Frontiers in Pharmacology最新文献

Ganoderic acid A (GAA), a major bioactive triterpenoid from Ganoderma lucidum, is known for its anti-inflammatory effects; however, its precise molecular targets in sepsis-related liver injury (SRLI) remain unclear. Integrating network pharmacology and transcriptomic analysis, we identified Tumor Necrosis Factor-alpha (TNFα) as a primary candidate target. Subsequent biophysical validation using surface plasmon resonance (SPR) and molecular dynamics (MD) simulations confirmed that GAA directly binds to TNFα. Functionally, this interaction inhibits the TNFα/NF-κB signaling axis, thereby suppressing macrophage M1 polarization and ameliorating liver injury in vitro and in vivo. This study identifies TNFα as a primary candidate target of GAA, providing a mechanistic basis for its hepatoprotective effects and therapeutic potential.

Ovarian aging is characterized by follicular depletion and declining oocyte quality, encompassing both physiological age-related decline and pathological forms such as diminished ovarian reserve, premature ovarian insufficiency and premature ovarian failure. These changes are associated with long-term systemic comorbidities across the female life course, particularly in the context of estrogen deficiency. Ginseng as a botanical drug (Panax ginseng C.A.Mey.) and its active compounds, including ginsenosides Rg1, Rb1 and Rg3, the gut-derived metabolite Compound K and ginseng polysaccharides, have emerged as multitarget candidates for delaying ovarian aging-associated functional decline and supporting reproductive health. This review integrates preclinical evidence on how ginseng-related compounds attenuate oxidative stress, preserve mitochondrial function, support energy metabolism and modulate ovarian inflammaging and the senescence-associated secretory phenotype. They also rebalance apoptosis and autophagy, thereby supporting granulosa cell survival and follicle development. We summarize their regulatory effects on hypothalamic-pituitary-ovarian axis activity and on ovarian hormone receptor expression, which may help preserve ovarian endocrine function during aging. Across mechanistic domains, the most consistent ovary-relevant evidence converges on redox control and mitochondrial integrity and function, together with dampening of NF-κB and NLRP3-linked inflammatory signaling and SASP-associated features, whereas evidence for direct hypothalamic-pituitary modulation and for durable multisystem outcome modification remains more exploratory. Preclinical studies indicate that ginseng-related compounds can influence skeletal, cardiovascular, hepatic, metabolic and neurocognitive phenotypes that accompany estrogen deficiency. However, the evidence base remains heterogeneous and largely preclinical, and causal links to long-term functional reproductive outcomes are still limited. Interpretation of the existing literature is hampered by differences in botanical sources, processing methods, formulations, dosing regimens, treatment duration and routes of administration, which complicate evaluation of in vivo exposure and pharmacodynamic response, particularly for orally administered ginsenosides that undergo microbiota-mediated biotransformation and show inter-individual pharmacokinetic variability in some studies, with consequent uncertainty in dose relevance and exposure consistency across populations. Further progress toward clinical application may be facilitated by traceable and chemically defined ginseng preparations, exposure-guided oral dosing and rigorously designed clinical trials that better define efficacy, safety, plausible drug-drug interaction considerations and long-term reproductive and systemic outcomes with stage-stratified designs and prioritized functional outcome measures.

Background: Given the lack of targeted therapies and frequent resistance to apoptosis-based treatments, triple-negative breast cancer (TNBC) remains a major clinical challenge. Exploring non-apoptotic cell death mechanisms may offer new therapeutic avenues to circumvent drug resistance in TNBC.

Methods: The anticancer activity of a novel cyclometalated iridium (III) compound, CIr2, was evaluated using cytotoxicity, clonogenic, and migration assays in multiple breast cancer cell lines. Mechanistic investigations included analyses of mitochondrial dysfunction, reactive oxygen species (ROS) production, ATP depletion, endoplasmic reticulum (ER) stress, and MAPK signaling. Transcriptomic profiling (RNA-seq), ultrastructural and morphological analyses, as well as pharmacological inhibitor studies targeting distinct cell death pathways, were performed to elucidate the mode of cell death induced by CIr2. The in vivo antitumor efficacy and safety of CIr2 were further assessed using a TNBC xenograft mouse model.

Results: CIr2 selectively inhibited the proliferation and migration of TNBC cells while exerting minimal cytotoxic effects on normal breast epithelial cells. CIr2 preferentially accumulated in mitochondria, leading to mitochondrial membrane potential collapse, excessive ROS production, and profound ATP depletion. Transcriptomic profiling and morphological analyses revealed pronounced ER stress, MAPK pathway activation, and paraptosis-associated ultrastructural alterations, including mitochondrial swelling and extensive cytoplasmic vacuolization. Pharmacological inhibition of apoptosis, necroptosis, ferroptosis, autophagy, ER stress, or p38 MAPK signaling failed to rescue CIr2-induced cytotoxicity, whereas ROS scavenging effectively reversed these effects, confirming a mitochondrial dysfunction and ROS-driven paraptotic mode of cell death. In vivo, CIr2 markedly suppressed TNBC xenograft tumor growth with minimal systemic toxicity.

Conclusion: CIr2 induces paraptosis through mitochondrial dysfunction and ER stress, offering a potential therapeutic strategy to overcome apoptosis resistance in TNBC. These findings provide a new mechanistic insight into iridium-based paraptosis induction.

Glial cells-comprising astrocytes, microglia, and oligodendrocytes-are fundamental to central nervous system (CNS) homeostasis, yet their interactions with anesthetics are not fully elucidated. This review narratively synthesizes current evidence on the differential effects of local and general anesthetics on these cells, revealing a complex duality of neuroprotective and neurotoxic outcomes. Local anesthetics such as lidocaine can confer protection by inducing astrocytic autophagy and suppressing microglial pro-inflammatory responses, whereas bupivacaine may impair astrocytic mitochondrial function and potentiate excitotoxicity. Conversely, general anesthetics exhibit divergent impacts: propofol demonstrates protective properties against oxidative stress and neuroinflammation, but isoflurane often induces astrocytic cytotoxicity, activates microglia via the NF-κB pathway, and triggers apoptosis in developing oligodendrocytes, thereby disrupting myelination. These effects are critically influenced by anesthetic type, concentration, exposure duration, and the pathological context. Our analysis underscores the necessity of understanding these glial-centric mechanisms to optimize anesthetic safety, particularly for vulnerable populations such as the young and the elderly. Ultimately, advancing the knowledge of how anesthetics modulate glial cell function is pivotal for developing personalized anesthesia strategies that minimize neurotoxicity and harness potential protective effects, thereby improving postoperative neurological outcomes and guiding future translational research.

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.

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.

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.

[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.