作者:
Hu Xiao-Bo;Duan Ting-Ting;Liu Jun;Zhu Gao-Lu;Cao Zhao-Hui;...
期刊:
中华医学杂志(英文版),2021年134(1):41-43 ISSN:0366-6999
作者机构:
[Duan Ting-Ting; Zhu Gao-Lu] The Key Laboratory of Ecological Environment and Critical Human Diseases Prevention, Education Department of Hunan Province, Department of Biochemistry, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China;The Key Laboratory of Typical Environmental Pollution and Health Hazards, Hunan Province, University of South China, Hengyang, Hunan 421001, China;[Feng Shao-Long] The Institute of Preventive Medicine, School of Public Health, Guilin Medical University, Guilin, Guangxi 541004, China.;[Hu Xiao-Bo; Liu Jun; Cao Zhao-Hui] The Key Laboratory of Ecological Environment and Critical Human Diseases Prevention, Education Department of Hunan Province, Department of Biochemistry, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China<&wdkj&>The Key Laboratory of Typical Environmental Pollution and Health Hazards, Hunan Province, University of South China, Hengyang, Hunan 421001, China
摘要:
Type 1 diabetes (T1D) is an organ-specific autoimmune disease with loss of pancreatic β-cells, characterized by reduced insulin levels and increased blood glucose. The incidence of T1D is increasing by approximately 2% to 5% worldwide every year and becoming a global health problem. Vitamin D (VD) deficiency was reported to be a risk factor in the development of T1D. Recent studies showed that supplementation of VD alleviated disease symptoms in T1D patients. However, a few randomized controled trials (RCTs) demonstrated the clinical effect of VD treatment with inconsistent findings. This article aimed to evaluate the effect of VD supplementation in T1D, which is helpful to develop an adjuvant therapy for T1D.
摘要:
Endoplasmic reticulum (ER) stress plays a critical role in pancreatic beta cell destruction which leads to the pathogenesis of type 1 diabetes mellitus (T1DM). Vitamin D (VD) has been reported to reduce the risk of T1DM; however, it remains unknown whether VD affects ER stress in pancreatic beta cells. In this study, we investigated the role of the active form of VD, 1,25-dihydroxyvitamin D3 [1,25-(OH)(2)D-3], in ER stress-induced beta cell apoptosis and explored its potential mechanism in mouse insulinoma cell line mouse insulinoma 6 (MIN6). The results of cell counting kit-8 (CCK8) and flow cytometric analyses showed that 1,25-(OH)(2)D-3 caused a significant increase in the viability of MIN6 cells injured by H2O2. The protein kinase like ER kinase (PERK) signal pathway, one of the most conserved branches of ER stress, was found to be involved in this process. H2O2 activated the phosphorylation of PERK, upregulated the activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) expression, and subsequently initiated cell apoptosis, which were significantly reversed by 1,25-(OH)(2)D-3 pretreatment. In addition, GSK2606414, a specific inhibitor of PERK, suppressed PERK phosphorylation and reduced the expressions of ATF4 and CHOP, leading to a significant decrease in beta cell apoptosis induced by H2O2. Taken together, the present findings firstly demonstrated that 1,25-(OH)(2)D-3 could prevent MIN6 cells against ER stress-associated apoptosis by inhibiting the PERK-ATF4-CHOP pathway. Therefore, our results suggested that 1,25-(OH)(2)D-3 might serve as a potential therapeutic target for preventing pancreatic beta cell destruction in T1DM.
