Frontiers In Pharmacology[JOURNAL]
Sun
200 papers
Pharmacological profiling of intravenous MP-04: sustained NAD augmentation, immune modulation, and renal protection in preclinical models.
Ghosh A, Pranesh G, Zachariah N … +8 more , Murakami E, Heredia A, Mathur P, Burns-Naas LA, Weng S, Ramanathan A, Kottilil S, Subramanian GM
Front Pharmacol · 2026 · PMID 42358367 · Full text
INTRODUCTION: Systemic inflammation and mitochondrial bioenergetic failure are central drivers of multi-organ dysfunction in advanced liver disease, sepsis, and acute kidney injury (AKI). Currently available therapies re...
INTRODUCTION: Systemic inflammation and mitochondrial bioenergetic failure are central drivers of multi-organ dysfunction in advanced liver disease, sepsis, and acute kidney injury (AKI). Currently available therapies remain largely supportive and fail to directly address intracellular NAD depletion and immune-metabolic dysregulation. We investigated MP-04, a novel intravenous formulation of dihydronicotinamide riboside (NRH), for its ability to restore NAD homeostasis, modulate immune metabolism, and confer organ protection in relevant preclinical models. METHODS: The NAD-enhancement activity of nicotinamide riboside (NR) and MP-04 was evaluated in human hepatoma (HepG2), T-cell (Jurkat), kidney (HEK293) cell lines, and peripheral blood mononuclear cells (PBMCs). Cellular bioenergetics were assessed using Seahorse extracellular flux analysis. Immunomodulatory effects were examined in polyclonally activated human PBMCs and in a murine endotoxin-induced systemic inflammation model. Pharmacokinetics and pharmacodynamics were assessed following intravenous (IV) dosing in rats, and organ protection was evaluated in a cisplatin-induced AKI mouse model. Safety of MP-04 was evaluated in rat and dog Good Laboratory Practice (GLP) toxicology studies. RESULTS: MP-04 produced rapid, distinct, and dose-dependent increases in intracellular NAD across all tested human cell types and was markedly more potent than NR. IV administration in rats resulted in sustained elevations of NAD and NADH in blood, liver, and kidney that persisted beyond the systemic clearance of MP-04, with strong correlations between blood and tissue NAD levels. In activated immune cells, MP-04 reduced reliance on aerobic glycolysis, and significantly attenuated pro-inflammatory cytokine production without affecting resting cells. , MP-04 reduced systemic inflammatory cytokines following endotoxin challenge and conferred significant biochemical and histological protection against cisplatin-induced AKI. MP-04 was safe and well tolerated in rat and dog following once daily IV administration for 7 days. CONCLUSION: MP-04 is a safe and highly potent intravenous NAD precursor that modulates cellular metabolism, reduces maladaptive immune activation, and protects against inflammation-associated organ injury in preclinical models. These findings support MP-04 as a promising metabolic-immunomodulatory therapeutic strategy for conditions characterized by systemic inflammation and organ failure, including hepatorenal syndrome-associated AKI, beyond the limits of current supportive care.
SPP1 and MMP1 as key therapeutic targets of Jingfang Granule in idiopathic pulmonary fibrosis: integrated bioinformatics and machine learning analysis.
Ren Y, Gao J, Shen K … +12 more , Jiang S, Xie Y, Wang Y, Sun X, Wang Y, Zhang N, Lou S, Ding J, Mu B, Yan G, Zhang G, Wang X
Front Pharmacol · 2026 · PMID 42358366 · Full text
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with limited therapeutic options. This study aims to identify potential efficacy biomarkers of Jingfang Granule (JFG) and investigat...
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with limited therapeutic options. This study aims to identify potential efficacy biomarkers of Jingfang Granule (JFG) and investigate the therapeutic mechanism of its key active components against critical targets in IPF. METHODS: IPF-related targets were identified through bioinformatics analysis of a public IPF dataset. Co-expressed gene modules were identified using Weighted Gene Co-expression Network Analysis (WGCNA). The JFG-PF interaction network was constructed employing protein-protein interaction (PPI) methods and functional enrichment analysis, which included Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Variation Analysis (GSVA). Additionally, five types of machine learning techniques were utilized to obtain diagnostic markers, which were further analyzed in immune infiltration assessments to evaluate their associations with immune cells and potential therapeutic effects. Molecular docking and molecular dynamics simulations were conducted to validate these analytical results. Finally, immunohistochemistry and immunofluorescence were used for verification. RESULTS: A total of 3, 360 upregulated and 240 downregulated differentially expressed genes (DEGs) were identified in IPF sample. Integration of WGCNA findings with 1, 077 targets of JFG pinpointed 57 key genes lingking with IPF and JFG. Machine learning algorithms further refined this list, identifying four diagnostic markers:SPP1, MMP1, AKR1B10, and HTR2A. Immune infiltration analysis revealed that these biomarkers are significantly correlated with alterations in multiple immune cell populations within the IPF microenvironment. Molecular docking experiments strong binding affinities between the active compounds of JFG and these protein biomarkers. Subsequent validation results demonstrated that JFG significantly regulates the expression of SPP1 and MMP1 in lung fibroblasts, thereby attenuating fibrotic responses through the suppression of pro-fibrotic pathways. CONCLUSION: The study identified four key genes as potential diagnostic markers for IPF and therapeutic targets for JFG. The finding preliminarily elucidate ther mechanisms of JFG in mitigating pulmonary fibrosis vis regulation of fibrotic pathways and the immune microenvironment, thereby providing an integrativeevidence chain for the development of novel-fibrotic therapeutic.
Efficacy of immune-based combinations across treatment lines in advanced hepatocellular carcinoma: a systematic review and network meta-analysis.
Zhao W, Wu Z, Qiao S … +3 more , Kou Q, Liu Z, Zhang X
Front Pharmacol · 2026 · PMID 42358365 · Full text
BACKGROUND: With the rapid introduction of immune checkpoint inhibitors (ICIs) for advanced hepatocellular carcinoma (HCC), optimal treatment sequencing remains unclear. Lacking direct comparisons, we aimed to evaluate t...
