Front Pharmacol [JOURNAL]
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200 papers
Core determinant of the enzyme activity of tenecteplase: primary structure over glycosylation modifications.
Wang LY, Xu KX, Chen JL … +4 more , Bai BW, Gao HS, Lv P, Li J
Front Pharmacol · 2026 · PMID 42367291 · Full text
INTRODUCTION: Tenecteplase (TNK), a novel genetically modified variant of tissue-type plasminogen activator (rt-PA), holds great promise as a first-line thrombolytic agent for thrombotic diseases owing to its convenient...
INTRODUCTION: Tenecteplase (TNK), a novel genetically modified variant of tissue-type plasminogen activator (rt-PA), holds great promise as a first-line thrombolytic agent for thrombotic diseases owing to its convenient administration and favorable pharmacological properties. However, glycosylation heterogeneity derived from distinct production processes has resulted in industry-wide inconsistencies in enzyme activity determination methods, reference materials, and activity units, severely impairing the accuracy of clinical medication. Compounded by its narrow therapeutic window, minor dosage deviations of TNK can not only drastically reduce thrombolytic efficacy but also trigger severe hemorrhagic adverse reactions. This study aimed to establish an accurate and standardized enzymatic activity assay for TNK, and to elucidate the dominant determinant of TNK enzyme activity between primary structure and glycosylation modifications. METHODS: An enzyme activity assay was established using an automatic coagulation analyzer and subjected to systematic methodological validation. The primary structures of two TNK products (TNK A and TNK B) were confirmed via LC-MS/MS, while their glycosylation profiles were characterized using HILIC coupled with mass spectrometry. Comparative activity assays were conducted under various conditions, including human serum albumin (HSA) protection, dithiothreitol (DTT) disruption, and single-chain to two-chain conversion. RESULTS: Methodological validation demonstrated that the automated assay possesses high accuracy (relative bias -0.24%-0.27%), precision (CV < 2.0%), and robustness, with results highly consistent with the traditional bubble-rising method. Characterization confirmed that TNK A and TNK B share identical amino acid sequences but exhibit significant differences in glycan distribution. Under stable conditions (using HSA-containing buffers), no statistically significant difference in clot lysis activity was observed between the two products (P > 0.05). Experimental data revealed that previously reported activity discrepancies were likely artifacts of buffer composition (lack of HSA) and environmental sensitivity rather than direct glycan-driven functional changes. DISCUSSION: The primary structure is the decisive factor determining the enzymatic activity of TNK, while glycosylation modifications appear to exert minimal impact under the specific stable assay conditions tested. The established automated coagulation analysis provides a reliable tool for quality control and the unification of clinical activity units for recombinant tissue-type plasminogen activator-based agents.
The relevance of phenotypic definition in treatment resistant forms of major depressive disorder: a narrative review.
Paribello P, Isayeva U, Lazzardi S … +7 more , Pinna M, Contu M, Meloni A, Pisanu C, Squassina A, Baune BT, Manchia M
Front Pharmacol · 2026 · PMID 42367290 · Full text
Treatment-resistant depression (TRD) represents a major clinical and public health challenge contributing disproportionately to disability, healthcare utilisation, and societal costs. Progress in the field may be hindere...
Treatment-resistant depression (TRD) represents a major clinical and public health challenge contributing disproportionately to disability, healthcare utilisation, and societal costs. Progress in the field may be hindered by substantial heterogeneity in TRD phenotypic definitions and inconsistencies in their operationalisation across research and clinical settings. In this narrative review, we provide an updated overview of TRD research, focusing on limitations of current phenotypic frameworks, key sources of heterogeneity, and emerging biologically informed predictive approaches. We examine how variability in clinical assessment, comorbidities, treatment adherence, and adequacy of therapeutic trials may contribute to pseudo-resistance and consequent phenotypic instability, given that current TRD definitions largely rely on the number of failed antidepressant trials. Evidence on genetic, inflammatory, cognitive, and personality correlates of TRD is also summarised, highlighting both promising signals and persisting gaps. In addition, we discuss the potential role of measurement-based care and algorithm-guided treatment strategies in improving TRD identification and management. Overall, convergence toward more standardised TRD phenotyping-particularly through systematic assessment of adherence and symptom dimensions-appears essential to enhance ecological validity, support precision psychiatry, and advance translational research.
The efficacy of ultrasonic ablation combined with medication in the treatment of adenomyosis: a systematic review and network meta-analysis.
Qin Q, Wang R, Yao Y … +5 more , Zhang L, Pang S, Zhang X, Ma R, Wang Y
Front Pharmacol · 2026 · PMID 42367289 · Full text
BACKGROUND: Adenomyosis occurs when tissue from the inner lining of the endometrium grows into the muscle wall of the myometrium. Previous studies have suggested that High-Intensity Focused Ultrasound (HIFU) combined wit...
