Frontiers in Pharmacology最新文献

Background: Lipids are vital biomolecules involved in the formation of various biofilms. Seizures can cause changes in lipid metabolism in the brain. In-depth studies at multiple levels are urgently needed to elucidate lipid composition, distribution, and metabolic pathways in the brain after seizure.

Methods: In this research, a cutting-edge targeted quantitative lipidomics study was conducted on the hippocampal tissues of six rats with temporal lobe epilepsy and six normal rats. Accurate lipid quantification based on linear equations was calculated using an internal standard. The lipids were quantitatively and qualitatively analyzed by ultra-high performance liquid chromatography (UPLC) and mass spectrometry (MS).

Results: A total of 21 lipid classes were identified. Among them, the most abundant were triacylglycerol (TG), phosphatidyl ethanolamine (PE-P), and fatty acids (FA). Cholesteryl ester (ChE) exhibits the most considerable difference between the normal and epileptic samples. ChE was found to be the most significantly upregulated lipid, while FA was observed to be the most significantly downregulated lipid.

Conclusion: Based on the absolute quantitative analysis of lipids in rat hippocampal specimens, the contents and change trends of different lipids were observed. Upregulation of ChE and dihydroceramide (DHCer) was observed, and an analysis of the distribution changes elucidated the causes and possible molecular mechanisms of lipid accumulation in temporal lobe epilepsy. The results and methods described provide a comprehensive analysis of lipid metabolism in temporal lobe epilepsy and a new therapeutic target for the treatment of epilepsy.

Carbohydrates, lipids, bile acids, various inorganic salt ions and organic acids are the main nutrients or indispensable components of the human body. Dysregulation in the processes of absorption, transport, metabolism, and excretion of these metabolites can lead to the onset of severe metabolic disorders, such as type 2 diabetes, non-alcoholic fatty liver disease, gout and hyperbilirubinemia. As the second largest membrane receptor supergroup, several major families in the solute carrier (SLC) supergroup have been found to play key roles in the transport of substances such as carbohydrates, lipids, urate, bile acids, monocarboxylates and zinc ions. Based on common metabolic dysregulation and related metabolic substances, we explored the relationship between several major families of SLC supergroup and metabolic diseases, providing examples of drugs targeting SLC proteins that have been approved or are currently in clinical/preclinical research as well as SLC-related diagnostic techniques that are in clinical use or under investigation. By highlighting these connections, we aim to provide insights that may contribute to the development of improved treatment strategies and targeted therapies for metabolic disorders.

The emergence of targeted anti-tumor drugs has significantly prolonged the lifespan and improved the prognosis of cancer patients. Among these drugs, vascular endothelial growth factor (VEGF) inhibitors, particularly novel small molecule tyrosine kinase inhibitors (TKIs), are extensively employed as VEGF inhibitors; however, they are also associated with a higher incidence of complications, with hypertension being the most prevalent cardiovascular toxic side effect. Currently, it is widely accepted that TKIs-induced hypertension involves multiple mechanisms including dysregulation of the endothelin (ET) axis, reduced bioavailability of nitric oxide (NO), imbalance in NO-ROS equilibrium system, vascular rarefaction, and activation of epithelial sodium calcium channels; nevertheless, excessive activation of ET system appears to be predominantly responsible for this condition. Moreover, studies have demonstrated that ET plays a pivotal role in driving TKIs-induced hypertension. Therefore, this review aims to explore the significance of ET in the pathogenesis of hypertension induced by targeted anti-tumor drugs and investigate the potential therapeutic value of endothelin antagonists in managing hypertension caused by targeted anti-tumor drugs.

Introduction: Eculizumab is a C5 complement inhibitor approved by the FDA for the targeted treatment of four rare diseases, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis (gMG), and aquaporin-4 immunoglobulin G-positive optic neuromyelitis optica spectrum disorders (AQP4-IgG+NMOSD). The current study was conducted to assess real-world adverse events (AEs) associated with eculizumab through data mining of the FDA Adverse Event Reporting System (FAERS).

Methods: Disproportionality analyses, including Reporting Ratio Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Item Gamma Poisson Shrinker (MGPS) algorithms were used to quantify the signals of eculizumab-associated AEs.

Results: A total of 46,316 eculizumab-related ADEs reports were identified by analyzing 19,418,776 reports in the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database. A total of 461 PTs were identified as satisfying by all four algorithms. These PTs reported adverse reactions consistent with the specifications, such as fatigue, nasopharyngitis, meningococcal infection, fever, and anemia. Some PTs, such as aplastic anemia, gene mutation, mastication disorder, kidney fibrosis, BK virus infection, abnormal neutrophil count, C3 glomerulopathy, neuroblastoma, and glomerulonephritis membranoproliferative, were also detected outside the instructions. The median time to onset of eculizumab adverse events was 159 days (interquartile range [IQR] 11∼738 days). In addition, at the PT level, 51 PTs were determined to have an imbalance in the occurrence of ADEs between the sexes.