BACKGROUND: With the rapid introduction of immune checkpoint inhibitors (ICIs) for advanced hepatocellular carcinoma (HCC), optimal treatment sequencing remains unclear. Lacking direct comparisons, we aimed to evaluate the efficacy and safety of systemic therapies across first- and second-line settings. METHODS: A frequentist network meta-analysis (PROSPERO: CRD420261296427) was performed using phase III RCTs from PubMed, Embase, Cochrane, and Web of Science (up to January 2026) evaluating systemic HCC therapies. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and Grade ≥3 treatment-related adverse events (TRAEs). Subgroup analysis compared treatment-naïve versus refractory populations. RESULTS: Twelve RCTs comprising 8,138 patients were analyzed. For OS, ICI-anti-angiogenic combinations ranked highest, notably sintilimab plus IBI305 (HR = 0.57 vs. sorafenib; SUCRA = 0.94) and camrelizumab plus rivoceranib (HR = 0.62 vs. sorafenib; SUCRA = 0.89). Combinations consistently outperformed monotherapies in PFS and ORR. Crucially, subgroup analysis revealed a statistically significant difference in the magnitude of survival benefit between first-line (HR = 0.74, 95% CI: 0.65-0.83) and second-line settings (HR = 1.09, 95%CI: 0.90-1.30) when compared to sorafenib (P = 0.0006). Regarding safety, ICI monotherapy/dual-blockade (e.g., pembrolizumab, nivolumab + ipilimumab) demonstrated better tolerability, whereas TKI-based combinations significantly increased Grade ≥3 TRAE rates. CONCLUSION: ICI-based combinations offer the most robust survival benefits in HCC via pharmacodynamic synergy, albeit with higher cumulative toxicity. The differing magnitude of survival benefit between first- and second-line settings when compared to sorafenib highlights their distinct clinical contexts. These findings support a tailored continuum of care, guiding optimal sequencing based on pharmacological efficacy and safety profiles. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261296427, identifier CRD420261296427.
Epithelial cell-based multi-omics integration identifies SPINK5 and SRI as novel diagnostic biomarkers for ulcerative colitis.
Li X, Liu Z, Ge Z … +5 more , Li Y, Yao K, Lin X, Liu X, Xia H
Front Pharmacol · 2026 · PMID 42358364 · Full text
OBJECTIVES: Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by epithelial barrier dysfunction, yet reliable epithelial-derived diagnostic biomarkers remain elusive. METHODS: We employed an i...
OBJECTIVES: Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by epithelial barrier dysfunction, yet reliable epithelial-derived diagnostic biomarkers remain elusive. METHODS: We employed an integrative multi-omics approach, combining single-cell RNA sequencing (scRNA-seq) and bulk transcriptomics from public datasets. Epithelial cell-specific signatures were identified and intersected with differentially expressed genes to pinpoint candidate markers. Four machine learning algorithms-LASSO, Random Forest, Support Vector Machine and K-Nearest Neighbor (KNN)-were applied for robust feature selection. The diagnostic model was validated in external cohorts, and its association with the immune microenvironment was assessed using CIBERSORT. Finally, key findings were experimentally confirmed in clinical UC tissues via qPCR, Western blot, and immunohistochemistry. RESULTS: scRNA-seq revealed significant transcriptional remodeling of epithelial cells in UC. Cross-algorithm analysis consistently identified SPINK5 and SRI as the most robust diagnostic biomarkers. A model built on these two genes demonstrated exceptional performance, with an area under the curve (AUC) > 0.90 in both training and external validation sets. Immune infiltration analysis revealed a pro-inflammatory shift in UC and delineated distinct correlations of SPINK5 and SRI with specific immune cell subsets. Experimental validation confirmed significant upregulation of SPINK5 and downregulation of SRI in UC patient tissues at both the mRNA and protein levels. CONCLUSION: Our study underscores the pivotal role of epithelial dysfunction in UC pathogenesis. By integrating multi-omics and machine learning, we have established SPINK5 and SRI as promising candidate diagnostic biomarkers, providing candidate biomarkers with potential utility for UC diagnosis and a basis for future studies on disease stratification.
Impact of oral bacterial lysates on asthma control and immune parameters in children: evidence from an updated systematic review and meta-analysis of randomized trials.
Chen Y, Shi L, Wang Y … +3 more , Chen L, Wang L, Ying Y
Front Pharmacol · 2026 · PMID 42358363 · Full text
BACKGROUND: The role of oral bacterial lysates (OBLs) as adjuvant immunomodulatory therapy in pediatric asthma requires clarification. This systematic review and meta-analysis evaluates their efficacy and safety. METHODS...
