Frontiers in Pharmacology最新文献

This review provides a comprehensive synthesis of the ethnopharmacological uses, modern applications, phytochemistry, and pharmacological mechanisms of Hippophae rhamnoides L. (H. rhamnoides) It begins by detailing its foundational role in traditional medical systems within its native range, including Tibetan, Mongolian, and Chinese medicine, as well as its broader Eurasian ethnobotanical applications. The work then systematically outlines the plant's diverse modern utilizations in nutraceuticals, cosmeceuticals, pharmaceuticals, and environmental remediation. A thorough organ-specific analysis of its phytochemical architecture that identifies key bioactive constituents in berries, seeds and leaves links to demonstrated pharmacological effects, including hepatoprotective, anti-inflammatory, cardioprotective and neuroprotective activities. A critical discussion on the potential interference of Pan-Assay Interference Compounds (PAINS) is included to provide a necessary caveat for interpreting bioactivity data. Finally, the review identifies persistent challenges including phytochemical standardization and the translational gap between preclinical and clinical research, and proposes future research directions focused on rigorous clinical trials, mechanistic studies and sustainable exploitation within a circular bioeconomy framework.

Background: Novel synthetic opioids (NSOs), including a variety of fentanyl analogs (FAs) and emerging non-fentanyl compounds, have increasingly been implicated in overdose fatalities worldwide. Among these, 4-fluoro-furanylfentanyl (4F-FUF) is a potent FA with limited in vivo pharmacotoxicological characterization. In this study, we aimed to i. evaluate the pharmacotoxicological effects of 4F-FUF in male and female mice, ii. determine its pharmacokinetic profile in plasma and tissues of both sexes, and iii. correlate behavioral and physiological responses with plasma concentrations.

Methods: Female and male mice were injected intraperitoneally with 4F-FUF at an effective dose of 5 mg/kg. Behavioral and physiological responses, including sensorimotor, motor, and respiratory parameters, were assessed at multiple timepoints post-administration. Plasma and tissue samples (brain, heart, liver, spleen, lung, kidney, and stomach) were collected to determine 4F-FUF concentrations and pharmacokinetic parameters. Correlations between plasma levels and behavioral or physiological outcomes were analyzed separately by sex.

Results: 4F-FUF impaired the sensorimotor and motor responses in females and males. Moreover, the FA induced persistent antinociception in males with respect to females. The respiratory depression was sudden and more pronounced in male mice. Plasma concentrations of 4F-FUF were higher and persisted longer in males, indicating slower clearance than in females. This drug was highly distributed in the brain and liver tissues of both sexes. Significant correlations were detected in visual placing, vibrissae responses, spontaneous locomotion, and mechanical analgesia in both sexes. Interestingly, the respiratory rate was only significantly correlated with plasma concentrations in females, highlighting potential sex-specific differences in the relationship between drug exposure and physiological effects.

Conclusion: The findings demonstrate marked sex-specific differences in the behavioral and physiological changes and pharmacokinetics of 4F-FUF. These results underscore the importance of considering sex-specific differences in assessing the toxicity and risk profiles of novel synthetic opioids.

Introduction: Spironolactone (SPI), a mineralocorticoid receptor antagonist with anti-androgenic activity, has emerged as a candidate for drug repurposing in prostate cancer (PCa). However, the cellular pharmacology governing its impact on the tumor microenvironment and specific molecular targets remains incompletely understood. This study aims to elucidate the regulatory circuitry linking SPI to immune modulation and tumor suppression in the PCa ecosystem.

Methods: We employed an integrated framework combining network pharmacology with bulk, single-cell (scRNA-seq), and spatial transcriptomics (ST) to prioritize SPI-associated targets and map their microenvironmental context. The clinical and immunological relevance of the top candidate, Wilms Tumor 1 (WT1), was assessed using TCGA and GEO datasets. Finally, molecular docking and in vitro gain-of-function assays (proliferation, migration, clonogenicity, and apoptosis) in DU145 and PC-3 cell lines were conducted to validate functional mechanisms.

