PHYTOMEDICINE
·
2025
·
IF 8.3
Jun-Han Wang,Min Li,Peng-Fei Xie,Jia-Yao Si,Zhen-Jie Feng,Chuan-Feng Tang,Jian-Mei Li
Background Aging-related skin fibrosis (SF) is a complex condition with limited treatment options. Procyanidin C1 (PCC1), a natural polyphenolic compound with demonstrated senolytic activity, has emerged as a potential therapeutic agent for fibrotic disorders through its selective elimination of senescent cells. However, its therapeutic efficacy and mechanisms in aging-related SF remain unclear. Purpose This study aimed to investigate the mechanisms of PCC1 in aging-related SF. Results In D-galactose-induced L929 cells, PCC1 treatment significantly attenuated the expression of both senescence-associated markers (IL-1β, P16, P21 and LMNB1) and fibrosis-related markers (α-SMA, LOXL2 and COL1). Network pharmacology and experimental validation (molecular docking, DARTS, CETSA, MST) identified EGFR as a primary target, with PCC1 directly binding to and inhibiting EGFR phosphorylation. Furthermore, PCC1 treatment effectively down-regulated TGFβ1 expression and suppressed SMAD2/3 phosphorylation in D-galactose-induced L929 cells. Notably, PCC1 blocked NSC228155-induced EGFR phosphorylation and inhibited ERK/MAPK, AKT/mTOR and TGFβ/SMAD pathway activation. In bleomycin-induced SF mice, PCC1 significantly attenuated epidermal hyperplasia, improved collagen structure, restored the collagen I/III ratio, and reduced EGFR phosphorylation along with TGFβ1 expression and SMAD2/3 phosphorylation. Conclusion This study elucidates that PCC1 exerts its anti-fibrotic effects through dual mechanisms: resistance to cellular senescence and modulation of fibroblast heterogeneity. By directly binding to EGFR and inhibiting its phosphorylation, PCC1 subsequently suppresses multiple downstream signaling cascades, ultimately ameliorating TGFβ/SMAD-mediated SF. These findings establish PCC1 as a promising therapeutic candidate for aging-related skin fibrosis, offering a novel approach through targeted EGFR inhibition and comprehensive pathway modulation .
研究领域:
医学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
ACS Nano
·
2023
·
IF 17.1
Lifeng Luo,Baoli Zhang,Feng Tao,Zhong Chen,Qingsong Ye,Xiaozhi Zhao,Jinhui Wu
Tumor metastasis contributes to the low overall survival of tumor patients, while transforming growth factor-β (TGFβ) has been recognized as a prominently promoting factor in the development of tumor metastasis. Platelets reserve abundant TGFβ, which will be secreted to peripheral blood after activation, and they are the dominant source of circulating TGFβ. Therefore, downregulation of platelet-derived TGFβ is expected to inhibit the metastasis of circulating tumor cells. Here, unfolded human serum albumin (HSA)-coated perfluorotributylamine (PFTBA) nanoparticles were constructed to display a favorable platelet delivery and an antiplatelet effect to downregulate platelet-derived TGFβ in vitro and in blood plasma. PFTBA@HSA-mediated TGFβ downregulation impaired epithelial-mesenchymal transition of tumor cells as well as their migration and invasion behaviors and enhanced immune surveillance of NK cells. Intravenous injection of PFTBA@HSA effectively reduced tumor metastasis on the lungs or liver to improve the survival rate of mice on multiple metastatic models, including CT26 colon cancer, B16F10 melanoma, and 4T1 breast cancer. Compared with the clinical antiplatelet drug ticagrelor, PFTBA@HSA reduced bleeding risk when displaying a favorable downregulation on platelet-derived TGFβ, thereby obtaining a higher therapy benefit. Together, this study confirmed that downregulation of platelet-derived TGFβ by PFTBA@HSA will be a potential approach and therapeutic candidate for the prevention of tumor metastasis.