BACKGROUND: The role of oral bacterial lysates (OBLs) as adjuvant immunomodulatory therapy in pediatric asthma requires clarification. This systematic review and meta-analysis evaluates their efficacy and safety. METHODS: We searched eight databases for randomized controlled trials (RCTs) in children comparing standard asthma therapy plus OBLs versus standard therapy/placebo. Primary outcomes were clinical (wheezing/infection frequency, symptom improvement time, treatment efficacy) and lung function parameters. Secondary outcomes included immune biomarkers and adverse events. Random-effects meta-analyses were performed. RESULTS: Twenty-eight RCTs (n = 2,893) were included. Adjunctive OBLs therapy significantly reduced wheezing/exacerbation frequency (Mean Difference (MD) = -3.00,95% confidence intervals (CI): 4.07 to -1.93), shortened symptom improvement time (MD = -3.13 days, 95%CI: 4.10 to -2.15), reduced Respiratory Tract Infection (RTI) frequency (MD = -2.43,95%CI: 3.62 to -1.23) and increased overall treatment efficacy rate (relative rates (RR) = 1.17, 95%CI: 1.13-1.21). Improvements occurred in lung function (Forced Expiratory Volume in 1 s [FEV1], Forced Vital Capacity [FVC], Peak Expiratory Flow [PEF]) and immune parameters (increased the level of T-lymphocyte subsets (CD3+,CD4+,CD4+/CD8+) and salivary secretory immunoglobulin A (sIgA), decreased peripheral eosinophil (EOS) count and the level of interleukin-4(IL-4), eosinophil cationic protein (ECP), fractional exhaled nitric oxide (FeNO). Adverse events did not increase significantly (RR = 1.26, 95%CI: 0.93-1.70). Subgroup analyses showed consistent benefits across follow-up duration, age, and sample size, with background inhaled corticosteroids (ICS) therapy being a potential effect modifier (P = 0.06). CONCLUSION: Adjunctive OBLs therapy is associated with improved clinical outcomes, lung function, and immune modulation in pediatric asthma, with a favorable safety profile. However, methodological limitations, substantial heterogeneity, and potential biases warrant caution. While promising, more rigorous and long-term trials are needed to define its precise therapeutic role and target population. SYSTEMATIC REVIEW REGISTRATION: Identifier CRD420261281796.
Development of a stacking model for personalized treatment of Crohn's disease: leveraging routine clinical features to forecast infliximab response.
Jiang S, Lin L, Yang D … +5 more , Zhang S, Zhang D, Chen Y, Lin R, Xu J
Front Pharmacol · 2026 · PMID 42358362 · Full text
AIMS: Infliximab (IFX) is widely used for treating Crohn's disease (CD), but a significant proportion of patients experience primary non-response or loss of response. Early prediction of IFX efficacy is crucial to avoid...
AIMS: Infliximab (IFX) is widely used for treating Crohn's disease (CD), but a significant proportion of patients experience primary non-response or loss of response. Early prediction of IFX efficacy is crucial to avoid ineffective treatment, adverse effects, and financial burden. The aim of this study was to develop a stacking model using routine clinical data to predict IFX clinical response. METHOD: This retrospective cohort study enrolled CD patients initiating IFX therapy between January 2019 and December 2025. Feature selection was performed using statistical analysis and Least Absolute Shrinkage and Selection Operator (LASSO) regression. Base models (Elastic Net, Support Vector Machine, Random Forest, XGBoost) were built and integrated into a stacking model. Model performance was evaluated using the Area Under the Receiver Operating Characteristic Curve (AUROC), accuracy, precision, sensitivity, specificity, recall, and F-score on a hold-out testing set. Class imbalance was addressed using the Synthetic Minority Over-sampling Technique. RESULT: A total of 319 patients were enrolled, comprising 237 responders and 82 non-responders, reflecting a class imbalance. An independent dataset containing 43 patients was used for temporal validation. LASSO regression identified five key predictors: erythrocyte sedimentation rate, C-reactive protein, Crohn's disease activity index, red blood cell count, and diagnostic age. The stacking model, composed of Elastic Net and Random Forest, achieved an AUROC of 0.897 (95% CI: 0.832-0.956) on the validation set and 0.874 (95% CI: 0.749-0.957) on the testing set, demonstrating robust predictive performance. CONCLUSION: The developed stacking model effectively predicts IFX response using readily available clinical variables, representing a preliminary step toward personalized treatment planning. Prospective validation is required before clinical implementation.
Comparative effects of combined omeprazole and dose-escalated striatin therapy versus monotherapy on VEGF, ITF, gastric ulcer area, epithelial thickness, and inflammatory response in rats with aspirin-induced gastric injury.
Purnomo HD, Hendrianingtyas M, Rachman R … +8 more , Roosana SN, Indiarso D, Hutami HT, Permatadewi CO, Istiadi H, Pralampita PW, Dharminto, Tjandrawinata RR
Front Pharmacol · 2026 · PMID 42358361 · Full text
INTRODUCTION: Aspirin-induced gastritis results from reduced prostaglandin synthesis and increased oxidative stress, compromising gastric mucosal integrity. While omeprazole effectively suppresses gastric acid secretion,...
INTRODUCTION: Aspirin-induced gastritis results from reduced prostaglandin synthesis and increased oxidative stress, compromising gastric mucosal integrity. While omeprazole effectively suppresses gastric acid secretion, it does not directly promote mucosal regeneration. Striatin, a bioactive fraction of , has anti-inflammatory and regenerative properties and may enhance mucosal healing. PURPOSE: This study aimed to evaluate whether adjunctive striatin at escalating doses enhances the therapeutic effect of omeprazole in aspirin-induced gastric injury. METHODS: A controlled experimental study was conducted in 30 male Wistar rats randomly assigned into six groups (n = 5 each): healthy control, negative control, omeprazole monotherapy (20 mg/kg BW), and three combination groups receiving omeprazole plus striatin (500, 1,000, and 1,500 mg/kg BW). Gastric injury was induced using aspirin. Vascular endothelial growth factor (VEGF; day 2) and intestinal trefoil factor (ITF; day 14) were measured as markers of angiogenesis and epithelial restitution, respectively. Histological and macroscopic assessments were performed at the end of treatment. RESULTS AND DISCUSSION: VEGF levels did not significantly differ across groups. In contrast, ITF significantly increased in the highest-dose striatin group (1,500 mg/kg BW, = 0.007), which also demonstrated improved epithelial thickness, reduced ulcer area, and lower inflammation scores. Lower doses did not produce significant changes in ITF levels. CONCLUSION: Adjunctive striatin, particularly at higher doses, enhances gastric mucosal healing primarily through epithelial restitution rather than angiogenesis. These findings suggest potential adjunctive benefits, although further studies are needed to establish optimal dosing and clinical relevance.
Post-marketing safety of tarlatamab in small cell lung cancer based on FAERS and WHO-VigiAccess with SHAP-based interpretable machine learning analysis of immune-related adverse events.
