DRUG DEVELOPMENT RESEARCH
·
2022
·Vol. 83
·期 5
·1176-1189
·
IF 5.004
Yanbo Xie,Xueyu Zhu,Ping Liu,Yunxiao Liu,Yadi Geng,Lei Zhang
Lung cancer is the cancer with the highest mortality, and non-small cell lung cancer (NSCLC) accounts for more than 80%. Tumor cells often have high reactive oxygen species (ROS) and antioxidant capacity. Redox balance is very important for tumor. The decline of antioxidant capacity and excessive ROS will induce the death of tumor cells. Destroying the redox balance of tumor cells is a promising tumor treatment strategy. Xanthatin is an active sesquiterpene lactone isolated from Xanthium strumarium L. We observed that xanthatin induced the up regulation of mitochondrial ROS and mitochondrial damage. Meanwhile, our results showed that xanthatin could inhibit system x c − and reduce glutathione (GSH) synthesis. Antioxidant GSH and N -acetyl- l -cysteine (NAC) significantly reversed cell proliferation inhibition and apoptosis induced by xanthatin. β-Mercaptoethanol (β-ME) which can avoid inhibition of system x c − can also reverse the inhibition of cell proliferation induced by xanthatin, si-SLC7A11 was the opposite. Based on these results, we believe that the inhibition of xanthatin on the proliferation of NSCLC cells may be related to breaking the intracellular redox balance. Our data suggest that xanthatin is a promising antitumor candidate for the treatment of NSCLC.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
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DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2026
·Vol. 87
·期 2
·e70265
·
IF 4.2
Jiao Li,Mingrong Song,Yifan Bu,Jing Chen
Vascular dementia (VD) is a cerebrovascular disease-associated cognitive disorder characterized by chronic neuroinflammation. Cinnamic acid (CA), a natural aromatic carboxylic acid, has been demonstrated to mitigate neurological dysfunction. In this study, a two-vessel occlusion (2-VO) rat model was established, and the rats were treated with CA at doses of 45 mg/kg and 90 mg/kg via intragastric gavage. CA treatment significantly restored cognitive function in 2-VO rats, which was attributed to the reduction of neuronal apoptosis. Furthermore, CA administration downregulated the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in the hippocampal tissues, while upregulating the expressions of arginase-1 (Arg-1), found in inflammatory zone 1 (Fizz1), and chitinase 3-like 3 (YM-1). These observations suggest that CA promotes the alternatively activated (M2) polarization of microglia in hippocampal tissues. To simulate the neuroinflammatory environment in vitro, BV2 cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) treatment. CA pretreatment promotes M2 polarization in OGD/R-induced BV2 cells, opposing OGD/R-driven M1 polarization in these cells. Importantly, network pharmacology analysis identified poly (ADP-ribose) polymerase 1 (PARP1) as a downstream target of CA. PARP1 expression was upregulated in the hippocampal tissues of 2-VO rats and OGD/R-induced BV2 cells, while CA treatment significantly reduced PARP1 expression. Notably, exogenous PARP1 reversed the CA-induced promotion of the microglial M2 phenotype, as evidenced by increased iNOS expression and decreased Arg-1 expression. In conclusion, CA targets PARP1 to promote the M2 polarization of microglia, thereby alleviating neuroinflammation and contributing to the recovery of neurological function in 2-VO rats.
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DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2020
·Vol. 81
·期 4
·526-533
·
IF 1.902
Dong Liu,Hailong Qin,Bixian Yang,Bin Du,Xuelin Yun
Liver fibrosis is characterized by the activation of hepatic stellate cells (HSCs) and accumulation of the extracellular matrix. There are limitations in the current therapies for liver fibrosis. Recently, oridonin was shown to induce apoptosis in HSCs. Thus, we aimed to determine the roles of oridonin in chronic liver injury and fibrosis. Liver fibrosis was induced by CCl 4 in mice injected intraperitoneally with oridonin for 6 weeks. The administration of oridonin significantly attenuated liver injury and reduced ALT levels. In addition, Sirius Red staining and the expression of α-smooth muscle actin (α-SMA) were significantly reduced by oridonin in murine livers with fibrosis. The expression of NLRP3, caspase-1, and IL-1β was downregulated with the oridonin treatment. Furthermore, the expression of F4/80 in liver tissues was also decreased by oridonin treatment. These results demonstrate that oridonin ameliorates chronic liver injury and fibrosis. Mechanically, oridonin may inhibit the activity of the NLRP3 inflammasome and inflammation in the liver. These results highlight the potential of oridonin as a therapeutic agent for liver fibrosis.
