CHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 15.1
Yanan Wang,Huichao Wei,Keyang Li,Liru Liu,Yingfei Zhu,Xinyuan Wang,Jiahui Yan,Liangmin Yu,Xuefeng Yan,Zhiyu He
Calcium overload in hepatocytes mediates the crosstalk and amplification loop with oxidative stress and severe inflammation that initiate pro-apoptotic and necrotic signaling pathways in acute liver injury (ALI). In this study, an N-acetylgalactosamine-modified amphiphilic dextran-silibinin conjugate (GalNAc-Dex-Sil) with ROS-sensitive phenylboronic acid (PBA) linkage was synthesized. The as-prepared amphiphilic polymer was self-assembled into GalNAc-Dex-Sil nanoparticles, which efficiently encapsulated the membrane-permeable calcium chelator BAPTA-AM (BA), achieving GalNAc-mediated hepatocyte-specific targeting and ROS-responsive release in injured hepatocytes through PBA cleavage. Accordingly, a single low-dose injection of formulation (BA: 150 μg·kg −1 ) significantly alleviated hepatocyte oxidative stress and inflammation, rescued dying hepatocytes, prevented further hepatocyte damage, and ultimately restored liver function in the ALI mouse model by 1) rapidly and effectively eliminating the overloaded calcium and scavenging excessive ROS via released BA to block the feed-forward vicious cycles of the cell damage, 2) inhibiting the inflammatory cascade by decreasing the expression of the key factor of the NF-κB/NLPR3 axis, 3) inhibiting the key branch of the mitochondrial apoptotic pathway (Cyt C/Bcl-2 family/caspase-3 axis) and death receptor pathway (TNFα/Caspase-8 axis), and 4) stabilizing hepatocyte membranes through the synergistic hepatoprotective effect of silibinin. Taken together, this formulation exhibited great potential as a potent and effective ALI treatment strategy.
研究领域:
药理学
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纳米技术
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肝病学
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炎症
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细胞凋亡
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产品关联
DOI
高影响因子
Advanced Science
·
2024
·
IF 14.3
Yunyun Liu,Lihua Xiang,Yitong Li,Shen Zhang,Ying Zhang,Hui Shi,Hui Liu,Dou Du,Bangguo Zhou,Beibei Ye,Shaoyue Li,Haohao Yin,Huixiong Xu,Yifeng Zhang
Pyroptosis, an inflammatory cell death, has attracted great attention for potentiating a strong immune response against tumor cells. However, developing powerful pyroptosis inducers and then activating specific pyroptosis still remains challenging. Herein, a PEG-CuP-COF@∆St nanosystem is rationally designed, consisting of PEG-CuP-COF nanozyme pyroptosis inducers and tumor-targeting bacteria of the Salmonella Typhimurium strain VNP20009 (ΔSt), with an affinity for the tumor hypoxic microenvironment. The PEG-CuP-COF nanozymes possessed excellent sonodynamic performance and multienzyme-mimicking activities to generate reactive oxygen species (ROS) and then induce potent pyroptosis. The superoxide dismutase- and peroxidase-mimicking activities of PEG-CuP-COF catalytically produced hydrogen peroxide (H 2 O 2 ) and hydroxyl radicals (•OH) which have important value in triggering acute inflammatory responses and pyroptosis. Moreover, PEG-CuP-COF showed outstanding glutathione peroxidase-mimicking activities, impairing the antioxidant defense in tumor cells and enhancing sonodynamic efficiency by making them more vulnerable to ROS-induced damage. During in vivo studies, PEG-CuP-COF@∆St nanosystem with its self-driven property exhibited impressive tumor-targeting capability and activated Caspase-3/gasdermin E-dependent pyroptosis to inhibit tumor growth. More importantly, it induced a powerful immune memory effect to prevent bone metastasis. In summary, this study introduces an innovative approach for combinatorial sono-catalytic immunotherapy using bacteria-mediated tumor-targeting delivery of nanozymes as specific pyroptosis inducers.
