Front Pharmacol [JOURNAL]
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200 papers
Stem cell-derived extracellular vesicles as immunomodulators: a novel paradigm for post-myocardial infarction repair and regeneration.
Raza A, Wang P, Liu F … +4 more , Arshad S, Asim MH, Yang Z, Cai Y
Front Pharmacol · 2026 · PMID 42344804 · Full text
Myocardial infarction (MI) initiates a rapid and highly coordinated immune response that is essential for the clearance of necrotic tissue and activation of reparative processes. However, prolonged or dysregulated post-M...
Myocardial infarction (MI) initiates a rapid and highly coordinated immune response that is essential for the clearance of necrotic tissue and activation of reparative processes. However, prolonged or dysregulated post-MI inflammation can exacerbate myocardial injury, promote adverse cardiac remodeling, and ultimately contribute to heart failure. Although current therapeutic strategies improve survival and symptom management, they remain limited in their ability to restore lost cardiomyocytes or effectively modulate the post-infarction immune microenvironment. In this context, stem cell-derived extracellular vesicles (EVs) have emerged as promising cell-free therapeutic candidates due to their immunomodulatory, regenerative, and paracrine properties. These nanoscale vesicles carry a diverse cargo of bioactive molecules, including microRNAs, proteins, lipids, and other signaling mediators that regulate intercellular communication and tissue repair. EVs derived from mesenchymal stem cells, cardiac progenitor cells, and induced pluripotent stem cells have demonstrated the ability to modulate key immune pathways by attenuating neutrophil-mediated inflammatory injury, promoting macrophage polarization towards a reparative M2 phenotype, and regulating T-cell responses by suppressing pro-inflammatory activity while enhancing regulatory T-cell function. Collectively, these effects help restore immune homeostasis and reduce adverse cardiac remodeling following MI. Moreover, advances in EVs engineering, cargo modification, and targeted delivery systems may enhance their therapeutic efficacy and translational potential. However, several critical challenges, including large-scale production, cargo heterogeneity, and the lack of standardized protocols for isolation and characterization, still need to be addressed before successful clinical translation. This review summarizes the current understanding of stem cell-derived EVs biology, comparative advantages over conventional and cell-based therapies, and their immunomodulatory mechanisms in post-MI repair. Moreover, it highlights recent innovations and the major challenges that must be addressed for successful clinical translation.
Effect of combined aspirin and statin therapy on mortality reduction in sepsis-induced myocardial injury.
Zhao Y, Zhang X, Mao S … +8 more , Liu H, Lv C, Yao Y, Wang Y, Wang Y, Wang S, Xu Y, Yin T
Front Pharmacol · 2026 · PMID 42344803 · Full text
INTRODUCTION: Sepsis-induced myocardial injury (SIMI) is a severe complication with high mortality and limited effective treatments. Although combined aspirin and statin therapy is cardioprotective in coronary artery dis...
INTRODUCTION: Sepsis-induced myocardial injury (SIMI) is a severe complication with high mortality and limited effective treatments. Although combined aspirin and statin therapy is cardioprotective in coronary artery disease, its impact on SIMI outcomes remains unclear. METHODS: Using the MIMIC-IV database, we evaluated the association of combined aspirin and statin therapy with 28-day, 90-day, and 1-year mortality in SIMI patients using multivariable Cox regression and Kaplan-Meier analysis. Robustness was assessed via floating absolute risk analysis. External validation was performed in an independent ICU cohort. RESULTS: Among 1,884 SIMI patients, 119 received combination therapy. Compared to those without aspirin or statin, combination therapy was associated with significantly lower mortality at 28 days (11.8% vs. 41.9%; HR = 0.22), 90 days (15.1% vs. 44.8%; HR = 0.23), and 1 year (29.4% vs. 50.9%; HR = 0.38) (all < 0.001). The combination consistently showed the greatest risk reduction. Subgroup analysis confirmed consistent benefits. External validation (n = 4,002) confirmed a lower 28-day mortality risk with combination therapy (HR = 0.48; < 0.001). CONCLUSION: Combined aspirin and statin therapy is associated with reduced mortality and improved outcomes in SIMI patients.
Correction: Analysis of proton pump inhibitor-associated drug problems and contributing factors among hospitalized nephrology patients.
Song N, Zhang X, Han M … +1 more , Guan Y
Front Pharmacol · 2026 · PMID 42344802 · Full text
[This corrects the article DOI: 10.3389/fphar.2026.1776655.].
[This corrects the article DOI: 10.3389/fphar.2026.1776655.].
Computational pharmacovigilance of tranexamic acid: implications for intracerebral hemorrhage based on FAERS database and network toxicology.