研究领域:
药理学
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肝病学
·
炎症
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DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2020
·Vol. 82
·期 3
·404-411
·
IF 1.902
Xiaolong Sun,Xu Wang,Zhenyu Zhao,Jing Chen,Cheng Li,Gang Zhao
Diabetic foot ulcer (DFU) is an invariably common complication of diabetes, characterized by delayed wound healing process and increased inflammation. Evidence has indicated that paeoniflorin exerts an anti-inflammatory effect in diabetic retinopathy. The current work was aimed to investigate the effect of paeoniflorin on inflammation and wound healing in DFU. DFU rat models by streptozotocin and skin biopsy punch, as well as high glucose-treated human immortalized keratinocytes (HaCaT) were established. Levels of blood glucose, wound contraction and proinflammatory cytokine were detected after paeoniflorin administration. Several essential targets associated with the NF-κB and Nod-like receptor protein-3 (NLRP3) signaling pathways were examined. Results showed markedly down-regulation of interleukin (IL)-1β, IL-18 and tumor necrosis factor-alpha in paeoniflorin-treated DFU rats. Paeoniflorin decreased the expression levels of chemokine receptor CXCR2, nuclear NF-κB and p-IκB (Ser36), as well as increased IκB level. Histological analysis and immunostaining showed lower inflammatory cells with decreased NLRP3 and cleaved caspase-1 levels following paeoniflorin treatment. Further in vitro evidence confirmed that paeoniflorin efficiently inhibited NLRP3 and NF-κB-mediated inflammation in DFU by inhibiting CXCR2. These findings are suggestive of greatly attenuated wound inflammation and better wound healing in paeoniflorin-treated DFU rats. Our study demonstrates that paeoniflorin is a potential therapeutic agent for DFU.
研究领域:
药理学
·
糖尿病
·
炎症研究
·
伤口愈合
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DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2018
·Vol. 79
·期 6
·307-312
·
IF 2.646
Zi-Li Ren,Hao Liu,Di Jiao,Hao-Tian Hu,Wei Wang,Jie-Xiu Gong,Ai-Li Wang,Hai-Qun Cao,Xian-Hai Lv
Hit, Lead & Candidate Discovery To discover succinate dehydrogenase inhibitors with a novel structure, we introduced cinnamic acid structure to optimize the lead structure 1 and synthesized four series of cinnamon–pyrazole carboxamide derivatives. The bioassay data showed that compounds (E)-N-(1-[4-chlorophenyl]-4-cyano-1H-pyrazol-5-yl)-3-(2-fluorophenyl) acrylamide ( 5III-d) and (E)-3-(2-chlorophenyl)-N-(1-[4-chlorophenyl]-4-cyano-1H-pyrazol-5-yl) acrylamide ( 5III-f) showed the significant antifungal activity against three fungi. In addition, 5III-d and 5III-f exhibited the excellent inhibitory effect against succinate dehydrogenase (SDH) enzymes with IC 50 values ranging from 19.4 to 28.7 μM. The study demonstrates that the chlorine substituent group is present on both the phenyl and pyrazole rings that have a very good effect on the antifungal effect, and the compounds 5III-d and 5III-f can act as potential SDH inhibitors (SDHI) and throw a sprat for a new generation of SDHI.
研究领域:
药物化学
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微生物学
·
植物保护学
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DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2019
·Vol. 80
·期 7
·958-969
·
IF 1.742
Ying Huang,Zhengwei Huang,Mingjun Wu,Yanpeng Liu,Cheng Ma,Xuejuan Zhang,Ziyu Zhao,Xuequn Bai,Hu Liu,Lili Wang,Xin Pan,Chuanbin Wu
To minimize the gastric and esophageal injury effect, a system to deliver doxycycline hyclate (DOXY) to the duodenum area is needed. DOXY-containing modified-release oral pellets (DMOP) coated with hydroxypropyl methylcellulose phthalate HP-55 (HPMCP HP-55) and hydroxypropyl methylcellulose E15 (HPMC E15) appear to be a reasonable choice. This coating layer dissolves at pH 5.5, which is the pH of the duodenum, but not at a gastric pH (1.2). The formulation and preparation of DMOP were optimized, and a scale-up test was performed. The results showed that the production reproducibility was acceptable, and the quality of DMOP well met the standards of Chinese Pharmacopeia (Ch.P, 2015 edition). Notably, the accumulated DOXY release was lower than 50% at pH 1.2 (20 min) and higher than 85% at pH 5.5, which met the USP40-NF35 standard for DOXY modified-release formulations. Moreover, the storage stability of DMOP with different packages was investigated by stress testing, accelerated and long-term testings. The stability of DMOP was maintained up to 12 months, in terms of DOXY content and in vitro release behavior. The results seem to suggest that DMOP could be a promising duodenum delivery system.
