Frontiers in Pharmacology最新文献

Natural killer (NK) cells play critical roles as effector cells by directly identifying and killing virus-infected and cancer cells. Pteryxin exhibits diverse antioxidant and anti-inflammatory effects; despite its known properties, the influence of pteryxin on NK cells is not understood fully. In this study, we evaluated the potential of pteryxin to enhance the cytotoxicity of NK cells. Pteryxin markedly enhanced the cytotoxic activities of both NK-92 and primary human NK cells against leukemia and colorectal cancer cell lines in a dose-dependent manner. Furthermore, it elevated the surface expression of key activating receptors NKp30, NKp46, and 2B4 in the NK-92 cells. This upregulation was accompanied by activation of the ERK and AKT signaling pathways, leading to increased production of cytotoxic mediators, including granzyme B and perforin. Moreover, in vivo studies using the CT26 mouse model revealed that pteryxin administration inhibited tumor growth in a dose-dependent manner. NK cells from the pteryxin-treated mice demonstrated enhanced cytotoxicity against YAC-1 leukemia cells. The anticancer effects of pteryxin were abolished when the NK cells were significantly reduced using anti-asGM1 antibody, confirming the critical role of the NK cells in its antitumor activity. Collectively, these findings demonstrate that pteryxin stimulates the ERK and AKT signaling pathways to enhance NK cell cytotoxicity against tumors, supporting its potential as a novel enhancer of NK-cell-driven antitumor responses.

Background: In the intensive care unit (ICU), septic patients frequently require endotracheal intubation followed by invasive mechanical ventilation. Nonetheless, the optimal sedation-analgesia regimen for these critically ill patients remains undetermined.

Methods: This retrospective observational study analyzed data from the Medical Information Mart for Intensive Care IV (MIMIC-IV version 3.0) database to examine septic patients who underwent endotracheal intubation and subsequent invasive mechanical ventilation in the intensive care unit. Initially, Kaplan-Meier survival analysis and Cox proportional hazards models were employed to evaluate the prognostic impact of different sedation-analgesia regimens. Subsequently, the least absolute shrinkage and selection operator (LASSO) regression was utilized to identify key prognostic factors. Multiple machine learning algorithms were then implemented to develop predictive models, and the SHapley Additive exPlanations (SHAP) method was used to interpret the model outputs and determine the most influential predictors.

Results: Following the initial screening process, seven distinct sedation-analgesia regimens with sample sizes greater than 100 were incorporated into the final analysis. Utilizing Kaplan-Meier estimates and Cox regression models, the combination of fentanyl and midazolam was identified as the most advantageous regimen. This association remained statistically significant after adjusting for confounding variables, demonstrating a reduction in the length of stay in the intensive care unit (length of stay in ICU, HR [95% CI]: 0.66 [0.52-0.85]) and a decrease in ICU mortality (OR [95% CI]: 0.62 [0.46-0.85]). Subsequently, LASSO regression analysis identified seven key prognostic factors associated with outcomes in this patient subgroup. Among the machine learning models developed for outcome prediction, the LightGBM model exhibited superior performance (AUC = 0.838). SHAP analysis indicated that the top three predictors of 28-day mortality were the Acute Physiology Score III (APS III), patient age, and the presence of acute renal failure.

Conclusion: The concurrent administration of fentanyl and midazolam was associated with lower ICU mortality and shorter length of ICU stay among septic patients necessitating endotracheal intubation and invasive mechanical ventilation, suggesting potential clinical benefit. Furthermore, the LightGBM algorithm exhibited superior predictive accuracy for ICU mortality within this cohort, suggesting its potential utility as a tool for supporting data-driven clinical decision-making.

Background: This study aimed to comprehensively investigate the therapeutic effects of ginsenoside Rk1 on LPS-induced cognitive impairment and elucidate its underlying mechanisms, with a particular focus on synaptic plasticity and related signaling pathways, thereby providing robust theoretical and experimental support for its neuroprotective application.

