Frontiers in Pharmacology最新文献

Gastric cancer is the fifth most common cancer and the third most common cause of cancer death globally. Patients with advanced gastric cancer have poor outcomes and short survival times. This case report presents a remarkable clinical response in a patient with advanced Epstein-Barr virus (EBV)-associated gastric adenocarcinoma treated with a combination of chemotherapy, Claudin18.2-targeted therapy (TST001), and PD-1 inhibition (nivolumab). The patient, initially diagnosed with stage IA disease (pT1bN0M0) after Billroth II gastric resection was performed due to early carcinoma, later developed metastases to the liver, cervicothoracic lymph nodes and abdominal lymph nodes. The patient received seven cycles of CAPOX (capecitabine + oxaliplatin), nivolumab, and TST001, achieving partial response (PR) after treatment. Treatment was discontinued due to aortic dissection requiring surgery. Surprisingly, despite no further antitumor therapy, follow-up imaging over 19 months revealed continued tumor shrinkage, culminating in a near complete response (CR). Therefore, the combination of chemotherapy, Claudin18.2-targeted therapy, and PD-1 inhibitor may be a good treatment strategy for gastric cancer.

Objective: To investigate the mechanism of Th17 cells in immunomodulation during periodontitis and develop a localized drug delivery system based on glycolysis inhibition for safer and more effective therapeutic interventions.

Methods: Periodontitis models were established via the use of IL17A-KO mice to evaluate the impact of Th17-related cytokine deficiency on pathological progression. Using single-cell RNA sequencing (scRNA-seq), we investigated the metabolic profile of CD4⁺ T cells under periodontitis conditions. The glycolysis inhibitor 2-deoxy-D-glucose (2-DG) was used to assess its ability to suppress CD4⁺ T-cell proliferation and Th17 differentiation. A thermosensitive PLGA-PEG-PLGA hydrogel encapsulating 2-DG was synthesized and locally administered to a murine periodontitis model.

Results: IL17A-KO mice exhibited significantly attenuated alveolar bone resorption. Single-cell RNA sequencing revealed that, under periodontitis conditions, CD4⁺ T cells exhibited enhanced differentiation toward Th17 cells and increased glycolysis. The 2-DG hydrogel inhibited CD4⁺ T-cell expansion and Th17 polarization. Local application of the 2-DG hydrogel reduced periodontal inflammation, decreased bone destruction, and diminished granulocyte infiltration in gingival tissues.

Conclusion: Th17-cell differentiation exacerbates periodontitis progression, and glycolysis inhibition effectively modulates Th17-driven immunity. The localized 2-DG hydrogel delivery system presents a promising translational strategy for periodontitis management.

Objective: Several previous studies have indicated that febuxostat can reduce uric acid (UA) levels and has a renoprotective effect on renal transplant recipients with hyperuricemia, but a comprehensive analysis of this effect is lacking. This meta-analysis aimed to analyze the effects of febuxostat on UA and renal function in renal transplant recipients with hyperuricemic disease.

Methods: Web of Science, PubMed, the Cochrane Library, Wan Fang, and CNKI were searched up to 17 October 2024.

Results: In renal transplant recipients with hyperuricemia, febuxostat decreased the UA level, with an MD of 129.981 μmol/L (P < 0.001). Creatinine (Cr) decreased (P = 0.337), whereas the estimated glomerular filtration rate (eGFR) increased, with a mean difference of -1.878 mL/min/1.73 m², reaching a margin of statistical significance (P = 0.075) after the administration of febuxostat. In terms of other biochemical indices, febuxostat increased only hemoglobin (P = 0.008) but did not affect white blood cells, aspartate transaminase, or alanine aminotransferase (all P > 0.05). Sensitivity analysis revealed that the omission of most studies did not affect the study findings. The quality of the included studies was acceptable, and no publication bias existed.

Conclusion: Febuxostat has a satisfactory UA-lowering effect, but its renoprotective effect is uncertain in renal transplant recipients with hyperuricemia. More studies are warranted to further explore its role in improving the prognosis of these patients.

Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261300034.

Object: This study aims to compare the efficacy and safety of ciprofol versus propofol in sedation for patients undergoing non-invasive positive pressure ventilation (NPPV), with a focus on evaluating sedative efficiency and systematically comparing the incidence of respiratory depression, circulatory depression, and adverse reactions.

Methods: A retrospective analysis was conducted on the clinical data of 120 patients receiving NPPV at our hospital between June 2024 and October 2025. According to the sedative agent used, patients were divided into a Ciprofol group (Group C, n = 56) and a Propofol group (Group P, n = 64). The primary outcome was the sedation induction time, defined as the duration from drug administration to the first achievement of the target Richmond Agitation-Sedation Scale (RASS) score of -2 to 0. Secondary outcomes included the recovery time, extubation time, dynamic changes in respiratory rate, peripheral oxygen saturation (SpO₂), and mean arterial pressure (MAP) during treatment, as well as the incidence of adverse reactions such as hypoxemia (SpO₂ < 90%), hypotension, and injection pain.