Ou Y, Zhong X, Mei M … +5 more , Gu X, Luo S, Chen G, Xie X, Sun D
Front Pharmacol · 2026 · PMID 42358360 · Full text
BACKGROUND: Tarlatamab is a DLL3-targeted bispecific T-cell engager approved for previously treated extensive-stage small cell lung cancer (ES-SCLC). However, its post-marketing safety profile in routine practice remains...
BACKGROUND: Tarlatamab is a DLL3-targeted bispecific T-cell engager approved for previously treated extensive-stage small cell lung cancer (ES-SCLC). However, its post-marketing safety profile in routine practice remains incompletely characterized. METHODS: We conducted a retrospective pharmacovigilance study using the FDA Adverse Event Reporting System from Q2 2024 to Q3 2025, with a descriptive cross-database comparison using WHO-VigiAccess. Disproportionality analyses were performed using reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker algorithms. Clinical priority scoring, subgroup analysis, time-to-onset analysis, multivariable logistic regression, and interpretable machine learning with SHAP (SHapley Additive exPlanations) were further applied. RESULTS: A total of 942 reports with tarlatamab as the primary suspect drug were identified, comprising 1,346 adverse events. At the preferred-term level, 30 signals met all four disproportionality criteria. The most frequent and strongest signals were cytokine release syndrome (CRS; n = 201; ROR 223.84, 95% CI 192.15-260.77) and immune effector cell-associated neurotoxicity syndrome (ICANS; n = 106; ROR 312.43, 95% CI 254.68-383.26). Common additional signals included pyrexia, dysgeusia, hypotension, and ageusia. Potentially under-recognized events, such as intestinal perforation, dyspnoea at rest, and incontinence, were also detected. Most adverse events occurred early after treatment initiation, with a median time to onset of 3 days; CRS and ICANS both showed a median onset of 1 day. In multivariable analysis, concomitant medication use was associated with higher reported odds of CRS (OR 2.551, 95% CI 1.353-4.811), whereas reports from Japan and the year 2025 were associated with lower reported odds. The CRS report-level classification model showed acceptable discrimination (AUC 0.733), whereas the best machine-learning model for adverse events of immune disorders classification within FAERS reports showed only modest performance (validation AUC 0.639). SHAP analysis indicated that country and therapy type contributed more to model output than age and sex, suggesting that the model primarily captured reporting context and treatment complexity rather than intrinsic biological susceptibility. Cross-database comparison with WHO-VigiAccess showed a broadly concordant reporting pattern, with CRS and ICANS remaining the most commonly reported toxicities. CONCLUSION: Post-marketing data indicate that tarlatamab has a distinct safety profile dominated by early-onset immune-mediated and neurologic toxicities, particularly CRS and ICANS. Early monitoring and prompt supportive management during initial treatment cycles are essential. These findings broaden current knowledge of tarlatamab safety in real-world practice and support prospective studies to pharmacovigilance-based signal stratification and monitoring strategies.
Global research trends and hotspots of exosome-mediated drug delivery across the blood-brain barrier: a bibliometric study from 2015 to 2025.
Chen Z, Jiang Y, Yin X … +5 more , Li Y, Sai H, Song Y, Shen Z, Chen Q
Front Pharmacol · 2026 · PMID 42358359 · Full text
BACKGROUND: The blood-brain barrier (BBB) is a major obstacle to targeted drug delivery for central nervous system (CNS) diseases. Although liposomes and polymeric nanoparticles have improved brain drug delivery, limitat...
BACKGROUND: The blood-brain barrier (BBB) is a major obstacle to targeted drug delivery for central nervous system (CNS) diseases. Although liposomes and polymeric nanoparticles have improved brain drug delivery, limitations remain in BBB targeting, long-term biocompatibility, and clearance. Exosomes are endogenous nanoscale extracellular vesicles with favourable biocompatibility, low immunogenicity, and BBB-crossing potential. Therefore, this bibliometric study summarises the current research status, future research trends, and challenges in the more specific field of exosome-mediated BBB drug delivery. METHODS: A comprehensive search was conducted across the Web of Science Core Collection (WoSCC), PubMed, and Embase databases for relevant English-language literature on exosome-mediated drug delivery across the blood-brain barrier from 2015 to 2025. WoSCC served as the primary source for bibliometric analysis. PubMed and Embase databases were used for supplementary validation. Software such as VOSviewer, CiteSpace, and R-bibliometrix was employed for literature visualisation analysis. RESULTS: This study included 1,365 relevant articles from the WoSCC database, and the annual publication volume showed a steady upward trend. China and the United States significantly lead in both the number of publications and the number of core contributing institutions in this field. Co-occurrence analysis of keywords showed that research hotspots are mainly focused on exosomes, the blood-brain barrier, drug delivery, and Alzheimer's disease. PubMed and Embase were used as supplementary validation databases, including 1,089 and 1,517 records, respectively. Their annual publication trends, major countries/regions, core journals, and keywords/themes were generally consistent with WoSCC, supporting the macro-level stability of the bibliometric findings. CONCLUSION: Unlike previous bibliometric analyses that mainly focused on overall trends in CNS exosome research, this study focuses specifically on the direction of exosome-mediated drug delivery across the BBB. The findings show a shift from basic vesicle characterisation toward engineered delivery systems, CNS disease applications, and translational evaluation. Mammalian-derived exosomes remain dominant, while plant-derived vesicles, AI-assisted design, biomimetic hybrid nanovesicles, and gut-brain axis strategies are emerging areas of focus. Future research should prioritise systematic platform comparisons, standardised evaluation, quality control, scalable production, long-term safety, and regulatory pathways.
The impact of garlic and its active metabolites on degenerative musculoskeletal diseases.
Cheng N, Zhao J, Feng C … +3 more , Li Z, Song Y, Sun X
Front Pharmacol · 2026 · PMID 42358358 · Full text
With the accelerating global population aging, the incidence of degenerative musculoskeletal diseases (such as osteoarthritis, osteoporosis, intervertebral disc degeneration and sarcopenia) continues to rise, posing a si...