研究领域:
药剂学
·
药物释放系统
·
生物医学工程
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DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2019
·Vol. 80
·期 8
·1080-1088
·
IF 1.742
Hang Hu,Bin Wang,Chao Lai,Xiangjian Xu,Zihan Zhen,Huan Zhou,Defeng Xu
Paclitaxel (PTX) is a chemotherapeutic agent which shows antitumor activities against a broad spectrum of cancers. Yet, the current formulation of PTX used in clinic may cause a number of adverse reactions, which significantly limit its application. To obtain better clinical use of PTX, we report, for the first time, iRGD-PTX conjugate nanoparticles (NPs) for targeted PTX delivery. iRGD-PTX conjugate was synthesized from thiolated iRGD and 6-maleimidocaproic acid-PTX through Michael addition reaction. iRGD-PTX NPs with hydrodynamic diameter of ~110 nm were self-assembled from iRGD-PTX conjugate in deionized water. The as-prepared iRGD-PTX NPs exhibit good stability in phosphate buffered saline (PBS) buffer and fetal bovine serum containing PBS buffer. iRGD-PTX NPs exhibit sustained drug release behaviors. The in vitro studies show that iRGD-PTX NPs can be internalized by 4T1 cells by integrin αV-mediated endocytosis, resulting in better in vitro antitumor activity as compared to free PTX. The in vivo studies demonstrate that iRGD-PTX NPs exhibit enhanced tumor accumulation. The iRGD-PTX NPs reported here represent a novel PTX nanoplatform to achieve targeted PTX delivery.
研究领域:
药学
·
纳米技术
·
癌症研究
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DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2018
·Vol. 80
·期 2
·230-245
·
IF 2.646
Michael Adu-Frimpong,Caleb Kesse Firempong,Emmanuel Omari-Siaw,Qilong Wang,Yusif Mohammed Mukhtar,Wenwen Deng,Qingtong Yu,Ximing Xu,Jiangnan Yu
Punicic acid of pomegranate oil (PAP) has gained heightened interest due to several health benefits, such as anticarcinogenic, antidiabetic, and antiatherosclerotic properties. However, these bioactivities have been hampered by chemical instability, poor water solubility, rapid metabolism, and low bioavailability of PAP. Therefore, this study was aimed at optimizing the liposomal formulation of Triacylglycerol-bound punicic acid with its regioisomers (TPAR) for improved oral bioavailability and increased hepatoprotection through antioxidation and anti-inflammation. Herein, the optimized TPAR nanoliposome (TPAR-NL) was developed using thin-film dispersion method and subsequently characterized with appropriate indices. The optimized TPAR-NL produced fairly stable spherical nanoparticles (˂ 200 nm) with encapsulation efficiency (%EE) of 85.77%, as well as enhanced in vitro release and improved oral bioavailability. The TPAR-NL exhibited profound antihepatotoxic effect in mice pretreated with carbon tetrachloride (CCl 4 ) via reduction of serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels compared with free TPAR. The TPAR-loaded liposome also significantly reduced oxidative stress by increasing superoxide dismutase and glutathione levels while lowering malonaldehyde concentration compared with the free TPAR. The TPAR-LNF further exhibited remarkable anti-inflammatory activity compared with the free drug via inhibition of interleukin-6 and tumor necrosis factor-alpha generation. Thus, the developed nanoliposomes potentiated the antihepatotoxic activity of TPAR via antioxidation and anti-inflammation.
研究领域:
药剂学
·
生物化学
·
肝脏病学
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DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2016
·Vol. 77
·期 1
·43-49
·
IF 0.984
Zheer Pan,Chengwei Chen,Yeli Zhou,Feng Xu,Yaozeng Xu
Preclinical Research A series of mono-carbonyl curcumin analogs with different substituents at the 4/4’-position of the phenyl group were synthesized and screened for in vitro cytotoxicity against a panel of human cancer cell lines using a methyl thiazolyl tetrazolium assay. Several of the curcumin analogs, especially B114, exhibited a wide-spectrum of anti-tumor properties in all tested cell lines, indicating their potential in as anti-cancer lead compounds. Further toxicity testing in the NRK-52E kidney cell line revealed that the analogs A111, A113, and B114 had comparable or higher safety than curcumin. These data suggested that the introduction of appropriate substituents in the 4/4’-positions could be a promising approach for curcumin-based drug design. Drug Dev Res 77 : 43–49, 2016. © 2016 Wiley Periodicals, Inc.