Research methods: Network pharmacology identified potential therapeutic targets and pathways of ginsenoside Rk1 relevant to inflammation-induced cognitive impairment, and molecular docking assessed its binding affinity with key predicted proteins. In vitro, mouse bone marrow-derived macrophages (BMDMs) were used to determine the optimal non-cytotoxic concentration of ginsenoside Rk1 via CCK-8 assay. LPS and ATP were used to induce inflammation, and ELISA and RT-qPCR quantified pro-inflammatory cytokines and mRNA expression of Akt isoforms. For in vivo validation, male C57BL/6 mice were administered ginsenoside Rk1 (at an optimal dose of 20 mg/kg·d^-1, i.g.) for 21 days, with LPS (500 μg/kg·d^-1, i.p.) challenging on Day 22 and continued treatment for 7 days post-LPS. Cognitive function was assessed using the Morris water maze (MWM). Hippocampal samples were then analyzed for inflammatory factors, synaptic protein expression (PSD-95, SYN by RT-qPCR and immunofluorescence), microglial activation (Iba1 immunofluorescence), and dendritic spine density (Golgi staining).

Results: Network pharmacology successfully identified significant overlaps between ginsenoside Rk1 targets and pathways associated with inflammation and cognitive impairment, prominently featuring the PI3K/Akt pathway. Molecular docking simulations confirmed strong binding affinities between ginsenoside Rk1 and key proteins in this pathway. In vitro, ginsenoside Rk1 significantly reduced LPS/ATP-induced levels of TNF-α, IL-1β, and IL-6, and attenuated the upregulation of Akt1, Akt2, and Akt3 mRNA expression. In vivo, ginsenoside Rk1 treatment profoundly improved spatial learning and memory in LPS-challenged mice. This cognitive improvement was paralleled by a significant attenuation of hippocampal neuroinflammation. Crucially, ginsenoside Rk1 significantly reversed LPS-induced synaptic dysfunction, characterized by increased mRNA and protein expression of PSD-95 and SYN, and a marked elevation in neuronal dendritic spine density in the hippocampus.

Conclusion: This study provides compelling evidence that ginsenoside Rk1 effectively alleviates LPS-induced cognitive dysfunction by ameliorating neuroinflammation and significantly enhancing synaptic plasticity. The mechanistic insights suggest that these neuroprotective effects are mediated, at least in part, through the modulation of the PI3K/Akt signaling pathway.

Therapy resistance is a major challenge in cancer treatment. Growing evidences reveal that the interaction between ubiquitination and autophagy plays a key role in regulating resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy. In this review, we systematically summarize recent studies that reveal how specific E3 ligases, deubiquitinating enzymes, and ubiquitin-like modifiers influence autophagic flux and modulate the tumor response. We focus on key regulatory circuits-such as the Tripartite-motif protein 65-miR-138-5p-Autophagy related 7 (TRIM65-miR-138-5p-ATG7)pathway in non-small cell lung cancer, the Cullin-RING Ligase 4(CRL4)-mitophagy signaling pathway in ovarian cancer, and the Ubiquitin Specific Peptidase 14-S-phase kinase-associated protein 2(USP14-Skp2) axis in B-Raf proto-oncogene (BRAF) inhibitor resistance-illustrating the dual regulatory functions of ubiquitin-dependent protein turnover and autophagy. Furthermore, we highlight how noncoding RNAs and the tumor microenvironment influence ubiquitination-modulated autophagy and contribute to immune resistance or DNA repair remodeling. Finally, we discuss potential therapeutic strategies, including Proteolysis Targeting Chimeras (PROTACs), dual E3 ligase/autophagy inhibitors, and autophagy flux modulators, to overcome resistance and enhance treatment efficacy across multiple cancer types. These insights establish the foundation for targeting the ubiquitin-autophagy network as a cohesive strategy to combat refractory cancer.

Background: Cisplatin (DDP) is the first-in-class drug for advanced and non-targetable non-small-cell lung cancer (NSCLC). Platinum-based chemotherapy combined with pemetrexed (PEM) is frequently recommended as the first-line therapeutic regimen for NSCLC. However, the mechanisms of how PEM boosts the antitumor activity of DDP are largely unknown. Emerging evidence indicated that DDP could induce ferroptosis, a new type of regulated cell death (RCD) characterized by iron-dependent toxic build-up of lipid peroxides on cellular membranes. It is tempting to speculate whether PEM increases the sensitivity of NSCLC to DDP through inducing ferroptosis.

