Frontiers in Pharmacology最新文献

{"title":"Polydatin protects against DSS-induced ulcerative colitis via Nrf2/Slc7a11/Gpx4-dependent inhibition of ferroptosis signalling activation.","authors":"Shimin Zheng, Jianbin Yin, Bingbing Wang, Qiujuan Ye, Jialuo Huang, Xinzhi Liang, Junfeng Wu, Hui Yue, Ting Zhang","doi":"10.3389/fphar.2024.1513020","DOIUrl":"10.3389/fphar.2024.1513020","url":null,"abstract":"<p><strong>Introduction: </strong>Ulcerative colitis (UC), a form of inflammatory irritable bowel disease, is characterized by a recurrent and persistent nonspecific inflammatory response. Polydatin (PD), a natural stilbenoid polyphenol with potent properties, exhibits unexpected beneficial effects beyond its well-documented anti-inflammatory and antioxidant activities. In this study, we presented evidence that PD confers protection against dextran sodium sulfate (DSS)-induced ulcerative colitis.</p><p><strong>Methods: </strong>The protective effect of PD on colitis was examined in cultured caco-2 cells and DSS-induced colitis mouse model. Bulk RNA sequencing and differential gene expression analysis were used to investigate the protective mechanism of PD on DSS-induced colitis. Ferroptosis was determined by MDA levels, SOD levels, mitochondrial iron accumulation and ROS production. Ferroptosis-related proteins Slc7a11, Nrf2 and Gpx4 levels were measured by western blot, immunohistochemical and immunofluorescence staining.</p><p><strong>Results: </strong>PD mitigated the DSS-induced increases in pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β), alleviated colon length shortening, reduced morphological damage to the intestinal mucosa, and preserved tight junction proteins (TJ) occludin and Zonula occludens-1 (ZO-1) in both caco-2 cells and murine models of colitis. Mechanistically, PD reversed the reduction of Nrf2, Slc7a11 and Gpx4, the degree of nuclear translocation of Nrf2 induced by DSS <i>in vitro</i> and <i>in vivo</i> significantly. Moreover, the protective effect of PD is attenuated by erastin and resembled that of Fer-1 in caco-2 cells model.</p><p><strong>Discussion: </strong>Our study suggested that PD protects against DSS-induced ulcerative colitis via Nrf2/Slc7a11/Gpx4-dependent inhibition of ferroptosis signalling activation. Further investigation into the precise mechanisms underlying this phenomenon is warranted. The findings presented herein indicated that PD may serve as a potential therapeutic agent for patients with UC.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"15 ","pages":"1513020"},"PeriodicalIF":4.4,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11772288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Panzerina lanata</i> accelerates methicillin-resistant <i>Staphylococcus aureus</i> eradication by promoting migration and activation of neutrophils.","authors":"Shuai Dong, Xingyuan Bai, Bin Chen, Minzhe Fan, Qi Liu, Yubo Zhao, Linsen Li, Dan Zhu","doi":"10.3389/fphar.2024.1501744","DOIUrl":"10.3389/fphar.2024.1501744","url":null,"abstract":"<p><strong>Background: </strong><i>Panzerina lanata</i> (Lanata) is generally used to treat pustule infection in Inner Mongolia folk medicine and is called \"the holy medicine for pustule.\" However, the pharmacological mechanism of Lanata in treating pustule infection is still unclear.</p><p><strong>Aims: </strong>This study aimed to investigate the therapeutic effects of Lanata on skin infection and explore the underlying mechanisms.</p><p><strong>Methods: </strong>A skin wound methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) infection mouse model was established to evaluate the healing effect of Lanata on infected wounds. <i>In vitro</i> assays were also conducted to determine the antibacterial activity of Lanata. Flow cytometry and immunohistochemistry were used to dynamically detect the number of neutrophils in the bone marrow, peripheral blood, and MRSA-infected wound. Protein expression in the infected wound skin was detected by a protein chip. Using an air pouch MRSA infection mouse model, the number of neutrophils, reactive oxygen species (ROS) level in neutrophils, and neutrophil extracellular trap (NET) formation were dynamically detected by flow cytometry and immunofluorescence. RNA-seq, RT-qPCR, flow cytometry, ELISA, and CXC chemokine receptor 2 (CXCR2) and P-selectin glycoprotein ligand-1 (PSGL-1) inhibitors were used to explore the mechanism of Lanata in regulating neutrophils.