With the accelerating global population aging, the incidence of degenerative musculoskeletal diseases (such as osteoarthritis, osteoporosis, intervertebral disc degeneration and sarcopenia) continues to rise, posing a significant public health challenge. Current conventional therapeutic approaches, while alleviating symptoms, are often accompanied by side effects and struggle to reverse the pathological process. Garlic and its various active metabolites (such as allicin, S-allylmercaptocysteine, diallyl sulfide and diallyl disulfide, etc.) have been confirmed to possess multiple biological activities, including anti-inflammatory, antioxidant effects, regulation of signaling pathways, and maintenance of extracellular matrix homeostasis. Numerous studies have demonstrated that the active metabolites of garlic can intervene in degenerative musculoskeletal diseases by regulating multiple signaling pathways such as PI3K/Akt/NF-κB, RANKL/RANK/OPG, Wnt/β-catenin, and Akt/mTOR, significantly delaying the progression of the diseases. Therefore, this review summarizes the regulatory effects and potential mechanisms of garlic and its bioactive metabolites on degenerative musculoskeletal diseases, aiming to provide a scientific basis for the further development of adjunctive therapeutic strategies based on garlic active metabolites.
Post-marketing safety evaluation of anthracycline for acute myeloid leukemia treatment: a real-world pharmacovigilance analysis.
Wang Y, Liu Q, Xu J … +8 more , Yang F, Wang M, Lu H, Wu J, Zhang A, Zhang X, Wu D, Qiu H
Front Pharmacol · 2026 · PMID 42358357 · Full text
BACKGROUND: Anthracyclines are key for acute myeloid leukemia (AML) but carry serious side effects. This study identifies their side effects across drugs and patient populations using the FDA Adverse Event Reporting Syst...
BACKGROUND: Anthracyclines are key for acute myeloid leukemia (AML) but carry serious side effects. This study identifies their side effects across drugs and patient populations using the FDA Adverse Event Reporting System (FAERS). MATERIALS AND METHODS: We analyzed 1,079 AML cases and 3,622 adverse events (AEs) from FAERS (2004-2024). Disproportionality analyses (PRR, ROR, BCPNN, MGPS) detected AE signals; Kruskal-Wallis tests evaluated time-to-onset by age/sex. RESULTS: Distinct risks emerged: epirubicin (strongest cardiotoxicity, ROR = 10.57), doxorubicin (highest pregnancy-related AEs, ROR = 9.97), daunorubicin (vascular disorders, ROR = 2.38), idarubicin (myelosuppression/infections). Most AEs occurred within 180 days. Idarubicin showed delayed onset in elderly (P < 0.05); males had delayed doxorubicin toxicity (P = 0.04) but accelerated idarubicin onset (P = 0.049) vs. females. CONCLUSION: This analysis identifies distinct safety profiles. Epirubicin and doxorubicin were associated with cardiac and pregnancy-related risks, while idarubicin showed signals suggesting potentially delayed onset in elderly patients. Observed sex differences indicate possible variations in AE patterns.
Pharmacovigilance analysis of cutaneous adverse drug reactions for cetuximab, panitumumab, and necitumumab based on EudraVigilance and WHO VigiAccess.
Sauer N, Giedziun P, Calik J … +1 more , Wiela-Hojeńska A
Front Pharmacol · 2026 · PMID 42358356 · Full text
INTRODUCTION: Anti-EGFR monoclonal antibodies (mAbs)--cetuximab, panitumumab, and necitumumab--are cornerstone therapies for selected solid tumors but are frequently associated with cutaneous adverse drug reactions (ADRs...
INTRODUCTION: Anti-EGFR monoclonal antibodies (mAbs)--cetuximab, panitumumab, and necitumumab--are cornerstone therapies for selected solid tumors but are frequently associated with cutaneous adverse drug reactions (ADRs). This study aimed to characterize and compare the dermatologic safety profiles of these agents using large-scale post-marketing pharmacovigilance data. METHODS: A comprehensive pharmacovigilance analysis was conducted using aggregated ADR reports from the WHO VigiAccess and European Medicines Agency (EMA) EudraVigilance databases. Disproportionality analyses were performed using reporting odds ratios (RORs) and proportional reporting ratios (PRRs). Dermatologic ADR diversity and similarity were further evaluated using Shannon entropy, principal component analysis (PCA), and multidimensional scaling (MDS). RESULTS: A total of 50,391, 18,806, and 355 ADR reports were identified for cetuximab, panitumumab, and necitumumab, respectively. Cutaneous ADRs accounted for up to 25% of all reported events. Panitumumab demonstrated the strongest association with skin-related toxicities (ROR = 1.51; PRR = 1.38), particularly acneiform dermatitis, pruritus, and xerosis. Cetuximab exhibited lower relative disproportionality despite higher absolute numbers of reported cases, whereas necitumumab showed a narrower dermatologic toxicity profile, potentially reflecting lower utilization or underreporting. Shannon entropy and dimensionality reduction analyses revealed greater heterogeneity of dermatologic ADRs associated with panitumumab compared with cetuximab and necitumumab. Significant differences in ADR distributions were observed between the WHO and EMA databases. DISCUSSION: These findings highlight distinct agent-specific dermatologic toxicity signatures among anti-EGFR monoclonal antibodies and demonstrate the value of real-world pharmacovigilance data in complementing clinical trial evidence. Improved recognition of differential toxicity patterns may support personalized monitoring and management strategies for patients receiving EGFR-targeted therapies.
Exploring early intervention in psychosis (EIP) perspectives towards pharmacogenomics (PGx) implementation to support antipsychotic prescribing: a multi-method qualitative exploration.
