JOURNAL OF CELLULAR BIOCHEMISTRY
·
2017
·Vol. 119
·期 2
·1501-1510
·
IF 3.085
Qing Wang,Pu Wang,Hong Zhou,Yan Hu,Chengshen Xie,Fei Gao,Ningjie Ma,Haoli Hou,Hao Zhang,Lijia Li
DNA methylation plays a crucial role in lots of biological processes and cancer. 5-azacytidine (5-AC), a DNA methylation inhibitor, has been used as a potential chemotherapeutic agent for cancer. In this study, we used 5-AC treatment to investigate whether DNA methylation was involved in regulation of programmed cell death (PCD) in mouse embryo fibroblast NIH-3T3 cells which could undergo PCD after treatment with TNF-α and cycloheximide (CHX). The results showed that the genomic DNA of NIH-3T3 cells was hypermethylated during PCD induced by TNF-α and CHX, and 5-AC might prevent this PCD process. However, treatment with the other three DNA methylation inhibitors, 5-aza-deoxycytidine, 6-thioguanine and RG108, did not interfere with the NIH-3T3 cell PCD process. Additionally, knockdown of DNMT1 did not affect the apoptosis process. The present results and observations indicated that 5-AC specifically inhibited the NIH-3T3 apoptosis process via a genomic DNA methylation-independent pathway. During the TNF-α and CHX-inducing apoptosis process, the PCD related BCL-2 family proteins were significantly down-regulated. Furthermore, after the small interference RNA-mediated knockdown of BCL-XL, one of the BCL-2 family proteins, 5-AC did not inhibit the apoptosis process, suggesting that 5-AC inhibited the PCD process induced by TNF-α and CHX by affecting the anti-apoptotic protein BCL-XL.
研究领域:
癌症研究
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细胞生物学
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表观遗传学
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DOI
PubMed
高影响因子
Advanced Science
·
2023
·
IF 15.1
Hao Yan,Xiangliang Huang,Jiangxin Xu,Ying Zhang,Jiajia Chen,Zhifei Xu,Hui Li,Zeng Wang,Xiaochun Yang,Bo Yang,Qiaojun He,Peihua Luo
Nephrotoxicity has become prominent due to the increase in the clinical use of nilotinib, a second-generation BCR-ABL1 inhibitor in the first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia. To date, the mechanism of nilotinib nephrotoxicity is still unknown, leading to a lack of clinical intervention strategies. Here, it is found that nilotinib could induce glomerular atrophy, renal tubular degeneration, and kidney fibrosis in an animal model. Mechanistically, nilotinib induces intrinsic apoptosis by specifically reducing the level of BCL2 like 1 (Bcl-XL) in both vascular endothelial cells and renal tubular epithelial cells, as well as in vivo. It is confirmed that chloroquine (CQ) intervenes with nilotinib-induced apoptosis and improves mitochondrial integrity, reactive oxygen species accumulation, and DNA damage by reversing the decreased Bcl-XL. The intervention effect is dependent on the alleviation of the nilotinib-induced reduction in ubiquitin specific peptidase 13 (USP13) and does not rely on autophagy inhibition. Additionally, it is found that USP13 abrogates cell apoptosis by preventing excessive ubiquitin‒proteasome degradation of Bcl-XL. In conclusion, the research reveals the molecular mechanism of nilotinib's nephrotoxicity, highlighting USP13 as an important regulator of Bcl-XL stability in determining cell fate, and provides CQ analogs as a clinical intervention strategy for nilotinib's nephrotoxicity.