</p><p><strong>Results: </strong><i>In vitro</i> assays showed that Lanata had no direct antibacterial activity. In skin wound MRSA-infected mouse, Lanata promoted the rapid migration of neutrophils from the bone marrow via peripheral blood to the wound site to eradicate MRSA in the acute stage of infection and accelerate wound healing. Skin protein chip analysis showed that Lanata upregulated CXCR2 and PSGL-1 protein levels in skin wounds. Furthermore, analysis using the air pouch MRSA infection mouse model found that Lanata not only promoted the rapid migration of neutrophils from peripheral blood to the air pouch but also enhanced the activation of neutrophils, including the increase of ROS and the release of NETs, and upregulated the expression of CXCR2, PSGL-1, and myeloperoxidase (MPO) in neutrophils. Inhibition of CXCR2 and MPO significantly attenuated the effect of Lanata on promoting migration and activation of neutrophils.</p><p><strong>Conclusion: </strong><i>Panzerina lanata</i> resists MRSA infection by promoting migration and activation of neutrophils to rapidly eradicate MRSA.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"15 ","pages":"1501744"},"PeriodicalIF":4.4,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11772359/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding nature: multi-target anti-inflammatory mechanisms of natural products in the TLR4/NF-κB pathway.","authors":"Yue Zhao, Jiacai Wu, Xiaolan Liu, Xu Chen, Juan Wang","doi":"10.3389/fphar.2024.1467193","DOIUrl":"10.3389/fphar.2024.1467193","url":null,"abstract":"<p><p>Natural products are valuable medicinal resources in the field of anti-inflammation due to their significant bioactivity and low antibiotic resistance. Research has demonstrated that many natural products exert notable anti-inflammatory effects by modulating the Toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-κB) signaling pathways. The research on related signal transduction mechanisms and pharmacological mechanisms is increasingly being discovered and validated. However, there is currently a lack of comprehensive reviews focusing on the pharmacological mechanisms of natural products targeting the TLR4/NF-κB pathway for anti-inflammatory effects. In light of these considerations, this review comprehensively synthesizes recent research findings concerning the TLR4/NF-κB signaling pathway, including the translocation of TLR4 activation to lysosomes within the cytoplasm, the assembly of protein complexes mediated by ubiquitin chains K63 and K48, and the deacetylation modification of p65. These discoveries are integrated into the classical TLR4/NF-κB pathway to systematically elucidate the latest mechanisms among various targets. Additionally, we summarize the pharmacological mechanisms by which natural products exert anti-inflammatory effects through the TLR4/NF-κB pathway. This aims to elucidate the multitarget advantages of natural products in the treatment of inflammation and their potential applications, thereby providing theoretical support for molecular pharmacology research on inflammation and the development of novel natural anti-inflammatory drugs.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"15 ","pages":"1467193"},"PeriodicalIF":4.4,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11772364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic potential of rutin in premenstrual depression: evidence from <i>in vivo</i> and <i>in vitro</i> studies.","authors":"Xiangjun Wang, Xiaowen Xia, Xianliang Song, Yi Zhou, Mingyu Ma, Yashuang Ren, Xitai Chen, Zenghui Xia, Yinghui Guo, Chunhong Song","doi":"10.3389/fphar.2024.1525753","DOIUrl":"10.3389/fphar.2024.1525753","url":null,"abstract":"<p><strong>Introduction: </strong>Premenstrual dysphoric disorder (PMDD) is a cyclical mood disorder that severely affects the daily life of women of reproductive age. Most of the medications being used clinically have limitations such as low efficacy, side effects, and high cost, so there is an urgent need to discover safer and more effective medications. Rutin is a natural flavonol glycoside with various pharmacological properties including antidepressant. The study of the efficacy and mechanism of action of rutin in PMDD-depressed subtype model rats plays an important role in the discovery of new drugs for the treatment of PMDD.