Results: Regarding the primary outcome, the sedation induction time was comparable between the two groups, with no statistically significant difference (p > 0.05). Analysis of secondary outcomes revealed that the Ciprofol group demonstrated several advantages: ① Enhanced Safety Profile: The incidences of hypoxemia and hypotension were significantly lower in the Ciprofol group (p < 0.05). ② Faster Recovery: Both emergence time and full recovery time were shorter in the Ciprofol group compared to the Propofol group (p < 0.05). ③ Improved Tolerability: The incidence of injection pain was markedly lower in the Ciprofol group (p < 0.001), and fluctuations in respiratory and circulatory parameters during treatment were also reduced.

Conclusion: For patients undergoing NPPV, ciprofol provides sedation efficacy comparable to propofol while demonstrating a superior safety profile, faster recovery, and enhanced injection tolerability. This combination of advantages makes ciprofol a preferable alternative for sedation in this clinical setting.

Background: Huangkui capsule (HKC), a Chinese herbal medicine derived from Abelmoschus manihot (L.) ethanol extract, has clinical efficacy against diabetic nephropathy (DN). Our research group has actively engaged in exploring the efficacy of HKC in treating DN. The underlying pharmacological mechanisms have progressively become clearer but its epigenetic mechanisms remain unclear.

Objective: To elucidate HKC's epigenetic role in the treatment of DN.

Methods: Db/db mice (a type 2 diabetes/DN model) were orally administered HKC or vehicle for 4 weeks. Kidney tissues underwent whole-genome bisulfite sequencing and transcriptome profiling to assess DNA methylation and gene expression patterns.

Results: HKC significantly reduced urinary albumin/creatinine ratios, indicating renal protection. Comparative methylation analysis revealed HKC regulated the distribution of 5 mC by modulating Tet2 expression, thereby influencing abnormal methylation patterns in DN. Integrative analysis identified 12 DN-associated genes with reversed methylation and expression post-HKC treatment, including Cdk8, Pde4d, Pisd-ps3, and Zc3h7a, which showed high susceptibility to DN progression and HKC intervention. Functional annotation linked these genes to immune regulation, synaptic signaling, and Notch pathways.

Conclusion: This study provides the first evidence that HKC ameliorates DN through epigenetic therapy effects, specifically by restoring DNA methylation and transcriptional activity of renal target genes. Further biological experiments to validate these findings are necessary.

Background: Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by the rapid proliferation of immature myeloblasts and resistance to apoptosis. Overcoming the differentiation block and apoptotic resistance remains a major challenge in AML therapy. Visomitin, a mitochondria-targeted antioxidant, has shown protective effects in other contexts, but its potential in AML has not been explored.

Methods: We examined the effects of Visomitin on AML cell differentiation and apoptosis using flowcytometry, including CD11b, CD14 staining and ROS measurement. Western blot analysis of Bcl-2 family proteins and p21/p16/Rb axis. Potential underlying mechanisms were explored through SYK activation. Additionally, primary AML patient samples were tested to assess translational relevance, and in vivo efficacy was evaluated in a xenograft mouse model.

Results: Treatment with Visomitin promoted differentiation of AML cells, as indicated by increased CD14 expression, and induced apoptosis by downregulating anti-apoptotic proteins (Mcl-1, Bcl-XL) while upregulating pro-apoptotic factors (Bak, Bax). Mechanistic studies suggested that Visomitin-induced ROS accumulation enhances AML differentiation and apoptosis. Notably, Visomitin selectively increased ROS in AML cells while reducing ROS levels in normal myeloid cells. Pharmacological and genetic rescue experiments further imply that Visomitin's anti-AML effects are mediated by ROS-dependent inhibition of SYK. In vivo, Visomitin suppressed tumor growth and elevated ROS within tumors. Furthermore, ex vivo treatment of primary AML cells reduced proliferation, highlighting potential clinical applicability.

Conclusion: These findings suggest that Visomitin exerts potent anti-leukemic effects by simultaneously promoting differentiation and apoptosis through ROS-mediated SYK inhibition. The selective activity against malignant cells and favorable in vivo efficacy suggest that Visomitin is a potential therapeutic agent for AML.

Background: This study aimed to systematically investigate the anti-colorectal cancer efficacy and the underlying mechanisms of Acanthopanax senticosus polysaccharide with a focus on its role in modulating the gut microbiota-metabolism-immune axis.