BACKGROUND: Adenomyosis occurs when tissue from the inner lining of the endometrium grows into the muscle wall of the myometrium. Previous studies have suggested that High-Intensity Focused Ultrasound (HIFU) combined with medications may improve treatment outcomes for adenomyosis; however, the comparative efficacy of different medication combinations remains unclear. This network meta-analysis aimed to compare and rank the efficacy of various medications combined with HIFU in patients with adenomyosis. METHODS: Randomized controlled trials reporting on HIFU combined with medications for adenomyosis were retrieved from 8 databases from their inception to 23 June 2025. The literature meeting the inclusion criteria was evaluated for quality and risk of bias using the Cochrane 5.1 manual and RoB2. Subsequently, a Bayesian network meta-analysis was conducted using R software. RESULTS: A total of six interventions (HIFU + GnRH-a, HIFU + testosterone propionate, HIFU + percutaneous ethanol injection, HIFU + microbubble contrast agent, HIFU + oxytocin, and HIFU + microbubble contrast agent + oxytocin) were included to evaluate their efficacy on intraoperative indicators of adenomyosis compared with HIFU alone. A total of 8,700 records were retrieved, with 16 studies ultimately included, involving 1,685 patients with adenomyosis. Compared with HIFU alone, HIFU combined with ethanol ablation demonstrated the highest efficacy in non-perfused volume ratios (NPVR) (Mean Difference (MD) = 27, 95% Confidence Interval (CI): 2.7 to 52), sonication energy (MD = -230%, 95% CI: -290 to -180), and treatment duration (MD = -44%, 95% CI: -80 to -7.8); Additionally, HIFU combined with Gonadotropin-releasing hormone agonist (GnRH-a) showed superiority in energy efficiency factor (MD = -31%, 95% CI: -90 to -13). CONCLUSION: The efficacy of HIFU combined with medications in the treatment of adenomyosis is superior to that of HIFU alone. Different medications offer distinct advantages in enhancing the therapeutic effect of HIFU. SYSTEMATIC REVIEW REGISTRATION: clinicaltrials.gov, identifier CRD420251143604.
Efficacy and safety of nab-paclitaxel in advanced or recurrent small cell lung cancer: a single-arm meta-analysis.
Liu JC, Yu HJ, Chen Z … +1 more , Deng Q
Front Pharmacol · 2026 · PMID 42367288 · Full text
BACKGROUND: Although various effective agents used as second- and third-line treatments for advanced or recurrent small cell lung cancer have improved overall survival, the optimal therapeutic regimen remains controversi...
BACKGROUND: Although various effective agents used as second- and third-line treatments for advanced or recurrent small cell lung cancer have improved overall survival, the optimal therapeutic regimen remains controversial. Previous studies have shown that albumin-bound paclitaxel exhibits favorable anticancer activity in many cancer types. However, almost all studies of albumin-bound paclitaxel for recurrent small cell lung cancer are non-randomized controlled trials with small sample sizes, diverse first-line treatment regimens, and non-controlled data analyses. This may result in a lack of valid indicators for evaluating the efficacy and safety of albumin-bound paclitaxel. Therefore, this meta-analysis aims to assess the efficacy and safety of albumin-bound paclitaxel in patients with advanced or recurrent small cell lung cancer. METHODS: PubMed, Embase, the Cochrane Library, and Web of Science databases were systematically searched for relevant studies. Outcomes including overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were extracted for further analysis. RESULTS: Nine studies involving 334 patients were enrolled in this meta-analysis. In terms of tumor response, the pooled ORR and DCR were 25.0% and 62.5%, respectively. With regard to survival analysis, the pooled PFS and OS were 3.16 months and 7.23 months, respectively. The most common treatment-related adverse events of nab-paclitaxel were Leukopenia (all grade: 59.3%, ≥grade III: 14.1%), Neutropenia (all grade: 54.9%, ≥grade III: 14.7%), and Anemia (all grade: 53.0%, ≥grade III: 6.2%). Subgroup analysis revealed that combination therapy with immunotherapy was associated with numerically higher response rates and survival. CONCLUSIONS: In summary, this meta-analysis demonstrated that albumin-bound paclitaxel has moderate efficacy and manageable safety in the later-line treatment of advanced or recurrent small cell lung cancer. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261350933, identifier 420261350933.
Phillygenin suppresses hepatocellular carcinoma progression by modulating the TNF signaling pathway and TCA cycle metabolism.
Luo J, Liu C, Pang Y … +1 more , Pan L
Front Pharmacol · 2026 · PMID 42367287 · Full text
BACKGROUND: Phillygenin (PLE) is a bioactive constituent of that exerts hepatoprotective, anti-inflammatory, and antitumor effects. However, its role in hepatocellular carcinoma (HCC) and the mechanisms underlying its a...
