Front Pharmacol [JOURNAL]
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200 papers
β-Caryophyllene protects against ischemic stroke by inhibiting H3K9 and H3K18 lactylation-mediated cellular pyroptosis.
Xin Q, Xu F, Wu J
Front Pharmacol · 2026 · PMID 42389269 · Full text
BACKGROUND: Ischemic stroke is a common and severe cerebrovascular disease with high mortality and disability. Accumulating evidence indicates that β-caryophyllene (BCP) exerts neuroprotective effects against cerebral is...
BACKGROUND: Ischemic stroke is a common and severe cerebrovascular disease with high mortality and disability. Accumulating evidence indicates that β-caryophyllene (BCP) exerts neuroprotective effects against cerebral ischemic injury; however, the precise underlying mechanisms remain largely unexplored. METHODS: Focal cerebral ischemia/reperfusion (I/R) mouse models were established and oxygen-glucose deprivation/reoxygenation (OGD/R) was conducted in BV2 microglial cells and primary microglia . RESULTS: We demonstrated that BCP administration significantly reduced cerebral infarct volume, alleviated neurological deficits, and enhanced motor function in mice subjected to transient focal cerebral ischemia. Mechanistically, BCP inhibited pyroptosis and glycolysis in the ischemic penumbra of mice and in BV2 cells following OGD/R. Concomitantly, BCP decreased the levels of H3K9 lactylation (H3K9la) and H3K18 lactylation (H3K18la) in brain tissues of ischemic penumbra and in OGD/R-induced BV2 cells. Notably, co-treatment with lactate attenuated these inhibitory effects and abrogated the neuroprotective efficacy of BCP. Similar results were also obtained in primary microglia. Additionnaly, oxamate (the LDHA inhibitor) simultaneously downregulated the protein levels of H3K9la, H3K18la, and pyroptosis-related factors, while MCC950 (the NLRP3 inflammasome inhibitor) only blocked downstream pyroptosis without affecting histone lactylation. Chip-PCR further demonstrated that OGD/R increased the enrichment of H3K9la and H3K18la at the NLRP3 promoter, which was decreased by BCP and oxamate but not by MCC950. Lactate supplementation partially restored the inhibitory effects of BCP. CONCLUSION: BCP protects against ischemic stroke by targeting the lactate-histone lactylation-pyroptosis axis, providing a potential therapeutic target for cerebral ischemia.
Machine learning applications in predicting pharmacological treatment outcomes and responses in esophageal cancer.
Yan Z, Zhou Y, Jia S … +5 more , Ung COL, Song M, Lai Y, Hu H, Yang Y
Front Pharmacol · 2026 · PMID 42389268 · Full text
INTRODUCTION: This study evaluated machine learning (ML) models predicting esophageal cancer (EC) treatment outcomes, focusing on data modalities, feature engineering, model frameworks, and validation. METHODS: Following...
INTRODUCTION: This study evaluated machine learning (ML) models predicting esophageal cancer (EC) treatment outcomes, focusing on data modalities, feature engineering, model frameworks, and validation. METHODS: Following PRISMA guidelines (PROSPERO: CRD42024619947), six databases (2015-2024) were systematically searched. Two reviewers independently extracted data on model methodologies and performance. Study quality was assessed using a modified TRIPOD (Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis) + AI checklist. RESULTS: Among 30 studies (14,342 patients), classical ML models were the most frequently employed approach (n = 43), followed by ensemble methods (n = 34), with deep learning being the least utilized (n = 11); however, the best-performing models across all studies demonstrated mean AUC values of 0.847 for deep learning, 0.835 for ensemble models, and 0.816 for classical approaches. Imaging and clinical data constituted the predominant both unimodal and multimodal modeling inputs, with supervised learning representing the dominant paradigm. Multimodal models achieved a significantly higher AUC (0.84 vs. 0.78) than single-modal models. Model validation primarily relied on k-fold cross-validation and external cohort approaches. Quality assessment showed moderate reporting completeness (64.79% median fulfillment). DISCUSSION: While ML (particularly deep learning and multimodal approaches) demonstrated potential for EC treatment prediction, key limitations persisted, such as opaque computational methods, poorly justified predictor selection, and unaddressed population heterogeneity/class imbalance. Addressing these challenges would be critical to enhancing the reliability and clinical applicability of ML models in future research.
Liquiritin restores metabolic homeostasis in NAFLD by modulating AKT1/FOXO1 signaling.
Zhang Z, Jiao S, Jiang T … +5 more , Zhang R, Sun Z, Zhang Z, Pan Y, Guo J
Front Pharmacol · 2026 · PMID 42389267 · Full text
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver condition with a complex and multifactorial pathogenesis. PURPOSE: This study aimed to investigate the mecha-nism of liquiritin (LQ) in N...
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver condition with a complex and multifactorial pathogenesis. PURPOSE: This study aimed to investigate the mecha-nism of liquiritin (LQ) in NAFLD for its treatment. METHODS: This study integrates bioinformatics analysis with validation. Bulk RNA-seq analysis and single-cell dataset analysis were performed using Gene Expression Omnibus database resources. Molecular docking and molecular dynamics simulations were employed to evaluate the binding affinity of liquiritin with lipid metabolism-related proteins AKT and FOXO1. validation was conducted using the HepG2, AML12 and RAW 264.7 to investigate the mechanism by which liquiritin regulates lipid metabolic homeostasis in HepG2 cells and AML12 cells via the AKT/FOXO1 pathway through protein immunoblotting and immunofluorescence. The effects of liquiritin on mitochondrial autophagy in RAW 264.7 cells were also examined. RESULTS: Bulk RNA-seq analysis identified FOXO1 as a key target, while single-cell analysis predicted interactions between hepatocytes and macrophages in non-alcoholic fatty liver disease (NAFLD). Molecular docking predicted a potential stable interaction between liquiritin and FOXO1. In HepG2 cells and AML12 cells, liquiritin improved NAFLD lipid metabolism disorders by regulating the AKT/FOXO1 pathway. Liquiritin also modulates the expression of mitophagy-associated proteins in RAW264.7 cells. CONCLUSION: Liquiritin improves lipid metabolism disorders in NAFLD by regulating the AKT/FOXO1 pathway, while also potentially influencing macrophage function. This suggests its potential as a candidate therapeutic agent for non-alcoholic fatty liver disease.
