JOURNAL OF MEDICINAL CHEMISTRY
·
2026
·
IF 7.3
Shuaiqi Feng,Yan Chen,Huicong Tang,Lili Wang,Zhifang Liu,Jun Han,Qingpeng Wang
The epithelial-to-mesenchymal transition (EMT) and immunosuppressive tumor microenvironment (TME) are key drivers of tumor metastasis. Here, a series of Telmisartan (TELM) platinum(IV) complexes targeting EMT and tumor immunity were developed. A lead candidate was screened out that exhibited potent antiproliferative and antimetastatic activities both in vitro and in vivo. It effectively induced DNA damage and upregulated the expression of γ-H2AX and p53, further triggering significant apoptosis via the mitochondria-mediated Bcl-2/Bax/caspase-3 pathway. Then, the Ang II/AT1R axis was suppressed by the TELM ligand. Subsequently, the JAK2/STAT3 and ERK1/2 pathways were downregulated, while the hypoxic microenvironment was also reversed by inhibiting HIF-1α/VEGFA and MMPs signaling. As a result, the EMT process was abrogated by modulating E-cadherin, N-cadherin, and Vimentin. Additionally, the immunosuppressive TME was reprogrammed by blocking the immune checkpoint PD-L1 and inducing immunogenic cell death, and the infiltration density of CD3+ and CD8+ T cells was increased in tumor tissues.
✓ 已验证
DOI
PubMed
高影响因子
Animal Diseases
·
2021
·Vol. 1
·期 1
·1-13
·
IF 0
Yang Xiaoqi,Fu Yang,Wu Lianfeng,Li Antong,Ji Luyao,Li Hao,Peng Yuxuan,Zhang Jiabin,Zhou Donghai,Zhou Huiping
The major cause of pulmonary vascular remodeling in broilers is abnormal proliferation of vascular smooth muscle cells (VSMCs), and one of the main causes of pulmonary hypertension syndrome (PHS) in broilers is pulmonary artery vascular remodeling. Forty Arbor Acres (AA) broilers were randomly divided into four groups ( n = 10): a control group (deionized water, 0 g/L NaCl), a freshwater group (FW, deionized water + 1 g/L NaCl), highly salinized freshwater group 1 (H-SFW-1, deionized water + 2.5 g/L NaCl) and highly salinized freshwater group 2 (H-SFW-2, deionized water + 5 g/L NaCl). The results of in vivo experiments showed that vascular smooth muscle of the broilers could be significantly proliferated by intake of high-salinity fresh water (H-SFW-1 & H-SFW-2), which significantly increased the content of angiotensin II (Ang II) and the expression of angiotensin II type 1 (AT1) receptor protein. Meanwhile, it significantly decreased the expression of dopamine receptor D4 (DRD4) protein. The results of in vitro experiments showed that exogenous Ang II induced the proliferation of primary VSMCs in broilers, which could be significantly inhibited by DRD4 agonists (D4A, HY-101384A) and enhanced by DRD4 inhibitors (D4I, HY-B0965). In addition, the results of immunoblotting and fluorescence quantitative PCR showed that AT1 receptors could be negatively regulated by DRD4 in VSMCs of broilers, either at the transcriptional or translational level. At the same time, the expression of AT1 receptor could be increased by DRD4 inhibition by D4I and decreased by DRD4 activation by D4A. The negative regulatory effect of DRD4 on AT1 receptor occurred in a dose-dependent manner. These results indicate that long-term intake of highly salinized fresh water can cause PHS in broilers, accompanied by varying degrees of proliferation of pulmonary artery smooth muscle. This mechanism may involve response of its receptor being induced by increased Ang II, while DRD4 can negatively regulate it.
研究领域:
兽医学
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生理学
·
分子生物学
·
药理学
✓ 已验证
DOI
BIOMATERIALS
·
2017
·
IF 8.402
Yujie Su,Yahui Hu,Yu Wang,Xiangting Xu,Yang Yuan,Yunman Li,Zeyuan Wang,Kerong Chen,Fangrong Zhang,Xuefang Ding,Min Li,Jianping Zhou,Yuan Liu,Wei Wang
Multi-walled carbon nanotube (MWNT) with its versatility has exhibited tremendous superiority in drug delivery. Despite plenty of researches on MWNT based delivery systems, precision-guided assistances to maximize their profitable properties are still lacking in substantive progress. We developed here a dual-targeting and co-delivery system based on MWNT for antiangiogenesis therapy in lung cancer which aimed at renin-angiotensin system (RAS) dysregulation by synergistically conducting angiotensin II type 1 receptor (AT 1 R) and type 2 receptor (AT 2 R) pathway. In this work, iRGD peptide connected to polyethyleneimine (PEI) was linked to MWNT skeleton, accompanying with candesartan (CD) conjugated to MWNT mediated by cystamine (SS). The functionalized MWNT is assembled with plasmid AT 2 (pAT 2 ) to form iRGD-PEI-MWNT-SS-CD/pAT 2 complexes. iRGD and CD act as pilots for complexes to dually target symbolic ανβ3-integrin and AT 1 R both overexpressed on tumor angiogenic endothelium and lung cancer cell. CD as chemotherapy showed synergistic downregulation of VEGF when combining of pAT 2 and efficiently inhibited angiogenesis . iRGD-PEI-MWNT-SS-CD/pAT 2 complexes greatly appreciated drug activities by changing drug distribution and exhibited remarkable tumor growth suppression in A549 xenograft nude mice . Our work presents that such dual-targeting strategy highly improves the delivery performance of MWNT and open a new avenue for RAS related lung cancer therapy.