研究领域:
药理学
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肿瘤学
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肾病学
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分子生物学
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DOI
PubMed
高影响因子
PHYTOCHEMICAL ANALYSIS
·
2026
·
IF 2.9
Yu Xia,Xinyi Zhong,Chenggang Zhang
Background Hypoxia is a core pathological factor in myocardial injury and is involved in the development of various cardiovascular diseases. Although baicalein shows cardiovascular protective potential, its mechanism against hypoxic injury remains unclear. Methods H9c2 cardiomyocytes were exposed to sodium sulfite to establish a chemical hypoxia model. Network pharmacology, molecular docking, molecular dynamics simulation, and molecular biology assays were employed to predict the core target and investigate the underlying mechanism. Results Network pharmacology identified ESR1 as a core target, with stable binding to baicalein confirmed by molecular docking and dynamics simulations. Baicalein alleviated hypoxia-induced oxidative stress by elevating key antioxidant markers and reducing malondialdehyde levels. It also ameliorated energy metabolism disorders, reduced lactate dehydrogenase release, suppressed reactive oxygen species production, and decreased cell apoptosis. Furthermore, baicalein upregulated hypoxia-suppressed ESR1 protein expression and enhanced its co‑localization with the antiapoptotic protein BCL-XL. The cytoprotective effects were abolished by the ESR1 inhibitor fulvestrant. Conclusion These findings demonstrate that baicalein protects cardiomyocytes against hypoxic injury through an ESR1‑dependent mechanism by modulating the BCL‑XL/BAX apoptotic balance, mitigating oxidative stress, and improving energy metabolism.
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DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2025
·
IF 6.3
Xiao-Man Ji,Xin-Xin Dong,Jia-Peng Li,Guang-Jie Tai,Shu Qiu,Wei Wei,Ceaser Wankumbu Silumbwe,Davaadagva Damdinjav,Joseph Nicolao Otieno,Xiao-Xue Li,Ming Xu
Vascular aging is a major contributor to age-related cardiovascular diseases (CVDs) and type 2 diabetes mellitus (T2DM) induced early arterial aging and excessive senescent cells (SCs) burden in vessels. Inhibiting cellular senescence or eliminating SCs could effectively improve aging-related CVDs. Fisetin, a flavonoid extracted from cotinus coggygria scop, has shown potential in alleviating aging by clearing SCs. This study investigated the unexplored mechanisms and efficacy of fisetin in alleviating T2DM-related aortic aging. The T2DM mouse model was induced using a high-fat diet and low-dose streptozotocin injection. Chronic fisetin treatment's protective effects against aortic aging were assessed via senescence-associated beta-galactosidase (SA-β-Gal) staining, histopathology, and vasomotor function. RNA-sequencing and western blotting identified relevant signaling pathways and protein expression. Fisetin's effects on SCs and senescence-associated secretory phenotype (SASP) factors were evaluated through cell viability, apoptosis, and co-culture assays. Docking simulations suggested fisetin as a potential Phosphoinositide 3-kinase (Pi3k) inhibitor. In vivo, chronic fisetin treatment reduced aortic SCs burden, alleviating T2DM-related and natural aortic aging. In vitro, fisetin selectively induced apoptosis of senescent endothelial cells via regulating the Pi3k-Protein Kinase B (Akt)-B-cell lymphoma (Bcl)-2/Bcl-xl pathway and suppressed SASP and its detrimental effects. Furthermore, fisetin combined with metformin therapy showed superior anti-aging effects on T2DM-related aortic aging compared to metformin monotherapy. In conclusion, chronic fisetin treatment alleviates T2DM-related aortic aging via clearing the SCs burden and abrogating the SASP factors. Fisetin combined with metformin therapy might be a potential therapeutic strategy for T2DM-related CVDs.