Wu JW, Shen CC, Wang P … +5 more , Wang BX, Chen CY, Miao ZL, Zhao XD, Gao W
Front Pharmacol · 2026 · PMID 42344801 · Full text
BACKGROUND: Tranexamic acid (TXA) is a widely used antifibrinolytic agent for the management of hemorrhagic disorders and has increasingly been investigated for the treatment of intracerebral hemorrhage (ICH). However, T...
BACKGROUND: Tranexamic acid (TXA) is a widely used antifibrinolytic agent for the management of hemorrhagic disorders and has increasingly been investigated for the treatment of intracerebral hemorrhage (ICH). However, TXA-associated adverse drug events (ADEs), particularly neurological complications, remain insufficiently characterized, despite their association with unfavorable neurological outcomes, prolonged hospitalization, and increased in-hospital mortality. A systematic evaluation of TXA-related safety risks and underlying mechanisms in ICH is warranted. MATERIALS AND METHODS: FAERS reports from the first quarter of 2004 to the third quarter of 2023 were analyzed to identify TXA-associated ADE signals using a hierarchical prediction framework integrating statistical learning algorithms. Network toxicology analyses were conducted to explore potential molecular mechanisms and key regulatory targets involved in TXA-related effects in ICH. Drug-target interactions were further assessed by molecular docking and molecular dynamics simulations. experiments using ICH-related cell models were performed to validate the predicted neurotoxic effects of TXA. RESULTS: Eight significant neurologically related ADE signals associated with TXA were identified, including myoclonic seizures and status epilepticus. Network toxicology analysis highlighted CASP3, PPARA, and BCL2 as key regulatory genes potentially mediating TXA-related neurotoxicity in ICH. Molecular docking demonstrated strong binding affinities between TXA and core targets, with binding energies lower than -8.0 kcal/mol. Molecular dynamics simulations confirmed stable binding conformations, with root mean square deviation values below 2.0 Å. experiments further supported the potential neurotoxic effects of TXA in ICH cell models. CONCLUSION: This study establishes an integrated computational-to-experimental framework for evaluating the safety of TXA in ICH. The FAERS analysis revealed overall neurological ADE signals for TXA. Combined with network toxicology and data, these findings suggest potential neurotoxic mechanisms that warrant cautious evaluation in future ICH-specific studies.
Efficacy of erector spinae plane block with liposomal bupivacaine for postoperative analgesia in patients undergoing open spinal surgery: a randomized controlled trial.
Wang W, Xiang H, Gong J … +4 more , Wu X, Xiao J, Zhang K, Zhou J
Front Pharmacol · 2026 · PMID 42344800 · Full text
BACKGROUND: Liposomal bupivacaine (LB) provides prolonged postoperative analgesia. This study aimed to evaluate the analgesic efficacy of erector spinae plane block (ESPB) using LB in patients undergoing spinal surgery....
BACKGROUND: Liposomal bupivacaine (LB) provides prolonged postoperative analgesia. This study aimed to evaluate the analgesic efficacy of erector spinae plane block (ESPB) using LB in patients undergoing spinal surgery. METHODS: A total of 64 patients undergoing elective spinal surgery were randomly assigned in a 1:1 ratio to receive ESPB with 0.44% liposomal bupivacaine (LB group) or 0.4% ropivacaine (RH group) for postoperative pain management. The primary outcome was the incidence of rescue analgesia on the first postoperative day. Secondary outcomes included the incidence of rescue analgesia on the second and third postoperative days, visual analog scale (VAS) scores at various postoperative time points; time to first use of rescue analgesic; the cumulative area under the curve (AUC) of VAS scores, the Riker Sedation-Agitation Scale (RSAS) score at tracheal extubation; Quality of Recovery-15 (QoR-15) scores; opioid consumption; patient satisfaction and adverse events. RESULTS: The RH group demonstrated a significantly higher incidence of rescue analgesic use than the LB group on postoperative days 1, 2, and 3 (37.5% vs. 9.4%, 59.4% vs. 18.8%, and 65.6% vs. 28.1%, respectively; all < 0.05) and required their first rescue analgesic significantly earlier. VAS scores were higher in the RH group at 6, 12, 24, and 48 h postoperatively, with no significant differences observed at 1 and 72 h. Sufentanil consumption was also significantly higher in the RH group at all postoperative intervals except the first hour. Additionally, the RH group exhibited higher VAS-AUC values, lower QoR-15 scores over the first three postoperative days, and lower postoperative satisfaction scores. The incidence of nausea and dizziness was higher in the RH group, while no respiratory depression was observed in either group. CONCLUSION: ESPB with LB provides prolonged postoperative analgesia, reduces opioid consumption, and enhances recovery quality following spinal surgery. These findings support the incorporation of LB as a valuable component of multimodal analgesia protocols for spinal procedures. CLINICAL TRIAL REGISTRATION: https://www.chictr.org.cn/showproj.html?proj=265855, identifier ChiCTR2500100055.