Clinodiside A, an active metabolite in Clinopodii herba, alleviates dextran-sulfate-sodium-induced ulcerative colitis.
Yang X, Fan Y, Lin Q … +4 more , Ni J, Tan X, Xu J, Sun M
Front Pharmacol · 2026 · PMID 42389266 · Full text
INTRODUCTION: Clinodiside A is a natural bioactive component of Clinopodii herba, a genuine regional herb from Anhui Province (China) with multiple biological activities. This study aimed to explore the therapeutic poten...
INTRODUCTION: Clinodiside A is a natural bioactive component of Clinopodii herba, a genuine regional herb from Anhui Province (China) with multiple biological activities. This study aimed to explore the therapeutic potential of Clinodiside A in ulcerative colitis (UC). METHODS: Dextran sulfate sodium (DSS) was used to establish UC models both and . The models were treated with Clinodiside A. Parameters including body weight, disease activity index (DAI) score, colon length, and inflammation were assessed. Iron overload, lipid peroxidation, and intestinal epithelial repair were also evaluated. experiments using HCT116 cells examined cell damage, motility, and recovery. RESULTS: Clinodiside A alleviated DSS-induced UC consequences, including weight loss, increased DAI score, colon shortening, and inflammation. These effects were associated with reduced iron overload, reduced lipid peroxidation, and enhanced intestinal epithelial repair. In HCT116 cells, Clinodiside A ameliorated damage, enhanced motility, and promoted recovery of the intestinal epithelium. DISCUSSION: Our research validates the therapeutic and protective effects of Clinodiside A from Clinopodii herba on UC and expands its application potential.
Advances in the treatment of Alzheimer's disease.
Temelli Goceroglu R, Hacimuftuoglu A
Front Pharmacol · 2026 · PMID 42389265 · Full text
Alzheimer's Disease (AD) is a progressive neurodegenerative disease for which disease-modifying therapies remain limited. Despite extensive efforts targeting amyloid-β and tau, these approaches have not translated into c...
Alzheimer's Disease (AD) is a progressive neurodegenerative disease for which disease-modifying therapies remain limited. Despite extensive efforts targeting amyloid-β and tau, these approaches have not translated into clear clinical benefit, underscoring the need for a more integrated understanding of AD pathogenesis. This narrative review summarizes recent advances in the molecular mechanisms underlying AD and evaluates current and emerging therapeutic strategies. A literature search was conducted using PubMed, Google Scholar, Web of Science and Scopus, focusing on preclinical and clinical studies addressing AD pathophysiology and treatment development. Conclusion: We summarize key pathogenic pathways, including Aβ aggregation, tau hyperphosphorylation, neuroinflammation, synaptic dysfunction, and metabolic dysregulation, and discuss how these interconnected processes have informed drug development efforts. Particular attention is given to limitations of single-target approaches and the growing interest in multi-target and combination therapies. In conclusion, a better understanding of the pathological mechanisms underlying AD may contribute to the development of more effective pharmacological therapies and integrated therapeutic approaches targeting the multifactorial nature of the disease.
Banxia xiexin decoction and its bioactive metabolites: multi-targeted mechanisms for suppressing gastric cancer progression, reversing chemoresistance, and remodeling the tumor microenvironment.
Xu D, Lin Z, Deng L … +4 more , Lu X, Guo Z, Yan P, Luo Y
Front Pharmacol · 2026 · PMID 42389264 · Full text
Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, primarily due to late diagnosis and limited benefit from surgery alone. Although chemotherapy, targeted agents, and immunotherapy have im...
Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, primarily due to late diagnosis and limited benefit from surgery alone. Although chemotherapy, targeted agents, and immunotherapy have improved outcomes for selected patients, their clinical benefits are often limited by significant toxicity, acquired resistance, and the pronounced molecular heterogeneity of GC. Multi-target therapeutic approaches are therefore urgently needed. Banxia Xiexin Decoction (BXD), a classic Traditional Chinese Medicine formula widely used for gastrointestinal disorders, has emerged as a promising adjuvant candidate for GC treatment. However, the bioactive metabolites and molecular mechanisms of BXD have not been fully clarified. This review comprehensively summarizes current evidence on the anti-GC actions of BXD and its key bioactive metabolites. Mechanistically, BXD inhibits GC cell proliferation and induces apoptosis by regulating cell-cycle checkpoints and inhibiting oncogenic pathways, particularly Wnt/β-catenin and the PI3K/AKT/mTOR axis. These coordinated effects facilitate apoptosis, autophagy modulation, and oxidative stress-related cytotoxicity, and are further linked to reduced epithelial-mesenchymal transition (EMT), invasion, migration, and angiogenesis. The major bioactive metabolites of BXD, such as berberine, baicalin, wogonoside, and glycyrrhizin further reverse chemoresistance by downregulating drug-efflux and survival signaling, thereby enhancing sensitivity to standard agents such as cisplatin, 5-fluorouracil, oxaliplatin, and paclitaxel. BXD also shows potential in suppressing peritoneal metastasis by disrupting pre-metastatic niche formation and in improving anti-tumor immunity through downregulation of PD-L1 via the IL-6/JAK/STAT3 pathway, reduction of immunosuppression, and promotion of immunogenic cell death (ICD). Furthermore, BXD-associated regulation of metabolic reprogramming (e.g., GSK3β and HNF4α) may undermine GC cellular adaptability under therapeutic stress. These findings highlight BXD as a promising multi-component, multi-pathway adjuvant candidate for GC, exerting cooordinated effects on tumor cell survival, metastasis, drug resistance, metabolism, and immune regulation. Nevertheless, limitations of current studies include insufficient investigation of tumor microenvironmental (TME) components (particularly macrophages, exosomes, and mesenchymal stem cells) and a lack of standardized pharmacokinetic/pharmacodynamic characterization (PK/PD). Future research should integrate multi-omics, spatial transcriptomics, and rigorous preclinical and clinical trials to improve reproducibility, clarify active metabolite-target relationships, elucidate BXD-mediated remodeling of the GC TEM to enhance therapeutic responsiveness.