研究领域:
药理学
·
肿瘤学
·
药物化学
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DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2021
·Vol. 83
·期 3
·669-679
·
IF 4.36
Dan Luo,Xing Li,Yonghui Hou,Yu Hou,Jiyao Luan,Jiaxian Weng,Jiheng Zhan,Dingkun Lin
Spinal cord injury (SCI) leads to microvascular damage and the destruction of the blood spinal cord barrier (BSCB), which can progress into secondary injuries, such as apoptosis and necrosis of neurons and glia, culminating in permanent neurological deficits. BSCB restoration is the primary goal of SCI therapy, although very few drugs can repair damaged barrier structure and permeability. Sodium tanshinone IIA sulfonate (STS) is commonly used to treat cardiovascular disease. However, the therapeutic effects of STS on damaged BSCB during the early stage of SCI remain uncertain. Therefore, we exposed spinal cord microvascular endothelial cells to H 2 O 2 and treated them with different doses of STS. In addition to protecting the cells from H 2 O 2 -induced apoptosis, STS also reduced cellular permeability. In the in vivo model of SCI, STS reduced BSCB permeability, relieved tissue edema and hemorrhage, suppressed MMP activation and prevented the loss of tight junction and adherens junction proteins. Our findings indicate that STS treatment promotes SCI recovery, and should be investigated further as a drug candidate against traumatic SCI.
研究领域:
神经科学
·
药理学
·
细胞生物学
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DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2021
·Vol. 83
·期 1
·167-175
·
IF 4.36
Jing Wei,Tao Yan,Yuanhong Liang
To clarify the role of TRAF3IP2 in high glucose (HG)-stimulated cardiomyocyte inflammation and apoptosis and its action mechanism. SiRNA plasmid of TRAF3IP2 was constructed and transfected into HG-stimulated cardiomyocytes to silence TRAF3IP2. The expression of TRAF3IP2 was determined by quantitative polymerase chain reaction (qPCR) and western blot. Cell viability and cytotoxicity were first observed using cell counting kit-8 and lactate dehydrogenase assays. The inflammatory injury of the cardiomyocytes was then examined by real time-qPCR (RT-qPCR) and western blot. The oxidative stress of the cardiomyocytes was evaluated using reactive oxygen species assay kit, RT-qPCR, western blot and enzyme activity assay kit. Next, cell apoptosis was detected employing TUNEL and western blot. Finally, RT-qPCR and western blot were performed to investigate the effects of inhibitors of dipeptidyl peptidase-4, including saxagliptin, empagliflozin and linagliptin, on TRAF3IP2. TRAF3IP2 expression was found to be increased in HG-stimulated cardiomyocytes. TRAF3IP2 interference inhibited HG-induced cell viability loss, cytotoxicity, inflammatory response, oxidative stress and apoptosis of the cardiomyocytes. Moreover, saxagliptin, empagliflozin and linagliptin inhibited the expression of TRAF3IP2. TRAF3IP2 interference alleviates HG-induced inflammation and apoptosis of cardiomyocytes. The result suggests that TRAF3IP2 may be a promising therapeutic target in treating diabetic cardiomyopathy.
研究领域:
心脏病学
·
分子生物学
·
糖尿病
·
药理学
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产品关联
DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2021
·Vol. 83
·期 2
·328-338
·
IF 4.36
Min Wu,Mengmeng Jin,Xiaohui Cao,Kun Qian,Lei Zhao
Adenosine deaminases acting on RNA 1 (ADAR1) has been identified to play key roles in non-small cell lung cancer (NSCLC) progression, and can modulate the sensitivity of cancer cells to anticancer drugs. The current study aimed to investigate the effect of ADAR1 on the sensitivity of NSCLC cells to anlotinib. We established anlotinib-resistant NSCLC (NSCLC/AR) cells, including NCI-H1975/AR and A549/AR cells. Results showed that ADAR1 was significantly upregulated in NSCLC/AR cells. Genetic-knockdown of ADAR1 increased the sensitivity of NSCLC/AR cells to anlotinib by inducing cell proliferation suppression, cell cycle arrest, and apoptosis. Furthermore, knockdown of ADAR1 decreased the level of C-X3-C motif chemokine ligand 1 (CX3CL1) in NCI-H1975/AR and A549/AR cells after anlotinib treatment. Introduction of exogenous CX3CL1 significantly reversed the positive effect of ADAR1 deficiency on NSCLC/AR cell sensitivity, exhibited by the increase of cell viability and decrease of apoptosis. Further in-vivo study demonstrated that knockdown of ADAR1 inhibited NCI-H1975/AR cell tumorigenesis by reducing CX3CL1 expression. Collectively, ADAR1 deficiency increased the sensitivity of NSCLC/AR cells to anlotinib by downregulating CX3CL1, which might provide a potential strategy for NSCLC/AR therapy.
研究领域:
肿瘤学
·
分子生物学
·
药理学
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产品关联
DOI
PubMed
高影响因子
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