Retz. As a resistance-modifying botanical drug against priority pathogens: a systematic review.
Zaman K, Ravedar S, R N … +9 more , Karun K, Patel J, Felix F, Akula KK, Hiremath N, Tendulkar S, Salunkhe T, Kavathekar A, Bhat J
Front Pharmacol · 2026 · PMID 42344799 · Full text
BACKGROUND: The global rise of antimicrobial resistance (AMR) among priority bacterial pathogens represents a critical threat to public health, necessitating the development of alternative therapeutic strategies. Retz....
BACKGROUND: The global rise of antimicrobial resistance (AMR) among priority bacterial pathogens represents a critical threat to public health, necessitating the development of alternative therapeutic strategies. Retz. (), a traditionally used medicinal plant rich in hydrolysable tannins, flavonoids, and polyphenolic metabolites, has emerged as a promising candidate due to its broad-spectrum antimicrobial and pharmacological properties. METHODS: This systematic review critically evaluates the antimicrobial activity and resistance-modifying potential of fruit extracts against ESKAPE pathogens, including species and as a representative of the Enterobacteriaceae (now Enterobacterales) family. A comprehensive literature search was conducted across PubMed, Scopus, ScienceDirect, and Google Scholar databases in accordance with PRISMA guidelines and registered in PROSPERO (CRD420251024476). Based on predefined criteria, 24 studies were included for qualitative analysis. RESULTS: The findings demonstrate that extracts exhibit antimicrobial activity, with ethanolic and methanolic extracts showing enhanced higher efficacy, particularly against multidrug-resistant strains of , and , and . Notably, few studies reported synergistic interactions between phytochemicals and conventional antibiotics, suggesting antibiotic resistance-modifying roles. Mechanistic insights suggest that metabolites such as chebulagic acid, chebulinic acid, and gallic acid contribute to antimicrobial activity by disrupting the bacterial cell membranes, inhibiting biofilm formation, and interfering with resistance pathways. However, substantial variations in extraction methods and experimental designs limit cross-study comparability, highlighting the need for standardized protocols. CONCLUSION: Overall, the evidence supports the potential of as a resistance-modifying and an antibiotic adjuvant. Future studies should prioritize bioassay-guided isolation, mechanistic validation, and preclinical evaluation to facilitate translational application in combating AMR.
Drying methods for : a comprehensive study of quality traits and metabolite dynamics.
Ye Z, Chen C, Zhao S … +4 more , Li J, Jin J, Wang T, Zhou G
Front Pharmacol · 2026 · PMID 42344798 · Full text
Rheum tanguticum () originates from high-altitude regions such as Qinghai and Gansu in China. It serves as both a precious traditional medicinal botanical drug and a potential functional food, and its extensive pharmacol...
Rheum tanguticum () originates from high-altitude regions such as Qinghai and Gansu in China. It serves as both a precious traditional medicinal botanical drug and a potential functional food, and its extensive pharmacological activities have stimulated global demand. However, existing research predominantly focuses on optimizing individual drying techniques or single bioactive metabolites, failing to integrate multi-omics technologies to elucidate the chemical and physical alterations induced by drying. To this end, we evaluated five drying methods by integrating an approach that links physical indicators with chemical composition, revealing that, for the preservation of physical indicators, especially color and rehydration properties, vacuum freeze drying (LD) is optimal; for the retention of the key pharmaceutical metabolite free anthraquinones, microwave drying (WB) is the most effective. Whereas in the comprehensive evaluation of multi-dimensional quality, SG is optimal. Metabolomic analysis confirmed that LD and YG were most effective in preserving key metabolites. Flavonoids, phenolic acids, and amino acids collectively form the core metabolites of differential metabolites in dried , primarily enriched in pathways such as purine metabolism. Collectively, this work systematically elucidates the impact of drying on 's metabolite profile and physicochemical traits, offering both a theoretical basis for its precision processing and a transferable framework for optimizing drying techniques in related medicinal edible plants.
The tumor microenvironment: a dynamic ecosystem and therapeutic nexus in modern oncology.
Zhang M, Lu Y, Yuan X
Front Pharmacol · 2026 · PMID 42344797 · Full text
The tumor microenvironment (TME) has emerged as a central orchestrator of carcinogenesis, therapeutic resistance, and immune evasion, fundamentally reshaping the understanding of cancer as an ecosystem disease rather tha...