Ameliorative effects of a and extract complex on hydrogen peroxide-induced oxidative damage in zebrafish.
Chen S, Tang T, Junhong Y … +7 more , Bosi L, Wang D, Lin D, Yang X, Li P, Zhang W, Zhang N
Front Pharmacol · 2026 · PMID 42389263 · Full text
OBJECTIVE: This study aimed to investigate the protective effects of a novel composite comprising paracasei and extract (Lac_PRE) against hydrogen peroxide (HO)-induced multi-organ oxidative damage in a zebrafish model...
OBJECTIVE: This study aimed to investigate the protective effects of a novel composite comprising paracasei and extract (Lac_PRE) against hydrogen peroxide (HO)-induced multi-organ oxidative damage in a zebrafish model. METHODS: An acute toxicity test was conducted to determine the optimal subacute HO exposure concentration in wild-type AB strain zebrafish. Subsequently, zebrafish were divided into four groups: control, HO exposure (2.0 mmol/L), HO exposure with Lac_PRE treatment, and Lac_PRE control. After 14 days, we assessed hepatic and cardiac function markers, inflammatory gene expression (cyclooxygenase, cox; tumor necrosis factor-alpha, tnf-α; interleukin-6, il-6), oxidative stress indicators (malondialdehyde, MDA), and the intestinal Firmicutes/Bacteroidetes (F/B) ratio. RESULTS: HO exposure induced significant oxidative and inflammatory damage in zebrafish, Kruskal-Wallis tests revealed significant overall differences among groups for hepatic ALT, hepatic MDA, cardiac cTnI, cardiac MDA, cardiac COX, cardiac TNF-α, cardiac IL-6, and the intestinal F/B ratio (all p < 0.05). Two a priori planned comparisons were tested using Dunn's post hoc test with Bonferroni ×2 correction. HO exposure significantly elevated cardiac cTnI (adjusted p = 0.002), cardiac MDA (adjusted p = 0.015), cardiac COX (adjusted p = 0.029), TNF-α (adjusted p = 0.023), IL-6 (adjusted p = 0.005), and significantly disrupted the F/B ratio (adjusted p = 0.012) compared to control. The Lac_PRE composite significantly reduced hepatic ALT (adjusted p < 0.001) and cardiac COX expression (adjusted p = 0.023). For the remaining indicators, the HO_Lac_PRE group showed consistent numerical improvements, but these differences did not reach statistical significance after Bonferroni correction. CONCLUSION: The L. paracasei and extract composite effectively alleviates HO-induced oxidative inflammatory damage in zebrafish by enhancing antioxidant defenses, suppressing inflammation, and modulating gut microbiota. These preliminary findings suggest that this probiotic-botanical combination may exert synergistic protective effects against oxidative damage. However, given the methodological limitations including small effective sample sizes, these results should be interpreted as exploratory and hypothesis-generating. Further validation in studies with larger sample sizes and individual-level analyses is warranted before translational applications can be considered.
2-Pentadecyl-2-oxazoline alleviates anxiety-like behaviour and modulates the microbiota-gut-brain axis in obese mice.
Opallo N, Lama A, Melini S … +11 more , Coretti L, Comella F, Del Piano F, Navatti NP, D'Andrea A, De Caro C, Lembo F, Ferrante MC, Meli R, Mattace Raso G, Pirozzi C
Front Pharmacol · 2026 · PMID 42389262 · Full text
A bidirectional relationship between obesity and anxiety disorders has been increasingly associated with neuroinflammation and dysregulation of the gut-brain axis. Here, we investigated the pharmacological effects of the...
A bidirectional relationship between obesity and anxiety disorders has been increasingly associated with neuroinflammation and dysregulation of the gut-brain axis. Here, we investigated the pharmacological effects of the N-palmitoylethanolamine oxazoline derivative 2-pentadecyl-2-oxazoline (C15OXA) in a mouse model of high-fat diet (HFD)-induced obesity, with particular attention to its central and peripheral mechanisms of action. Male C57Bl/6J mice were fed an HFD for 12 weeks and subsequently treated with C15OXA (30 mg·kg, p. o.) for 7 weeks. Behavioural, molecular, and microbiota analyses were performed to evaluate the effects of the compound. C15OXA significantly reduced anxiety-like behaviour in obese mice without affecting body weight, fat mass, or glucose tolerance. At the central level, C15OXA attenuated hippocampal neuroinflammation, as shown by reduced expression of COX-2, TLR4, NLRP3 and IL-1β. In parallel, C15OXA restored tight junction gene expression associated with blood-brain barrier integrity, and modulated unfolded protein response signalling. In addition, C15OXA enhanced markers of neurogenesis and synaptic plasticity. At the peripheral level, C15OXA treatment reduced colonic inflammation and improved gut barrier integrity. These effects were associated with a targeted reshaping of gut microbiota composition. In particular, C15OXA promoted the enrichment of butyrate- and menaquinone-producing bacteria, as taxa linked to beneficial metabolic functions. Overall, these findings suggest that C15OXA exerts anxiolytic-like effects associated with coordinated central and peripheral pathways involving the modulation of neuroinflammatory pathways, barrier integrity, and gut-brain axis signalling. This study provides novel pharmacological insight into the therapeutic potential of C15OXA for the treatment of obesity-associated neuropsychiatric disorders.