Methods: A homogeneous ASP fraction was structurally characterized using HPSEC, monosaccharide composition analysis, SEM, and FT-IR. Its anti-tumor activity was evaluated in a CT-26 tumor-bearing mouse model through histopathology, tumor inhibition rate, immune organ indices, and serum cytokine (IFN-γ, TNF-α, IL-2) assays. The potential mechanisms of action were elucidated by integrating 16S rDNA sequencing of gut microbiota, determination of short-chain fatty acids (SCFAs), untargeted serum metabolomics using UPLC-Q-TOF/MS, molecular docking studies, Western blot analysis of key signaling proteins, and validation through in vitro cell experiments.

Results: ASP demonstrated significant dose-dependent anti-tumor activity, with the medium dose showing the highest efficacy (50.84% inhibition). It induced tumor cell apoptosis, normalized tumor-associated immune organ hypertrophy, and rebalanced pro- and anti-tumor cytokines. Metabolomics identified 12 key biomarkers, revealing that ASP primarily reversed CRC-induced disruptions in glycerophospholipid and tryptophan metabolism. Concurrently, ASP restored gut microbiota diversity, suppressed pro-inflammatory genera, and promoted beneficial bacteria and some SCFAs. Integrated correlation analysis established a robust link between microbiota remodeling and metabolic correction. Molecular docking, Western blot validation and vitro cell experiments confirmed that ASP and its regulated metabolites could inhibit the activity of PLA2/TLR4/MyD88/NF-κB signaling pathway.

Conclusion: The results indicate that anti-CRC effect of ASP may be jointly regulated through multiple pathways: correcting abnormal glycerophospholipid and tryptophan metabolism in the host, restoring the homeostasis of the intestinal microbiota, increase the content of some SCFAs, and inhibiting the TLR4/NF-κB signaling pathway.

Ischemia stroke is a highly disabling and fatal disease in China. Neuroinflammation is the predominant pathological change in ischemic stroke. Various immune cells such as microglia and T cells are involved in the process of brain tissue damage during ischemic stroke; they play different roles during the acute and chronic phases, the disruption of which may directly affect the functional prognosis of stroke in animals and humans. Therefore, a deep understanding regarding the bidirectional regulatory mechanisms of neuroinflammation is essential for developing novel therapeutic strategies. In this review, we aim to introduce the recent research progress on neuroinflammation in the pathogenesis of ischemic stroke, while elucidating the energy metabolism changed induced immunity cells activation in ischemic stroke including glycolysis, lactic acid and succinate. We also review the RNA modification on energy metabolism changed. The information in this review provides valuable insights for further transitional research on stroke.

The critical role of gut microbiota in the initiation and progression of colorectal cancer (CRC) has garnered widespread recognition. Leveraging their precise targeting capabilities and programmable properties, nanomaterials are emerging as novel strategy for modulating the interplay between microbiota and tumors. This comprehensive review examines functional nanomaterials-including nanoparticles, nanocapsules, and nanoreactors-and elucidates their mechanisms of action in remodeling the CRC immune microenvironment and potentiating responses to chemoradiotherapy and immunotherapy through microbiota modulation. We further highlight the synergistic value of nanomaterials in multimodal CRC theranostics: (i) serving as microbiota modulation carriers for integrated diagnosis and therapy; (ii) activating systemic anti-tumor immunity via the gut-microbiota-immune axis; and (iii) targeting CRC drug resistance and metastasis. Finally, we discuss challenges associated with clinical translation, including assessment of long-term nanomaterial biosafety and optimization of personalized microbiota intervention protocols. This review provides theoretical foundations and technical insights for developing precision diagnostic and therapeutic strategies for CRC based on nano-microbiota interactions.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly emerging as a public health issue across the globe. Its complex etiopathology and association with diverse comorbidities poses significant challenges to conventional pharmacological drugs derived from the "lock-and-key" paradigm of pharmacology. To overcome the challenges of complexity and non-linear dynamics underlying the disease biology of MASLD, this article proposes a transdisciplinary framework combining holistic disease management principles of traditional medicines with molecular precision of modern biomedicine. Ayurveda - an exceptionally designed and widely practiced Indian Systems of Medicine (ISM) - is explored as a representative model for this framework. This article outlines a unified, biologically plausible transdisciplinary approach incorporating dual-diagnostic workflows, integrative decision interface, and stage-adaptive management algorithm for prevention, early intervention, and advanced disease care. The framework emphasizes integrative and personalized strategies integrating nutrition, lifestyle modification and drug interventions, harnessing the molecular precision of biomedicine alongside the systemic effects of phytochemical diversity. The transdisciplinary model seeks to shift the focus from 'disease treatment' to 'health restoration' and long-term wellness. The article highlights the scopes and challenges of this framework to offer more comprehensive, sustainable, and patient-centred solutions for MASLD.