研究领域:
肿瘤学
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药理学
·
纳米技术
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免疫学
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DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2020
·Vol. 9
·期 14
·2000318
·
IF 7.367
Zhenfei Huang,Yu He,Xiao Chang,Jieying Liu,Lingjia Yu,Yuanhao Wu,Yaqian Li,Jingjing Tian,Lin Kang,Di Wu,Hai Wang,Zhihong Wu,Guixing Qiu
3D-printed porous titanium–aluminum–vanadium (Ti6Al4V, pTi) scaffolds offer surgeons a good option for the reconstruction of large bone defects, especially at the load-bearing sites. However, poor osteogenesis limits its application in clinic. In this study, a new magnetic coating is successfully fabricated by codepositing of Fe 3 O 4 nanoparticles and polydopamine (PDA) on the surface of 3D-printed pTi scaffolds, which enhances cell attachment, proliferation, and osteogenic differentiation of hBMSCs in vitro and new bone formation of rabbit femoral bone defects in vivo with/without a static magnetic field (SMF). Furthermore, through proteomic analysis, the enhanced osteogenic effect of the magnetic Fe 3 O 4 /PDA coating with the SMF is found to be related to upregulate the TGF β -Smads signaling pathway. Therefore, this work provides a simple protocol to improve the osteogenesis of 3D-printed porous pTi scaffolds, which will help their application in clinic.
研究领域:
材料科学
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生物材料
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生物医学工程
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骨科
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产品关联
DOI
PubMed
高影响因子
Cancer Nanotechnology
·
2023
·Vol. 14
·期 1
·1-34
·
IF 5.7
Tan Tiantian,Feng Yuxin,Wang Weimin,Wang Rongrong,Yin Liyan,Zeng Yiying,Zeng Zhaowu,Xie Tian
Background In the current treatment of non-small cell lung cancer (NSCLC), traditional chemotherapy causes high toxicity, so it is necessary to develop safe chemical drug delivery vehicles clinically. Chemotherapy monotherapy is prone to drug resistance. Chemotherapy combined with other therapies such as nucleic acid drugs is an effective way to avoid drug resistance and the toxicity of continuous chemotherapy. In this study, chemotherapy and siRNA therapy were combined to treat paclitaxel-resistant NSCLC in order to increase efficacy and reduce toxicity. This study aims to develop a cabazitaxel-loaded human serum albumin nanoparticles (CTX-HSA-NPs) to improve the toxicity of traditional CTX-Tween 80 and increase targeting, and to develop a TGFβ-1 siRNA lipid Nanoparticles (TGFβ-1 siRNA LNP) combined with chemotherapy in the treatment of paclitaxel-resistant NSCLC. Results This study prepared CTX-HSA-NPs and TGFβ-1 siRNA LNP had small particle size, high encapsulation efficiency (EE). CTX-HSA-NPs lyophilized powder has high stability after dissolved. The antitumor effect of CTX-HSA-NPs on paclitaxel-resistant NSCLC was higher than that of CTX-Tween, and the toxicity was 1.8 times lower than that of CTX-Tween. More importantly, the combined treatment of TGFβ-1 siRNA LNP and CTX-HSA-NPs could effectively improve the antitumor efficacy of paclitaxel-resistant NSCLC in vivo and in vitro. The results of tumor immunohistochemistry showed that TGFβ-1 siRNA LNP significantly inhibited the expression of TGFβ-1, and compared with other groups, the expression of P-gp after low-dose CTX-HSA-NPs treatment was lower, which did not cause obvious drug resistance. Conclusions The antitumor effect of CTX-HSA-NPs on paclitaxel-resistant NSCLC was higher than that of CTX-Tween, and the toxicity was lower than that of CTX-Tween. TGFβ-1 siRNA LNP can treat paclitaxel-resistant NSCLC by inhibiting the express of TGFβ-1 mRNA. The combined treatment of TGFβ-1 siRNA LNP and CTX-HSA-NPs could effectively improve the antitumor efficacy of paclitaxel-resistant NSCLC. A combination therapy of chemotherapy and nucleic acid drugs could be an effective approach for treating paclitaxel-resistant NSCLC.
研究领域:
肿瘤学
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药学
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分子生物学
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纳米技术
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DOI
高影响因子
ACTA BIOCHIMICA ET BIOPHYSICA SINICA
·
2026
·
IF 4.5
Zhanpeng Tang,Jian Li,Rongyang Li,Luyuan Ma,Renchang Zhao,Zhenguo Sun,Hui Tian
Esophageal squamous cell carcinoma (ESCC) represents a common malignancy of the digestive system. Circular RNAs (circRNAs) are a distinct class of single-stranded non-coding RNAs that are essential in the progression of various tumors given that they can act as microRNA (miRNA) sponges in a manner similar to that of mRNAs. In this study, circ_0006156 is screened to be highly expressed in ESCC tissues through high-throughput sequencing and quantitative real-time polymerase chain reaction. Subsequent in vitro and in vivo experiments are conducted to validate its biological functions. Furthermore, the regulatory relationships among circ_0006156, miR-202-5p, and TGFBR1 are investigated using RNA antisense purification, miRNA sequencing, RNA immunoprecipitation, fluorescence in situ hybridization, dual-luciferase reporter assay, and bioinformatics analyses. The results show significant overexpression of circ_0006156 in ESCC tissues, with relatively shorter overall survival observed in patients with high circ_0006156 expression. circ_0006156 is further identified to directly bind to miR-202-5p. miR-202-5p inhibits the proliferation, migration, and invasion of ESCC cells in vitro and partially rescues the effects induced by circ_0006156. Consistent results are reported by subcutaneous xenograft tumor experiments in nude mice. In addition, circ_0006156 is confirmed to act as an endogenous sponge for miR-202-5p, which results in a relieved suppression of its target gene TGFβR1 . In summary, circ_0006156 can regulate TGFβR1 expression by sponging miR-202-5p, which may further activate the TGFβ/Smad pathway and promote ESCC progression. Collectively, circ_0006156 functions as a novel oncogenic RNA in ESCC and may serve as a potential tumor marker.