BACKGROUND: Phillygenin (PLE) is a bioactive constituent of that exerts hepatoprotective, anti-inflammatory, and antitumor effects. However, its role in hepatocellular carcinoma (HCC) and the mechanisms underlying its activity remain insufficiently characterized. METHODS: The effect of PLE on HCCLM3 and Hep3B tumor cells was assessed using immunofluorescence (IF) staining, TUNEL assay, qRT-PCR, and Western blotting experimental methodology. RNA-sequencing (RNA-seq) was used to detect changes in gene expression and to explore the gene targets and related pathways. Liquid chromatography-mass spectrometry (LC-MS) was used to identify the effects of PLE on primary metabolite targets and metabolism-related pathways. Tumor xenograft models were used for verification. RESULTS: PLE inhibited HCC cell proliferation through the inhibition of cell cycle progression and induction of cell apoptosis indicating a dual antiproliferative and pro-apoptotic effect. These responses were associated with the modulation of the TNF signaling pathway. Moreover, PLE induced significant alterations in the central carbon metabolism, including the regulation of citrate synthesis and upregulation of oxoglutarate dehydrogenase (OGDH) expression in HCC cells. Finally, PLE treatment significantly reduced tumor growth , thereby confirming its therapeutic potential. CONCLUSION: PLE exerts antitumor effects in HCC through the coordinated regulation of tricarboxylic acid (TCA) cycle metabolism while simultaneously inhibiting the TNF signaling pathway, highlighting its potential as a candidate antitumor drug for the treatment of HCC.
Regulation of doxorubicin resistance and cellular metabolism by miR-203a-3p via p53 and TAp63 signaling in hepatocellular carcinoma.
Abdelaal NM, Abdelnaser A
Front Pharmacol · 2026 · PMID 42367286 · Full text
Doxorubicin (DOX) is a cornerstone chemotherapeutic drug in the treatment of hepatocellular carcinoma (HCC). However, its efficacy is often limited by the development of drug resistance linked to increased cellular capac...
Doxorubicin (DOX) is a cornerstone chemotherapeutic drug in the treatment of hepatocellular carcinoma (HCC). However, its efficacy is often limited by the development of drug resistance linked to increased cellular capacity to repair DNA damage. Altered tumor metabolism allows cancer cells to meet increased energy demands for rapid proliferation while evading apoptosis and adapting to therapeutic interventions. MiR-203a-3p is associated with regulating members of the p53 family and has been implicated in regulating chemoresistance and metabolic rewiring in various cancers, yet its role in HCC remains to be elucidated. This study investigated the functional role of miR-203a-3p in response to DOX in HCC cell lines differing in p53 status. HepG2 (wild-type p53) and Huh7 (mutant p53) cells were transfected with miR-203a-3p mimics or inhibitors, alone or in combination with DOX. Cell viability was assessed by MTT assay, and the expression levels of p53 family members and Bax were measured by qPCR. Apoptosis was evaluated by flow cytometry, and mitochondrial function was examined using the Seahorse XFe96 analyzer. MiR-203a-3p expression was significantly higher in DOX-resistant HepG2 cells relative to DOX-sensitive Huh7 cells. In HepG2 cells, miR-203a-3p promoted resistance through p53/Δ133p53-driven survival and enhanced oxidative phosphorylation. In Huh7 cells, it suppressed TAp63/Bax-mediated apoptosis while driving both oxidative phosphorylation and glycolysis, promoting resistance despite the absence of wild-type p53. These findings identify miR-203a-3p as a key modulator of DOX resistance in HCC through coordinated regulation of p53 family expression, apoptotic signaling, and metabolic rewiring, highlighting its potential as a therapeutic target for miRNA-based combination therapies.
Qualitative analysis of pharmacogenetic applications in pediatric clinical trials registered on ClinicalTrials.gov.
Hareeri RH, Aldurdunji MM
Front Pharmacol · 2026 · PMID 42367285 · Full text
BACKGROUND: Pharmacogenetics (PGx) may support more individualized pediatric therapy by accounting for genetic variability in drug response, toxicity, and dose requirements. However, the extent and manner in which pharma...
BACKGROUND: Pharmacogenetics (PGx) may support more individualized pediatric therapy by accounting for genetic variability in drug response, toxicity, and dose requirements. However, the extent and manner in which pharmacogenetic and biomarker-related components are incorporated into pediatric clinical trials remain incompletely characterized. OBJECTIVES: To qualitatively examine how pharmacogenetic and biomarker-related components are represented and operationalized in pediatric clinical trials registered on ClinicalTrials.gov, with emphasis on disease distribution, apparent roles within trial design, and the primary and secondary outcome domains reported in these studies. METHODS: A registry-based qualitative analysis was conducted using ClinicalTrials.gov. Interventional Phase II to IV trials enrolling participants younger than 18 years of age were screened from database inception through July 2025 using pharmacogenetic-related search terms. Eligible studies included pediatric trials incorporating pharmacogenetic or pharmacogenomic components relevant to drug response, efficacy, toxicity, pharmacokinetics/pharmacodynamics, dose optimization, or treatment selection. Included trials were classified by primary clinical disease category, apparent level of pharmacogenetic integration, and primary and secondary outcome domains. RESULTS: A total of 198 pediatric trials met the inclusion criteria. Infectious diseases and oncology were the most frequently represented primary clinical disease categories, each accounting for 37 (18.7%) of included trials, followed by psychiatry and respiratory diseases at 20 (10.1%) each. Exploratory or observational incorporation of pharmacogenetic or biomarker-related information was the most common pattern, accounting for 121 (61.1%) of trials, whereas guided intervention and decision-informing use accounted for 39 (19.7%) and 25 (12.6%), respectively. At the primary outcome level, clinical efficacy was the dominant domain, accounting for 82 (41.4%) of trials, followed by biomarkers/molecular outcomes at 48 (24.2%). Among secondary outcomes coded as inclusive occurrences, biomarkers/molecular outcomes were the leading category at 116 (27.0%), followed by clinical efficacy at 103 (24.0%). CONCLUSION: Pediatric pharmacogenetic trials appear to be advancing but remain largely positioned at an intermediate translational stage. Pharmacogenetic and biomarker-related components were more often exploratory than treatment-guiding, highlighting the need for clearer registry reporting and more explicit trial designs that distinguish exploratory, decision-informing, and clinically actionable PGx roles.
