Scientific Reports
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2022
·Vol. 12
·期 1
·1-13
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IF 4.996
Zhou Bin,Sha Shanshan,Tao Juan,Li Jun,Shen Chen,Zhu Jinjin,Tan Lulu,Dong Liyun,Huang Changzheng
Cutaneous melanoma (CM, hereafter referred to as melanoma) is a highly malignant tumor that typically undergoes early metastasis. Pyroptosis, as a special programmed cell death process that releases inflammatory factors and has been widely studied in tumors, but its role in melanoma has not been fully elucidated. In this study, we examined the relationship between pyroptosis and the prognosis of melanoma through bioinformatic analysis of RNA-sequencing data. Our results demonstrated that pyroptosis is a protective factor associated with melanoma prognosis. A higher pyroptosis score was associated with a more favorable overall survival. We used weighted gene co-expression networks analysis (WGCNA) to establish an effective prognosis model based on 12 pyroptosis-related genes. We then validated it in two independent cohorts. Furthermore, a nomogram combining clinicopathological characteristics and a pyroptosis-related gene signature (PGS) score was designed to effectively evaluate the prognosis of melanoma. Additionally, we analyzed the potential roles of pyroptosis in the tumor immune microenvironment and drug response. Interestingly, we found that the elevated infiltration of multiple immune cells, such as CD4 + T cells, CD8 + T cells, dendritic cells, and M1 macrophages, may be associated with the occurrence of pyroptosis. Pyroptosis was also related to a better response of melanoma to interferon-α, paclitaxel, cisplatin and imatinib. Through Spearman correlation analysis of the 12 pyroptosis-related genes and 135 chemotherapeutic agents in the Genomics of Drug Sensitivity in Cancer database, we identified solute carrier family 31 member 2 ( SLC31A2 ) and collagen type 4 alpha 5 chain ( COL4A5 ) as being associated with resistance to most of these drugs. In conclusion, this PGS is an effective and novelty prognostic indicator in melanoma, and also has an association with the melanoma immune microenvironment and melanoma treatment decision-making.
研究领域:
肿瘤学
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生物信息学
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免疫学
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产品关联
DOI
PubMed
高影响因子
Cancer Management and Research
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2024
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IF 2.5
Yantao Yu,Chenkai Zhang,Qiannan Sun,Shantanu Baral,Jianyue Ding,Fanyu Zhao,Qing Yao,Shuyang Gao,Bin Liu,Daorong Wang
Background Gastric cancer (GC) is a highly phenotypically heterogeneous disease and is caused by a combination of factors. Retinol binding protein 4 (RBP4) is a member of a family of lipid transport proteins that are involved in the transport of substances between cells and play a crucial role in a variety of cancers. However, the expression and role of RBP4 in GC remain unknown.Methods In this study, we explored the expression, prognostic significance, immune microenvironment, drug responsiveness and function of associated signaling pathways of RBP4 in GC using web-based bioinformatics tools. Immunohistochemistry and real-time quantitative PCR were utilized to analyze the tissue and cell expression levels of RBP4. CCK-8, colony formation, EDU incorporation, wound healing and transwell assays were applied to demonstrate the effect of RBP4 on GC cell function. Flow cytometric detection of apoptosis after RBP4 knockdown. Nude mice xenograft model elucidates the role of RBP4 for GC in vivo. Related proteins of the RAS signaling pathway were analyzed by employing Western blot assays.Results RBP4 is highly expressed in GC. RBP4 is closely associated with patient survival and sensitivity to a wide range of antitumor agents. Knockdown of RBP4 promoted apoptosis and inhibited cell proliferation, invasion and migration. RBP4 promotes GC tumorigenesis in vivo. Finally, RBP4 modulates the RAS/RAF/ERK axis.Conclusion RBP4 may promote gastric carcinogenesis and development through the RAS/RAF/ERK axis and is expected to be a novel target for GC treatment.
研究领域:
肿瘤学
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分子生物学
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癌症生物学
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生物信息学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
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2017
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IF 3.756
Enfang Shan,Zhu Zhu,Shuangcheng He,Dongbao Chu,Dinghao Ge,Yunran Zhan,Wei Liu,Jian Yang,Jing Xiong
Type 2 diabetes mellitus (T2D) is a complex metabolic disorder requiring polypharmacy treatment in clinic, with metformin being widely used antihyperglycemic drug. However, the mechanisms of metformin as a perpetrator inducing potential drug-drug interactions and adverse drug reactions are scarcely known to date. Carboxylesterases (CESs) are major hydrolytic enzymes highly expressed in the liver, including mouse carboxylesterase 1d (Ces1d) and Ces1e. In the present study, experiments are designed to investigate the effects and mechanisms of metformin on Ces1d and Ces1e in vivo and in vitro. In results, metformin suppresses the expression and activity of Ces1d and Ces1e in a dose- and time-dependent manner. The decreased expression of nuclear receptor PXR and its target gene P-gp indicates the involvements of PXR in the suppressed expression of carboxylesterases by metformin. Furthermore, metformin significantly suppresses the phosphorylation of AMPK and JNK, and the suppression of carboxylesterases induced by metformin is repeatedly abolished by AMPK inhibitor Compound C and JNK inhibitor SP600125 . It implies that the activation of AMPK and JNK pathways mediates the suppression of carboxylesterases by metformin. The findings deserve further elucidation including clinical trials and have a potential to make contribution for the rational medication in the treatment of T2D patients.