Jameson A, Fylan B, Sagoo GS … +5 more , Dalton CF, Cardno AG, Sohal J, Bristow GC, McLean SL
Front Pharmacol · 2026 · PMID 42358355 · Full text
INTRODUCTION: Pharmacogenomics (PGx) is an emerging medicines optimization tool that may support efficacy and safety relating to antipsychotic prescribing. Despite growing drug-gene evidence linked to antipsychotic respo...
INTRODUCTION: Pharmacogenomics (PGx) is an emerging medicines optimization tool that may support efficacy and safety relating to antipsychotic prescribing. Despite growing drug-gene evidence linked to antipsychotic response, how PGx could be implemented within Early Intervention in Psychosis (EIP) services, including the views of staff, service users, and carers remains underexplored. METHODS: Semi-structured interviews with service users (n = 12), and online focus groups with EIP staff (n = 18), and carers (n = 3) across three National Health Service (NHS) EIP sites were analyzed using an integrative approach to reflexive thematic analysis. RESULTS: Five themes and seven sub-themes were synthesized to describe stakeholder perspectives on implementing PGx to support antipsychotic prescribing in EIP services. Participants characterized EIP as a complex care ecosystem and described varying levels of understanding about PGx. Findings highlighted key implementation considerations, including when PGx should be offered, communication strategies, concerns about its integration into EIP pathways, and preferences for embedding PGx within routine care. DISCUSSION: PGx was broadly perceived as an acceptable clinical intervention, analogous to established medicines-safety checks. However, implementation should prioritize shared decision-making, set realistic expectations about clinical utility, and be adequately resourced to avoid displacing other therapeutic approaches. This study complements existing drug-gene evidence by providing insights into clinical workflow integration, governance, and service design considerations specific to EIP contexts. As the evidence base for routine PGx use matures, its introduction in EIP services should be framed as a supportive, person-centered adjunct, and not a determinant of antipsychotic decision-making.
Efficacy and safety of compound Qingdai enema in rapidly alleviating inflammatory activity in ulcerative colitis: a prospective study.
Huang Y, Qin D, Yang Q … +5 more , Yang X, Fang Y, Zheng S, Zhang C, Liu S
Front Pharmacol · 2026 · PMID 42358354 · Full text
AIM OF THE STUDY: To observe the efficacy and safety of CQE in rapidly alleviating inflammatory activity in UC. MATERIALS AND METHODS: CQE extracts were analyzed by UHPLC-Q Exactive Orbitrap-HRMS. This study used a self-...
AIM OF THE STUDY: To observe the efficacy and safety of CQE in rapidly alleviating inflammatory activity in UC. MATERIALS AND METHODS: CQE extracts were analyzed by UHPLC-Q Exactive Orbitrap-HRMS. This study used a self-controlled design before and after treatment. A total of 114 UC patients were included and treated with traditional rectal enema administration of CQE. Among them, 107 patients completed the treatment, and 101 patients with complete clinical and laboratory data were included in the final analysis. The primary clinical intestinal symptoms, mucosal endoscopic and pathological changes, laboratory indicators, quality of life scores, and adverse reactions were compared before and after 14 days of enema treatment. A historical comparison was made with previous studies. The expression of intestinal tight junction proteins in the colons of UC patients during active periods was detected using Quantitative Real-time PCR (RT-qPCR) and Western blot (WB). RESULTS: The main compounds in CQE were identified, including Gallic acid, Matrine, Oxysophocarpine, Ellagic acid, Prim-O-glucosylcimifugin, Cytisinicline, Danshensu, Protocatechuic acid, Cimifugin, Salvianolic acid A Cytisinicline, Indigo, Indirubin, Tryptanthrin and others. The primary endpoint, defined as the change in modified Mayo score, showed a significant improvement after 14 days of CQE treatment ( < 0.001). The clinical response rate was 94.06% (95/101), and the clinical remission rate was 66.34% (67/101). The endoscopic mucosal healing rate was 76.24% (77/101), and the histological remission rate was 38.61% (39/101). Compared to before treatment, post-treatment scores for clinical intestinal symptoms, Mayo endoscopic scores (MES), Geboes index, fecal calprotectin (FC), and fecal occult blood test (OB) were significantly reduced ( < 0.001). The UCEIS score for the distal rectum and sigmoid colon showed more improvement than the proximal colon ( < 0.01). Hemoglobin (HGB), albumin (ALB), and quality of life scores increased ( < 0.05), while liver and kidney function indicators showed no abnormal elevations after treatment ( < 0.05). Compared to historical data from previous studies using steroids and biologics, CQE significantly improved clinical and endoscopic remission rates. RT-qPCR and WB results demonstrated that the herbal enema helps repair the intestinal mucosal barrier in UC patients. CONCLUSION: CQE can rapidly alleviate inflammatory activity in UC within 14 days and improve patients' quality of life, with a low incidence of adverse events.
Inhibition of pathogenic tau signaling via blocking of the phosphatase-activating domain by novel small molecules.
Nowar R, Velma GR, Fu J … +6 more , Kidwai A, Bauc G, Ackerman-Berrier M, Thatcher GRJ, Brady ST, Ben Aissa M
Front Pharmacol · 2026 · PMID 42358353 · Full text
INTRODUCTION: Tau pathology is a major feature of Alzheimer's disease (AD) and multiple other adult-onset neurodegenerative diseases. Aberrant exposure of an N-terminal phosphatase-activating domain (PAD) is characterist...