Japanese evidence on Janus kinase inhibitors for rheumatoid arthritis: a narrative review of risk-optimized use.
Matsumoto H, Yoshida S, Tahara M … +10 more , Nibu H, Yamamoto S, Sakamoto T, Ogawa S, Saito K, Sumichika Y, Suzuki E, Asano T, Sato S, Shimojima Y
Front Pharmacol · 2026 · PMID 42367284 · Full text
BACKGROUND: Janus kinase inhibitors (JAKi) have expanded treatment options for rheumatoid arthritis (RA) by providing rapid and effective oral therapy. However, their optimal use has become increasingly complex after the...
BACKGROUND: Janus kinase inhibitors (JAKi) have expanded treatment options for rheumatoid arthritis (RA) by providing rapid and effective oral therapy. However, their optimal use has become increasingly complex after the emergence of safety concerns involving serious infections, herpes zoster (HZ), major adverse cardiovascular events (MACE), venous thromboembolism (VTE), and malignancy. This issue is particularly relevant in Japan, where the RA population is older and has a higher prevalence of comorbidities. OBJECTIVE: To review the risk-optimized use of JAKi for RA based on Japanese evidence, with particular emphasis on older patients, comorbidity-rich populations, and practical real-world treatment decision-making. EVIDENCE ACQUISITION: We conducted a literature search of PubMed/MEDLINE and Ichushi-Web to identify Japan-specific studies on JAKi in RA. Randomized trials, long-term extension studies, registry analyses, database studies, postmarketing surveillance reports, and observational studies were reviewed. Because of heterogeneity in design, patient background, and outcome definitions, the evidence was synthesized narratively. CONTENT: Japanese evidence indicates that older age is an important but insufficient determinant of JAKi safety. Across studies, treatment outcomes were more strongly influenced by comorbidities, glucocorticoid exposure, laboratory abnormalities, and other patient-related risk factors. HZ emerged as the most consistent safety signal, supporting the importance of vaccination and early monitoring. By contrast, the risk of hospitalized infection was not consistently higher with JAKi than with biologic disease-modifying antirheumatic drugs in older patients, and Japanese evidence on MACE, VTE, and malignancy remained limited or inconsistent. Real-world studies also supported individualized dose optimization, whereas current data did not support routine within-class selection based primarily on JAK selectivity. CONCLUSION: Current Japanese evidence supports a risk-optimized approach to the use of JAKi in RA. Age alone should not determine treatment decisions. Instead, rheumatologists should individualize JAKi selection, dosing, and monitoring according to comorbidity profile, infection and vascular risk, malignancy background, and therapeutic priorities, particularly in increasingly older and multimorbid patients.
Efficacy and safety of sintilimab combined with histology-specific chemotherapy in advanced NSCLC: a real-world retrospective study.
Chen CL, Chen QQ, Pan LL … +5 more , Wang N, Li JX, Liang NS, Wu Q, Guo YJ
Front Pharmacol · 2026 · PMID 42367283 · Full text
OBJECTIVES: This study aimed to evaluate whether the clinical efficacy of first-line sintilimab combined with histology-specific chemotherapy (adenocarcinoma [ADC]: pemetrexed/platinum [Pem/Plat]; squamous cell carcinoma...