期刊:
International Journal of Cancer,2019年144(3):651-664 ISSN:0020-7136
通讯作者:
Zu, Xuyu;Jiang, Yuyang
作者机构:
[Zhong, Jing; Zu, Xuyu; Cao, Renxian; Peng, Xiuda; Liu, Jianghua; Ding, Wenjun; Shen, Yingying] Univ South China, Inst Clin Med, Affiliated Hosp 1, 69 Chuanshan Rd, Hengyang 421001, Hunan, Peoples R China.;[Zhang, Wei] Tsinghua Univ, Sch Med, Dept Biol, Beijing, Peoples R China.;[Cao, Renxian; Liu, Jianghua] Univ South China, Affiliated Hosp 1, Dept Metab & Endocrinol, Hengyang, Hunan, Peoples R China.;[He, Jun] Univ South China, Affiliated Hosp 1, Dept Spine Surg, Hengyang, Hunan, Peoples R China.;[Chen, Xiguang] Univ South China, Affiliated Hosp 1, Dept Med Oncol, Hengyang, Hunan, Peoples R China.
通讯机构:
[Zu, Xuyu] U;[Jiang, Yuyang] T;Univ South China, Inst Clin Med, Affiliated Hosp 1, 69 Chuanshan Rd, Hengyang 421001, Hunan, Peoples R China.;Tsinghua Univ, Grad Sch Shenzhen, Guangdong Prov Key Lab Chem Biol, Lishui Rd, Shenzhen 518055, Peoples R China.
关键词:
*AXL;*DCC-2036;*MET;*PDX;*TNBC
摘要:
Triple-negative breast cancer (TNBC) is insensitive to endocrine therapies and targeted therapies to human epidermal growth factor receptor-2 (HER2), estrogen receptor (ER) and progesterone receptor (PR). New targets and new targeted therapeutic drugs for TNBC are desperately needed. Our study confirmed that DCC-2036 inhibited the proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) of TNBC cells as well as induced apoptosis. Moreover, the antiproliferative activity of DCC-2036 was more efficient than that of most clinical drugs. In addition, the combination of DCC-2036 and cisplatin or lapatinib had synergistic effects on TNBC cells. Mechanistically, DCC-2036 targeted AXL/MET, especially AXL, and regulated the downstream PI3K/Akt-NFkappaB signaling to exert its antitumor effect in TNBC. DCC-2036 also inhibited the growth and metastasis of xenografted MDA-MB-231 cells (AXL/MET-high TNBC cells) but not MDA-MB-468 cells (AXL-low TNBC cells) in NSG mice in vivo. Furthermore, DCC-2036 significantly inhibited tumor growth and invasion of AXL/MET-high TNBC PDX tumors but not AXL/MET-low TNBC PDX tumors. These results highlighted the roles of AXL/MET in cancer growth and metastasis and further verified that the critical targets of DCC-2036 are AXL and MET, especially AXL. In addition, there was no significant toxicity of DCC-2036 even at a high dosage. Therefore, DCC-2036 may be a potential compound to treat TNBC, especially for tumors with AXL/MET overexpression.
作者机构:
[Xie, Wan-Ying; Liu, Jie; Mcleod, Howard L.; He, Ruo-Hui; Li, Zhi; Tang, Yong-Jun; Wan, Zan; He, Yi-Jing; Zhou, Cheng-Fang] Cent S Univ, Xiangya Hosp, Dept Clin Pharmacol, 110 Xiangya Rd, Changsha 410008, Hunan, Peoples R China.;[Xie, Wan-Ying; Liu, Jie; He, Ruo-Hui; Li, Zhi; Wan, Zan; He, Yi-Jing; Zhou, Cheng-Fang] Cent S Univ, Inst Clin Pharmacol, Hunan Key Lab Pharmacogenet, Changsha 410078, Hunan, Peoples R China.;[Liu, Jie; He, Ruo-Hui; Li, Zhi; He, Yi-Jing] Univ South China, Cooperat Innovat Ctr Mol Target New Drug Study, Hengyang 421001, Hunan, Peoples R China.;[Zhang, Jun] Cent S Univ, Xiangya Hosp, Dept Nephrol, Changsha 410008, Hunan, Peoples R China.;[Tang, Yong-Jun] Cent S Univ, Xiangya Hosp, Dept Pediat, Changsha 410008, Hunan, Peoples R China.