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DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Xuming Song,Zehao Pan,Yi Zhang,Wenmin Yang,Te Zhang,Hui Wang,Yuzhong Chen,Xinnian Yu,Hanlin Ding,Rutao Li,Pengfei Ge,Lin Xu,Gaochao Dong,Feng Jiang
Current understanding of micropapillary (MP)-subtype lung adenocarcinoma (LUAD) remains confined to biological activities and genomic landscapes. Unraveling the major regulatory programs underlying MP patterned malignancy offers opportunities to identify more feasible therapeutic targets for patients with MP LUAD. This study shows that patients with MP subtype LUAD have aberrant activation of the MYC pathway compared to patients with other subtypes. In vitro and xenograft mouse model studies reveal that MP pattern in malignancy cannot be solely due to aberrant MYC expression but requires the involvement of M2-like macrophages. Excessively expressed MYC leads to the accumulation of M2-like macrophages from the bone marrow, which secretes TGFβ, to induce the expression of FOSL2 in tumor cells, thereby remodeling chromatin accessibility at promoter regions of MP-pattern genes to promote the MYC-mediated de novo transcriptional regulation of these genes. Additionally, the MP-pattern in malignancy can be effectively alleviated by disrupting the TGFβ-FOSL2 axis. These findings reveal new functions for the M2-like macrophage-TGFβ-FOSL2 axis in MYC-overexpressing MP-subtype LUAD, identifying targetable vulnerabilities in this pathway.
研究领域:
肿瘤学
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分子生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR & CELLULAR PROTEOMICS
·
2018
·Vol. 17
·期 10
·2005-2017
·
IF 5.236
Weixuan Wang,Yadong Hu,Changmei Yang,Songbiao Zhu,Xiaofei Wang,Zhenyu Zhang,Haiteng Deng
Nicotinamide adenine dinucleotide (NAD) plays an essential role in all aspects of human life. NAD levels decrease as humans age, and supplementation with NAD precursors plays a protective role against aging and associated disease. Less is known about the effects of decreased NAD on cellular processes, which is the basis for understanding the relationship between cellular NAD levels and aging-associated disease. In the present study, cellular NAD levels were decreased by overexpression of CD38, a NAD hydrolase, or by treating cells with FK866, an inhibitor of nicotinamide phosphoribosyltransferase (NAMPT). Quantitative proteomics revealed that declining NAD levels downregulated proteins associated with primary metabolism and suppressed cell growth in culture and nude mice. Decreased glutathione synthesis caused a 4-fold increase in cellular reactive oxygen species levels, and more importantly upregulated proteins related to movement and adhesion. In turn, this significantly changed cell morphology and caused cells to undergo epithelial to mesenchymal transition (EMT). Secretomic analysis also showed that decreased NAD triggered interleukin-6 and transforming growth factor beta (TGFβ) secretion, which activated integrin-β-catenin, TGFβ-MAPK, and inflammation signaling pathways to sustain the signaling required for EMT. We further revealed that decreased NAD inactivated sirtuin 1, resulting in increased signal transducer and activator of transcription 3 (STAT3) acetylation and phosphorylation, and STAT3 activation. Repletion of nicotinamide or nicotinic acid inactivated STAT3 and reversed EMT, as did STAT3 inhibition. Taken together, these results indicate that decreased NAD activates multiple signaling pathways to promote EMT and suggests that age-dependent decreases in NAD may contribute to tumor progression. Consequently, repletion of NAD precursors has potential benefits for inhibiting cancer progression.