Mechanism-informed neuroprotection in acute ischemic stroke treated with thrombectomy: a systematic review and meta-analysis of randomized controlled trials.
Wang Y, Xu J, Zhao Z … +3 more , Yang R, Zhou X, Yang Z
Front Pharmacol · 2026 · PMID 42389261 · Full text
BACKGROUND: Despite the success of endovascular thrombectomy (EVT) in restoring large-vessel patency in acute ischemic stroke (AIS), a substantial proportion of patients fail to achieve functional independence, largely d...
BACKGROUND: Despite the success of endovascular thrombectomy (EVT) in restoring large-vessel patency in acute ischemic stroke (AIS), a substantial proportion of patients fail to achieve functional independence, largely due to ischemia-reperfusion injury (IRI) at the tissue level. Pharmacological neuroprotection has re-emerged as a potential strategy to mitigate these downstream injury cascades in the thrombectomy era; however, clinical evidence remains heterogeneous and mechanism-specific effects are unclear. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials evaluating neuroprotective pharmacotherapies administered as adjuncts to EVT in AIS. PubMed, Embase, and the Cochrane Library were searched from inception to 31 January 2026. The primary outcome was functional independence at 90 days (mRS 0-2). Random-effects models were used for pairwise meta-analysis, with an exploratory network meta-analysis (NMA) performed as a secondary, hypothesis-generating analysis. RESULTS: Nine RCTs involving 4,420 patients were included. Adjunctive neuroprotective therapy was associated with a modest increase in functional independence compared with control (OR 1.13, 95% CI 1.01-1.28). However, most secondary efficacy outcomes did not show clear statistically significant benefits, and no significant differences were observed in mortality, symptomatic intracranial hemorrhage, or serious adverse events. Exploratory subgroup analyses suggested possible effect modification by treatment timing and reperfusion context, while the exploratory NMA indicated heterogeneous treatment rankings. These findings should be interpreted as a modest and heterogeneous efficacy signal rather than definitive evidence that neuroprotection is effective as a general therapeutic class. CONCLUSION: In the thrombectomy era, adjunctive pharmacological neuroprotection may provide a modest field-level signal of potential benefit without clear evidence of increased major safety risks. However, given the heterogeneity in pharmacological mechanisms, treatment timing, and reperfusion contexts, these findings should not be interpreted as definitive evidence of efficacy for neuroprotection as a general therapeutic class. Future mechanism-informed trials are needed to determine which neuroprotective approaches, if any, provide clinically meaningful benefit in AIS. This study was prospectively registered in PROSPERO (CRD420261284814). SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261284814, identifier PROSPERO (CRD420261284814).
Mangiferin alleviates metabolic-associated fatty liver disease by modulating gut microbiota and FXR signaling pathway to regulate bile acid metabolism.
Zheng L, Xie Q, Yao S … +5 more , Chen M, Zhao W, Li R, Cheng J, Zhang Y
Front Pharmacol · 2026 · PMID 42382178 · Full text
BACKGROUND: Metabolic-associated fatty liver disease (MAFLD) is characterized by excessive hepatic lipid accumulation, with limited safe and effective therapeutic options currently available. Previous studies have demons...
BACKGROUND: Metabolic-associated fatty liver disease (MAFLD) is characterized by excessive hepatic lipid accumulation, with limited safe and effective therapeutic options currently available. Previous studies have demonstrated that mangiferin (MAN) alleviates nonalcoholic fatty liver disease via modulation of the AMPK and NLRP3 signaling pathways. However, there are no reports to date investigating whether MAN exerts anti-MAFLD effects by regulating bile acid (BAs) metabolism and its underlying molecular mechanisms. METHODS: In the present study, the anti-MAFLD effects of MAN were systematically investigated using a high-fat diet (HFD)-induced MAFLD mouse model. We evaluated the therapeutic mechanisms of MAN specifically from the perspectives of BAs metabolism regulated by the farnesoid X receptor (FXR) signaling pathway and the modulation of the gut microbiota, utilizing 16S rRNA sequencing and molecular docking analyses. RESULTS: MAN treatment (100 mg/kg) significantly ameliorated glucose and lipid metabolic disorders, as well as hepatic lipid accumulation in the HFD-induced MAFLD mice, which was accompanied by marked alterations in the BAs metabolic profile. Mechanistically, MAN activated the FXR signaling pathway, and molecular docking analysis predicted stable interactions with key FXR residues (Y365, M369, and Y373). Furthermore, 16S rRNA sequencing revealed that MAN significantly decreased the relative abundance of and , which were positively correlated with abnormal BAs (including 6,7-DKLCA, ILCA, GHDCA, and GUDCA), dyslipidemia, and liver injury markers. In contrast, MAN increased the relative abundance of , which was negatively correlated with these BAs and associated with an improved metabolic status. CONCLUSION: MAN exerts anti-MAFLD effects through dual mechanisms: direct activation of the FXR signaling pathway to regulate BAs homeostasis and indirect modulation of the gut microbiota to influence BAs metabolism. These findings highlight the therapeutic potential of MAN and provide new insights into natural product-based strategies for MAFLD treatment.
The recent progression of extracellular vesicles application in osteoporosis.
Liu R, Li W, Yang J
Front Pharmacol · 2026 · PMID 42382177 · Full text
Osteoporosis is a type of chronic disease that leads to elevated bone fragility and increased risk of fractures. The principal characteristics of this condition include reduced bone density and bone quality, impaired bon...