研究领域:
肿瘤学
·
纳米医学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2020
·
IF 4.545
Gaojun Wu,Zhengxian Wang,Peiren Shan,Shanjun Huang,Shuang Lin,Weijian Huang,Zhouqing Huang
Background Myocardial remodeling caused by angiotensin II (Ang II) is essential for the pathological process of heart failure. Netrin-1, which is an axonal guidance cue, has been shown to be involved in the inflammatory response, tumorigenesis, and angiogenesis in non-neuronal tissues. However, the role of Netrin-1 in cardiac remodeling has not been fully elucidated. Methods The rat cardiomyocyte cell line H9c2 and primary neonatal rat cardiomyocytes were treated with Ang II. Cells were transfected with siRNA to silence Netrin-1 expression. Real-time polymerase chain reaction and Western blot analysis were used to detect the markers for fibrosis, apoptosis, and hypertrophy in cardiomyocytes. An Annexin V-EGFP/PI cell apoptosis detection kit was used to measure the level of apoptosis caused by angiotensin II. Results We found that Netrin-1 expression was upregulated in the H9c2 cells and the neonatal rat cardiomyocytes stimulated by Ang II. The increased Netrin-1 expression was decreased by valsartan to block AT1R. Importantly, the application of Netrin-1 siRNA significantly alleviated the degrees of myocardial hypertrophy, fibrosis (reflected by Myhc, collagen I, and TGF-β) and apoptosis (reflected by the level of Caspase 3, Bax, and Bcl-2) induced by Ang II. In addition, the silencing of Netrin-1 substantially decreased the phosphorylation of PKCα, JNK, and P38. We treated H9c2 cells with LY317615, SP600125, and SB203580, inhibitors of PKCα, JNK, and P38, respectively, thereby resulting in a substantial decrease in hypertrophy, fibrosis, and apoptosis. Conclusions Ang II produces cardiac hypertrophy, fibrosis, and apoptosis through the upregulation of Netrin-1 and the activation of the AT1R/PKCα/MAPK (JNK, P38) pathway. Suppression of Netrin-1 can relieve Ang II-induced cardiac remodeling via inhibition of the PKCα/MAPK (JNK and P38) signaling pathway. Thus, Netrin-1 may be a novel therapeutic target for Ang II-mediated cardiac remodeling.
研究领域:
心脏病学
·
分子生物学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2024
·
IF 5.4
Lu Xu,Qin Zhao,Yiqiong Xie,Ge Bai,Hongwen Liu,Qi Chen,Hongjue Duan,Lishan Wang,Hang Xu,Yuxiang Sun,Gao Ling,Weihong Ge,Yun Zhu
Inflammatory bowel disease (IBD) remains a global health concern with a complex and incompletely understood pathogenesis. In the course of IBD development, damage to intestinal epithelial cells and a reduction in the expression of tight junction (TJ) proteins compromise the integrity of the intestinal barrier, exacerbating inflammation. Notably, the renin-angiotensin system and angiotensin II receptor type 1 (AT1R) play a crucial role in regulating the pathological progression including vascular permeability, and immune microenvironment. Thus, Telmisartan (Tel), an AT1R inhibitor, loading thermosensitive hydrogel was constructed to investigate the potential of alleviating inflammatory bowel disease through rectal administration. The constructed hydrogel exhibits an advantageous property of rapid transformation from a solution to a gel state at 37°C, facilitating prolonged drug retention within the gut while mitigating irritation associated with rectal administration. Results indicate that Tel also exhibits a beneficial effect in ameliorating colon shortening, colon wall thickening, cup cell lacking, crypt disappearance, and inflammatory cell infiltration into the mucosa in colitis mice. Moreover, it significantly upregulates the expression of TJ proteins in colonic tissues thereby repairing the intestinal barrier damage and alleviating the ulcerative colitis (UC) disease process. In conclusion, Tel-loaded hydrogel demonstrates substantial promise as a potential treatment modality for IBD.
研究领域:
药理学
·
胃肠病学
·
生物医学工程
·
炎症
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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）