研究领域:
药理学
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内分泌学
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分子生物学
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DOI
PubMed
高影响因子
MICROCHEMICAL JOURNAL
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2024
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IF 4.9
Yingchang Song,Jiayu Zeng,Jianglan Long,Aiting Wang,Kuan Chen,Jia'an Qin,Dan Yan
Cytochrome P450 (CYP450) inhibition induced drug interactions (DDIs) are a primary cause of adverse drug reactions (ADRs). The rapid identification of CYP450 inhibitors is an important method for reducing potential ADRs. However, the existing methods are often intricate and time consuming, making them difficult to use for high-throughput rapid monitoring. Based on the specificity of CYP450 to the catalysis of different fluorescent substrate probes, an assay was developed to monitor the activity of six CYP450 isoforms simultaneously. The production rate of fluorescent metabolites characterized CYP450 activity. Method specificity was evaluated using inhibitors recommended by the FDA Guidelines for Drug Interaction Studies. We screened 28 clinically utilized medications for inhibition of CYP450 and evaluated the potential interaction by comparing inhibition constants ( K i ) and maximum plasma concentration (C max ). The analysis of the positive inhibitors using this method suggests that it allows for quick screening and identification of CYP450 inhibitors. Six drugs, including latoxefin, diclofenac, erythromycin lactate, labetalol, cimetidine, and droperidol, showed an interaction risk. The three isoforms of the CYP1A2, CYP3A4 and CYP3A5 metabolizing enzyme mediate a greater number of interactions, which should be specifically monitored in clinical applications. The established method permits rapid screening for inhibiting CYP1A2, CYP2E1, CYP2B6, CYP2A6, CYP3A4 and CYP3A5 with simple, stable, inexpensive, and high-throughput. This method will provide technical support for rapid discovery of clinical CYP450 inhibitors and risk avoidance of drug combination.
研究领域:
药理学
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分析化学
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药物发现
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临床药理学
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产品关联
DOI
高影响因子
American Journal of Translational Research
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2025
·Vol. 17
·期 7
·5081
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IF 1.6
Pengyu Huang,Suhua Jiang,Beihong Zheng,Yun Fu,Wenqiang You,Haiyan Li
Objective: To evaluate the therapeutic outcomes of combining ethinylestradiol-cyproterone acetate (EE-CPA) with raloxifene in the management of polycystic ovary syndrome (PCOS)-associated infertility. Methods: The study included 115 women diagnosed with PCOS-associated infertility, admitted between January 2021 and January 2025. The participants were divided into two groups: 55 women receiving raloxifene monotherapy (control group) and 60 treated with EE-CPA plus raloxifene (observation group). The following were assessed: therapeutic effectiveness, adverse drug reactions (abdominal/pelvic pain, nausea/vomiting, body weight fluctuations, and breast tenderness), metabolic markers (fasting plasma glucose [FPG], fasting serum insulin [FINS], and homeostasis model assessment of insulin resistance [HOMA-IR]), sex hormones (estradiol [E2], follicle-stimulating hormone [FSH], and luteinizing hormone [LH]), ovarian function (ovarian volume and endometrial thickness), endometrial receptivity (resistance index [RI] and pulsatility index [PI]), and pregnancy outcomes (ovulation, miscarriage, and clinical pregnancy). Results: The combination therapy showed superior outcomes, including enhanced overall effectiveness, increased ovulation and pregnancy rates, and a reduced miscarriage rate (all P>0.05). No significant differences in adverse drug reactions were found between the two groups (P>0.05). After treatment, the observation group showed greater improvements in metabolic markers, FSH, LH, ovarian volume, RI, and PI (all P>0.05). Additionally, E2 levels and endometrial thickness were more significantly enhanced in the observation group compared to the control group (all P>0.05). Conclusions: The combination of EE-CPA and raloxifene is highly effective in managing PCOS-associated infertility, improving therapeutic outcomes without significantly increasing adverse effects. It also leads to notable improvements in metabolism, sex hormones, ovarian function, and endometrial receptivity, ultimately enhancing pregnancy outcomes.