Methods: In the present study, we first used RNA-seq and KEGG analysis to examine differentially expressed genes in PEM-challenged NSCLC cells. The effect of PEM on increased DDP-mediated anticancer activity was examined via a cytotoxicity assay and Western blot. PEM-triggered ferroptosis in DDP-treated NSCLC was observed via a lipid peroxidation assay, a labile iron pool assay, and a Western blot in the presence or absence of ferroptosis inhibitors.

Results: In the present study, we found that the ferroptosis-related pathway was enriched by PEM. PEM significantly enhanced the ability of cisplatin to inhibit cell viability and proliferation in NSCLC cells. The combination of PEM and DDP synergistically induced ferroptosis, as evidenced by the increased reactive oxygen species (ROS), lipid peroxidation, and Fe²⁺ and decreased SOD. PEM facilitated DDP-mediated upregulated expression of pro-ferroptosis proteins (ACSL4, 12LOX, COX2, DMT1, TFR1, and TF) and downregulated the expression of anti-ferroptosis proteins (SLC7A11, GPX4, FPN1, FTH1, FTL, DHODH, FSP1, and GCH1). However, the effects were reversed by ferroptosis inhibitor ferrostatin-1 or deferoxamine in NSCLC cells.

Conclusion: In summary, these results provide in vitro experimental evidence that PEM boosts the antitumor activity and increases the sensitivity of NSCLC cells to DDP by inducing ferroptosis.

Objective: To explore the effect and mechanism of the Yiqi Huoxue Granule in improving the survival of mesenchymal stem cells (MSCs) induced by hypoxia and promoting angiogenesis in damaged tissues.

Methods: Animal experiments: A rat skin injury model was established. The skin healing degrees were compared among the model group, MSC group, and Yiqi Huoxue Granule group and Yiqi Huoxue Granule combined with MSC group. The intensity of DIR-labeled MSCs was observed by frozen section, and the expression of CD31 in tissues was detected by immunofluorescence. Cell experiments: A hypoxic MSC model was constructed. The effect of the Yiqi Huoxue Granule on the viability of hypoxic MSCs was detected by CCK8. Flow cytometry was used to observe the apoptosis rate of MSCs. The effect of Yiqi Huoxue Granule on tube formation of MSCs was observed by tube formation assay. Differentially expressed genes were analyzed using transcriptomics and verified through RT-PCR. Key factors were analyzed by PPI.

Results: DIR-labeled MSCs showed that at a concentration of 50 μM, the count of red spots in MSCs significantly increased compared to 12.5 μM and 25 μM (P < 0.01 or 0.001), and there was no statistical difference in cell viability compared to the 12.5 μM and 25 μM groups (P > 0.05), thus 50 μM DIR was selected for in vivo tracing. On the 11th day of intervention, compared to the model group, MSC group, and Yiqi Huoxue Granule alone group, the wound diameter in the Yiqi Huoxue Granule combined with MSC group was significantly reduced (P < 0.05). On the 7th day of intervention, the percentage of CD31 fluorescence area in the Yiqi Huoxue Granule combined with MSC group was significantly increased compared to the MSC group (P < 0.01), and compared to the MSC group, the MSC combined with Yiqi Huoxue Granule increased the MSC DIR fluorescence area and intensity (P < 0.05). Cell experiment results showed that compared to the hypoxic model group, high-dose Yiqi Huoxue Granule reduced MSC apoptosis (P < 0.001) and promoted lumen formation. Transcriptomic analysis identified 19 apoptosis-related genes linked to hypoxia. Following RT-PCR and PPI analysis, 9 genes centered around Csf2 were selected. Among these, Csf2, Il1a, Il6, Fgf10, and Cd274 were found to be upregulated, while Ccl2, Pde1a, Nptx1, and Igfbp3 were downregulated.

Conclusion: This research offers a novel perspective for MSC apoptosis using Yiqi Huoxue Granule. Yiqi Huoxue Granule promotes the survival of MSCs under hypoxia and in damaged skin tissue, improves angiogenesis in damaged skin tissue, accelerates skin wound healing, and is closely related to the elevation of Csf2.

Background: Antiretroviral therapy (ART) has revolutionized the clinical management of people with human immunodeficiency virus (HIV), transforming HIV infection into a chronic condition. Yet, the mechanisms of action and off-target effects of modern combination ART regimens versus individual ART medications are not fully understood.