</p><p><strong>Methods: </strong>Binding of rutin to gamma-aminobutyric acid type A receptors (GABA_A receptors) was probed using molecular docking, microscale thermophoresis, radioactive receptor ligand binding assay and cell membrane clamp experiment. Behavioral tests in mice were performed to screen the optimal dose of rutin. Behavioral tests were performed to evaluate the effects of rutin on depressed mood, memory impairment, and social impairment in PMDD-depressed subtype model rats. HE staining and Golgi staining were performed to observe the neuronal damage in rat hippocampus. UHPLC-MS/MS targeted metabolomics was performed to detect the changes of neurotransmitter content in rat hippocampus. PCR array to detect the effect of rutin on mRNA expression of GABA_A receptor partial subunits in rat hippocampus.</p><p><strong>Results: </strong>The docking score of rutin with the GABA_A receptor benzodiazepine site was -11.442 and the gliding score was -11.470. The Kd of rutin with the GABA_A receptor (α1β2γ2) was 1.17 ± 0.89 μM. Rutin competed with [H³]-flunitrazepam for the GABA_A receptor benzodiazepine site and inhibited the inward flow of chloride ions (<i>P <</i> 0.05). In PMDD-depressed subtype rats, rutin alleviated depressed mood, memory impairment and social impairment, ameliorated hippocampal neuronal damage and reduces gamma-aminobutyric acid (GABA) and acetylcholine (ACh) levels (<i>P <</i> 0.05). Moreover, we found that rutin did not affect the relative mRNA expression of GABA_A receptor subunits in rat hippocampus.</p><p><strong>Discussion: </strong>Overall, rutin alleviated depressed mood, memory impairment and social impairment in PMDD-depressed subtype rats, which may be related to binding to GABA_A receptor benzodiazepine sites, inhibiting chloride ions inward flow, ameliorating hippocampal neuronal damage and reducing GABA and ACh levels. The results of this study provide an experimental basis and scientific evidence for the development of new drugs for the treatment of PMDD.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"15 ","pages":"1525753"},"PeriodicalIF":4.4,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11772486/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discussion on the optimization of personalized medication using information systems based on pharmacogenomics: an example using colorectal cancer.","authors":"Mengying Yuan, Yuankun Zheng, Fei Wang, Niuniu Bai, Haoling Zhang, Yuan Bian, Hao Liu, Xia He","doi":"10.3389/fphar.2024.1516469","DOIUrl":"10.3389/fphar.2024.1516469","url":null,"abstract":"<p><p>Pharmacogenomics (PGx) is a powerful tool for clinical optimization of drug efficacy and safety. However, due to many factors affecting drugs in the real world, PGx still accounts for a small proportion of actual clinical application scenarios. Therefore, based on the information software, pharmacists use their professional advantages to integrate PGx into all aspects of pharmaceutical care, which is conducive to promoting the development of personalized medicine. In this paper, the establishment of an information software platform is summarized for the optimization of a personalized medication program based on PGx. Taking colorectal cancers (CRC) as an example, this paper also discusses the role of PGx in different working modes and participation in drug management of CRC patients by pharmacists with the help of information systems. Finally, we summarized the recommendations of different PGx guidelines to provide reference for the follow-up personalized pharmaceutical care.