研究领域:
妇产科学
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内分泌学
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生殖医学
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药理学
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临床研究
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产品关联
DOI
PubMed
高影响因子
Nature Protocols
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2025
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IF 16
Qiao Tianhong,He Chaofan,Xia Pengcheng,Liu Guofeng,Sun Yuan,Sun Miao,Wang Yi,Cheng Yiyu,Yu Mengfei,He Yong
Projection-based three-dimensional bioprinting offers an approach for manufacturing biomimetic tissues with complex spatial structures and bioactivity, presenting potential for creating implantable organs or organoids to test drug response. Nevertheless, the extended printing times required for organ-scale manufacturing represents a challenge. Here we provide step-by-step instructions to manufacture organ-scale structures using bioinks while preserving high bioactivity. This approach incorporates Ficoll 400 to mitigate the heterogeneity of bioink with respect to refractive index and density, while 4-(2-aminoethyl)benzenesulfonyl fluoride and oil-sealing ensure the stability of the bioink components, thereby allowing extended printing times. This procedure also enables high-cell-viability printing via the calibration of the pH value of the bioink. This Protocol is appropriate for users with basic laboratory skills and fundamental knowledge in biotechnology to manufacture organ-scale structures for utilization in a wide variety of experimental designs. The approach is generalizable, as demonstrated by the successful printing of corpora cavernosa structures with a cell density of 10 million per milliliter, measuring 10 mm × 10 mm × 10 mm. After 7 d of culture, the cell viability was measured at 82.5%, highlighting the potential applicability in tissue engineering. All bioink preparation and printing steps are expected to take 5 h, while the development of printed structures requires 7 d of continuous culture.
研究领域:
生物医学工程
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组织工程
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三维生物打印
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再生医学
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药物研发
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产品关联
DOI
PubMed
高影响因子
Biofabrication
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2023
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IF 9
Jianpei Dong,Jianhua Zhou,Hao Tang,Baiqi Chen,Lu Huang
Cell-laden hydrogel microstructures have been used in broad applications in tissue engineering, translational medicine, and cell-based assays for pharmaceutical research. However, the construction of cell-laden hydrogel microstructures in vitro remains challenging. The technologies permitting generation of multicellular structures with different cellular compositions and spatial distributions are needed. Herein, we propose a laser-guided programmable hydrogel-microstructures-construction platform, allowing controllable and heterogeneous assembly of multiple cellular spheroids into spatially organized multicellular structures with good bioactivity. And the cell-laden hydrogel microstructures could be further leveraged for in vitro drug evaluation. We demonstrate that cells within hydrogels exhibit significantly higher half-maximal inhibitory concentration values against doxorubicin (DOX) compared with traditional 2D plate culture. Moreover, we reveal the differences in drug responses between heterogeneous and homogeneous cell-laden hydrogel microstructures, providing valuable insight into in vitro drug evaluation.
研究领域:
组织工程
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转化医学
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药物研究
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生物技术
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-17
·
IF 14.7
Wu Min,Wang Tingting,Ji Nan,Lu Ting,Yuan Ran,Wu Lingxiang,Zhang Junxia,Li Mengyuan,Cao Penghui,Zhao Jiarui,Li Guanzhang,Li Jianyu,Li Yu,Tang Yujie,Gao Zhengliang,Wang Xiuxing,Cheng Wen,Ge Ming,Cui Gang,Li Rui,Wu Anhua,You Yongping,Zhang Wei,Wang Qianghu,Chen Jian
Glioblastoma (GBM) is the most common brain tumor and remains incurable. Primary GBM cultures are widely used tools for drug screening, but there is a lack of genomic and pharmacological characterization for these primary GBM cultures. Here, we collect 50 patient-derived glioma cell (PDGC) lines and characterize them by whole genome sequencing, RNA sequencing, and drug response screening. We identify three molecular subtypes among PDGCs: mesenchymal (MES), proneural (PN), and oxidative phosphorylation (OXPHOS). Drug response profiling reveals that PN subtype PDGCs are sensitive to tyrosine kinase inhibitors, whereas OXPHOS subtype PDGCs are sensitive to histone deacetylase inhibitors, oxidative phosphorylation inhibitors, and HMG-CoA reductase inhibitors. PN and OXPHOS subtype PDGCs stably form tumors in vivo upon intracranial transplantation into immunodeficient mice, whereas most MES subtype PDGCs fail to form tumors in vivo. In addition, PDGCs cultured by serum-free medium, especially long-passage PDGCs, carry MYC/MYCN amplification, which is rare in GBM patients. Our study provides a valuable resource for understanding primary glioma cell cultures and clinical translation and highlights the problems of serum-free PDGC culture systems that cannot be ignored.
研究领域:
肿瘤学
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基因组学
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药理学
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神经科学
✓ 已验证
DOI
PubMed
高影响因子
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