研究领域:
癌症治疗
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纳米技术
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免疫学
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生物工程
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医学生物技术
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产品关联
DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
·
2017
·
IF 4.521
Jing Zhang,Li Li,Yueting Peng,Yu Chen,Xiaoying Lv,Shun Li,Xiang Qin,Hong Yang,Chunhui Wu,Yiyao Liu
Tumor cell can be significantly influenced by various chemical groups of the extracellular matrix proteins. However, the underlying molecular mechanisms involved in the interaction between cancer cells and functional groups in the extracellular matrix remain unknown. Using chemically modified surfaces with biological functional groups (CH 3 , NH 2 , OH), it was found that hydrophobic surfaces modified with CH 3 and NH 2 suppressed cell proliferation and induced the number of apoptotic cells. Mitochondrial dysfunction, cytochrome c release, Bax upregulation, cleaved caspase-3 and PARP, and Bcl-2 downregulation indicated that hydrophobic surfaces with CH 3 and NH 2 triggered the activation of intrinsic apoptotic signaling pathway. Cells on the CH 3 - and NH 2 -modified hydrophobic surfaces showed downregulated expression and activation of integrin β1, with a subsequent decrease of focal adhesion kinase (FAK) activity. The RhoA/ROCK/PTEN signaling was then activated to inhibit the phosphorylation of PI3K and AKT, which are essential for cell proliferation. However, pretreatment of MDA-MB-231 cells with SF1670, a PTEN inhibitor, abolished the hydrophobic surface-induced activation of the intrinsic pathway. Taken together, the present results indicate that CH 3 - and NH 2 -modified hydrophobic surfaces induce mitochondria-mediated apoptosis by suppressing the PTEN/PI3K/AKT pathway, but not OH surfaces. These findings are helpful to understand the interaction between extracellular matrix and cancer cells, which might provide new insights into the mechanism potential intervention strategies for tumor prognosis.
研究领域:
癌症生物学
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细胞生物学
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分子生物学
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生物化学
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产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2023
·
IF 6.6
Weichu Zhu,Jian Xu,Xianxian Yao,Shuting Mai,Dan Shu,Wuli Yang
Pyroptosis is a proinflammatory form of cell death mediated by members of the gasdermin family, and is a powerful tool against cancer. Herein, a pH-responsive doxorubicin (DOX)-encapsulating zeolitic imidazolate framework-8 (ZIF-8) nanoparticle coated with a carboxybetaine-based zwitterionic polymer (DOX@ZIF-8@PCBMA) was prepared. Furthermore, decitabine (DAC) was loaded to obtain a pyroptosis nanotuner (DOX@ZIF-8@PCBMA-DAC). This nanotuner displayed extended blood circulation and enhanced tumor accumulation. In addition, the ZIF-8 structure and disulfide-crosslinked PCBMA coating endowed DOX@ZIF-8@PCBMA-DAC with acidic-pH- and glutathione-responsive degradation. The nanotuner could robustly activate caspase-3 to induce gasdermin E (GSDME)-dependent pyroptosis via the sustained release of DAC and DOX, contributing to excellent tumor suppression with negligible side effects, which may provide novel insights into traditional chemotherapy.
研究领域:
纳米技术
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药学
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癌症治疗
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
Regenerative Biomaterials
·
2016
·Vol. 3
·期 5
·299-307
·
IF 0
Sun Hong-Ji,Wang Yan,Hao Tong,Wang Chang-Yong,Wang Qi-Yu,Jiang Xiao-Xia
Glutathione (GSH) depletion has been an important contributor to the dysfunction of dopamine neurons. Polyamidoamine-GSH (PAMAM-GSH) was synthesized and the delivery effect of GSH into PC12 cells was tested. MTT assessment for cytotoxicity and reactive oxygen species (ROS) as well as nitrite oxide (NO) and intracelluar superoxide dismutase (SOD) detection for antioxidative ability were performed. Furthermore, the antiapoptotic ability was analysed by assessing caspase-3, JNK1/2 and Erk1/2 expression. Our data indicated that PAMAM-GSH is an effective agent to replenish GSH into PC12 cells. PAMAM-GSH developed its antioxidative and protective ability for 1-methyl-4-phenylpyridinium (MPP)-induced PC12 cells by reducing the intracellular levels of ROS and SOD activity as well as decreasing the release of NO. Meanwhile, PAMAM-GSH could inhibit caspase-3 activation and might show its antiapoptotic ability to MPP-induced PC12 cells through JNK2/Erk1/2 pathway. In summary, these studies suggest that PAMAM-GSH conjugate has an intrinsic ability to penetrate PC12 cells and deliver GSH into these cells which may provide a new strategy for clinical applications in the treatment of Parkinson’s disease.