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"15 ","pages":"1516469"},"PeriodicalIF":4.4,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11772163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-target regulatory effects of rhaponticin in a rat model of hepatic fibrosis revealed by non-targeted metabolomics.","authors":"Min Yang, Dihua Jiang, Longfei Huang, Tao Zhang, Wenfen Guo, Wenyan Lin, Jiali Zhao, Yunsheng Wei, Lang Peng, Yong-Jia Hao, Ying Zhou","doi":"10.3389/fphar.2024.1505309","DOIUrl":"10.3389/fphar.2024.1505309","url":null,"abstract":"<p><strong>Introduction: </strong>Hepatic fibrosis (HF), a progressive chronic liver disease, is a serious threat to global public health. The lack of preventive and therapeutic strategies has created an urgent need for effective anti-fibrosis agents. There is growing evidence that natural products might provide safe and effective interventions for HF. Among them, rhaponticin (RHA), a stilbenoid glucoside natural product isolated from medicinal plants of <i>Rheum</i> L. of <i>Polygonaceae</i> Juss. has many pharmacological activities such as anti-inflammatory, antioxidant, antiproliferative, and antithrombotic properties. However, its effects on HF remain unclear.</p><p><strong>Methods: </strong>Herein, we investigated the effects of RHA against HF on the carbon tetrachloride (CCl₄)-induced hepatic fibrosis and the underlying mechanism in rats. Functional, histopathological, and protein-level indicators of liver insult were evaluated. Moreover, serum metabolites were assessed by non-targeted metabolomics.</p><p><strong>Results and discussion: </strong>The results showed that RHA improved liver functions and histopathological features in the liver of CCl₄-treated rats, and alleviated the expression of α-SMA and type I collagen. Meanwhile, RHA also modulated endogenous metabolite levels in rats with HF, targeting glycerophospholipid metabolism signaling and other pathways. These findings confirmed the protective effects of RHA against hepatic fibrosis in rats by exerting multi-target effects via multiple signaling and metabolic pathways. Which may be of use in developing more effective RHA-based therapeutic strategies for hepatic fibrosis.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"15 ","pages":"1505309"},"PeriodicalIF":4.4,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11772292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integration of histone modification-based risk signature with drug sensitivity analysis reveals novel therapeutic strategies for lower-grade glioma.","authors":"Jingyuan Wang, Shuai Yan","doi":"10.3389/fphar.2024.1523779","DOIUrl":"10.3389/fphar.2024.1523779","url":null,"abstract":"<p><strong>Background: </strong>Lower-grade glioma (LGG) exhibits significant heterogeneity in clinical outcomes, and current prognostic markers have limited predictive value. Despite the growing recognition of histone modifications in tumor progression, their role in LGG remains poorly understood. This study aimed to develop a histone modification-based risk signature and investigate its relationship with drug sensitivity to guide personalized treatment strategies.</p><p><strong>Methods: </strong>We performed single-cell RNA sequencing analysis on LGG samples (n = 4) to characterize histone modification patterns. Through integrative analysis of TCGA-LGG (n = 513) and CGGA datasets (n = 693 and n = 325), we constructed a histone modification-related risk signature (HMRS) using machine learning approaches. The model's performance was validated in multiple independent cohorts. We further conducted comprehensive analyses of molecular mechanisms, immune microenvironment, and drug sensitivity associated with the risk stratification.</p><p><strong>Results: </strong>We identified distinct histone modification patterns across five major cell populations in LGG and developed a robust 20-gene HMRS from 129 candidate genes that effectively stratified patients into high- and low-risk groups with significantly different survival outcomes (training set: AUC = 0.77, 0.73, and 0.71 for 1-, 3-, and 5-year survival; <i>P</i> < 0.001). Integration of HMRS with clinical features further improved prognostic accuracy (C-index >0.70). High-risk tumors showed activation of TGF-β and IL6-JAK-STAT3 signaling pathways, and distinct mutation profiles including TP53 (63% vs 28%), IDH1 (68% vs 85%), and ATRX (46% vs 20%) mutations. The high-risk group demonstrated significantly elevated immune and stromal scores (<i>P</i> < 0.001), with distinct patterns of immune cell infiltration, particularly in memory CD4⁺ T cells (<i>P</i> < 0.001) and CD8⁺ T cells (<i>P</i> = 0.001). Drug sensitivity analysis revealed significant differential responses to six therapeutic agents including Temozolomide and targeted drugs (<i>P</i> < 0.05).