Results: Network pharmacology identified WT1 as a central regulatory node in the SPI-PCa interaction network. In clinical cohorts, WT1 was significantly downregulated in tumor tissues compared to normal prostate; however, preserved high WT1 expression correlated with improved disease-free survival. Crucially, WT1-high tumors exhibited an "immune-hot" phenotype characterized by enhanced T-cell infiltration and antigen presentation pathways. scRNA-seq and ST analyses revealed that WT1 is heterogeneously expressed across malignant and stromal compartments, localizing to specific immune-interacting niches. Molecular docking suggested a potential structural compatibility between SPI and WT1, although direct binding remains to be experimentally confirmed. Functionally, restoring WT1 expression in PCa cells potently suppressed malignant behaviors, inhibiting proliferation and migration while triggering apoptosis.

Conclusion: This study defines a novel SPI-WT1 axis, positioning WT1 as a druggable, immune-correlated biomarker in prostate cancer. By linking SPI pharmacology to WT1-associated microenvironmental features and tumor suppression, our findings provide a mechanistic rationale for repurposing Spironolactone as an immunomodulator to overcome therapeutic resistance in genitourinary oncology.

Background: Cyclovirobuxine D (CVB-D), an alkaloid from Buxus microphylla, exhibits anticancer effects in various tumors, but its role in osteosarcoma remains unexplored. This study investigates its efficacy and mechanism in osteosarcoma.

Methods: We screened a drug library and evaluated CVB-D's effects on osteosarcoma cell lines using CCK-8 and colony formation assays. Saos2 and K7M2 cells were selected for further analysis. Flow cytometry assessed apoptosis and cell cycle. RNA-seq identified downstream pathways, including NF-kappaB, and stemness markers (CD24, ALDH1A1). Stemness was examined via serum-free suspension culture, and NF-kappaB pathway activator Diprovocim was used in rescue experiments. A xenograft mouse model validated the findings.

Results: CVB-D suppressed proliferation, stemness, and induced apoptosis in osteosarcoma. These effects may be partially mediated through the p-NF-kappaB2/NF-kappaB2 axis and were reversible upon NF-kappaB pathway activation.

Conclusion: CVB-D inhibits osteosarcoma possibly via the non-canonical NF-kappaB pathway, suggesting a potential therapeutic strategy.

The advent of optogenetics, chemogenetics, and high-density neural recording technologies has propelled systems neuroscience into a golden age, generating unprecedented mechanistic insights into how defined neural circuits orchestrate behaviour. These tools have allowed us to move beyond correlational observations to establish causal links between specific circuit dynamics and behavioural states. However, a profound and disheartening translational dilemma has emerged: the pace at which these foundational discoveries in model organisms have yielded novel, effective therapeutics for human neuropsychiatric disorders remains glacial. This review argues that this dilemma is not a failure of the science itself but a consequence of a multi-layered gulf between basic discovery and clinical application. This gulf encompasses technological, phenomenological, and biological disparities. We analyse the roots of this impasse and propose a concerted, multi-pronged strategy to bridge it, focusing on back-translation, cross-species behavioural dimensionalization, the development of non-invasive neuromodulation, and the fostering of deeply integrated interdisciplinary collaborations. The path forward requires a fundamental shift in how we design, interpret, and prioritize neural circuit research with translation in mind.

Background: Fixed-dose combination (FDC) antihypertensive therapy is recommended by contemporary guidelines to improve adherence and blood pressure control. However, real-world evidence evaluating its impact on healthcare utilization, compared with the multi-pill combination (MPC) therapy in hypertension (HTN) patients, remains limited. This study compared healthcare utilization among US adults with HTN receiving FDC versus MPC therapy.

Methods: We conducted a cross-sectional study on nationally representative data from the Medical Expenditure Panel Survey (2013-2022). Adults aged ≥18 years with a diagnosed HTN on ≥2 antihypertensive classes were classified as FDC or MPC users. Inverse probability of treatment weighting was applied to balance covariates. Weighted negative binomial regression models were used to assess the impact of FDC versus MPC on healthcare utilization, including office-based visits, outpatient visits, emergency department visits, hospitalizations, and prescription fills. A 1:1 propensity score matching (PSM) analysis was conducted as a sensitivity analysis to assess findings robustness.