研究领域:
神经科学
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药理学
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细胞生物学
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疾病模型
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产品关联
DOI
PubMed
COLLOIDS AND SURFACES B-BIOINTERFACES
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2015
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IF 4.152
Zhiyuan Li,Liu Zhang,Quanshun Li
Herein, N -acetyl- l -leucine-modified polyethylenimine was successfully constructed through the EDC/NHS-mediated coupling reaction and employed as vectors to accomplish p53 gene delivery using HeLa (p53wt) and PC-3 cells (p53null) as models. Compared with PEI25K, the derivatives exhibited lower cytotoxicity, protein adsorption and hemolytic activity, together with satisfactory pDNA condensation capability and gene transfection efficiency. After p53 transfection, MTT analysis confirmed that the cell proliferation was inhibited. Flow cytometric analysis showed that the derivative-mediated p53 delivery could induce stronger early apoptosis than PEI25K and Lipofectamine 2000 . Further, PC-3 cells showed higher sensitivity to the exogenous p53 transfection than HeLa cells. The mechanism for inducing apoptosis was determined to be up-regulation of p53 expression at both mRNA and protein levels using RT-PCR and western blotting analysis. Expression level and activity analysis of caspase-3, -8 and -9, and mitochondrial membrane potential measurement revealed that p53 transfection mediated by these derivatives facilitated early apoptosis of tumor cells via a mitochondria-dependent apoptosis pathway. Thus, the derivatives showed potential as biocompatible carriers for realizing effective tumor gene therapy.
研究领域:
癌症生物学
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分子生物学
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基因治疗
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药学
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产品关联
DOI
PubMed
高影响因子
NEW JOURNAL OF CHEMISTRY
·
2021
·Vol. 46
·期 3
·1295-1307
·
IF 3.591
Zhi-Gang Yin,Xiong-Wei Liu,Hui-Juan Wang,Min Zhang,Xiong-Li Liu,Ying Zhou
A highly efficient synthesis of structurally diverse ortho-acylphenol–diindolylmethane hybrids 3 using carboxylic acid-activated chromones as versatile synthetic building blocks is reported here for the first time, through 1,4-nucleophilic addition and followed by a decarboxylation and pyrone ring opening reaction process. The newly synthesized compounds were evaluated for their in vitro anticancer activity, and most of the compounds displayed good anticancer activities against four tested tumor cells (A549, PC-3, NCI-H1299, Caco-2). Among these compounds, compound 3t displayed the most potent and broad-spectrum anti-proliferative inhibition against the tested cell lines, especially A549 cells, and was more potent than arundine and cisplatin drugs, and had selectivity in cancer cells compared to MRC-5 and HK-2 normal cells. Preliminary mechanism studies showed that compound 3t exerted an anti-tumor effect in A549 cells by inhibiting the proliferation, colony formation and migration of A549 cells, and inducing cycle arrest at the G0/G1 phase and apoptosis. Furthermore, treatment of A549 cells with compound 3t caused increased ROS content and induced MMP collapse; western blot analysis showed that the expression level of p53 was significantly increased; Bax/Bcl-2 ratio and Cyt c were increased, and caspase-9, -3, and PARP were cleaved. These studies showed that compound 3t could induce apoptosis of A549 cells through the mitochondrial pathway, which was related to the activation of p53 and the generation of ROS. Thus, our results indicate that compound 3t may be used as a promising skeleton for the development of new anti-tumour drugs.