The tumor microenvironment (TME) has emerged as a central orchestrator of carcinogenesis, therapeutic resistance, and immune evasion, fundamentally reshaping the understanding of cancer as an ecosystem disease rather than a cell-autonomous genetic disorder. This review synthesizes contemporary advances in deconstructing the cellular and acellular architecture of the TME, encompassing cancer-associated fibroblasts, tumor-associated macrophages, aberrant vasculature, and a dynamically remodeled extracellular matrix. The molecular underpinnings of TME-mediated pathogenesis are critically evaluated, including metabolic reprogramming, epigenetic dysregulation, and systemic microbiome crosstalk, which collectively enforce immunosuppression and drive adaptive resistance. Building on this mechanistic framework, a new generation of therapeutic strategies designed to reprogram this malignant niche is highlighted: precision nanotechnologies for targeted and stimuli-responsive delivery; next-generation immunotherapies such as logic-gated CAR-T cells, bispecific engagers, and oncolytic viruses; metabolic and epigenetic modulators; stromal and vascular normalization approaches; and microbiome-based interventions, for instance fecal microbiota transplantation and defined bacterial consortia. Transformative tools, including patient-derived organoids, tumor-on-a-chip systems, 3D bioprinting, and artificial intelligence-powered multi-omics, are now enabling predictive modeling and personalized therapeutic forecasting. Despite persistent challenges posed by intratumoral heterogeneity, cellular plasticity, and the complexity of combination trial design, the convergence of these multidisciplinary approaches provides an unprecedented toolkit to durably reprogram the TME. Mastering this dynamic ecosystem is paramount to overcoming therapeutic roadblocks, and the strategic integration of these advances heralds a definitive paradigm shift toward TME-centric, adaptive, and personalized cancer therapy.
The TASK-1 and TASK-3 activator JG-C3-98 attenuates cold and mechanical responses in primary somatosensory neurons.
De-la-Torre P, Valencia M, Gálvez J … +20 more , Flores Del Pino V, Gómez Del Campo A, Romero S, Mendoza E, Rinné S, Kiper A, Prent L, Vergara-Jaque A, Mazola Y, Olivera-Fuentes C, Zúñiga R, Márquez Montesinos JCE, Rojas B, Peña L, Quiroga J, Pertusa M, Decher N, Zúñiga L, González W, Madrid R
Front Pharmacol · 2026 · PMID 42344796 · Full text
K2P channels underlie background K currents that act as brakes on neuronal excitability. In the somatosensory system, the K2P channels TASK-1 and TASK-3 play a relevant role in cold sensing, mechanosensitivity, and pain....
K2P channels underlie background K currents that act as brakes on neuronal excitability. In the somatosensory system, the K2P channels TASK-1 and TASK-3 play a relevant role in cold sensing, mechanosensitivity, and pain. Combining molecular docking and molecular dynamic simulations, patch-clamp recordings of recombinant channels, Ca-imaging and patch-clamp analysis in cultured primary somatosensory neurons from trigeminal and dorsal root ganglia, extracellular recording of the nerve endings of trigeminal neurons at the corneal surface, and behavioral analysis in mice models of acute, irritative, and neuropathic pain, we described and characterized the novel and rationally designed activator of TASK-1 and TASK-3 channels JG-C3-98. In HEK293 cells, JG-C3-98 showed a strong activation effect on TASK-1 and TASK-3, but not on TRAAK, TREK-1, TREK-2, and TRESK. In cultured primary somatosensory neurons, we have found that JG-C3-98 shifted the thermal threshold of cold thermoreceptor neurons to lower temperatures and reduced the maximal mechanically evoked responses in neurons responding to hypoosmotic stimulation. In recordings of corneal cold-sensitive neurons, JG-C3-98 also shifted the thermal threshold of these nerve endings to lower temperatures. In a group of cultured dorsal root ganglia neurons, electrophysiological analysis suggests that JG-C3-98 reduces excitability and activates an outward current compatible with TASK-1/3 channels. Besides, intraplantar administration of a single dose of JG-C3-98 in the hind paw increases the threshold of the mechanically evoked pain sensitivity and reduces AITC-evoked nociceptive responses in mice. Importantly, in a model of neuropathic pain induced by chronic constriction of the sciatic nerve, we have found that cold allodynia resulting from this form of peripheral nerve damage is also reduced by intraplantar administration of a single dose of JG-C3-98 in the hind paw. Altogether, these results suggest that JG-C3-98 could be a new and potentially effective pharmacological tool for reducing cold and mechanical sensitivity across different somatosensory territories, both in physiological and pathophysiological conditions, and serve as a molecular scaffold for developing novel, more effective antinociceptive compounds that specifically act as TASK channels activators.
Advances in phytochemical-derived nanotherapeutics for multimodal eradication of multidrug-resistant .