Results: Among 18,269 adults receiving ≥2 antihypertensive therapies, 5,849 were FDC users, and 12,420 were MPC users. Compared with MPC users, FDC users had significantly lower emergency department visits (rate ratio [RR] = 0.712; 95% confidence interval [CI]: 0.636-0.796; p < 0.0001), hospitalizations (RR = 0.721; 95% CI: 0.545-0.953; p = 0.0219), office-based visits (RR = 0.934; 95% CI: 0.879-0.993; p 0.0281), and prescription fills (RR = 0.853; 95% CI: 0.815-0.893; p < 0.0001). No significant difference was observed in the outpatient visit rate. Findings were consistent in PSM analysis.

Conclusion: FDC antihypertensive therapy was associated with significantly lower acute care utilization and prescription burden while preserving routine outpatient care, compared with the MPC therapy. These findings support FDC therapy use as a high-value strategy to enhance real-world HTN management and reduce acute healthcare utilization.

Introduction: Major depressive disorder (MDD) is a leading cause of global disability. Current treatments are limited by poor efficacy in approximately one-third of patients. Neuroinflammation may be an underlying mechanism of MDD and represents a novel target for pharmacological therapy. This study aimed to investigate the effects of a putative centrally acting anti-inflammatory agent, low-dose naltrexone (LDN), in MDD.

Methods: Patients with MDD experiencing moderate depressive symptoms and receiving antidepressant treatment were randomized to receive 12 weeks of LDN (up to 4.5 mg per day) or 12 weeks of inactive placebo. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale (MADRS) at 12 weeks, analyzed using a linear mixed-effects model adjusted for baseline.

Results: Thirty-seven patients were randomized. At 12 weeks, MADRS scores (M ± SD) were reduced by 10.5 ± 5.6 in the LDN group and 9.8 ± 5.9 placebo group; with no difference between groups (p = 0.97). LDN did not affect high-sensitivity C-reactive protein (hsCRP) levels or exploratory measures of depression, behavioral activation, quality of life, sickness symptoms and mood. There was no evidence that baseline hsCRP modified the effect of LDN on MADRS score.

Discussion: Adjunctive LDN does not appear to alter depressive symptoms in moderate MDD. Larger studies are warranted to evaluate LDN in a population with a higher likelihood of neuroinflammatory pathology, such as those with severe, treatment-resistant MDD or comorbid inflammatory conditions. Future studies should utilize stratification tools that are more sensitive and specific to neuroinflammation than hsCRP.

Clinical trial registration: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=383741&isReview=true, identifier [ACTRN12622000881730].

Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer with increasing incidence. The anti-PD-1 therapy cemiplimab has shown its antitumor activity in locally advanced (lacSCC) and metastatic cSCC (mcSCC). This retrospective study assessed the real-life effectiveness and safety of cemiplimab in 83 patients with lacSCC (n = 53) and mcSCC (n = 30). The objective response rate (ORR) was 49.4%, with a complete response (CR) in 15.7% and a partial response (PR) in 33.7%. The median progression-free survival (PFS) was 14 months (95% CI 9-55) and the median overall survival (OS) 19 months (95% CI 10-39). Half of patients (50.6%) experienced adverse events (AE) of any grade, with 8.4% discontinuing therapy due to the severe AEs. The subset of patients who experienced progression during therapy displayed younger age (p = 0.002), a higher disease stage at baseline (p = 0.003), and a nodal disease (p = 0.041). No differences in survival outcome emerged between patients with nodal vs. distant metastases, previous radiotherapy recipient vs. radiotherapy-naïve, and immunosuppressed vs. immunocompetent patients. Head&neck tumor site was associated with a longer OS after first progression (OS2, HR 0.29, 95% CI 0.09-0.89). This study supports the safe and effective use of cemiplimab in real life clinical practice yet highlights the need for further identification of new predictors of clinical response.