Osteoporosis is a type of chronic disease that leads to elevated bone fragility and increased risk of fractures. The principal characteristics of this condition include reduced bone density and bone quality, impaired bone microstructure, and increased vulnerability to fractures. These fractures frequently occur in elderly individuals, resulting in significant health impairment and disruption to their daily lives. The economic consequences of osteoporosis and osteoporosis-related fractures can be substantial. Extracellular vesicles (EVs) are a category of small particles that are secreted by cells under both normal and pathological conditions. These particles contain various active substances, including proteins, lipids, and nucleic acids. These elements play a pivotal role in various processes within the human body, including cell growth, differentiation, and apoptosis. Recent studies have indicated that EVs have also made significant progress in the field of osteoporosis, demonstrating considerable potential for application. In this review, we summarize the pathogenesis and risk factors of osteoporosis, and the therapeutic and diagnostic application of EVs in osteoporosis and the underlying mechanisms. Furthermore, the current limitations of applications and potential solutions are also discussed. This review will provide researchers with new insights and research direction in the future.
Gastrodin alleviates cardiomyocyte senescence by regulating autophagy through the AMPK/mTOR/4EBP1 pathway.
Yao M, Zhang S, Wu Y … +8 more , Huang Y, Song Y, Wang L, Li S, Jia L, Yao B, Li B, Dong L
Front Pharmacol · 2026 · PMID 42382176 · Full text
OBJECTIVE: To investigate whether Gastrodin (Gas) attenuates doxorubicin (Dox)-induced cardiomyocyte senescence and apoptosis by regulating the AMPK/mTOR/4EBP1 signaling pathway and autophagy-related processes. METHODS:...
OBJECTIVE: To investigate whether Gastrodin (Gas) attenuates doxorubicin (Dox)-induced cardiomyocyte senescence and apoptosis by regulating the AMPK/mTOR/4EBP1 signaling pathway and autophagy-related processes. METHODS: A Dox-induced senescence model was established in H9c2 cardiomyocytes, and different concentrations of Gas (0.5 mM and 1 mM) were used for intervention. Senescence phenotypes were evaluated using SA-β-gal staining and senescence-associated proteins (P16, P21, and P53). Furthermore, the autophagy inhibitor 3-MA and the AMPK inhibitor Compound C (CC) were applied. Combined with Western blotting, Annexin V/PI flow cytometry, and immunofluorescence techniques, the expression levels of senescence-related proteins, autophagy-related markers (LC3-II/I, Beclin-1, and p62), and the phosphorylation levels of key proteins in the AMPK/mTOR/4EBP1 signaling pathway were analyzed to explore the potential mechanism of Gas. RESULTS: Compared with the Dox model group, Gas intervention dose-dependently reduced the percentage of SA-β-gal-positive cells, downregulated the protein expression levels of P16, P21, P53, and γ-H2AX, and significantly inhibited apoptosis. Mechanistically, Gas treatment partially ameliorated the abnormalities in autophagy-related markers induced by Dox, as evidenced by increased expression of LC3 and Beclin-1 and decreased accumulation of p62, and this ameliorative effect was partially attenuated by 3-MA. Further signaling pathway analysis demonstrated that Gas significantly increased the p-AMPK/AMPK ratio while decreasing the p-mTOR/mTOR and p-4EBP1/4EBP1 ratios. After AMPK inhibition with CC, the activation effect of Gas on autophagy and its protective effects against senescence and apoptosis were both attenuated. CONCLUSION: These findings indicate that Gas alleviates Dox-induced cardiomyocyte senescence and apoptosis, and its protective effects may be associated with regulation of the AMPK/mTOR/4EBP1 signaling pathway and improvement of autophagy-related processes.
Pharmacogenomic impact and genetic architecture of toxicity in pediatric acute lymphoblastic leukemia induction therapy: an exploratory modeling approach.
Gutierrez-Cáceres C, Alarcón-Concha C, Aracena-Farías J … +8 more , Torres E, Acuña I, Sandoval T, Silva P, Ormeño M, Oyarce V, Cerpa LC, Martínez MF
Front Pharmacol · 2026 · PMID 42382175 · Full text
Induction chemotherapy for pediatric Acute Lymphoblastic Leukemia (ALL) is highly curative but accompanied by a severe toxicity profile. Evaluating the genetic susceptibility to these adverse events could inform hypothes...
Induction chemotherapy for pediatric Acute Lymphoblastic Leukemia (ALL) is highly curative but accompanied by a severe toxicity profile. Evaluating the genetic susceptibility to these adverse events could inform hypothesis-generating risk stratification. In this exploratory retrospective cohort study (N = 178), we investigated the influence of 14 candidate pharmacogenetic variants on the development of prevalent Adverse Drug Reactions (ADRs, ≥ 10 events). Multiple logistic regression, adjusted for basic demographic and anthropometric covariates (age and body surface area), was utilized across comprehensive inheritance architectures (additive, dominant, recessive, and co-dominant). For clinical translation hypothesis generation, we applied LASSO-penalized logistic regression (α = 1), 10-fold cross-validation to derive parsimonious Pharmacogenetic Risk Scores (PGRS). Model performance was evaluated using the optimism-corrected Area Under the Receiver Operating Characteristic Curve (AUC) via 1000-iteration bootstrap resampling, and calibration was assessed via the Brier score. We observed several complex interactions, notably suggesting an increased risk of severe neutropenia in patients carrying a homozygous variant rs776746 genotype (nominally significant OR 5.58, p = 0.006) and a potential pleiotropic protective effect from rs6021191 (OR 0.09, p = 0.001). Penalized selection allowed the construction of compact, multi-locus mathematical risk scores that demonstrated promising diagnostic discrimination for Neutropenia (optimism-corrected AUC 0.793, 95% CI 0.72-0.85; Brier score 0.12), while displaying limited to moderate performance for other clinically discriminating toxicities like Infection (AUC 0.650) and Gastrointestinal complications (AUC 0.607). The primary contribution of this study is the prioritization of pharmacogenomic candidate signals rather than the proposal of models ready for clinical intervention. The integration of alternative genotype parameterizations and regularized machine learning highlights pathways for future predictive research. However, given the retrospective nature of the study and inherent risks of internal optimism, these scores serve as biologically informed proof-of-concept models that strictly require robust prospective external validation.