OBJECTIVES: This study aimed to evaluate whether the clinical efficacy of first-line sintilimab combined with histology-specific chemotherapy (adenocarcinoma [ADC]: pemetrexed/platinum [Pem/Plat]; squamous cell carcinoma [SqCC]: paclitaxel/platinum [Pac/Plat]) differs by histological subtype in advanced non-small cell lung cancer (NSCLC). METHODS: This retrospective, real-world study included 210 patients with advanced NSCLC treated between January 2019 and April 2025 (ADC: n = 124; SqCC: n = 86). The primary endpoints were progression-free survival (PFS) and overall survival (OS). Survival data were analyzed using the Kaplan-Meier method and Cox proportional hazards models, with efficacy heterogeneity tested by incorporating an interaction term. RESULTS: In the overall population, sintilimab plus chemotherapy significantly improved both PFS (median PFS: 12.30 vs. 7.30 months, HR = 0.547, = 0.001) and OS (median OS: 24.30 vs. 17.93 months, HR = 0.647, = 0.016). Testing for heterogeneity of treatment effect revealed a statistically significant difference in benefit between histological subtypes (PFS interaction = 0.025; OS interaction = 0.001). In patients with SqCC, the combination conferred significant PFS (median PFS: 17.17 vs. 6.10 months, HR = 0.382, = 0.001) and OS benefits (median OS: 52.33 vs. 11.57 months, HR = 0.312, < 0.001) and emerged as the strongest independent favorable prognostic factor in multivariable analysis. However, in patients with ADC, the combination only showed a trend toward improved PFS (median PFS: 11.53 vs. 8.23 months, HR = 0.641, = 0.057) and did not lead to a significant OS benefit (median OS: 21.87 vs. 30.50 months, HR = 1.043, = 0.865). The presence of ≥2 distant metastatic sites was an independent negative prognostic factor in ADC. The safety profile was consistent with the known spectrum of the agents, with no new safety signals identified. CONCLUSION: In real-world practice, the survival benefit of sintilimab combined with histology-specific chemotherapy is significantly dependent on the histological subtype in advanced NSCLC. Patients with SqCC derived a clear and substantial survival advantage, whereas the benefit for patients with ADC was more limited and influenced by high metastatic burden. These findings suggest that in the immunotherapy era, histological subtyping remains a crucial yet insufficient guide for clinical decision-making, and future strategies should integrate subtype-specific biomarkers for further treatment optimization.
Polydopamine-polyethylene glycol-liproxstatin-1 nanoparticles inhibit ferroptosis for enhanced treatment of neutrophilic asthma.
Bao C, Wang D, Liu C … +5 more , Zhang M, Liu Q, Hu J, Wu Y, Xu S
Front Pharmacol · 2026 · PMID 42367282 · Full text
Ferroptosis is an iron-dependent programmed cell death mechanism triggered by the accumulation of lipid-based reactive oxygen species (ROS). It is closely implicated in the pathogenesis of asthma. Liproxstatin-1 (LIP-1)...
Ferroptosis is an iron-dependent programmed cell death mechanism triggered by the accumulation of lipid-based reactive oxygen species (ROS). It is closely implicated in the pathogenesis of asthma. Liproxstatin-1 (LIP-1) is a ferroptosis inhibitor that is beneficial for treating neutrophilic asthma. However, low water solubility, limited blood concentration, and poor mucus permeability and biocompatibility limit the therapeutic efficacy of LIP-1. In this study, we successfully constructed polydopamine-polyethylene glycol-LIP-1 nanoparticles (PDA-PEG-LIP-1 NPs) for the treatment of neutrophilic asthma. Inhalation of PDA-PEG-LIP-1 NPs effectively inhibited lipopolysaccharide (LPS)- and interleukin (IL)-13-induced ferroptosis by alleviating lipid peroxidation and ROS production and chelating free ferrous ions (Fe). In addition, results from asthma mouse models demonstrated that inhalation of PDA-PEG-LIP-1 NPs could overcome the limitations of LIP-1 and effectively inhibit ferroptosis. This research suggests that PDA-PEG-LIP-1 NPs are an effective, practical, and safe option for treating neutrophilic asthma.
From heart to brain: a Case Report of individualized antithrombotic management for left ventricular thrombus and stroke in a young patient with acute myocardial infarction.
Wang J, Zhang X, Jin Q … +3 more , Chen Q, Guo F, Xue Q
Front Pharmacol · 2026 · PMID 42367281 · Full text
BACKGROUND: Left ventricular thrombus (LVT) is a serious complication of acute myocardial infarction (AMI), conferring a high risk of systemic embolism. The management of LVT becomes exceedingly challenging when complica...
BACKGROUND: Left ventricular thrombus (LVT) is a serious complication of acute myocardial infarction (AMI), conferring a high risk of systemic embolism. The management of LVT becomes exceedingly challenging when complicated by acute ischemic stroke and recent percutaneous coronary intervention (PCI), creating a therapeutic trilemma that lacks guideline-directed recommendations. CASE SUMMARY: A 27-year-old male with hypertension and diabetes presented with acute anterior ST-segment elevation myocardial infarction. Due to unsuccessful initial revascularization at a local hospital, he underwent delayed PCI on day 10 post-infarction at our center. On the first post-PCI day, he developed acute ischemic stroke, and echocardiography confirmed a mobile left ventricular thrombus as the embolic source. Navigating competing risks of stent thrombosis, hemorrhagic transformation, and recurrent embolism, an individualized six-phase antithrombotic strategy was implemented. This dynamic approach included acute-phase de-escalation, sequential anticoagulation with rivaroxaban followed by warfarin guided by thrombus response, stepwise de-escalation after complete revascularization, and eventual transition to long-term dual-pathway inhibition. Complete LVT resolution was achieved within 6 months, and the patient's neurological deficits fully recovered. No recurrent LVT, ischemic events, or major bleeding occurred during 18 months of follow-up. CONCLUSION: This case highlights the complex management challenges of left ventricular thrombus and acute stroke following myocardial infarction, and underscores the value of individualized, phased antithrombotic strategies guided by dynamic risk assessment and serial imaging, rather than rigid adherence to single-disease guidelines.