研究领域:
药理学
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心血管疾病
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分子生物学
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DOI
PubMed
高影响因子
ONCOLOGY REPORTS
·
2020
·Vol. 44
·期 3
·927-938
·
IF 3.417
Songhui Zhou,Ruicheng Wang,Hong Xiao
The resistance of cancer cells to carboplatin restricts their efficacy in the clinical setting, and a solution to reverse the resistance is urgently required for the treatment of ovarian cancer. An increasing number of studies have found associations between obesity and the incidence, and mortality rates of female cancer. However, the association between adipocytes and the resistance of ovarian cancer has rarely been reported. Based on this, the present study first revealed the inductive effect of adipocytes on the resistance of ovarian cancer to carboplatin using in vivo and in vitro experiments. Subsequently, it was identified that the angiopoietin‑like 4 (ANGPTL4) secreted by adipocytes played a vital role in the resistance of ovarian cancer using bioinformatics analysis, cellular and molecular biological experiments, as well as forward and backward validation. The glycosylated ANGPTL4 protein could bind with integrin α5β1 on the surface of ovarian cancer cells; following which, it could activate the c‑myc/NF‑κB pathway and stimulate the expression of the antiapoptotic protein Bcl‑xL, as well as the ABC transporter family members ABCB1, ABCC1 and ABCG2. Thus, inducing the resistance of ovarian cancer to carboplatin. In conclusion, targeting the adipocyte‑derived ANGPTL4 combined with the application of carboplatin contributes to the clinical treatment for ovarian cancer.
研究领域:
肿瘤学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Food Bioscience
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2022
·
IF 5.318
Jingru Zheng,Yuanhong Gao,Jie Ding,Na Sun,Songyi Lin
The study aims to investigate the repair effects of Ser-Ser-Asp-Ala-Phe-Phe-Pro-Phe-Arg (SSDAFFPFR) and Ser-Asn-Val-Phe-Asp-Met-Phe (SNVFDMF) peptides on scopolamine-caused memory impairment in mice. Behavioral experiments have revealed that Antarctic krill peptides can ameliorate scopolamine caused memory impairment by changing the behavior of mice. In comparison with the scopolamine group, the two peptides at a dose of 40 mg/kg could improve memory impairment. The serum SOD activity (82.82 ± 0.19 vs 79.47 ± 2.42 U/mg prot) and hippocampal ACh level (101.46 ± 3.23 vs 99.85 ± 7.13 μg/mg prot) of SSDAFFPFR were higher than those of SNVFDMF. Hippocampal AChE activity (0.20 ± 0.03 vs 0.53 ± 0.02 U/mg prot), hippocampal MDA level (1.56 ± 0.01 vs 1.63 ± 0.05 nmol/mg prot) and the serum MDA level (3.38 ± 0.24 vs 3.88 ± 0.21 nmol/mg prot) was lower than that of SNVFDMF. The state of mouse hippocampal cells was further observed by a microscopic imaging system. In addition, western blot analysis showed that SSDAFFPFR could significantly inhibit the expression of Bax, caspase-3, and p53, and promote the expression of BCL-XL, CREB, and BDNF, thus protecting hippocampal neurons in mice. In conclusion, the Antarctic krill peptide can repair scopolamine-induced memory impairment in mice.
研究领域:
神经科学
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药理学
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生物化学
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DOI
高影响因子
Marine Drugs
·
2024
·Vol. 22
·期 6
·250
·
IF 4.9
Wanting Hao,Leyan Wang,Tongqiang Xu,Geng Jia,Yuqi Jiang,Chong Qin,Xiaoyang Li
Acute myeloid leukemia (AML) is a hematologic malignancy characterized by infiltration of the blood and bone marrow, exhibiting a low remission rate and high recurrence rate. Current research has demonstrated that class I HDAC inhibitors can downregulate anti-apoptotic proteins, leading to apoptosis of AML cells. In the present investigation, we conducted structural modifications of marine cytotoxin Santacruzamate A (SCA), a compound known for its inhibitory activity towards HDACs, resulting in the development of a novel series of potent class I HDACs hydrazide inhibitors. Representative hydrazide-based compound25cexhibited concentration-dependent induction of apoptosis in AML cells as a single agent. Moreover,25cexhibited a synergistic anti-AML effect when combined with Venetoclax, a clinical Bcl-2 inhibitor employed in AML therapy. This combination resulted in a more pronounced downregulation of anti-apoptotic proteins Mcl-1 and Bcl-xL, along with a significant upregulation of the pro-apoptotic protein cleaved-caspase3 and the DNA double-strand break biomarker γ-H2AX compared to monotherapy. These results highlighted the potential of25cas a promising lead compound for AML treatment, particularly when used in combination with Venetoclax.
