Frontiers in Pharmacology最新文献

Systemic inflammation induced by adipose tissue is common in obese individuals and is often overlooked due to its subclinical nature. The constant secretion of proinflammatory factors shifts the balance toward inflammation, affecting the body's homeostasis and facilitating the development of various chronic diseases. In the liver, proinflammatory markers, free fatty acids (FFAs), and the hormone leptin, all of which originate from adipose tissue, trigger an inflammatory response that favors fibrogenesis. Conversely, serum levels of proinflammatory factors can be used to assess both the risk of liver fibrosis and the effectiveness of treatment. Their application is straightforward due to their non-invasive nature, but it is important to confirm their reliability in future investigations. Moreover, dietary approaches to therapy, along with physical activity, deserve more attention as their effectiveness has frequently been demonstrated and they are recommended by official guidelines. The focus on reducing body weight through fat loss is especially crucial. To enhance the quality and value of dietary strategies in therapy, it is also necessary to refine and expand their potential.

Background: The development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) dramatically altered the treatment for non-small cell lung cancer (NSCLC). The implementation of comprehensive genomic profiling for NSCLC facilitates to identify more uncommon genetic alterations in EGFR. S768I and V769L are two rare mutations in exon 20 of EGFR. However, the clinical reactivity of afatinib to the S768I/V769L compound mutation remains controversial, and there are no reports on whether osimertinib is effective against S768I/V769L. This case study aims to describe a clinical experience with these mutations, detailing the therapeutic strategy adopted and its outcomes, alongside a literature review to understand the broader implications for treatment.

Case presentation: A 47-year-old man was referred to the Affilated Cancer Hospital of Zhengzhou University due to dry cough for more than 2 months and was diagnosed with Stage IIIB (T1cN3M0) lung adenocarcinoma. Mutation analysis of 26 lung cancer-related genes was performed using pathological tissue sample by targeted next-generation sequencing. A compound mutation of S768I and V769L in epidermal growth factor receptor exon 20 were observed. After multi-disciplinary treatment, the patient received concurrent chemoradiotherapy with pemetrexed and cisplatin, and achieved partial response. This patient did not receive durvalumab immunoconsolidation therapy for economic reasons. He developed disease progression 6 months after the end of radiotherapy. The patient was treated with afatinib at 40 mg daily by oral administration from January 2023. At the 1-month response assessment, the primary tumor in the right lung shrank and remained stable for 13 months. Magnetic resonance imaging revealed multiple nodules with brain metastases. We performed NGS testing of peripheral blood, and no mutation was found. Considering the superior intracranial efficacy of osimertinib, we tried high dose osimertinib for the patient. He achieved partial response after 15 days, and there were no intolerable adverse reactions. Three months later, the intracranial metastasis progressed, and headache appeared. The patient was switched to whole brain radiotherapy. The intracranial metastases remained stable after radiotherapy. The patient died 3 months later due to the progression of intracranial metastasis. overall survival was 26 months, slightly poorer than anticipated for patients with single driver gene mutations.

Conclusion: The S768I/V769L mutation should be considered a poor-prognosis compound mutation. Patients with EGFR S768I/V769L compound mutated NSCLC may benefit from afatinib and osimertinib. Drugs with strong brain penetration capabilities are still needed for patients with S768I/V769L compound mutation to further improve survival outcomes.

Background: Glioma is the most common primary brain tumor of the central nervous system and is associated with poor clinical outcomes, particularly in high-grade diease. The immune checkpoint protein B7-H3 (CD276) is significantly overexpressed in glioma and multiple other solid tumors, highlighting its potential as a diagnostic biomarker and therapeutic target. However, the availability of high-performance antibodies suitable for clinic in vitro diagnosis (IVD) applications remains limited.

Objective: This study aimed to develop a novel rabbit monoclonal antibody (clone 36H7) targeting human B7-H3, and to evaluate its suitability for clinical diagnostic use.

Methods: Rabbits were immunized with recombinant human B7-H3 protein, followed by monoclonal antibody generation and systematic screening. The resulting antibody was assessed for specificity, affinity and stability. Its performance was validated through Western blot, ELISA, surface plasmon resonance (SPR), flow cytometry, immunofluorescence, and immunohistochemistry (IHC).

Results: Clone 36H7 demonstrated high specificity and robust stability across multiple assay platforms. In IHC analysis of glioma samples (n = 206), B7-H3 positivity was detected in 97% of cases. In addition, B7-H3 expression was observed in 85.4% of vascular endothelial cells, supporting its strong detection capability in tumor-associated compartments. Tonsil tissue was established as a reliable quality control material to ensure assay consistency and reproducibility.

Conclusion: The rabbit monoclonal antibody 36H7 exhibits excellent specificity, stability and board applicability across analytical platforams, meeting key requirments for clinical diagnostic development targeting B7-H3 in glioma.

Objective: This study aimed to investigate the ameliorative effect of the ethyl acetate extract of Gastrodia elata (EEGE) on vascular dementia (VD) and its underlying mechanisms.