Analysis of the interaction network relationship between drugs using a graph neural network.
Chai Z, Wang J, Du H
Front Pharmacol · 2026 · PMID 42367280 · Full text
INTRODUCTION: The ever-increasing complexity of biochemical systems, alongside the rapid growth of pharmaceutical and biomedical data, underscores the urgent need for intelligent, scalable, and interpretable computationa...
INTRODUCTION: The ever-increasing complexity of biochemical systems, alongside the rapid growth of pharmaceutical and biomedical data, underscores the urgent need for intelligent, scalable, and interpretable computational models. These models must be capable of supporting next-generation decision-support systems and driving knowledge discovery in the realm of computational science. Traditional approaches to relational biomedical modeling, however, often struggle to accurately capture intricate multi-relational dependencies and typically lack robustness in sparse or incomplete interaction domains. To address these pressing limitations, we present a novel, biologically grounded graph-based learning framework designed to overcome such challenges. METHODS: Our approach comprises a two-tiered system: PHARMNet, a multi-relational graph neural network (GNN) equipped with memory-augmented attention mechanisms, and INTERACT-SCOPE, an advanced, context-aware optimization strategy that leverages structured biomedical ontologies and domain knowledge. PHARMNet employs relation-specific graph convolutions and semantic embedding alignment to effectively model latent relational dependencies in biochemical and pharmacological datasets. In parallel, INTERACT-SCOPE improves predictive generalization and stability by incorporating ontology-guided constraints, estimating epistemic uncertainty, and applying adaptive graph regularization techniques tailored to biomedical structures. RESULTS AND DISCUSSION: Through rigorous experimental evaluations across a variety of pharmacological interaction categories, our framework consistently achieves state-of-the-art (SOTA) predictive performance, enhanced model interpretability, and notable robustness-especially in low-data or high-noise scenarios. These outcomes strongly align with the journal's mission to promote innovative and knowledge-driven advances in software engineering, artificial intelligence, and biomedical informatics. Ultimately, our article illustrates the synergistic integration of computational intelligence, domain-informed graph representation learning, and scalable modeling, contributing a powerful and interpretable solution to real-world challenges in healthcare informatics and biomedical discovery. Experimental results demonstrate that MGTNSyn outperforms existing methods, achieving an AUC of 0.873 and an F1-score of 0.831 on drug-drug interaction (DDI) benchmark datasets.
Editorial: Optimizing GLP-1 receptor agonist use: mechanisms, clinical applications, and safety profiles.
Rasineni K, Grigson PS
Front Pharmacol · 2026 · PMID 42367279 · Full text
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Comparative neuroprotective and exercise capacity effects of prophylactic intermittent fasting and probiotics in sleep-deprived rats: insights into anti-inflammatory marker modulation and gene regulation.
Elgizawy EI, Abo-Elsoud RAA, Shaban AM … +5 more , Kamel HFM, Al-Amodi HS, Abdelsattar S, Hikal RT, Hassan SM
Front Pharmacol · 2026 · PMID 42358374 · Full text
BACKGROUND: Prophylactic probiotics and intermittent fasting (IF) substantially modulate the neuropsychological functions and exercise capacity in rats subjected to sleep deprivation (SD). A comparative study was conduct...
BACKGROUND: Prophylactic probiotics and intermittent fasting (IF) substantially modulate the neuropsychological functions and exercise capacity in rats subjected to sleep deprivation (SD). A comparative study was conducted to analyze the effects of probiotics and IF on SD-induced neuropsychological disturbances and compromised muscle endurance. METHODS: Forty albino Wistar rats were randomly assigned to four groups. The NSD group was maintained on a standard chow diet for 12 weeks. The SD group followed an SD regimen for 72 h per week over 8 weeks, starting from the fifth week. The SDP group received probiotics at a dose of colony-forming units (CFUs)/100 g/day for 4 weeks prior to SD, followed by 8 weeks of concurrent probiotic administration with SD. The SDIF group underwent an alternate-day fasting regimen for 4 weeks before SD, followed by 8 weeks of simultaneous SD combined with IF. Neuropsychological functions and exercise capacity were tested, and then the brains were carefully dissected, sectioned, and processed for hematoxylin and eosin, cresyl violet, and immunohistochemical staining. RESULTS: Inflammatory markers, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and hippocampal expression of the circadian locomotor output cycles kaput () gene, were significantly elevated in the SD group. Conversely, it showed significant decreases in endurance, exploratory behavior, hippocampal superoxide dismutase (SOD) activity, and fecal short-chain fatty acids (SCFAs). Histological analysis also revealed hippocampal gliosis, apoptosis, CA1 pyramidal cell degeneration, layer disorganization, and upregulation of glial fibrillary acidic protein (GFAP), NF-κB, and cleaved caspase-3. Nevertheless, both probiotics and IF markedly reduced serum MDA, hippocampal gene expression, gliosis, and apoptosis and enhanced memory performance. In addition, they significantly increased hippocampal SOD activity and SCFAs. CONCLUSION: These findings indicate that prophylactic probiotics decrease cognitive disruption and impaired muscle endurance caused by SD through gene regulation compared to that with IF. This highlights the need for further research to elucidate these mechanisms. Histological findings also supported these results, showing improved neuronal structure in the hippocampus following probiotic treatment.
antidiarrheal activity of aqueous and hydroethanolic extracts of and used in Benin (West Africa) in a castor oil-induced diarrhea model traditionally.