Gupta N, Bhattacharya S, Lela L … +7 more , Dutta A, Faraone I, Fernández-Cusimamani E, Sarker SD, Milella L, Nahar L, Leuner O
Front Pharmacol · 2026 · PMID 42344795 · Full text
The past decade, particularly the post-pandemic period, has intensified the challenge of managing bacterial infections. Multidrug-resistant (MDR-SA) has emerged as a dominant cause of hospital-acquired infections, creat...
The past decade, particularly the post-pandemic period, has intensified the challenge of managing bacterial infections. Multidrug-resistant (MDR-SA) has emerged as a dominant cause of hospital-acquired infections, creating a sustained public health emergency and underscoring the need for alternative antimicrobial strategies. Plant-derived secondary metabolites have gained attention as promising antibacterial agents; however, their therapeutic potential is constrained by poor solubility, limited target selectivity, low drug-loading capacity, rapid metabolism, and reduced systemic bioavailability. Nanoparticle carriers provide a corrective platform by improving physicochemical stability, enhancing solubility, enabling controlled release, and strengthening pharmacokinetic and pharmacodynamic behavior. Phytochemical-based nanoparticles (phyto-NPs) form a multitarget antibacterial architecture capable of weakening bacterial defense networks through efflux pump interference, disruption of metal-ion homeostasis, and alteration of membrane permeability. These systems also induce reactive oxygen species, leading to DNA damage, protein denaturation, mitochondrial impairment, and peptidoglycan disruption. In parallel, phyto-NPs inhibit biofilm formation and quorum-sensing pathways, reducing virulence and limiting dissemination. Their ability to penetrate the extracellular matrix enhances antibiotic access and restores susceptibility in resistant strains. Recent investigations demonstrate strong activity of phyto-NPs both as independent therapeutics and as synergistic partners to conventional antibiotics. Microenvironment-responsive release, intracellular targeting, and improved delivery efficiency further strengthen their translational relevance. Curcumin-loaded nanosystems disrupt MRSA membranes and impair biofilm formation, while quercetin-loaded liposomes penetrate biofilms more effectively than free quercetin. These examples illustrate the capacity of nanoscale engineering to overcome the pharmacological constraints of phytochemicals. This review examines recent advances in phyto-NP strategies targeting MDR-SA, with emphasis on phytochemical selection, nanoscale design principles, and the multifunctional antibacterial mechanisms underpinning next-generation antimicrobial development.
Case Report: Is it COPD? It is Fabry disease: a case in which bronchodilators were briefly used but not continued, prioritizing enzyme replacement therapy.
Li Y, Zhu H, Zhan Z … +6 more , Li G, Huang S, Xiao C, Li Y, Zheng C, Huang F
Front Pharmacol · 2026 · PMID 42344794 · Full text
BACKGROUND: Fabry disease, an X-linked lysosomal storage disorder, can present with mixed ventilatory dysfunction on pulmonary function testing. In patients with a smoking history, this finding may trigger a reflexive co...
BACKGROUND: Fabry disease, an X-linked lysosomal storage disorder, can present with mixed ventilatory dysfunction on pulmonary function testing. In patients with a smoking history, this finding may trigger a reflexive consideration of COPD and unnecessary bronchodilator use. We report a case where bronchodilators were briefly used following the diagnosis of Fabry disease, highlighting the clinical inertia that persists even after a definitive diagnosis. CASE PRESENTATION: A 39-year-old male with a 20-pack-year smoking history was diagnosed with Fabry disease through family cascade screening (α-galactosidase A activity: 4.93 nmol/L; plasma lyso-Gb3: 328.92 nmol/L; hemizygous GLA variant). Multisystem evaluation revealed mixed ventilatory dysfunction (FEV/FVC 54.59%) without respiratory symptoms, left ventricular hypertrophy (septum 14-17 mm, posterior wall 15 mm), proteinuria (1.01 g/24 h), and corneal verticillata. Chest CT showed no emphysema. During hospitalization, inhaled budesonide plus ipratropium bromide (a bronchodilator) was briefly administered. However, recognizing that the ventilatory dysfunction was a manifestation of Fabry disease itself rather than COPD, the patient was discharged without a bronchodilator prescription. Enzyme replacement therapy (ERT) with agalsidase alfa (0.2 mg/kg every 2 weeks) was initiated as long-term disease-modifying treatment. CONCLUSION: Even after Fabry disease is confirmed, the presence of a smoking history and abnormal spirometry can trigger reflexive bronchodilator use, illustrating powerful clinical inertia. Respiratory physicians should strictly adhere to COPD diagnostic criteria. Once Fabry disease is diagnosed, ERT should be prioritized as the disease-modifying therapy, and bronchodilators, if used at all, should be reserved for symptomatic patients as an adjunct, not a substitute.