研究领域:
肿瘤学
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药理学
·
血液学
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DOI
高影响因子
JOURNAL OF INORGANIC BIOCHEMISTRY
·
2022
·
IF 4.336
Hong-shuang Liu,Man-yu Zhou,Xi Zhang,Ya-lan Li,Jing-wei Kong,Xin Gao,Dong-yu Ge,Jia-jing Liu,Pei-guang Ma,Gui-ying Peng,Yan Liao
The hepatic protective role of Sagittaria sagittifolia polysaccharide (SSP) and its possible mechanism were discussed in mice and L02 hepatocytes injured by heavy metals mixture of Cd + Cr (VI) + Pb + Mn + Zn + Cu. After 30-day intervention, blood and liver samples were collected for the relevant assessments. Methyl thiazolyl tetrazolium (MTT) assay showed 24 h was the best protecting point and the SSP protection at 1 mg/mL was strongest in L02 hepatocytes. SSP can alleviated hepatic injury, as evidenced by significantly decreased the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and the malondialdehyde (MDA) content, also increased the superoxide dismutase (SOD) activity and glutathione (GSH), total sulphydryl (T-SH) contents. SSP effectively reduced pathological damage of mice and accumulation of heavy metals in liver, as well as decreased the level of reactive oxygen species (ROS) in L02 hepatocytes. After SSP treatment, the protein expressions or gene transcription of nuclear factor erythroid 2-related factor 2 (Nrf2), NAD( P )H dehydrogenase, quinone 1 (NQO1) and heme oxygenase1 (HO-1) decreased in L02. The protein expression of Nrf2 and NQO1 were increased while HO-1 was decreased in liver. Besides, SSP can attenuates apoptosis through reducing the protein expression of Bcl-2-associated X protein (Bax) and caspase-3, and increasing B-cell lymphoma gene 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xl). SSP protects against six-heavy-metal-induced hepatic injury in mice and L02 hepatocytes. Supported by Nrf2 gene silencing, the mechanisms may correlate with activating Nrf2 pathway to mitigate oxidative stress and apoptosis.
研究领域:
药理学
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毒理学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Quanjuan Guo,Ailu Yang,Rongrong Zhao,Huajun Zhao,Yongliang Mu,Jian Zhang,Qiuju Han,Yuhang Su
Nimodipine, a calcium antagonist, exert beneficial neurovascular protective effects in clinic. Recently, Calcium channel blockers (CCBs) was reported to protect against liver fibrosis in mice, while the exact effects of Nimodipine on liver injury and hepatic fibrosis remain unclear. In this study, we assessed the effect of nimodipine in Thioacetamide (TAA)-induced liver fibrosis mouse model. Then, the collagen deposition and liver inflammation were assessed by HE straining. Also, the frequency and phenotype of NK cells, CD4 + T and CD8 + T cells and MDSC in liver and spleen were analyzed using flow cytometry. Furthermore, activation and apoptosis of primary Hepatic stellate cells (HSCs) and HSC line LX2 were detected using α-SMA staining and TUNEL assay, respectively. We found that nimodipine administration significantly attenuated liver inflammation and fibrosis. And the increase of the numbers of hepatic NK and NKT cells, a reversed CD4 + /CD8 + T ratio, and reduced the numbers of MDSC were observed after nimodipine treatment. Furthermore, nimodipine administration significantly decreased α-SMA expression in liver tissues, and increased TUNEL staining adjacent to hepatic stellate cells. Nimodipine also reduced the proliferation of LX2, and significantly promoted high level of apoptosis in vitro . Moreover, nimodipine downregulated Bcl-2 and Bcl-xl, simultaneously increased expression of JNK, p-JNK, and Caspase-3. Together, nimodipine mediated suppression of growth and fibrogenesis of HSCs may warrant its potential use in the treatment of liver fibrosis.