研究领域:
细胞生物学
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分子生物学
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癌症研究
·
衰老研究
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2026
·Vol. 27
·期 3
·1228
·
IF 4.9
Ruifang Guo,Yihang Wang,Aiwen Zhang,Siwanon Jirawatnotai,Chen Chu,Lijun Liu
Beyond their canonical role in promoting G1/S progression, the complexes formed by cyclin D and cyclin-dependent kinase (CDK) 4/6 have emerged as contributors to enhanced cell migration. However, a direct link between this complex and cytoskeletal remodeling during cell motility has remained poorly understood. Here, we show that CDK4/6 inhibition in HeLa cells disrupts lamellipodia formation and subsequent focal adhesion assembly, leading to a reduction in cell migration and invasion. Notably, CDK4, but not CDK6, in complex with cyclin D1/D2, localizes to membrane ruffles to facilitate cytoskeletal reorganization. Mechanistically, proteomic and phosphoproteomic analyses revealed that CDK4 inhibition attenuates the transforming growth factor β (TGFβ) pathway via reduced Smad3 phosphorylation at Thr8, downregulating integrin subunits (α5, α6, and β1). Furthermore, CDK4 inhibition significantly decreased focal adhesion kinase (FAK) phosphorylation at Tyr397 and Rac1-GTP levels. Importantly, the resulting migration defect was largely restored by activation of either Rac1 or FAK. Thus, our data support a model in which cyclin D1/D2–CDK4 promotes phosphorylation of Smad3, leading to upregulation of integrin subunits, activation of FAK and Rac1, and consequent lamellipodia formation and cell migration. These findings provide direct evidence that CDK4 regulates actin cytoskeletal reorganization during cell migration and suggest that CDK4/6 inhibitors may dampen cytoskeleton-dependent tumor invasion, in addition to their antiproliferative effects.
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DOI
PubMed
高影响因子
iScience
·
2024
·
IF 4.6
Yixiao Li,Yuhan Jiang,Haoyi Yan,Ziheng Qin,Yidi Peng,Danyu Lv,Hongquan Zhang
Histone lysine isonicotinylation (Kinic) induced by isoniazid (INH) was recently identified as a post-translational modification in cells. However, global cellular non-histone proteins Kinic remains unclear. Using proteomic technology, we identified 11,442 Kinic sites across 2,792 proteins and demonstrated that Kinic of non-histone proteins is involved in multiple function pathways. Non-histone proteins Kinic can be regulated by isonicotinyl-transferases, including CBP and Tip60, and deisonicotinylases, including HDAC8 and HDAC6. In particular, the Kinic of poly (ADP-ribose) (PAR) polymerase 1 (PARP1) can be catalyzed by CBP and deisonicotinylation can be catalyzed by HDAC8. Tip60 and HDAC6 are isonicotinyl-transferase and the deisonicotinylase of SMAD3, respectively. Importantly, we found the K378inic of SMAD3 increases its phosphorylation, activates TGFβ pathway, and promotes liver cancer cells migration and invasion. In conclusion, our study demonstrated non-histone proteins Kinic occur extensively in cells and plays an important role in regulation of various cellular functions, including cancer progression.
研究领域:
癌症生物学
·
分子生物学
·
细胞生物学
·
蛋白质组学
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DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2022
·
IF 14.224
Tianyu Gao,Bingbing Sun,Zhenbiao Xu,Qiaoyun Chen,Meng Yang,Qinli Wan,Linxia Song,Guo Chen,Chunxia Jing,Eddy Y. Zeng,Guang Yang
The potential adverse effects of microplastics (MPs) on ecosystems and human health have received much attention in recent years. However, only limited data are available on the mechanisms for the uptake, distribution, and effects of MPs in freshwater organisms , especially with respect to tissue repair, regeneration and impairment of stem cell functions. To address this knowledge gap, we conducted exposure experiments in which planarians ( Dugesia japonica ) were exposed to polystyrene (PS)-MPs mixed in liver homogenate and examined the tissue growth and regeneration, stem cell functions, and oxidative stress . The body and blastema areas decreased upon exposure to PS-MPs, indicating that the growth and regeneration of planarians were delayed. The proliferation and differentiation processes of stem cells were inhibited, and the proportion of mitotic stem cells decreased, which may be related to the activation of the TGFβ/SMAD4 and Notch signaling pathways. The enhancement of antioxidant enzyme activities and malondialdehyde on the first day of exposure to PS-MPs confirmed the oxidative stress response of planarians to PS-MPs. The present study demonstrated the likelihood of biotoxicity induced by PS-MPs. These results will provide clues for further investigations into the potential risks of PS-MPs to human stem cells.