Hounsa E, Fagla SM, Agbodjento E … +2 more , Klotoe JR, Dougnon VT
Front Pharmacol · 2026 · PMID 42358373 · Full text
BACKGROUND: The management of diarrheal diseases involves the use of medicinal plants, particularly in developing countries, where access to conventional treatments remains limited. METHODS: The study evaluated the anti...
BACKGROUND: The management of diarrheal diseases involves the use of medicinal plants, particularly in developing countries, where access to conventional treatments remains limited. METHODS: The study evaluated the antidiarrheal activity of aqueous and hydroethanolic extracts of stem bark and leaves using castor oil induced diarrhea model in male Wistar rats. RESULTS: The hydroethanolic extracts of both plants studied delayed the onset of diarrhea, reduced stool frequency, decreased stool water content, and lowered the purgation index. Particularly, the hydroethanolic extract of at 200 mg/kg showed effects similar to Loperamide for certain specific parameters, including the percentage of diarrhea inhibition. However, no reduction in fecal weight was observed. The extracts also showed antioxidant activity associated with their polyphenol and tannin contents. CONCLUSION: These findings support the traditional use of and as an antidiarrheal protective effects may involve modulation of intestinal secretion, motility and oxidative stress. This study provides preliminary experimental evidence supporting the therapeutic potential of these botanical drugs, although further mechanistic investigations are required.
Mechanisms, prevention, and management of aminoglycoside-induced hearing loss in neonates and children: a translational review.
Illamola SM, Sherwin CM, Ferguson LC … +3 more , Birnbaum AK, Elluru RG, Vaughns JD
Front Pharmacol · 2026 · PMID 42358372 · Full text
OBJECTIVE: Aminoglycoside antibiotics remain essential for treating serious neonatal and pediatric infections, yet carry a well-documented risk of permanent auditory and vestibular toxicity. This review examines the phar...
OBJECTIVE: Aminoglycoside antibiotics remain essential for treating serious neonatal and pediatric infections, yet carry a well-documented risk of permanent auditory and vestibular toxicity. This review examines the pharmacological mechanisms of ototoxicity in pediatric populations, identifies those at highest risk, and assesses current prevention, monitoring, and management strategies. METHODS: PubMed, EMBASE, Cochrane Library, Web of Science, and CINAHL were searched for relevant literature from 2000 to 2025. The primary focus was pediatric populations, though mechanistic and translational pharmacology work from other age groups was included. RESULTS: The ototoxicity pathway is increasingly well characterized: aminoglycosides accumulate in cochlear hair cells via mechanoelectrical transduction channels, disrupt mitochondrial function, trigger oxidative stress, and cause cell death through apoptotic, necroptotic, and ferroptotic mechanisms. Susceptibility varies substantially. Patients carrying the MT-RNR1 m.1555A>G pharmacogenomic variant face a markedly elevated risk of profound hearing loss even with a single standard course. Preterm neonates are at higher risk than older children owing to renal immaturity, altered volume of distribution, and incomplete blood-labyrinth barrier development. Co-administration of loop diuretics and vancomycin further amplifies ototoxic risk. Extended-interval dosing is associated with equivalent efficacy and reduced nephrotoxicity, with a non-significant trend toward lower ototoxicity in pooled analyses. Point-of-care genetic screening allows identification of high-risk patients before the first dose, though debate continues over universal versus targeted implementation. Model-informed dosing approaches, including Bayesian forecasting and AUC-targeted monitoring, offer individualized pharmacokinetic optimization but remain underutilized. Antimicrobial stewardship and minimizing concomitant ototoxin exposure are complementary strategies. When ototoxicity occurs, early audiological and vestibular identification enables timely intervention through hearing aid fitting, cochlear implantation, vestibular rehabilitation, and family-centered support, though vestibular ototoxicity remains widely under-recognized in pediatric populations. CONCLUSION: Evidence-based interventions to reduce aminoglycoside ototoxicity in children exist, including pharmacogenomic screening and dosing optimization, as well as structured monitoring and rehabilitation. However, a persistent gap remains between available evidence and routine clinical implementation. Key research priorities include pediatric otoprotective trials, validated cochlear injury biomarkers, and implementation strategies for diverse healthcare settings. Given the permanence of aminoglycoside-induced ototoxic injury and its downstream effects on speech, language, and developmental outcomes, closing this gap represents an urgent clinical priority.
Correction: Reversal of anxiety-like depression induced by chronic corticosterone by crocin I and surface-enhanced Raman spectroscopy monitoring of plasma metabolites.
Zhang D, Wu Z, Yang D … +4 more , Zhao G, Zhang Y, Mou W, Liang Y
Front Pharmacol · 2026 · PMID 42358371 · Full text
[This corrects the article DOI: 10.3389/fphar.2025.1540551.].