</p><p><strong>Conclusion: </strong>Our study establishes a novel histone modification-based prognostic model that not only accurately predicts LGG patient outcomes but also reveals potential therapeutic targets. The identified associations between risk stratification and drug sensitivity provide valuable insights for personalized treatment strategies. This integrated approach offers a promising framework for improving LGG patient care through molecular-based risk assessment and treatment selection.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"15 ","pages":"1523779"},"PeriodicalIF":4.4,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11770009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CSNK1E is involved in TGF-β1 induced epithelial mesenchymal transformationas and related to melanoma immune heterogeneity.","authors":"Wangbing Hong, Xin Wang, Xinyu Huang, Pengfei Chen, Yifan Liu, Ziying Zheng, Xin You, Yinghua Chen, Zengxin Xie, Gongnan Zhan, Heping Huang","doi":"10.3389/fphar.2024.1501849","DOIUrl":"10.3389/fphar.2024.1501849","url":null,"abstract":"<p><strong>Introduction: </strong>Melanoma (MM), the deadliest form of skin cancer, originates from melanocytes. Despite advances in immunotherapy that have somewhat improved the prognosis for MM patients, high levels of resistance to treatment continue to result in poor clinical outcomes. Identifying novel biomarkers and therapeutic targets is critical for improving the prognosis and treatment of MM.</p><p><strong>Methods: </strong>In this study, we analyzed the expression patterns of WNT signaling pathway genes in MM and explored their potential mechanisms. Using Cox regression analysis, we identified 19 prognostic-related genes. Consistency clustering was performed to evaluate the potential of these genes as classifiers for prognosis. The Least Absolute Shrinkage and Selection Operator (LASSO) algorithm was then applied to refine the gene set and construct a 13-gene prognostic model. We validated the model at multiple time points to assess its predictive performance. Additionally, correlation analyses were performed to investigate the relationships between key genes and processes, including epithelial-to-mesenchymal transition (EMT) and immune responses.</p><p><strong>Results: </strong>We identified that CSNK1E and RAC3 were significantly positively correlated with the EMT process, with CSNK1E showing a similar expression trend to EMT-related genes. Both genes were also negatively correlated with multiple immune cell types and immune checkpoint genes. The 13-gene prognostic model demonstrated excellent predictive performance in MM prognosis. Pan-cancer analysis further revealed heterogeneous expression patterns and prognostic potential of CSNK1E across various cancers. Wet experiments confirmed that CSNK1E promotes MM cell proliferation, invasion, and migration, and enhances malignant progression through the TGF-β signaling pathway.</p><p><strong>Discussion: </strong>Our findings suggest that CSNK1E plays a crucial role in MM progression and could serve as a potential therapeutic target. The WNT and TGF-β pathways may work synergistically in regulating the EMT process in MM, highlighting their potential as novel therapeutic targets. These insights may contribute to the development of more effective treatments for MM, particularly for overcoming resistance to current therapies.