Conclusion: These findings provide valuable insights into the occurrence of ADEs following the use of eculizumab and could support clinical monitoring and risk identification efforts.

N⁷-methylguanosine (m7G) modification is one of the most prevalent forms of chemical modification in RNA molecules, which plays an important role in biological processes such as RNA stability, translation regulation and ribosome recognition. Methyl-transferation of m7G modification is catalyzed by the enzyme complex of methyltransferase-like 1 (METTL1) and WD repeat domain 4 (WDR4), and Quaking (QKI) recognizes internal m7G methylated mRNA and regulates mRNA translation and stabilization. Recent studies have found that m7G modification - related enzymes are associated with the onset and progression of digestive cancer, such as colorectal cancer, liver cancer, and other digestive diseases such as ulcerative colitis. This review will focus on the latest research progress on the roles of m7G methyltransferase METTL1/WDR4 and recognized enzyme QKI in digestive diseases.

Objective: This study aimed to evaluate the risk of tumor formation with infliximab or azathioprine monotherapy versus their combination, using the FDA Adverse Event Reporting System (FAERS) database.

Methods: Data were extracted from the FAERS database for patients treated with infliximab, azathioprine, and combination therapy from Q1 2004 to Q2 2024. Signal mining employed methods such as Reported Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Multiple Gamma-Poisson Scaling Assessment (MGPSA) and Bayesian Confidence Interval Progressive Neural Network (BCPNN).

Results: Our analysis of the FAERS database revealed that the highest number of reported cases involved skin-related tumors, both individually and in combination. In terms of sex, the risk of cancer was higher in men compared to women in the infliximab-only and combination groups; however, no sex difference was observed in the azathioprine-only group. Regarding age, we noted an increasing incidence of adverse tumor events in middle-aged and elderly individuals compared to minors, except in the azathioprine group, where age was not identified as an independent risk factor. Additionally, body weight was not found to be an independent risk factor in any of the three medication groups. After controlling for age, sex, and body weight, combination therapy did not increase the risk of tumor development compared to the azathioprine group alone. In contrast, for patients using infliximab alone, combination therapy not only did not elevate the risk of tumor development but also appeared to reduce it. The results of the Weber distribution suggest a random failure-type profile for the infliximab and azathioprine-only group, while an early failure-type profile was observed for the combination therapy. Furthermore, we analyzed the median time to onset and cumulative incidence rates, revealing no significant differences in median time to tumor onset or cumulative incidence rates between the combination therapy and the single agent.

Conclusion: After adjusting for age, sex, and body weight, combination therapy did not significantly increase tumor development risk compared to the azathioprine-only group. Additionally, in patients on infliximab monotherapy, combination therapy appeared to reduce the risk of tumor development.

Introduction: In patients with acute respiratory distress syndrome, mechanical ventilation often leads to ventilation-induced lung injury (VILI), which is attributed to unphysiological lung strain (UPLS) in respiratory dynamics. Platelet endothelial cell adhesion molecule-1 (PECAM-1), a transmembrane receptor, senses mechanical signals. The Src/STAT3 pathway plays a crucial role in the mechanotransduction network, concurrently triggering pyroptosis related inflammatory responses. We hypothesized that the mechanical stretch caused by UPLS can be sensed by PECAM-1 in the lungs, leading to VILI via the Src/STAT3 and pyroptosis pathway.

Methods: A VILI model was established in rats through UPLS. The link between lung strain and VILI as well as the change in the activation of PECAM-1, Src/STAT3, and pyroptosis was firstly being explored. Then, the inhibitors of PECAM-1, Src, STAT3 were adopted respectively, the effect on VILI, inflammation, the Src/STAT3 pathway, and pyroptosis was evaluated. In vitro, human umbilical vein endothelial cells (HUVECs) were used to validate the findings in vivo.

Results: UPLS activated PECAM-1, Src/STAT3 signaling pathway, inflammation, and pyroptosis in the VILI model with rats, whereas inhibition of PECAM-1 or the Src/STAT3 signaling pathway decreased lung injury, inflammatory responses, and pyroptosis. Inhibition of PECAM-1 also reduced activation of the Src/STAT3 signaling pathway. The mechanism was validated with HUVECs exposed to overload mechanical cyclic stretch.