Efficacy and safety of huanglian wendan decoction as an adjuvant therapy for metabolic syndrome: a systematic review and meta-analysis.
Jiang T, Dong J, Zhu Y … +1 more , Nie J
Front Pharmacol · 2026 · PMID 42382174 · Full text
BACKGROUND: Metabolic syndrome (MetS) is a prevalent metabolic disorder with a rising global prevalence, serving as a risk factor for cardiovascular disease and type 2 diabetes. Huanglian Wendan Decoction, a commonly use...
BACKGROUND: Metabolic syndrome (MetS) is a prevalent metabolic disorder with a rising global prevalence, serving as a risk factor for cardiovascular disease and type 2 diabetes. Huanglian Wendan Decoction, a commonly used formula in traditional Chinese medicine, has increasingly been used to treat MetS. This study aims to evaluate the efficacy and safety of Huanglian Wendan Decoction as an adjunctive therapy for MetS. OBJECTIVE: This meta-analysis aims to systematically evaluate the efficacy and safety of Huanglian Wendan Decoction in treating metabolic syndrome, thereby providing new approaches and insights for its management. METHODS: Literature searches were conducted using English-language databases (PubMed, Web of Science, Embase, and the Cochrane Library) and Chinese databases (China National Knowledge Infrastructure Wanfang, the VIP Chinese Science Journal Database, and the Chinese Biomedical Literature Database). The search period extended through 1 October 2025. Data were analyzed using RevMan 5.3 and Stata 17.0. The study protocol is registered in PROSPERO (registration number: CRD420251151304). RESULTS: A total of 17 randomized controlled trials, involving 1,549 patients, were ultimately included. Huanglian Wendan Decoction combined with conventional treatment for MetS significantly improved waist circumference (WC) (MD = -1.82 cm, 95% CI:-2.53 to -1.12, P < 0.00001), body mass index (BMI) (MD = -0.76 kg/m2, 95% CI: -0.99 to -0.54, P < 0.00001), systolic blood pressure (SBP) (MD = -6.62 mmHg, 95% CI: -7.58 to -5.66, P < 0.00001), diastolic blood pressure (DBP) (MD = -4.88 mmHg, 95% CI: -5.69 to -4.08, P < 0.00001), fasting plasma glucose (FPG) (MD = -0.71 mmol/L, 95% CI: -0.81 to -0.61, P < 0.00001), 2-h postprandial glucose (2 hPG) (MD = -0.71 mmol/L, 95% CI: -0.83 to -0.58, P < 0.00001), glycated haemoglobin (HbA1c) (MD = -0.47%, 95% CI: -0.68 to -0.26, P < 0.00001), triglycerides (TG) (MD = -0.38 mmol/L, 95% CI: -0.44 to -0.33, P < 0.00001), low-density lipoprotein cholesterol (LDL-C) (MD = -0.57 mmol/L, 95% CI: -0.73 to -0.42, P < 0.00001), and homeostasis model assessment of insulin resistance (HOMA-IR) (MD = -0.93, 95% CI: -1.09 to -0.78, P < 0.00001). However, conventional therapy demonstrated greater improvement in high-density lipoprotein cholesterol (HDL-C) (MD = 0.16 mmol/L, 95% CI: 0.14 to 0.18, P < 0.00001). Nevertheless, the safety of Huanglian Wendan Decoction combined with conventional therapy for MetS remains inconclusive, as the safety indicators showed no statistically significant differences (OR = 0.24, 95% CI: 0.03 to 2.26, P = 0.21). CONCLUSION: According to the results of the meta-analysis, Huanglian Wendan Decoction combined with standard treatment for metabolic syndrome (MetS) offers greater benefits than standard treatment alone; it can control blood pressure, blood lipid levels, and blood glucose, improve waist circumference (WC) and body mass index (BMI), and reduce insulin resistance. Huanglian Wendan Decoction is relatively safe. However, due to the limited number and quality of the included studies, the data from this study remain uncertain; further large-scale, double-blind, randomised controlled trials are required to validate these findings. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251151304. Identifier CRD420251151304.
Filling the mechanistic and methodological gaps for predicting cytokine release syndrome in humans.
Clerbaux LA, Alb M, Fogal B … +11 more , Hartung T, Hench VK, Morgan H, Gavins FNE, Lindeman B, Margiotta-Casaluci L, Ostaszewski M, Reiche K, Sachana M, Wittwehr C, Sewald K
Front Pharmacol · 2026 · PMID 42382173 · Full text
Cytokine release syndrome (CRS) is a severe immune-mediated toxicity frequently associated with immunotherapies such as CAR-T cells and bispecific T-cell engagers. Predicting CRS in humans remains difficult because curre...
Cytokine release syndrome (CRS) is a severe immune-mediated toxicity frequently associated with immunotherapies such as CAR-T cells and bispecific T-cell engagers. Predicting CRS in humans remains difficult because current animal models and systems do not adequately capture the complex, systemic, and patient-specific nature of pathological inflammation. This perspective highlights key mechanistic and methodological limitations in current immunotoxicology approaches and proposes an immune-related Adverse Outcome Pathway (irAOP) framework adapted for biotherapeutics. The irAOP approach structures CRS as a sequence of interconnected key events (KEs), including immune cell activation, recruitment of pro-inflammatory cells, and excessive cytokine release. These KEs are harmonized from existing AOPs to distinguish pathological inflammation from normal immune responses. Emphasis is placed on downstream effects such as endothelial activation and vascular leakage, which are central to CRS severity. Clinical manifestations - including fever, hypotension, hypoxia, edema, and multi-organ dysfunction - are linked to late-stage KEs, enabling a mechanistic bridge between molecular events and patient outcomes. Insights from COVID-19-related irAOP development and international initiatives like the imSAVAR consortium inform a roadmap for improving CRS prediction. This includes defining context of use, strengthening mechanistic evidence through quantitative key event relationships, and advancing human-relevant New Approach Methodologies (NAMs). By integrating advanced and systems within an irAOP framework, fragmented data can be transformed into coherent, decision-relevant tools. Overall, this strategy supports a shift toward predictive, human-centered approaches for assessing and managing CRS risk in immunotherapy.