通讯机构:
[Liu, Jie] C;Cent S Univ, Xiangya Hosp, Dept Clin Pharmacol, 110 Xiangya Rd, Changsha 410008, Hunan, Peoples R China.
关键词:
triple-negative breast cancer;-blocker;-adrenergic receptor;mitogen-activated protein kinase signaling pathway;(2)-adrenergic receptor single-nucleotide polymorphisms
摘要:
The (2)-adrenergic receptor ((2)-AR, encoded by the ADRB2 gene) is a member of the G-protein-coupled receptor superfamily that can be stimulated by catecholamines. Studies in vivo and in vitro have confirmed that -blockers (-AR antagonists) exert antitumor effects on various tumors. Furthermore, ADRB2 single-nucleotide polymorphisms (SNPs) have been identified to alter the expression and conformation of (2)-AR, which may alter the -blocker drug response. The aim of the present study was to investigate the effect of -blockers on triple-negative breast cancer cells and determine whether ADRB2 SNPs affect the response to -blocker drugs. Propranolol and ICI 118,551 significantly inhibited the viability of MDA-MB-231 cells, arrested cell cycle progression at G(0)/G(1) and S phase and induced cell apoptosis. Western blot analysis indicated that the phosphorylation levels of extracellular-signal-regulated kinase (ERK)1/2 and the expression levels of cyclo-oxygenase 2 (COX-2) were significantly decreased following -blocker treatment. Four haplotypes, which comprised ADRB2 SNPs rs1042713 and rs1042714, were transfected into 293 cells. After 24 and 48 h of transfection, ADRB2 mRNA expression was significantly decreased in mutant groups compared with the wild-type group. The ADRB2 SNPs exerted no effect on cell viability, but did affect the drug response of ICI 118,551. Furthermore, ADRB2 SNPs also affected the regulatory function of ICI 118,551 on the ERK/COX-2 signaling pathway. Collectively, propranolol and ICI 118,551 inhibited the viability of MDA-MB-231 cells by downregulating the ERK/COX-2 signaling pathway and inducing apoptosis. The results of the present study indicated that SNPs rs1042713 and rs1042714 of ADRB2 affected the response to ICI 118,551, and the underlying molecular mechanism was elucidated.
作者机构:
[Deng, Xiangping; Xie, Zhizhong; Liu, Juan; Lei, Xiaoyong; Tang, Guotao; He, Dongxiu; Peng, Junmei; Xiong, Runde; Cao, Xuan] Univ South China, Inst Pharm & Pharmacol, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Hengyang, Peoples R China.;[Chen, Yanming] Jiuzhitang Co Ltd, Changsha, Hunan, Peoples R China.
通讯机构:
[Tang, Guotao] U;Univ South China, Inst Pharm & Pharmacol, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Hengyang, Peoples R China.
摘要:
A series of tryptamine salicylic acid derivatives were synthesized and their antiproliferative activity against MGC-803, MCF-7, HepG2, A549 and HeLa cell lines was evaluated. The structure-activity relationship (SAR) study revealed that different substitutions of the C5 and C3'-C5' positions have certain effects on the anti-proliferation activity. The growth assay revealed that N-[2-(5-bromo-1H-indol-3-yl)-ethyl]-2-hydroxy-3-methyl-benzamide (E20) showed the most potent and broad-spectrum anticancer inhibition of all the cell lines evaluated, and was only more potent than 5-Fu for the gastric cancer cell line. Preliminary studies indicated that compound E20 could inhibit colony formation and migration of MGC-803 cells. The flow cytometry (FCM) results showed that compound E20 arrested the cell cycle in the G2/M phase and induced apoptosis of MGC-803 cells in a concentration-dependent manner. In addition, the western blot results showed that E20 can down-regulate the expression of hexokinase 2. Our studies suggest that the framework of N-[2-(5-bromo-1H-indol-3-yl)-ethyl]-2-hydroxy-3-methyl-benzamide may be consider as a new type of chemical for designing effective anti-cancer drugs targeting gastric cancer cells.