研究领域:
生态学
·
毒理学
·
细胞生物学
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DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2023
·
IF 8
Aftab Ullah,Kaikai Wang,Pengkai Wu,David Oupicky,Minjie Sun
Background: Liver fibrosis is a chronic liver disease associated with an excessive accumulation of extracellualr matrix (ECM) proteins which ultimately lead to cirrohosis and hepatocellular carcinoma.Purpose: Liver fibrosis therapies that use combination approaches with the ability to affect multiple disease pathways have proven higher efficacies. This study aimed at optimizing and characterizing the co-encapsulation of pirfenidone (PF) and AMD3100 (AMD) into CXCR4-targeted combination liposomes (CTC liposome) for CXCR4 targeting, and the inhibition of major molecular culprits ie α-SMA, CXCR4, TGFβ, and P-p38 involved in liver fibrosis in-vitro.Methods: The CTC liposomes were prepared using the thin-film hydration method. The concentration of encapsulated AMD and PF was measured by HPLC and UV spectrophotometry, respectively. Tramsmission electron microscopy (TEM) was used to determine the liposomal morphology. The CXCR4 targeting ability was determined by CXCR4 redistribution assay. Confocal microscopy and flowcytometry were used to determine the CXCR4 mediated cell uptake. The apoptosis inducing and protein downreguating ability of CTC liposomes were determined by apoptosis assay and western blot analysis, respectively. In-vivo biodistribution and Hoechst staining were used to confirm the feasibility of CTC liposome for the in-vivo applications and drug targeted accumulation, respectively.Results: The TEM studies revealed that CTC liposomes were spherical in shape. The cumulative release of AMD and PF from CTC liposome was 67% and 84%, respectively, at 48 h. Compared to the free drug counterparts, encapsulated drugs displayed higher cell viability. The CXCR4 redistribution assay confirmed the CXCR4 targeting and antagonistic ability of CTC liposomes. The CTC liposomes were internalized more effectively via caveolae-mediated endocytic pathways. CTC liposomes displayed aggressive apoptosis (87.3%) in TGFβ-induced activated HSC-T6 cells suggesting a propensity to fibrosis regression. Also, CTC liposomes significantly reduced α-SMA (65%), CXCR4 (77%), TGFβ (89%), and P-p38 (66%) expressions, better than free drugs. CTC@IR780 liposomes (CTC liposomes incorporating IR780 dye) were more accumulated in fibrotic livers compared to free IR780, as judged by in-vivo imaging, biodistribution analysis, and Hoechst staining. These findings suggest that this simple and stable CTC liposomal system holds a great promise for the treatment and prevention of liver fibrosis.
研究领域:
药理学
·
生物技术
·
细胞生物学
·
分子生物学
·
治疗学
✓ 已验证
DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2017
·Vol. 16
·期 2
·2211-2216
·
IF 1.692
Xuefeng Yang,Handong Huang,Maijian Wang,Xingbin Zheng,Jie Xu,Ming Xie
Nonylphenol (NP) is a well-known endocrine-disrupting chemical (EDC), which can enhance the progression of cancer by functioning as an estrogen‑like factor. In the present study, the effects of different concentrations of NP on COLO205 colorectal cancer (CRC) cells were examined. The results of flow cytometric analysis revealed that NP significantly decreased the proportion of cells in the G0/G1 phase in a dose‑dependent manner, which was accompanied by a marginal increase in the proportions of cells in S and G2/M phases. NP did not induce apoptosis, whereas estradiol (E2) did induce apoptosis. To elucidate the mechanisms underlying the action of NP on COLO205 cells, the transcriptional levels of extracellular signal‑regulated kinase (ERK)1, ERK2 and phosphoinositide 3‑kinase (PI3K) were assessed using reverse transcription‑quantitative polymerase chain reaction analysis. The expressions levels of ERK1, ERK2 and PI3K were increased by treatment with NP in a dose‑dependent manner. On examining protein levels, the expression of PI3K p38 was increased by NP and E2, and the expression of ERK1/2 was increased by NP. The phosphorylation of the ERK protein was significantly increased by treatment with NP at a high concentration (10‑4 M; P<0.01), but significantly decreased by E2 (P<0.01). Two key proteins in the transforming growth factor (TGF)β pathway (c‑Fos and SnoN) were selected for analysis using western blot analysis in the COLO205 cells treated with NP and E2. The expression levels of c‑Fos and SnoN were significantly increased by treatment with E2 (10‑7 M; P<0.01) and NP (10‑7‑10‑4 M; P<0.01). Taken together, these results indicated that NP affected the development of CRC via the ERK signaling pathway and TGFβ pathway.
研究领域:
肿瘤学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）