Methods: A VD rat model was established using the two-vessel occlusion method, while an in vitro cerebral ischemia injury model was constructed by subjecting HT22 cells to oxygen-glucose deprivation. The mechanisms were systematically explored through behavioral tests, ELISA, integrated network analysis, and combined metabolomic and transcriptomic techniques. Key targets were further validated by Western blot.

Results: EEGE significantly improved cognitive function in VD rats. Integrated multi-omics and network analysis predicted that its effects involved two key targets, TNF and IGF1, and identified Parishin A and p-hydroxybenzaldehyde as prioritized drug metabolites for assessment. Subsequent experiments confirmed that EEGE effectively downregulated serum levels of IL-6, TNF-α, and IL-1β by modulating the IGF1-TREM2 signaling axis and the AMPK-SIRT1-FoxO1-NF-κB pathway.

Conclusion: The improvement of cognitive dysfunction in vascular dementia by EEGE is closely associated with its regulation of the IGF1-TREM2 axis and the AMPK-SIRT1-FoxO1-NF-κB pathway, thereby mitigating neuroinflammation. This study provides experimental evidence and a potential mechanistic basis for further exploration of EEGE in VD intervention.

[This corrects the article DOI: 10.3389/fphar.2020.00951.].

Background: Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by cartilage destruction and functional impairment. Dysregulated autophagy plays a pivotal role in chondrocyte apoptosis and extracellular matrix (ECM) degradation. Pterostilbene (PT), a natural polyphenolic metabolite with high bioavailability, exhibits potent anti-inflammatory and antioxidant activities. However, its precise role in regulating autophagy during OA progression remains unclear.

Methods: Network analysis was employed to predict PT's potential molecular targets and signaling pathways. To experimentally evaluate the drug-target interaction, the cellular thermal shift assay (CETSA) was performed. Functional validation was subsequently conducted in vitro using IL-1β-stimulated C28/I2 chondrocytes and in vivo in a monosodium iodoacetate-induced OA rat model. The p53 inhibitor pifithrin-α was applied to verify the mechanistic dependency.

Results: Network analysis and molecular docking suggested p53 as a core target of PT. CETSA results supported the cellular target engagement of p53 by PT, showing that PT enhanced the thermal stability of p53 protein. In chondrocytes, PT mitigated IL-1β-induced ECM imbalance and apoptosis while enhancing Beclin1 expression and the LC3II/I ratio with reduced p62 accumulation. Mechanistically, PT promoted p53 nuclear accumulation, activated AMPK, and inhibited mTOR phosphorylation; these effects were attenuated by 3-methyladenine or pifithrin-α. In vivo, PT exhibited a dose-dependent chondroprotective effect, significantly reducing OARSI scores and restoring autophagy marker expression in cartilage tissue.

Conclusion: This study demonstrates that PT exerts chondroprotective effects by activating autophagy through the p53/AMPK/mTOR axis, supported by evidence of specific p53 target engagement. These findings unveil a previously unrecognized molecular mechanism and underscore the translational potential of PT as a promising disease-modifying metabolite for OA therapy.

Background: Ovarian cancer remains one of the most lethal gynecologic malignancies, characterized by high recurrence rates and chemoresistance. Recent advances suggest that neuroactive drugs such as lorazepam may exert off-target molecular effects beyond the central nervous system. However, their pharmacological relevance in tumor biology remains largely unexplored. This study aimed to identify and validate shared molecular targets of lorazepam and ovarian cancer, uncovering novel biomarkers and therapeutic mechanisms.

Methods: Potential lorazepam targets were retrieved from the CTD, STITCH, and SwissTargetPrediction databases and cross-referenced with ovarian cancer-related genes from GeneCards. Bioinformatic analyses were conducted, including target screening, protein-protein interaction network construction, Lasso-Cox modeling, and functional enrichment. We further performed immune infiltration profiling, single-cell and spatial transcriptomics analyses, followed by experimental validation using qPCR, CCK-8, colony formation, wound-healing, and flow cytometry assays.

Results: Fifty-one overlapping genes were identified between lorazepam and ovarian cancer, with PTK2 emerging as a central hub gene. PTK2 overexpression was significantly associated with poor prognosis, enhanced immune activation, stromal remodeling, and metabolic reprogramming. Spatial transcriptomics revealed PTK2 enrichment in malignant and fibroblast-rich regions. Functional assays confirmed that stable PTK2 knockdown inhibited proliferation, colony formation, and migration while promoting apoptosis in ovarian cancer cells.

Conclusion: Our findings suggest that PTK2 may act as a putative oncogenic mediator and potential pharmacological link between lorazepam signaling and ovarian cancer progression. PTK2 functions as a biomarker and druggable target that integrates tumor growth, immune modulation, and metabolic adaptation. Targeting PTK2 may provide a promising therapeutic strategy for precision oncology and rational drug repurposing.