Prediction model of thrombocytopenia on patients using linezolid: a ranked-based covariate selection with multi-center data.
Nguyen NH, Le H, Tang AQ … +9 more , Nguyen HTH, Tran HN, Nguyen TT, Bui TTN, Dang ATL, Khuat OT, Vu HD, Trinh NTH, Nguyen AH
Front Pharmacol · 2026 · PMID 42382172 · Full text
BACKGROUND: Thrombocytopenia is a common adverse reaction of linezolid, often leading to severe complications. It is challenging to externally validate directly apply developed in other countries. We aim to develop and v...
BACKGROUND: Thrombocytopenia is a common adverse reaction of linezolid, often leading to severe complications. It is challenging to externally validate directly apply developed in other countries. We aim to develop and validate a risk prediction model of linezolid-associated thrombocytopenia (LAT) tailored to Vietnamese setting and to construct a simplified risk score calculation to support clinical decision-making. MATERIALS AND METHODS: Data was collected retrospectively from three large hospitals in Northern Vietnam. We selected inpatients treated with linezolid from November 2019 to March 2023. Potential predictors were chosen based on literature review and clinical experts' opinions. Final predictors were selected using Bayesian model selection. Thrombocytopenia was defined as platelet count value ≤112.5 G/L and a decrease more than 25% from the baseline. A multivariable logistic regression model was constructed to predict the occurrence of LAT. The final model was further validated using internal-external cross-validation. RESULTS: Of 776 patients included, 247 patients (31.8%) developed LAT. Logistic regression model selection indicated that the risk predictors were age, duration of linezolid ≥14 days, baseline platelet count, creatinine clearance, sepsis, cirrhosis, continuous renal replacement therapy (CRRT) and heparin use. The model had moderate discrimination, with area under the curve (AUC) of 0.77 (95% confidence interval (CI): 0.72-0.83). Model calibration was good, with calibration-in-the-large and calibration slope of 0.00 (-0.38 to 0.38), and 0.92 (0.59-1.26) respectively. A risk score scale was established, with the optimal cut-off value being 23 points. Patients were categorised based on this score into three groups: low risk (-1 to 13 points), moderate risk (14-22 points) and high risk (≥23 points). CONCLUSION: Our newly developed risk prediction model demonstrated moderate discriminatory ability in predicting the occurrence of LAT. From there, a simplified risk score was constructed to facilitate its applicability in clinical practice.
Proteomic profiling reveals treatment-dependent inflammatory signatures and identifies biomarkers of refractory age-related macular degeneration.
Eandi CM, Borgo A, de Oliveira Figueiredo E … +3 more , de Haro D, Kaufmann DE, Roduit R
Front Pharmacol · 2026 · PMID 42382171 · Full text
BACKGROUND: Age-related macular degeneration (AMD) is a severe eye disease that affects the macula, the central area of the retina. Current treatment consists of intravitreal injections of vascular endothelial growth fac...
BACKGROUND: Age-related macular degeneration (AMD) is a severe eye disease that affects the macula, the central area of the retina. Current treatment consists of intravitreal injections of vascular endothelial growth factor (VEGF) inhibitors. However, some patients remain refractory to treatment even after maximal anti-VEGF dosage. We longitudinally analyzed angiogenic and inflammatory biomarkers in the aqueous humor (AH) of these patients. OBJECTIVES: 1) To confirm the presence of angiogenic and inflammatory biomarkers before (in the naive state) and after two anti-VEGF injections; and 2) to characterize the inflammatory response according to the type of anti-VEGF used (ranibizumab, aflibercept, brolucizumab, or faricimab). METHODS: AH samples were collected from two groups of patients: 35 patients with AMD and 17 control patients with no retinopathy. Eleven of the 35 patients with AMD were characterized as refractory (rAMD) after long-term anti-VEGF treatment. Multiplex and proximity extension assays (PEA) were performed on these samples to define their inflammatory profiles. Free VEGFA was detected using an additional AlphaLISA VEGFA assay. RESULTS: Several inflammatory molecules are upregulated in AMD, while a smaller subset is downregulated in rAMD, indicating that these could serve as markers of a refractory state. In contrast, no differences were observed in the biomarkers previously reported as increased in rAMD after long term treatment. These findings suggest that anti-VEGF treatment induces the expression of angiogenic and inflammatory biomarkers. Analysis of the inflammatory response following the injection of different anti-VEGF agents revealed exacerbated inflammation in patients treated with brolucizumab, whereas ranibizumab caused the lowest inflammatory response. In addition, we compared three different assays to assess AH VEGFA, but only the AlphaLISA assay could detect free VEGFA. CONCLUSION: Our results indicate that anti-VEGFA therapy shapes AMD-associated inflammation; therefore, the choice of anti-VEGFA therapy remains important in reducing secondary inflammatory effects. Furthermore, the detection of free VEGF is dependent on the assay used.
Immunomodulatory effects of Yang He decoction on cyclophosphamide-induced immunosuppression in mice: restoration of immune organ integrity and cytokine balance.
Wang Y, Xu Q, Xu W … +5 more , Wang Y, Wang Y, Qin M, Dai J, Zhang S
Front Pharmacol · 2026 · PMID 42382170 · Full text
OBJECTIVE: To evaluate the protective effects and potential mechanisms of Yang He decoction (YHD), a classic traditional Chinese medicine formula, against cyclophosphamide (CTX)-induced immunosuppression in mice. METHODS...