Conclusions: This study suggests that UPLS contributes to VILI by activating the PECAM-1/Src/STAT3 pathway and inducing inflammatory responses as well aspyroptosis.

Background: The application of nanomedicine in inflammatory bowel disease (IBD) has gained significant attention in the recent years. As the field rapidly evolves, analyzing research trends and identifying research hotpots are essential for guiding future advancements, and a comprehensive bibliometric can provide valuable insights.

Methods: The current research focused on publications from 2001 to 2024, and was sourced from the Web of Science Core Collection (WoSCC). CiteSpace and VOSviewer were employed to visualize authors, institutions, countries, co-cited references, and keywords, thereby mapping the intellectual structure and identifying emerging trends in the field.

Results: The analysis covered 1,518 literature across 447 journals, authored by 9,334 researchers from 5,459 institutions and 287 countries/regions. The global publication numbers exhibited an upward trend, particularly in the last decade, with China leading as the top publishing country and the Chinese Academy of Sciences emerging as the foremost institution. Dr. Xiao Bo is the prominent figure in advanced drug delivery systems. This interdisciplinary field, which spans materials science, pharmacy, and medicine, has seen influential publications mainly concentrated on targeted nanoparticles treatment for IBD. Keyword analysis revealed that current research hotspots include drug delivery, immune cell regulation, antioxidant damage, intestinal microbiota homeostasis, and nanovesicles.

Conclusion: This study offers a comprehensive overview of global research landscape, emphasizing the rapid growth and increasing complexity of this field. It identifies key research hotspots and trends, including efforts to enhance the precision, efficacy, and safety of nanomedicine applications. Emerging directions are highlighted as crucial for further progress in this evolving area.

Introduction: Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer to treat. While previous studies have demonstrated that ginsenoside Rh2 induces apoptosis in TNBC cells, the specific molecular targets and underlying mechanisms remain poorly understood. This study aims to uncover the molecular mechanisms through which ginsenoside Rh2 regulates apoptosis and proliferation in TNBC, offering new insights into its therapeutic potential.

Methods: Network analysis and transcriptome sequencing were utilized to explore the potential mechanisms of ginsenoside Rh2 in treating TNBC. In vivo imaging and immunohistochemistry were employed to examine the effects of ginsenoside Rh2 in a TNBC mouse model. Functional assays were conducted to assess the impact of ginsenoside Rh2 on TNBC cell behavior. Additionally, ELISA, Western blot, and quantitative real-time PCR were used to further investigate the mechanisms of ginsenoside Rh2-induced apoptosis in TNBC cells.

Results: Through network analysis, 47 common targets were identified, and Gene Ontology (GO) enrichment analysis suggested that ginsenoside Rh2 may exert therapeutic effects in TNBC by influencing apoptosis, cell proliferation, and protein kinase activity. Both transcriptomic analysis and network analysis revealed the JAK/STAT signaling pathway as a key mechanism. Ginsenoside Rh2 inhibited tumor growth in TNBC mice and reduced the expression of IL- 6, IL-6R, STAT3, Bcl-2, and Bcl-xL in tumor tissues. The ability of ginsenoside Rh2 to inhibit TNBC cell proliferation was further confirmed by attenuating the activation of the IL-6/JAK2/STAT3 apoptosis pathway and reducing the expression of protein kinases AMPK-α1 and PKA-Cα.

Conclusion: Based on network analysis and experimental validation, our findings demonstrate that ginsenoside Rh2 regulates TNBC proliferation and apoptosis through suppression of the IL-6/JAK2/STAT3 pathway, both in vitro and in vivo. This comprehensive approach represents a significant advancement in understanding the therapeutic potential of ginsenoside Rh2 in treating TNBC.

Gastric cancer is the fifth most common cancer and the fourth leading cause of cancer-related deaths worldwide, accounting for nearly 800,000 fatalities annually. ITGAX (Integrin alpha X) is closely associated with immune cells, such as macrophages and dendritic cells. Its involvement in gastric cancer was identified through an analysis of The Gene Expression Omnibus (GEO) database, which highlighted ITGAX as one of four key gastric cancer-related genes. Our study demonstrates that ITGAX expression is significantly elevated in tumor tissues compared to normal tissues and is positively correlated with clinical prognosis in gastric cancer patients from the GEO database. Moreover, ITGAX enhanced cell proliferation, invasion, and tumorigenic capacity in mouse models. Furthermore, we explored the underlying role of ITGAX using Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction networks (PPI) analysis. Our findings reveal that ITGAX promotes gastric cancer progression by driving epithelial-mesenchymal transition pathway (EMT), suggesting its potential as a biomarker for early diagnosis and prognosis in gastric cancer.