研究领域:
药物化学
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肿瘤学
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药学
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细胞生物学
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DOI
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2022
·
IF 5.195
Tingting Wang,Xiaoting Huang,Kefeng Zhai,Jialin Yu,Jiaxi Li,Hong Duan,Jinhong Liu,Zhuojian Lu,Jia Guo,Fei Li
Ethnopharmacological relevance Panax japonicus C. A. Meye (PJ) has unique effects on diseases by “qi” stagnation and blood stasis in ancient. Modern studies have shown that PJ can treat diabetic kidney disease (DKD) caused by deficiency and blood stasis. Aim of the study This study evaluated the potential effects of PJ on DKD, a microvascular complication, and investigated its possible mechanisms. Materials and methods In this study, the chemical constituents of PJ were analyzed by HPLC. In vivo studies, we constructed a diabetic mice model by HDF combined with STZ , then administered PJ to diabetic mice for 6 weeks. Blood lipid, BUN, 24h urine protein, and renal tissue HE staining were detected to comprehensively evaluate the protective effect of PJ on DKD. Metabolomics investigated the metabolic pathways influenced by PJ in the treatment of DKD. Moreover, the potential targets and signal pathways were investigated using network pharmacology . Finally, molecular docking predicts affinity of active compounds and core targets, and western blotting was used to detect core target expression levels. Results In vivo study, PJ can reduce hyperlipidemia , serum BUN, and 24-h urinary protein in diabetic mice, and protect the pathological changes in renal tissue. Metabolomics results showed that PJ had significant regulatory effect on unsaturated fatty acids , glycerophospholipid metabolism, and purine metabolism. Network pharmacology showed that MAPK1, MAPK8, Bcl-2, and Caspase 3 were the core targets in PJ against DKD. Molecular docking revealed that Bcl-2 and Caspase 3 have a strong affinity for Chikusetsusaponin Iva , Ginsenoside Rb1 , and Ginsenoside Rg1 . Moreover, when compared to the model group, the PJ group had higher levels of anti-apoptosis protein Bcl-2 and lower levels of pro-apoptosis protein Caspase 3. Conclusion PJ can reduce blood lipids, regulate the biosynthesis of unsaturated fatty acids and purine metabolism, thereby alleviating the renal injury of diabetic mice. Moreover, it can regulate the Bcl-2/caspase 3 apoptosis signaling pathway to prevent the apoptosis of renal cells and protect the renal function of diabetic mice.
研究领域:
药理学
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代谢组学
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糖尿病研究
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分子生物学
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病理学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2022
·
IF 6.656
Yule Wang,Huimin Wu,Zhu Han,Hongda Sheng,Yuhan Wu,Yingchao Wang,Xinran Guo,Yan Zhu,Xuecai Li,Yi Wang
Background As a leading cause of death and disability, alternative therapies for stroke are still limited by its complicated pathophysiological manifestations. Guhong injection (GHI), consisting of safflower aqueous extract and aceglutamide, has been widely applied for the clinical treatment of cerebrovascular diseases , especially ischemic stroke and post-stroke recovery, in China. Recently, a series of studies have reported the positive effect of GHI against cerebral ischemia/reperfusion injury via targeting various molecular mechanisms. However, questions remain on whether treatment with GHI contributes to better functional recovery after stroke and if so, the potential mechanisms and active substances. Purpose The aim of this work was to explore the potential therapeutic possibilities of GHI for the neurological and behavioral recovery after stroke and to investigate the underlying molecular mechanisms as well as active substances. Methods The neural and motor deficits as well as cortical lesions after GHI treatment were investigated in a mouse model of transient ischemic stroke. Based on the substance identification of GHI, network pharmacology combined with an experimental verification method was used to systematically decipher the biological processes and signaling pathways closely related to GHI intervention in response to post-stroke functional outcomes. Subsequently, ingenuity pathway analysis (IPA) analysis was performed to determine the anti-stroke active substances targeting to the hub targets involved in the significant molecular pathways regulated by GHI treatment. Results Therapeutically, administration of GHI observably