OBJECTIVE: To evaluate the protective effects and potential mechanisms of Yang He decoction (YHD), a classic traditional Chinese medicine formula, against cyclophosphamide (CTX)-induced immunosuppression in mice. METHODS: An immunosuppression model was established in Kunming mice intraperitoneal injection of CTX (80 mg/kg). The mice were then treated with low, medium, or high doses of YHD (50, 100, or 200 mg/kg) or Astragalus polysaccharide (APS, 24 mg/kg) as a positive control for 15 consecutive day. Body weight changes, immune organ (spleen and thymus) index and histopathology, splenic lymphocyte proliferation and cell cycle distribution, and serum levels of cytokines (IL-1β, IFN-γ, TNF-α, IL-6, and IL-10) were systematically assessed. RESULTS: YHD treatment significantly ameliorated CTX-induced immunosuppression. The medium dose (100 mg/kg) increased body weight by 58.5% (vs. 17.3% in the APS group), restored the spleen index to 9.41 ± 0.94 (0.52-fold vs. Model group 1.8 ± 0.3), and enhanced ConA-stimulated lymphocyte proliferation (27.03% ± 0.92% vs. Model group 10.60% ± 4.78%, < 0.01). Cell cycle analysis revealed that the percentage of S-phase cells increased from 4.13% to 13.47% in the YHDH group. YHD also rebalanced cytokines: the concentration of IL-1β increased from 25.73 to 77.10 pg/mL, while IL-10 decreased from 222.83 to 20.77 pg/mL. Histopathology confirmed restoration of organ integrity without necrosis. CONCLUSION: The multiherbal formula YHD confers substantial protection against CTX-induced immunosuppression. Its mechanisms are associated with the restoration of immune organ integrity, promotion of lymphocyte activity, and rebalancing of the cytokine profile. These findings provide a pharmacological basis for the traditional use of YHD and support its potential as an adjuvant therapy for managing chemotherapy-related immunosuppression.
First case report of polymyxin B-induced drug fever in a patient with carbapenem-resistant pneumonia.
Liu Y, Liu X, Zou L … +4 more , Wang C, Xu XX, Min L, Guo P
Front Pharmacol · 2026 · PMID 42382169 · Full text
The escalating global prevalence of carbapenem-resistant Gram-negative bacteria has significantly constrained therapeutic options, leading to the revived use of polymyxins. However, this resurgence has been paralleled by...
The escalating global prevalence of carbapenem-resistant Gram-negative bacteria has significantly constrained therapeutic options, leading to the revived use of polymyxins. However, this resurgence has been paralleled by an increase in reports of associated adverse effects. No case of drug fever induced by polymyxin B (PMB) has been reported in the literature to date. We report the first case of drug fever (≥39 °C) induced by intravenous PMB in a patient with severe pneumonia caused by carbapenem-resistant , accompanied by tachypnea following concomitant nebulized PMB administration. Upon intervention by the clinical pharmacist, which involved discontinuation of PMB and adjustment of the anti-infective regimen, the patient's fever resolved promptly and the infection was successfully controlled. This case highlights a severe and previously unreported adverse drug reaction to PMB, underscoring the necessity for vigilant monitoring and proactive antimicrobial stewardship in managing infections.
Formulation of hispidulin-loaded sodium carboxymethyl cellulose nanoparticles: characterisation, biological activities and molecular insights.
Hadkar VM, Selvaraj CI
Front Pharmacol · 2026 · PMID 42382168 · Full text
BACKGROUND: Hispidulin is a bioactive flavonoid with promising antioxidant and anticancer properties; however, its poor aqueous solubility and stability limit its usage in therapeutic application. This study aimed to dev...
BACKGROUND: Hispidulin is a bioactive flavonoid with promising antioxidant and anticancer properties; however, its poor aqueous solubility and stability limit its usage in therapeutic application. This study aimed to develop a suitable nanocarrier system to enhance its bioavailability and biological efficacy. METHODS: Hispidulin-loaded sodium carboxymethyl cellulose nanoparticles (HIS-CMC NPs) were synthesised via ionic gelation. Physicochemical characterisation was performed using UV-Vis, FTIR, XRD, DLS and TGA, along with microscopic analysis. Encapsulation efficiency and drug loading were determined. drug release and kinetic modelling were conducted. Biological activities, including antioxidant, anti-inflammatory, metal chelating, lipid peroxidation inhibition, hemocompatibility, thrombolytic activity, and cytotoxicity (MCF-7 and 3T3-L1 cells) were evaluated. Apoptosis and mitochondrial membrane potential were assessed using Hoechst and TMRE staining. Molecular docking with VEGFR and ADMET analysis were also performed. RESULTS: The HIS-CMC NPs showed a hydrodynamic size of 243.3 nm and a zeta potential of -39.1 mV, indicating good stability. High encapsulation efficiency (94.84% ± 1.2%) and drug loading (35.13% ± 1.5%) were achieved. Sustained drug release (87.5% ± 1.3%, pH 5.4) followed Korsmeyer-Peppas kinetics. The nanoparticles exhibited enhanced antioxidant, anti-inflammatory and metal chelating activities compared to free hispidulin. They demonstrated good hemocompatibility (3.60%) and thrombolytic activity (69.62%). Selective cytotoxicity towards MCF-7 cells (IC = 35.33 μg/mL) with minimal toxicity to 3T3-L1 cells was observed. Biopolymeric NPs showed apoptosis and mitochondrial depolarisation in MCF-7 cells. Docking studies revealed strong binding affinity to VEGFR (-9.7 kcal/mol), supported by favourable ADMET properties. CONCLUSION: HIS-CMC NPs exhibit improved stability, sustained release and enhanced biological activity, indicating their potential as an effective nanocarrier for anticancer applications.
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