INTRODUCTION: Tau pathology is a major feature of Alzheimer's disease (AD) and multiple other adult-onset neurodegenerative diseases. Aberrant exposure of an N-terminal phosphatase-activating domain (PAD) is characteristic of pathological tau, representing a toxic gain of function. Exposure of the PAD in pathological tau leads to dysregulation of protein phosphatase 1/glycogen synthase kinase 3 (PP1/ GSK3β) signaling, inhibition of fast axonal transport, synaptic dysfunction, and altered transcription, along with other pathological consequences. Previous studies showed that TNT1, an antibody against the PAD, blocked toxicity of pathogenic forms of tau. METHODS: In this article, we describe a high-throughput screen for small molecules that block TNT1 binding to the PAD in an AlphaLISA screen and bind specifically to the PAD in surface plasmon resonance assays. Candidate PAD ligands (PADis) were identified, and initial biochemical and biophysical optimization produced PADis with increased affinity and selectivity. Three candidate PADis were evaluated in neuronal (rat E18 embryonic cortical neurons) and non-neuronal cells (HEK293T human embryonic kidney cells) using a nano-bioluminescence resonance energy transfer (nanoBRET) assay to assess PP1 binding and cell toxicity. RESULTS AND DISCUSSION: All three compounds prevented PP1 binding to PAD and neurite degeneration due to pathological tau in primary cultured cortical neurons. The final candidates had an IC value between 10 and 20 nM in neurons with low cytotoxicity, CC > 75 μM in primary cultured neurons, and 40-100 μM in non-neuronal cells. PADi treatment of primary cultured neurons transfected with pathogenic tau restored axonal growth and prevented neurodegeneration. These studies establish a novel approach to therapeutics for Alzheimer's disease and tauopathies.
Extreme and rapidly reversible prolongation of prothrombin time during cefoperazone/sulbactam therapy in a patient with gastrointestinal dysfunction and parenteral nutrition: a case report.
Gao TR, Zhu GW, Zhang QH … +1 more , Gao ZP
Front Pharmacol · 2026 · PMID 42358352 · Full text
This case report describes a suspected coagulation disorder induced by cefoperazone/sulbactam administered for anti-infective therapy. The coagulopathy may be associated with the inhibition of vitamin K synthesis and uti...
This case report describes a suspected coagulation disorder induced by cefoperazone/sulbactam administered for anti-infective therapy. The coagulopathy may be associated with the inhibition of vitamin K synthesis and utilization caused by cefoperazone/sulbactam. The patient was admitted with severe right thalamic intracerebral hemorrhage complicated by infection and remained on total parenteral nutrition (TPN) due to concomitant gastrointestinal dysfunction. We initiated anti-infective therapy with cefoperazone/sulbactam at a dose of 2 g administered intravenously every 12 h for seven consecutive days. On the eighth day of treatment, the patient developed severe coagulation dysfunction, with prothrombin time (PT) markedly prolonged to 262.9 s. Cefoperazone/sulbactam was immediately discontinued, and vitamin K1 along with plasma transfusion was administered. By the third day after intervention, the patient's coagulation function significantly improved, and PT returned to normal levels. Causality assessment using the Naranjo Adverse Drug Reaction Probability Scale yielded a score of 7, indicating a probable association between the adverse event and cefoperazone/sulbactam use. This case report emphasizes that cefoperazone/sulbactam may cause extremely severe coagulation dysfunction, manifested as markedly prolonged PT in this patient. Clinicians should remain vigilant for this potential adverse reaction and closely monitor coagulation parameters during treatment.
Dahuang-mudanpi decoction mitigates ALI/ARDS pulmonary inflammation via multi-target regulation of HMGB1.
Chen X, Li S, Li X … +8 more , Ye P, Zhong J, Lv J, Ding W, Lin R, Miao J, Li H, Ye S
Front Pharmacol · 2026 · PMID 42358351 · Full text
BACKGROUND: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe inflammatory conditions with high mortality and limited treatment options. Targeting pulmonary inflammation is a critical stra...
BACKGROUND: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe inflammatory conditions with high mortality and limited treatment options. Targeting pulmonary inflammation is a critical strategy for improving clinical outcomes. This study was performed to investigate the therapeutic effects and underlying mechanisms of Dahuang-Mudanpi Decoction (DMD), specifically focusing on its active ingredients, paeonol (PAE) and emodin (EMO), and their regulatory role in high mobility group box 1 (HMGB1)-mediated inflammation in ALI/ARDS. METHODS: The therapeutic efficacy of DMD was evaluated using a lipopolysaccharide (LPS)-induced ALI mouse model (n = 8 per group for the DMD dose-screening experiment and n = 6 per group for the component-comparison experiment). High-performance liquid chromatography (HPLC) was employed to quantify the active compounds within DMD. The protective effects were comprehensively assessed by analyzing body weight changes, lung wet/dry (W/D) ratios, and histopathological lung injury scores. Additionally, systemic and localized inflammatory responses were evaluated by measuring hematological parameters and the levels of key inflammatory cytokines, including interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and HMGB1. Data were analyzed using one-way analysis of variance (ANOVA) or nonparametric tests, as appropriate. RESULTS: DMD administration significantly mitigated LPS-induced pulmonary inflammation and attenuated lung injury in the mouse model. Mechanistic evaluations revealed distinct, complementary roles for DMD's active components, with molecular docking providing supportive structural evidence rather than definitive proof of direct molecular binding. Specifically, PAE was predicted to interact with the first nuclear localization signal (NLS1) region of HMGB1 (Vina score: -4.7 kcal/mol), which corresponded to its observed ability to effectively inhibit the nuclear translocation of HMGB1 and reduce its extracellular release. Conversely, EMO was predicted to bind near the receptor-binding region of HMGB1 (Vina score: -6.3 kcal/mol), suppressing the pro-inflammatory function of extracellular HMGB1. CONCLUSION: These findings demonstrate the multi-target regulatory effects of DMD in mitigating ALI-associated inflammation, highlighting PAE and EMO as promising therapeutic agents for ALI/ARDS. The mechanistic insights provide novel perspectives on HMGB1-targeted treatments, suggesting that further optimization of this compound combination could yield advanced therapeutic strategies for severe pulmonary inflammation.
Targeting phosphofructokinase in cancer: integrating natural products for metabolic reprogramming and therapeutic innovation.