The hypoglycemic metabolites and potential mechanisms of ( lily).
Wu Q, Xiao K, Zhao D … +5 more , Tang R, Liu W, Li F, Wang H, Chen F
Front Pharmacol · 2026 · PMID 42338973 · Full text
In Chinese folk medicine, lily bulbs have traditionally been used to help lower blood glucose levels. Numerous studies have demonstrated that extracts from lily bulbs possess significant hypoglycemic activity. However, t...
In Chinese folk medicine, lily bulbs have traditionally been used to help lower blood glucose levels. Numerous studies have demonstrated that extracts from lily bulbs possess significant hypoglycemic activity. However, the specific active metabolites and their underlying mechanisms remain unclear. This study first evaluated the hypoglycemic activities of extracts from four common lily species: Thunb ( lily), var. Unicolor ( lily), var. Viridulum ( lily), and lily. The findings revealed that lily extract exhibited the most potent hypoglycemic activity. Subsequently, UPLC-Q-TOF-MS analysis was employed to profile the major metabolites of lily, resulting in the identification of 25 high-abundance metabolites. These included 8 regalosides, 5 flavonoids, 4 dioscin-type saponins, 5 phenylpropanoids, and 3 other types of metabolites. Notably, six of them were reported for the first time in lilies. To further investigate the hypoglycemic metabolites, three high-content metabolites (caffeic acid, regaloside A, and regaloside B) from lily were subjected to hypoglycemic activity assessment. The results indicated that both regaloside A and regaloside B possessed significant hypoglycemic activity, with regaloside B demonstrating the strongest effect, reducing blood glucose levels in hyperglycemic model mice from an initial values of 27.87 ± 0.67 mmol/L to 14.11 ± 1.09 mmol/L. Furthermore, regaloside A and B were found to inhibit postprandial blood glucose elevation in mice, with an efficacy comparable to that of the positive control drug. This effect was attributed to the inhibition of α-glucosidase activity. Molecular docking studies revealed that regaloside A and B could bind to α-glucosidase (including maltase-glucoamylase and sucrase-isomaltase). These interactions may inhibit the α-glucosidase activity and contribute to the observed hypoglycemic effect. This study elucidates the active metabolites and the potential mechanism underlying the hypoglycemic activity of lily bulbs for the first time, thereby providing a foundation for the development of novel hypoglycemic agents and the high-value utilization of lily resources.
Neuroinflammation and treatment resistance in major depressive disorder.
Miyata S, Ishino Y, Shimizu S
Front Pharmacol · 2026 · PMID 42338972 · Full text
Major depressive disorder (MDD) is increasingly recognized as a multi-system disease that extends beyond neurotransmitter dysregulation. Treatment-resistant depression (TRD), which affects approximately one-third of pati...
Major depressive disorder (MDD) is increasingly recognized as a multi-system disease that extends beyond neurotransmitter dysregulation. Treatment-resistant depression (TRD), which affects approximately one-third of patients who do not achieve remission with monoaminergic antidepressants, poses a significant global challenge because of its association with a heightened risk of suicide and impaired social functioning. Low-grade chronic inflammation, a hallmark of TRD, increases blood-brain barrier (BBB) permeability. These inflammatory signals can affect the central nervous system, induce alterations in neural circuits, and contribute to depressive symptom development. A shift is necessary in the treatment of patients with TRD, moving from conventional symptom-based diagnosis to personalized medicine based on biological subtypes using inflammatory markers. In the future, complex interventions that facilitate a restorative immune environment in the brain-such as enhancing the M2 phenotype and restoring homeostasis in the nervous, immune, and endocrine systems-are anticipated to become central to next-generation antidepressant therapies. This review provides a comprehensive overview of the molecular and cellular mechanisms through which peripheral and central inflammation contribute to the pathophysiology of TRD.
Correction: EZH2 blockade reverses doxorubicin resistance by inducing metabolic vulnerability and enhancing DNA damage in breast cancer.
Wang X, Ding Y, Mai Y … +11 more , Li R, Shao X, Chen W, Li Y, Liu L, Wang H, Liu K, Niu Y, Li J, Xu G, Zhao Y
Front Pharmacol · 2026 · PMID 42338971 · Full text
[This corrects the article DOI: 10.3389/fphar.2026.1786648.].
[This corrects the article DOI: 10.3389/fphar.2026.1786648.].
Comparative evaluation of isolation protocols for -derived extracellular vesicles.
Zhou J, Hao W, Zhang Z … +4 more , Zhang H, Kong Y, Wang X, Wang Z
Front Pharmacol · 2026 · PMID 42338970 · Full text
The primary objective of this investigation was to systematically evaluate four distinct protocols for extracting extracellular vesicles (EVs) from , aiming to establish a methodology that maximizes both yield and purity...
