKC/NF-κB inflammatory pathway and transforming growth factor-beta (TGF-β)-driven fibrosis, thereby explaining the molecular basis of functional improvement. CONCLUSION: Dual therapy with EMPA and PFD achieves compartmentalized synergy, effectively eliminating cellular hypertrophy and deep fibrosis, thereby restoring cardiac mechanics. These findings provide mechanistic proof of concept that multi-axis metabolic and antifibrotic combinations can disrupt the complex pathological cycle of HFpEF.
Old tale new admirers, cetuximab maintenance in metastatic colorectal cancer: a systematic review and meta-analysis.
Yan Y, Lin Z, Yuan J … +4 more , Gao W, Jiao C, Sun L, Sun X
Front Pharmacol · 2026 · PMID 42318350 · Full text
BACKGROUND: metastatic colorectal cancer (mCRC) represents a major global burden and the decision on whether to pursue maintenance with cetuximab (CET) remains controversial. Therefore, this meta-analysis was performed t...
BACKGROUND: metastatic colorectal cancer (mCRC) represents a major global burden and the decision on whether to pursue maintenance with cetuximab (CET) remains controversial. Therefore, this meta-analysis was performed to assess the efficacy and safety of CET maintenance therapy. METHODS: After literature search of PubMed, Embase, Cochrane Library and Scopus from inception to March 2026, two investigators selected eligible studies and extracted relevant data. The key outcomes were progression-free survival (PFS) and overall survival (OS). A random-effects model was used for pooling. The relative risks (RRs) with 95% confidence interval (CI) of all-grade and high-grade (≥3) adverse effects (AEs) were used to study its safety. Heterogeneity was also investigated through subgroup and sensitivity analysis. RESULTS: A total of 6 studies with 727 patients were included. CET maintenance therapy prolonged the PFS (HR: 0.42, 95% CI: 0.27 to 0.57, P < 0.01) and OS (HR: 0.47, 95% CI: 0.19 to 0.74, P < 0.01) of mCRC patients. Subgroup analysis showed that Asian patients (HR: 0.53, 95% CI: 0.15 to 0.60, P = 0.010) received more survival benefit from CET maintenance therapy than non-CET therapy or observation. Although diarrhea and rash were more common, the RR of all-grade AEs revealed no statistical significance. CONCLUSION: CET maintenance therapy may be associated with improved outcomes compared with observation, especially in Asian patients. But it may slightly increase treatment-related toxicities. Therefore, subsequent large sample, multi-center randomized controlled trials (RCTs) are needed to further verify our conclusions. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024513879, identifier CRD42024513879.
The current status and influencing factors of medication literacy among patients with cardiovascular diseases: a systematic review and meta-analysis.
Xu T, Yao Q, Ni Y … +1 more , Li X
Front Pharmacol · 2026 · PMID 42318349 · Full text
BACKGROUND: As an important domain of health literacy, medication literacy plays a critical role in ensuring the safe and effective use of medicines, especially among individuals with Cardiovascular Diseases (CVDs). Neve...
BACKGROUND: As an important domain of health literacy, medication literacy plays a critical role in ensuring the safe and effective use of medicines, especially among individuals with Cardiovascular Diseases (CVDs). Nevertheless, evidence regarding the overall level of medication literacy and the factors influencing it in this population remains limited. This study aimed to systematically evaluate medication literacy levels among patients with CVDs and to identify associated factors based on the Health Ecological Model (HEM). METHODS: This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We systematically searched PubMed, Web of Science, the Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), Wanfang Data, and the Vertically Integrated Projects database (VIP) for studies published in English or Chinese from database inception to 30 December 2025. Two reviewers independently performed study selection, quality assessment, data extraction, and analysis. Mean medication literacy scores and corresponding effect sizes were pooled using meta-analysis in Stata 18.0. Random-effects models were applied for all analyses due to substantial heterogeneity across studies. Heterogeneity was assessed using the I test. Sensitivity analyses and publication bias were also assessed. RESULTS: A total of 34 studies involving 9,599 patients were included. Of these, 30 studies reported medication literacy levels. Given the substantial heterogeneity observed across all instrument subgroups, random-effects models were applied for pooling. The pooled mean scores were as follows: the Medication Literacy Questionnaire (MLQ): 4.56 [95% CI (4.36, 4.77), I = 95.7%]; the Medication Literacy Scale in Spanish and English (MedLitRxSE): 7.49 [95% CI (6.46, 8.52), I = 97.7%]; and the Chinese Medication Literacy Scale for Hypertensive Patients (C-MLSHP): 24.09 [95% CI (23.72, 24.45), I = 64.2%]. Twenty-four studies reported factors associated with medication literacy. Significant factors included age, department of hospitalization, comorbid hypertension, and number of discharge medications (personal traits); self-efficacy (psychological and behavioral characteristics); social support (social networking); income level and educational attainment (work and living conditions); and receipt of medication education (policy and environmental factors). CONCLUSION: Medication literacy among patients with CVDs remains suboptimal and is influenced by multidimensional factors. Individualized patient education, standardized counseling protocols, community-based services, and healthcare provider training are urgently needed. Multilevel interventions grounded in the HEM hold promise for improving medication use and informing policy development. Future large-scale, longitudinal studies employing standardized assessment tools are needed to elucidate causal relationships, underlying mechanisms, and sources of heterogeneity. SYSTEMATIC REVIEW REGISTRATION: The protocol for this systematic review has been registered in PROSPERO (CRD420251208289, available at: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251208289).
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