Background: Systematically evaluate the effects of Kang'ai Injection (KAI) combined with platinum-based chemotherapy on immune function, clinical efficacy, and safety in patients with advanced non-small cell lung cancer.

Materials and methods: Relevant literature published from the inception of each database through September 2025 will be identified through systematic searches of Chinese and English electronic databases. Randomized controlled trials (RCTs) evaluating Kang'ai injection combined with chemotherapy for advanced non-small cell lung cancer will be screened against predefined inclusion and exclusion criteria. Two investigators will independently perform data extraction and quality assessment. Meta-analyses will be conducted using RevMan 5.3 and Stata 18.0 software. Publication bias will be assessed using funnel plots and Egger's test, while the robustness of findings will be examined through trial sequential analysis (TSA). The quality of evidence for critical outcomes will be evaluated using the GRADE approach.

Results: A total of 14 randomized controlled trials involving 1,214 patients were included. The meta-analysis demonstrated that compared with chemotherapy alone, KAI combined with chemotherapy significantly improved the objective response rate and enhanced immune function parameters, including increased CD3⁺ and CD4⁺ T-cell counts, elevated CD4⁺/CD8⁺ ratio, and higher natural killer cell percentage, while reducing CD8⁺ T-cell percentage. The combination therapy group also showed superior outcomes in reducing tumor marker and vascular endothelial growth factor levels compared to the chemotherapy-alone group. Furthermore, combination treatment significantly reduced the incidence of chemotherapy-related adverse reactions including leukopenia, myelosuppression, nausea and vomiting, and gastrointestinal reactions.

Conclusion: As an adjunctive therapy, KAI can enhance immune function (low-quality evidence), improve the objective response rate to chemotherapy (moderate-quality evidence), and alleviate chemotherapy-related toxicities (predominantly moderate-quality evidence) in patients with advanced NSCLC, providing an evidence-based reference for comprehensive clinical management.

Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251168090.

Background: Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by a lipid overload-induced pathological cascade featuring hepatocyte injury, inflammation, and progressive fibrosis. This study aims to systematically investigate the role of EMMPRIN in MASH progression, and to elucidate its mechanisms in reprogramming the hepatic metabolic microenvironment.

Methods: Murine models induced by methionine-choline -deficient diet, hepatocyte-specific EMMPRIN overexpression and knockout mice models were used to evaluate EMMPRIN' roles in steatohepatitis. Parallel in vitro studies were conducted in corresponding cellular models. Proteomic sequencing, mass spectrometry, co-immunoprecipitation, Western blotting, quantitative PCR, and immunofluorescence were employed to identify downstream targets and characterize ubiquitination modifications.

Results: EMMPRIN overexpression significantly exacerbated MASH phenotypes, including hepatic steatosis, inflammatory infiltration, and collagen deposition. Conversely, EMMPRIN knockout conferred substantial protection against these pathological changes both in vivo and in vitro. Mechanistically, EMMPRIN downregulated UBA52 expression, resulting in reduction in the free ubiquitin pool and subsequent decrease in K63-linked polyubiquitination of monocarboxylate transporter 1 (MCT1). This ubiquitination defect led to destabilization of MCT1 and was associated with a global increase in protein lactylation in EMMPRIN-deficient models. Furthermore, EMMPRIN suppression inhibited several signaling pathways critically involved in MASH pathogenesis, including PPAR signaling, Notch signaling, and TGF-β-mediated fibrotic response.

Conclusion: Our findings demonstrate that EMMPRIN promotes MASH progression through the UBA52-MCT1 regulatory axis, which modulated ubiquitin-dependent protein stability and induced metabolic reprogramming, thereby driving lipid accumulation, inflammation, and fibrosis. These results position EMMPRIN as a promising therapeutic target for MASH intervention.

The increasing use of extended kidney grafts to bridge organ shortage has led to delayed and impaired graft function, warranting the development of new preservation strategies. In addition to hypothermic machine perfusion, the addition of pharmacological agents to preservation solutions has been primarily investigated, with a few promising agents making their way into clinical trials. This review aimed to identify and summarize current literature studies on pharmacological treatment additives for hypothermic kidney graft preservation. A scoping review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. A comprehensive literature search was performed using Medline and Cochrane Library databases until 1 December 2023. All studies published in English reporting on pharmacological supplementation of preservation solutions to improve hypothermic kidney graft preservation were included. A total of 67 records were retrieved, all of which were preclinical except one. Of these, 8 were conducted on cellular models, 21 on ex vivo kidneys, and 38 on animal kidney transplantations. A total of 40 pharmacological agents were evaluated based on the key markers of ischemia-reperfusion injury (IRI) pathophysiology, most of them showing promise in kidney preservation. Although promising, with numerous preclinical studies identifying various effective additives, the pharmacological treatment additive strategy to improve hypothermic kidney preservation has still not been translated into clinical practice. Clinical investigations should be promoted to support few ongoing trials offering encouraging outcomes.