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"15 ","pages":"1501849"},"PeriodicalIF":4.4,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of ultrasound combined with microbubbles therapy on tumor hypoxic microenvironment.","authors":"Yuyi Feng, Danxia Qiu, Yangcheng He, Hai Jin, Liping Chen, Fen Xi, Zhiwen Hu, Yanlin Xie, Yucai Li, Minhua Lin, Pengxiao Sun, Yan He, Jianhua Liu","doi":"10.3389/fphar.2024.1502349","DOIUrl":"10.3389/fphar.2024.1502349","url":null,"abstract":"<p><strong>Introduction: </strong>Tumor tissues exhibit significantly lower oxygen partial pressure compared to normal tissues, leading to hypoxia in the tumor microenvironment and result in resistance to tumor treatments. Strategies to mitigate hypoxia include enhancing blood perfusion and oxygen supply, for example,by decomposing hydrogen peroxide within the tumor. Improving hypoxia in the tumor microenvironment could potentially improve the efficacy of cancer treatments. Previous studies have demonstrated that ultrasound of appropriate intensity when combined with microbubbles, can improve tumor blood perfusion. However, its effects on tumor hypoxia remain unclear. This study aimed to assess the effects of low-frequency non-focused ultrasound combined with microbubbles at different intensities on tumor microenvironment hypoxia and to identify the optimal ultrasound parameters for alleviating tumor hypoxia.</p><p><strong>Method: </strong>Rabbits with VX2 tumors received ultrasound and microbubble treatments at different acoustic pressures and pulse repetition frequencies. The changes in tumor tissue blood perfusion before and after treatment were observed by contrast enhanced ultrasound (CEUS). The changes in tumor tissue hypoxia before and after treatment were observed by measuring oxygen partial pressure directly with in tumor tissue and immunohistochemical staining for hypoxia-inducible factor-1α (HIF-1α).</p><p><strong>Results: </strong>Results indicated that low frequency, non-focused ultrasound at 0.5 MPa/20 Hz and 0.5 MPa/40 Hz, when combined with microbubbles, could increase tumor tissue blood perfusion and improve the hypoxia in tumor tissues.</p><p><strong>Discussion: </strong>This study provides a new method for improving hypoxia in the tumor microenvironment (TME) which could potentially improve the cancer treatments resistance.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"15 ","pages":"1502349"},"PeriodicalIF":4.4,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11769831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD146 promotes resistance of NSCLC brain metastases to pemetrexed via the NF-κB signaling pathway.","authors":"Hao Qu, Yan Fang, Feng Zhang, Wenwen Liu, Shengkai Xia, Wenzhe Duan, Kun Zou","doi":"10.3389/fphar.2024.1502165","DOIUrl":"10.3389/fphar.2024.1502165","url":null,"abstract":"<p><strong>Introduction: </strong>Pemetrexed is a first line drug for brain metastases from lung cancer, either as monotherapy or combined with other drugs. The frequent occurrence of initial and acquired resistance to pemetrexed results in limited treatment effectiveness in brain metastases. CD146 was recently found to play important roles in chemoresistance and tumor progression. However, the underlying mechanisms of CD146's effects in pemetrexed resistance remain undefined.</p><p><strong>Method and results: </strong>Sensitivity to pemetrexed was assessed with a preclinical brain metastasis (BM) model based on lung adenocarcinoma PC9 cells. The role and mechanism of CD146 in pemetrexed resistance in non-small cell lung cancer (NSCLC) brain metastasis were explored <i>in vitro</i> and <i>in vivo</i>. A subpopulation of brain metastatic cells derived from progenitor PC9 cells (PC9-BrMS) was significantly resistant to pemetrexed. CD146 levels were significantly increased in pemetrexed resistant brain metastases, while CD146 inhibition suppressed pemetrexed resistance in BM cells. Mechanistically, CD146 mediated pemetrexed resistance in brain metastatic cells by promoting DNA damage repair, maintaining normal cell cycle progression, and regulating the NF-KB pathway to counter apoptosis, and these effects was based on increased DNA damage, cell cycle arrest, and occurrence of apoptosis after CD146 inhibition as well as the reemergence of pemetrexed resistance after CD146 restoration.</p><p><strong>Discussion: </strong>In summary, this study revealed that the resistance of NSCLC brain metastatic cells to PEM was dependent on CD146.Thus CD146 might be targeted in clinic to overcome pemetrexed resistance in brain metastases from NSCLC.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"15 ","pages":"1502165"},"PeriodicalIF":4.4,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11770010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}