ameliorated the post-stroke recovery of neural and locomotor function as well as reduced infarct volume and histopathological damage to the cerebral cortex in subacute stroke mice. According to 26 identified or tentatively characterized substances in GHI, the compound-target-pathway network was built. Bioinformatics analysis suggested that inflammatory and apoptotic pathways were tightly associated with the anti-stroke effect of GHI. Based on protein-protein interaction network analysis, the hub targets (such as NF-κB p65, TNF-α, IL-6, IL-1β, Bax, Bcl-2, and Caspase-3) involved in inflammation and apoptosis were selected. On the one hand, immunofluorescence and ELISA results showed that GHI (10 ml/kg) treatment obviously reduced NF-κB p65 nuclear translocation as well as decreased the abnormally elevated concentrations of proinflammatory cytokines (TNF-α, IL-6, and IL-1β) in damaged cortex tissues. On the other hand, GHI (10 ml/kg) treatment significantly downregulated the number of TUNEL-positive apoptotic cells in ischemic cortex and effectively restored the abnormal expression of Bax, Bcl-2, and Caspase-3. Based on the results of IPA, hydroxysafflor yellow A, baicalin , scutellarin , gallic acid , syringin , chlorogenic acid , kaempferol , kaempferol-3-O-β-rutinoside, and rutin acted synergistically on core targets, which could be considered as the active substances of GHI. Conclusion Overall, the current findings showed that the beneficial action of GHI on improving post-stroke functional recovery of subacute stroke mice partly via the modulation of cortical inflammation and apoptosis. These findings not only provide a reliable reference for the clinical application of GHI, but also shed light on a promising alternative therapeutic strategy for ischemic stroke patients .
研究领域:
神经病学
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药理学
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分子生物学
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中风研究
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产品关联
DOI
PubMed
高影响因子
IUBMB LIFE
·
2020
·Vol. 72
·期 9
·1997-2009
·
IF 3.244
Li Wang,Xintong Bi,Jiarui Han
Diabetic cardiomyopathy (DCM) is a cardiac disorder, which affects around 12% diabetic patients, resulting in overt heart death. Our initial bioinformatic analysis identified the differentially expressed gene 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 (HMGCS2) in DCM, which may be activated by peroxisome proliferator-activated receptor-alpha (PPARα) based on previous evidence. Therefore, the present study aims to explore the effect of PPARα on the development of DCM through regulating HMGCS2. The expression of PPARα and HMGCS2 was detected by reverse transcription quantitative polymerase chain reaction in cardiomyocytes and high-glucose-cultured cardiomyocytes. The proliferation and apoptosis of cardiomyocytes were examined by 5-ethynyl-2′-deoxyuridine assay and flow cytometry, separately. Mitoehondrial membrane potential (MMP) and intracellular reactive oxygen species (ROS) levels were determined. Then, the protein levels of B-cell lymphoma 2, Bcl-2-associated X protein, and cleaved Caspase-3 were detected by Western blot analysis. The myocardial apoptosis index, heart weight, and serum lipids of rats were examined. At last, the expressions of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), transforming growth factor β1 (TGFβ1), peroxisome proliferator activator receptor gamma coactivator-1 alpha (PGC1α), nuclear respiratory factor (NRF)-1, NRF-2, NAD(P)H oxidase 1, and superoxide dismutase-1 were examined. HMGCS2 was the most differentially expressed gene in DCM. The levels of HMGCS2 and PPARα were upregulated in patients with DCM. HMGCS2 silencing was shown to inhibit HMGCS2 expression to suppress the apoptosis of high-glucose-induced cardiomyocytes and the loss of MMP, reduce the accumulation of ROS, and promote cardiomyocyte proliferation. Silencing of HMGCS2 and PPARα alleviated myocardial injury, decreased blood glucose, and lipid in DCM rats, downregulated the expression of ANP, BNP, and TGFβ1 to reduce myocardial injury, and elevated PGC1α, NRF-1, and NRF-2 levels to enhance oxidative stress levels. Our results demonstrated that silencing of PPARα could alleviate cardiomyocyte injury and oxidative stress via a mechanism related to the downregulation of HMGCS2, which could provide a novel target for DCM treatment.
研究领域:
心脏病学
·
分子生物学
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内分泌学
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病理生理学
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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）