The integration of clinical and real-world evidence represents one of the most critical transformations in modern drug development and health technology assessment (HTA). Despite increasing regulatory openness, however, clinical trial evidence and real-world data (RWD) still operate largely as parallel rather than fully complementary systems. This commentary argues that experimental and observational research are not competing paradigms but two interdependent components of a unified evidence ecosystem, each capturing distinct yet equally essential dimensions of patient reality. Randomized controlled trials (RCTs) typically enrol highly selected populations and are optimised for internal validity, whereas RWD reflect the heterogeneity, comorbidities, and lived experiences of patients in routine clinical practice. Integrating these two evidence streams is therefore fundamental for personalised medicine, where the objective is to generate evidence that is both scientifically rigorous and meaningfully reflective of individual patient needs. This narrative Policy & Practice Commentary synthesises regulatory guidance, methodological literature, and applied case examples to examine how leading regulatorsand HTA agencies, including the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA), Medicines and Healthcare products Regulatory Agency (MHRA), Pharmaceuticals and Medical Devices Agency (PMDA), and National Institute for Health and Care Excellence (NICE), are developing frameworks to support the use of RWD and real-world evidence (RWE) in regulatory approval and reimbursement decision-making. Areas of convergence and divergence are explored, with particular emphasis on methodological transparency, data provenance, causal inference, and reproducibility as shared quality anchors across jurisdictions. Illustrative case examples from oncology and ophthalmology are used to demonstrate both the opportunities and challenges of hybrid evidence generation. In oncology, RWD are increasingly applied in external and hybrid control arms, pragmatic designs, and post-authorisation safety and effectiveness studies. In ophthalmology, advances in artificial intelligence-enabled image analytics and disease registries illustrate how routinely collected clinical data and patient-reported outcomes can be integrated to inform real-world value assessment. The commentary concludes by proposing actionable policy and practice recommendations to operationalise integrated evidence models, focusing on harmonised governance and methodological standards, transparent reporting and cross-sector collaboration, systematic incorporation of patient-generated data, and incentives for early and lifecycle-oriented RWD generation. By aligning regulatory policy, analytical methodology, and patient-centred design, integrated RWE frameworks can support decisions that are both scientifically robust and genuinely reflective of real-world patient experience.

Objective: To assess the clinical value of the ALBI score and age in predicting trastuzumab resistance in patients with HER-2 positive breast cancer (BC).

Methods: A retrospective cohort study was conducted on patients with HER-2 positive BC treated with trastuzumab at the Department of Thyroid and Breast Surgery of Affiliated Hospital of Shandong University of Traditional Chinese Medicine from December 2017 to December 2023. Patients were divided into a resistance group and a non-resistance group based on the development of resistance after trastuzumab treatment. Multivariate logistic regression models were used to identify independent predictors of trastuzumab resistance, and ROC curves analysis was conducted to evaluate the predictive value of ALBI score and patients age.

Results: This study included 95 female patients with HER-2 positive BC treated with trastuzumab, aged 31-71 years (mean age 53.15 ± 10.063 years). Based on the development of resistance after trastuzumab treatment, patients were divided into a resistant group (11 cases, 11.6%) and a non-resistant group (84 cases, 88.4%). Compared with the non-resistant group, the resistant group showed significantly higher age, ALBI score, and carcinoembryonic antigen (CEA) levels (P < 0.05). Both ALBI score (OR = 0.113, 95% CI: 0.014-0.904) and age (OR = 0.935, 95% CI: 0.875-1.000) were independent predictors of trastuzumab resistance in HER2-positive BC patients. ROC curve analysis showed that the combination of age and ALBI score predicted resistance with an AUC of 0.771 (95% CI: 0.642-0.900), sensitivity of 72.7%, and specificity of 77.4%, demonstrating significantly superior predictive performance compared to ALBI score or age alone.

Conclusion: Both ALBI score and age are independent predictors influencing trastuzumab resistance in HER-2 positive BC patients. Their combined use enhances predictive accuracy and may facilitate early identification of patients at increased risk of developing resistance to trastuzumab.