通讯机构:
[Tang, Guotao] U;Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Inst Pharm & Pharmacol, Hengyang 421001, Hunan, Peoples R China.
摘要:
According to the pharmacophore combination principle, a set of new 3,4,5-trimethoxy flavonoid salicylate derivatives were designed, synthesized, and evaluated for biological activity. The cytotoxicity evaluation revealed that compound 10v exhibited higher potency than 5-Fu against HCT-116 cells. Preliminary biological activity studies showed that compound 10v could inhibit the colony formation and migration of HCT-116 cells. Besides, the Hoechst 33258 staining assay and flow cytometry revealed that treatment with compound 10v induced the apoptosis of HCT-116 cells in a concentration-dependent manner, while it had no effect on their cell cycle. The WB analysis suggested that HIF-1, tubulin, HK-2, and PFK might be the potential pharmacophore targets of compound 10v. Tubulin was a potential drug target for compound 10v, which was explained by analyzing the crystal structure of compound 10v complexed with tubulin. These results indicated that compound 10v might be a promising anti-tumor agent candidate, deserving further optimization and evaluation.
摘要:
APJ, an orphan G protein-coupled receptor, is first identified through homology cloning in 1993. Apelin is endogenous ligand of APJ extracted from bovine stomach tissue in 1998. Apelin/APJ system is widely expressed in many kinds of cells such as endothelial cells, cardiomyocytes, especially vascular smooth muscle cell. Vascular smooth muscle cell (VSMC), an integral part of the vascular wall, takes part in many normal physiological processes. Our experiment firstly finds that apelin/APJ system enhances VSMC proliferation by ERK1/2-cyclin D1 signal pathway. Accumulating studies also show that apelin/APJ system plays a pivotal role in mediating the function of VSMC. In this paper, we review the exact role of apelin/APJ system in VSMC, including induction of proliferation and migration, enhance of contraction and relaxation, inhibition of calcification. Furthermore, we discuss the role of apelin/APJ system in vascular diseases, such as atherosclerosis, hypertension, and chronic kidney disease (CKD) from the point of VSMC. Above all, apelin/APJ system is a promising target for managing vascular disease.
摘要:
To improve the clinical effect of scutellarin by extending the action time in vivo, scutellarin loaded polymeric micelles were developed by D-alpha tocopherol polyethylene glycol 1000 succinate (Scu/TPGS). Scu/TPGS were prepared using film solvent diffusion methods and characterized on the basis of their particle size, zeta potential, and drug encapsulation efficiency. Dynamic dialysis was used to study the release behavior of the polymeric micelles in vitro. Its pharmacokinetic characteristics and antithrombotic efficacy were studied by intravenous injection in rats. The results showed that Scu/TPGS were spherical, 20.09 +/- 2.62 nm in size and a slow release in vitro. The pharmacokinetic parameter T-1/2 of Scu/TPGS was 762.12 +/- 46.56 min compared with commercial injection of 59.30 +/- 10.67 min (p < 0.05). At the 1 mg/kg dose, the thrombolysis effect of micellar group was stronger than that of the commercial group (p < 0.05). In conclusion, TPGS polymer micelles provided a valid strategy in chemotherapy for cerebrovascular diseases with poor water solubility and poor lipid solubility drugs such as scutellarin.
摘要:
A series of chrysin salicylate derivatives as potential antitumour agents were synthesised and evaluated their antitumour activities in vitro and in vivo. Most of the compounds exhibited moderate to good activities against MCF-7 cells, HepG2 cells, MGC-803cells and MFC cells. Among them, compound 3f showed the most potent activity against MGC-803 cells and MFC cells with IC50 values of 23.83 ± 3.68 and 27.34 ± 5.21 μM, respectively. The flow cytometry assay reconfirmed that compound 3f promoted the occurrence of tumour cells’ G1/S block under the inhibiting effect of compound 3f. Compound 3f possessed higher antitumour efficacy in tumour-bearing mice, compared with the positive control 5-Fu and the blank control saline.