The primary objective of this investigation was to systematically evaluate four distinct protocols for extracting extracellular vesicles (EVs) from , aiming to establish a methodology that maximizes both yield and purity. Fresh gel served as the source material for EV isolation via four approaches: (A) Conventional ultracentrifugation (UC); (B) UC preceded by cellulase digestion; (C) a hybrid approach involving cellulase treatment, membrane filtration, and subsequent UC; and (D) cellulase pretreatment integrated with the EXODUS technique. Characterization of the harvested vesicles was performed using BCA protein quantification, transmission electron microscopy (TEM), and nanoflow cytometry. Morphological analysis confirmed that EVs obtained through all four strategies possessed intact lipid bilayers with diameters ranging from 50 to 100 nm. However, protocol (A) resulted in significantly lower particle recovery and exhibited an elevated protein-to-particle ratio relative to protocols (B) (C), and (D). Statistical analysis revealed no substantial variations in particle concentration or purity among methods (B) (C), and (D). Collectively, these findings indicate that enzymatic degradation of the matrix using cellulase prior to isolation markedly enhances EV recovery and purity. Compared to direct ultracentrifugation, cellulase-assisted methods yield higher particle counts, minimize co-isolated contaminants, and produce a more homogeneous size distribution.
Exploring the molecular link between arecoline exposure and prostate cancer-related alterations: integrative evidence from network toxicology, single-cell transcriptomics, molecular simulation, and experimental validation.
Zhu X, Liu H, Zeng Z … +3 more , Zou L, Zhou Y, Zhou T
Front Pharmacol · 2026 · PMID 42338969 · Full text
Arecoline, the major alkaloid of areca nut, is a common exposure in chewing products, but its relationship with prostate cancer (PCa) is unclear. We integrated network toxicology, bulk RNA machine learning, single-cell t...
Arecoline, the major alkaloid of areca nut, is a common exposure in chewing products, but its relationship with prostate cancer (PCa) is unclear. We integrated network toxicology, bulk RNA machine learning, single-cell transcriptomics, molecular simulation, and validation to prioritize candidate molecular nodes potentially linking arecoline exposure to PCa-related alterations. Potential arecoline targets were intersected with PCa-related genes, followed by protein-protein interaction and enrichment analyses. Candidate genes were prioritized using TCGA-PRAD and external GEO cohorts, then refined in GWAS-relevant epithelial subpopulations from GSE141445. AR was further evaluated by the Human Protein Atlas, molecular docking, molecular dynamics, RT-qPCR, and Western blotting. We identified 97 overlapping targets enriched mainly in apoptosis-, p53-, and MAPK-related pathways. The optimal bulk RNA model showed good external performance (AUC = 0.956). Integrative analyses identified androgen receptor (AR) as the only consensus core gene. AR-high epithelial cells showed increased androgen response, mTORC1 signaling, and MYC targets. Molecular simulation provided computational support for structural compatibility between arecoline and AR, while experiments showed increased AR mRNA and protein expression after arecoline treatment in LNCaP cells. These findings suggest AR as a plausible candidate molecular node linking arecoline exposure to PCa-related molecular alterations and provide a hypothesis-generating framework for future mechanistic and exposure-focused studies.
Crude Astragalus polysaccharides ameliorate cognitive impairment by preserving blood-brain barrier integrity and suppressing GSDMD-mediated pyroptosis in jellyfish-envenomed mice.
Yao Z, Li R, Li M … +3 more , Liang J, Chen H, Wang R
Front Pharmacol · 2026 · PMID 42338968 · Full text
INTRODUCTION: Jellyfish envenomation is an escalating global health threat that can induce severe neurotoxic consequences, but effective therapeutic strategies remain limited. This study investigated whether crude astrag...