Methods: Using the L1000 assay, we profiled transcriptional responses to 11 single ART drugs and 6 ART combination regimens across three human cell lines, HepPG2 (liver), HK2 (kidney), and THP-1 (monocyte). Differentially expressed genes were analyzed against host-HIV protein-protein interactions (PPIs) and genes implicated in ART-associated side effects.

Results: Across all cell types, ART combination regimens induced distinct transcriptional profiles compared with their component drugs. Combinations more strongly perturbed genes encoding proteins involved in HIV-host PPIs, consistent with their enhanced antiviral efficacy. Transcriptional responses also recapitulated known ART-induced adverse effects related to dyslipidemia, altered body composition, and renal impairment. Combination regimens were less coupled to these gene signatures, suggesting mechanisms that may underlie their improved safety profiles. Several genes and pathways were consistently modulated across treatments: ACTG1, or actin gamma 1 - a gene that encodes gamma actin, a protein crucial for the localization of the HIV reverse transcription complex, was downregulated in four combination regimens, while ORM2, Orosomucoid 2, upregulation emerged as a common response to individual drugs. ACTG1 was previously found to be downregulated in ART naïve people living with HIV who naturally control HIV replication, suggesting its role as a candidate host mediator. To facilitate data exploration, we developed ARTexpress, an interactive portal enabling visualization of gene expression changes before and after ART exposure across all three cell lines.

Conclusion: ART regimens affected transcriptional signatures of genes involved in HIV-host PPIs and were less tied to common ART-related side effects. Our findings support the use of high-throughput transcriptomics to detect specific mechanisms of ART on- and off-target effects to help prioritize new drug targets and compounds in future development and optimization of safer and more efficient ART.

Objective: This study aimed to detect risk signals of drug-related ocular injuries, delineate their real-world epidemiological features, and provide evidence-based guidance for safe clinical use by utilizing the US Food and Drug Administration Adverse Event Reporting System (FAERS).

Methods: Adverse event reports classified under "Eye disorders" (System Organ Class, SOC) were extracted from the FAERS database covering Q1 2004 to Q4 2024. Disproportionality analyses were employed to identify drug-ocular injury associations, and the time-to-onset (TTO) of adverse reactions was analyzed using Weibull distribution modeling.

Results: A total of 1,242,518 reports from 832,314 patients were included, with females accounting for 60.56% and elderly patients (≥65 years) for 21.63%. Serious outcomes comprised 62.80% of the reports. In total, 2,696 primary suspect drugs were identified, of which 359 met the signal detection criteria. High-risk drug categories included sensory organ drugs (ATC: S class, ROR = 4.93) and antineoplastic/immunomodulating agents (ATC: L class, most reports but ROR = 0.84). The top three drugs by signal strength were brolucizumab (ROR = 132.15), macrogol 400 (ROR = 117.96), and cenegermin (ROR = 60.19). The most common ocular injury types were blurred vision (121,517 cases), visual impairment (113,320 cases), and cataract (51,826 cases). TTO analysis indicated that most drugs exhibited an "early failure type" (β < 1), such as dupilumab (β = 0.68); only two drugs exhibited a random failure type.

Conclusion: The risk of drug-related ocular injuries is primarily associated with sensory organ drugs and biologics, with the greatest risk occurring during the early treatment phase. Clinical monitoring should prioritize female and elderly patients, especially regarding ocular symptoms at the onset of drug therapy, to strengthen pharmacovigilance and inform personalized medication.

Stroke poses a severe threat to human health, with limited therapeutic options currently available. Astragaloside IV (AS-IV), a primary bioactive metabolite derived from Astragalus membranaceus, exhibits multifaceted pharmacological effects, including anti-inflammatory, anti-fibrotic, and antioxidative properties. This review systematically examines recent advances in AS-IV research for stroke treatment, detailing its sources, physicochemical characteristics, mechanisms of action, and therapeutic efficacy in both in vitro and in vivo models. We critically analyze the potential of AS-IV as an adjunctive therapy for stroke, addressing current research hotspots, challenges, and emerging strategies. Notably, AS-IV synergistically enhances neuroprotection when combined with other plant-derived metabolites. This work provides a theoretical foundation for further development of AS-IV in stroke management. In summary, AS-IV demonstrates significant promise as a natural neuroprotective agent worthy of continued exploration for adjuvant stroke therapy.