Cao C, Lv C, ElFar A
Front Pharmacol · 2026 · PMID 42358350 · Full text
The metabolism of cancer cells is reprogrammed toward aerobic glycolysis (the Warburg effect), which stimulates tumor growth. Phosphofructokinase (PFK) and its isoforms, PFKP, PFKM, and PFKL, are highly conserved central...
The metabolism of cancer cells is reprogrammed toward aerobic glycolysis (the Warburg effect), which stimulates tumor growth. Phosphofructokinase (PFK) and its isoforms, PFKP, PFKM, and PFKL, are highly conserved central glycolytic controllers and a potential therapeutic intervention. This review discusses the complex functions of PFK in tumor biology, including its roles in regulating proliferation, invasion, metastasis, and therapy resistance. It further discusses the tumor microenvironmental role of PFK, which influences immune evasion, angiogenesis, and stromal interactions, as well as its non-metabolic signaling functions. The therapeutic approaches to PFK, such as synthetic (e.g., PFK15) and natural (e.g., curcumin) compounds, are considered alongside strategies to address specific difficulties. Lastly, the review is based on a combination of expression analysis of PFK isoforms and a closer analysis of synthetic and natural inhibitors, and it suggests a prospective framework for implementing PFK-targeted therapies in clinical practice that incorporates AI-based drug design, nanodelivery, and immune-metabolic modulation.
HCN4 gain-of-function mutation increases intrinsic heart rate and limits maladaptive remodeling under pressure overload.
Hennis K, Rilling J, Pham L … +13 more , Rötzer R, Piantoni C, Wu Y, Auerbach N, Groher J, Kruck D, Koplitz-Weißgerber S, Gruner C, Scharr A, Mehlfeld V, Biel M, Wahl-Schott C, Fenske S
Front Pharmacol · 2026 · PMID 42358349 · Full text
INTRODUCTION: Gain-of-function (GOF) mutations in the cardiac pacemaker channel HCN4 have been associated with inappropriate sinus tachycardia in human patients. Chronic tachycardia is generally associated with adverse c...
INTRODUCTION: Gain-of-function (GOF) mutations in the cardiac pacemaker channel HCN4 have been associated with inappropriate sinus tachycardia in human patients. Chronic tachycardia is generally associated with adverse cardiac remodeling and cardiomyopathy, but whether enhanced HCN4 activity can induce or modulate such remodeling remains unknown. We aimed to investigate the influence of an HCN4 gain-of-function mutation on cardiac function and structure under baseline and pressure overload conditions. METHODS AND RESULTS: We generated HCN4(Y527F) knock-in mice (HCN4F) carrying a GOF mutation in the C-linker of HCN4 channels, which shifts their activation curves to more positive potentials. Electrophysiological recordings confirmed increased channel availability at physiological membrane potentials. Telemetric ECGs and electrophysiological studies revealed an elevated mean and intrinsic heart rate, faster sinus node and atrioventricular conduction in HCN4F mice, but no spontaneous arrhythmias. In HCN4F mice, the heart rate histogram was truncated at lower heart rates, indicating fewer low-rate intervals and more frequent periods of elevated heart rate, while maximal heart rates remained comparable between the two phenotypes. Histological analysis did not reveal structural changes consistent with tachycardia-induced cardiomyopathy. Cardiac morphology, fibrosis, and contractility were indistinguishable between genotypes up to 12 months of age. Following transverse aortic constriction, both WT and HCN4F mice developed left ventricular hypertrophy, but HCN4F hearts exhibited less chamber dilatation, smaller left ventricular lumen, and preserved systolic function compared to WT. Gene expression and RNA-sequencing analyses revealed activation of a typical hypertrophic gene program in both genotypes, but distinct remodeling signatures. DISCUSSION: The HCN4(Y527F) gain-of-function mutation increases intrinsic heart rate without inducing structural or functional deterioration. Under pressure overload, it even confers considerable protection against maladaptive dilatation and contractile dysfunction. These findings challenge the concept that persistent inappropriately elevated heart rate is necessarily detrimental and suggest that enhanced HCN4 activity may facilitate adaptive cardiac responses to stress.
A novel prenylflavonoid with efficacy in cancer therapy by targeting ceramide-orchestrated signaling.
Du R, Zhang C, Lei H … +7 more , Gao X, Xiang Q, Zhang Z, Dai Y, Li X, Zhang L, Chen G
Front Pharmacol · 2026 · PMID 42344805 · Full text
BACKGROUND: Ceramide, acting as an important second messenger, plays a pivotal role in the induction of apoptosis in cancer cells. As one of the active prenylflavonoid ingredients in , icariside I (GH01) has been shown t...
BACKGROUND: Ceramide, acting as an important second messenger, plays a pivotal role in the induction of apoptosis in cancer cells. As one of the active prenylflavonoid ingredients in , icariside I (GH01) has been shown to exhibit significant anticancer activity. However, the mechanism by which GH01 induces tumor cell apoptosis by targeting ceramide-orchestrated signaling remains unclear. PURPOSE: This study aimed to analyze the potential mechanism of GH01 for cancer therapy by generating ceramide formation and . METHODS: A B16F10 melanoma-bearing mouse model was first established and treated with GH01 at different doses. Targeted quantification of ceramide was performed and using HPLC-QQQ-MS. A series of biological assays coupled with immunofluorescence staining and confocal microscope were utilized to analyze the apoptotic mechanism of tumor cells. RESULTS: GH01 treatment markedly enhanced ceramide levels through the activation of ceramide synthesis and sphingomyelin hydrolysis pathways coupled with the simultaneous suppression of sphingosine 1-phosphate generation. Consequently, high levels of ceramide promoted tumor cell apoptosis via both intrinsic and extrinsic apoptosis pathways. Notably, ceramide induced by GH01 interacted with mitochondria, thus releasing cytochrome c, which in turn activated caspase-9 and caspase-3, ultimately triggering cellular apoptosis. Additionally, the supplementation of inhibitors of caspase-3 and exogenous ceramide further confirmed the above apoptosis mechanism.
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