INTRODUCTION: Jellyfish envenomation is an escalating global health threat that can induce severe neurotoxic consequences, but effective therapeutic strategies remain limited. This study investigated whether crude astragalus polysaccharides (APS) protect against jellyfish venom-induced cognitive impairment and explored the underlying mechanisms involving blood-brain barrier (BBB) integrity and pyroptosis. METHODS: A murine jellyfish envenomation model was established by intravenous venom injection. Mice were treated with APS, edaravone, or the Caspase-1-specific inhibitor VX-765. Behavioral performance was evaluated using the open field test and Morris water maze. Histopathological injury, cerebral edema, BBB permeability, tight junction protein expression, matrix metalloproteinase-9 (MMP9) expression, inflammasome/pyroptosis-related markers, and inflammatory cytokines were assessed using H&E staining, wet/dry weight measurement, Evans blue extravasation, western blotting, RT-qPCR, and ELISA. RESULTS: APS ameliorated venom-induced anxiety-like behaviors, locomotor deficits, and spatial memory impairment. Histopathologically, APS preserved hippocampal neuronal integrity and attenuated cerebral edema and hemorrhage. APS also reduced BBB disruption by suppressing MMP9 upregulation and restoring tight junction proteins, including ZO-1, Occludin, and Claudin-5. In addition, APS decreased JNK1 expression and inhibited activation of the NLRP3/Caspase-1/GSDMD pyroptotic pathway, as shown by reduced NLRP3 expression, Caspase-1 cleavage, GSDMD-N formation, and inflammatory cytokine release. VX-765 recapitulated the inhibitory effects of APS on pyroptotic markers and cytokines, including IL-1β, IL-18, and TNF-α. Co-administration of APS and VX-765 produced no additive benefit. DISCUSSION: These findings indicate that APS protects against jellyfish venom-induced neurotoxicity mainly by preserving BBB integrity and suppressing canonical Caspase-1-dependent GSDMD-mediated pyroptosis. APS may therefore represent a potential therapeutic candidate for marine envenomation-associated neurological injury.
Correction: Synthesis, characterization, and and profiling of selective cyclo-oxygenase-2 inhibitors of indazole-indolinone derivatives with anti-inflammatory and analgesic potency.
Alkubaysi SI, Sadiq Mantargi MJ, Almalki FA … +4 more , Alqahtani AM, Baryyan AO, Tayeb SM, Muathen HA
Front Pharmacol · 2026 · PMID 42338967 · Full text
[This corrects the article DOI: 10.3389/fphar.2025.1723200.].
[This corrects the article DOI: 10.3389/fphar.2025.1723200.].
Editorial: Plant polyphenols: new chemical and pharmacological approaches.
Boylan F, Kozyra M, Kukula-Koch W
Front Pharmacol · 2026 · PMID 42338966 · Full text
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GABA receptor dysfunction in autism spectrum disorder: molecular mechanisms and therapeutic opportunities.
Ragu Varman D, Sivamaruthi BS, Kesika P … +3 more , Martínez-Torres A, Reyes-Haro D, Chaiyasut C
Front Pharmacol · 2026 · PMID 42338965 · Full text
Autism spectrum disorder (ASD) comprises diverse neurodevelopmental trajectories in which altered circuit dynamics converge on a disturbance of excitation-inhibition balance. Genetic, , neuroimaging, and model-system evi...
Autism spectrum disorder (ASD) comprises diverse neurodevelopmental trajectories in which altered circuit dynamics converge on a disturbance of excitation-inhibition balance. Genetic, , neuroimaging, and model-system evidence implicates γ-aminobutyric acid type A (GABA) receptors as a major molecular node within this imbalance. ASD has been associated with changes in GABA receptor subunit expression and assembly, notably within 15q11-q13 clusters, impaired receptor trafficking and synaptic anchoring, and a shift in the relative contribution of phasic (synaptic, containing the γ2 subunit) tonic (extra-synaptic with δ or ρ) inhibition. studies reported reduced expression of GABA subunits, which correlates with decreased expression of glutamic acid decarboxylase 65/67, interneuron loss, particularly in parvalbumin networks that support gamma oscillations, and disrupted chloride homeostasis, which can delay the developmental "GABA switch" from depolarizing to hyperpolarizing signalling. Here, we review mechanistic advances across environmental and monogenic ASD models [e.g., prenatal valproate exposure, maternal immune activation, (SH3 and multiple ankyrin repeat domains 3), (fragile X messenger ribonucleoprotein 1), and (methyl-CpG binding protein 2) alongside human biomarker studies using proton magnetic resonance spectroscopy and positron emission tomography, highlighting how GABA receptor subtype- and circuit-specific inhibitory deficits map onto sensory, social, cognitive, and comorbid seizure phenotypes. We evaluate emerging therapeutic strategies that move beyond nonselective sedation, including α2/α3-and α5-preferring positive allosteric modulators, neurosteroid-based enhancers of tonic inhibition, and interventions targeting sodium-potassium chloride cotransporter 1/potassium chloride cotransporter 2-regulated chloride gradients, as well as activity-dependent approaches such as environmental enrichment. Finally, we outline priorities for precision translation: multimodal biomarker-guided stratification, developmentally timed intervention windows, and trials aligned to receptor subtype pharmacology and circuit endpoints. This review integrates molecular and translational research on GABA receptor dysfunction in ASD, emphasizing key mechanistic insights and potential therapeutic approaches. To develop precise GABAergic treatments, a comprehensive strategy that includes molecular profiling, biomarker-guided clinical trials, and insights from developmental neuroscience is necessary.
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