[This corrects the article DOI: 10.3389/fphar.2025.1540551.].
Correction: The potential of Lisosan G as a possible treatment for glaucoma.
Amato R, Rossino MG, Cammalleri M … +5 more , Timperio AM, Fanelli G, Dal Monte M, Pucci L, Casini G
Front Pharmacol · 2026 · PMID 42358370 · Full text
[This corrects the article DOI: 10.3389/fphar.2021.719951.].
[This corrects the article DOI: 10.3389/fphar.2021.719951.].
Thrombotic outcomes and mortality with roxadustat for anemia in chronic kidney disease: a systematic review and meta-analysis of randomized trials.
Tang J, Zheng Y, Pan L … +2 more , Li X, Zhong Y
Front Pharmacol · 2026 · PMID 42358369 · Full text
BACKGROUND: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor used to treat anemia in patients with chronic kidney disease (CKD); however, evidence from randomized trials has not fully clarified...
BACKGROUND: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor used to treat anemia in patients with chronic kidney disease (CKD); however, evidence from randomized trials has not fully clarified its associations with thrombotic outcomes and all-cause mortality. METHODS: We searched PubMed, Embase, Web of Science, and the Cochrane Library from inception to 21 August 2025 for randomized controlled trials comparing roxadustat with placebo or erythropoiesis-stimulating agents (ESAs) in adults with CKD. The primary outcome was vascular access thrombosis (VAT), while the secondary outcomes were all-cause mortality, any venous thromboembolism (VTE), and adverse events (AEs) leading to treatment discontinuation. We used the random-effects model for primary analyses and conducted sensitivity analyses using the leave-one-out and fixed-effects models. Furthermore, certainty of evidence was assessed using the GRADE framework. RESULTS: Twenty randomized comparisons (involving 11,418 participants) were included in this study. Roxadustat was associated with higher odds of VAT (odds ratio (OR): 1.50; 95% confidence interval (CI): 1.06-2.12) and all-cause mortality (OR: 1.14; 95% CI: 1.06-1.22) with minimal heterogeneity; it was also found to increase AEs leading to discontinuation (OR: 1.76; 95% CI: 1.48-2.10). For any VTE, the estimate was imprecise and had a wide CI including the null value (OR: 3.69; 95% CI: 0.71-19.14). Subgroup analyses showed no evidence of effect modification for mortality by dialysis status or comparator type. For VAT, the subgroup estimates were directionally adverse for both the dialysis-dependent (DD) and non-dialysis-dependent (NDD) populations. However, the primary clinical interpretation of VAT pertained to the DD population because the majority of NDD patients lacked established vascular access; thus, the NDD findings warrant cautious interpretation. Discontinuation due to AEs increased in both the DD and NDD trials, with larger effects in the DD and ESA-controlled trials. Certainty of evidence was moderate for mortality and VAT but low for any VTE and AE-related discontinuation. CONCLUSION: In this meta-analysis of anemia in CKD, roxadustat was found to be associated with higher odds of VAT and all-cause mortality, along with increased AEs leading to treatment discontinuation, whereas the effects on any VTE remained uncertain because of imprecise results. These findings support careful selection of patients, close surveillance of hemoglobin levels after treatment initiation or dose adjustment, and continued monitoring of vascular access when using roxadustat in dialysis settings.
Cenobamate in pediatric Dravet syndrome: two responder cases highlighting the limits of simple "sodium-channel blocker" labeling.
Makridis KL, Laux LC, Kaindl AM
Front Pharmacol · 2026 · PMID 42358368 · Full text
Dravet syndrome (DS), caused by loss-of-function variants in , is classically aggravated by chronic sodium-channel blocker treatment, reflecting impaired interneuron excitability as a core disease mechanism. Cenobamate (...
Dravet syndrome (DS), caused by loss-of-function variants in , is classically aggravated by chronic sodium-channel blocker treatment, reflecting impaired interneuron excitability as a core disease mechanism. Cenobamate (CNB) challenges this: adult DS cases with substantial seizure reduction have been reported, while pediatric experience is mixed and includes a small cohort with no responders and frequent worsening. We report a 7-year-old girl with -associated DS and severe developmental impairment who showed marked reduction of generalized tonic-clonic seizures (GTCS) and total seizure burden with adjunctive CNB therapy. At maintenance CNB dose, which was added to valproate, clobazam and cannabidiol, a total seizure reduction of 80% was noted. An attempt to taper CNB failed because of marked seizure increase nearly back to the pre-CNB state. When CNB was returned to stable maintenance therapy levels, seizures markedly improved with no GTCS noted since October 2025. In addition, we describe a 17-year adolescent male with DS who had GTCS and daily eyelid myoclonia. He achieved suppression of seizures on low-dose CNB (50 mg/day), with only one breakthrough GTCS secondary to a missed evening medication and no reported adverse effects. Taken together with prior pediatric reports, these cases highlight the need for controlled studies to balance potential efficacy against the risk of seizure worsening when considering cenobamate in pediatric DS.
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