研究领域:
药理学
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免疫学
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肝病学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2017
·
IF 2.759
Yanyan Zhu,Yameng Jiang,Lei Shi,Linying Du,Xiaodong Xu,Enxia Wang,Yong Sun,Xin Guo,Boyang Zou,Huaxin Wang,Changyuan Wang,Lidan Sun,Yuhong Zhen
7- O -Geranylquercetin (GQ) is a novel O -alkylated derivate of quercetin . In this study, we evaluated its apoptosis induction effects in human gastric cancer cell lines SGC-7901 and MGC-803 and explored the potential molecular mechanisms. The results demonstrated that GQ lowered viability of SGC-7901 and MGC-803 cells in a dose- and time-dependent manner without apparent cytotoxicity to human gastric epithelial cell line GES-1. GQ could induce apoptosis in SGC-7901 and MGC-803cells, and arrest the gastric cancer cells at G2/M phase. Mechanism study showed that GQ triggered generation of reactive oxygen species (ROS), then activated p38 and JNK signaling pathways , subsequently led to mitochondrial impairment by regulating the expression of Bcl-2, Bcl-xl and Bax, and finally promoted the release of cytochrome c and the activation of caspases to induce apoptosis. In addition, Z-VAD-FMK (caspase inhibitor) could reverse GQ-induced apoptosis. SB203580 (p38 inhibitor) and SP600125 (JNK inhibitor) could rescue GQ-induced cell death and attenuate mitochondrial signal pathway activation. Furthermore, NAC (ROS inhibitor) could rescue GQ-induced cell death, reduce ROS generation, decrease the phosphorylation of p38 and JNK, and then attenuate the activation of mitochondrial signal pathway. Taken together, GQ induces caspase-dependent apoptosis in gastric cancer cells through activating ROS-MAPK mediated mitochondrial signal pathway. This study highlights the potential use of GQ as a gastric cancer therapeutic agent.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Nano Today
·
2024
·
IF 13.2
Di Nie,Yishan Lv,Duo Gao,Anqi Xu,Qinyu Li,Jiaxin Li,Xiang Lu,Bingqi Wang,Jie Wang,Chang Liu,Zhuan Zhang,Xiang Li,Ning Wang,Shiyan Guo,Chunliu Zhu,Miaorong Yu,Yong Gan
Achieving efficient and secure cytosolic delivery is crucial for RNA therapeutics. Presently, delivery systems predominantly attain cytosolic release through membrane rupture or destabilization of late endosomes and lysosomes. However, these approaches lead to restricted RNA release and undesirable cytotoxicity, ultimately diminishing therapeutic efficacy. Herein, we proposed an efficient strategy based on early endosome fusion-mediated release, employing probiotic-derived lipopolysaccharide (LPS)-incorporated vesicles to enhance RNA delivery. The LPS is derived from Escherichia coli Nissle 1917 (EcN) and has a high safety confirmed by the authoritative pyrogen test. The LPS-rich outer membrane vesicles (OMVs) and synthetic chimeric liposomes (LPS-Lips) are found capable of efficient cytosolic RNA delivery by using LPS to fuse with early endosomes, as evidenced by super-resolution and real-time imaging. The OMVs and LPS-Lips (containing 10 % and 30 % EcN-derived LPS) exhibit enhanced ability to deliver functional BCL-xL siRNA, leading to more significant gene silencing and cell apoptosis in comparison to the commercial Lipofectamine 2000 and RNAiMAX groups. The in vivo results demonstrate their superior efficacy on inhibiting tumor growth and prolonged survival time with enhanced safety. These findings highlight the early endosome fusion strategy with facilitated release efficiency and safety, offering guidelines for the rational design of enhanced RNA delivery systems.
研究领域:
药学
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分子生物学
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癌症研究
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生物技术
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药物递送系统
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产品关联
DOI
高影响因子
BIOORGANIC CHEMISTRY
·
2023
·
IF 5.1
Shuai Wang,Jian-Tao Shi,Xing-Rong Wang,Hong-Xia Mu,Xue-Ting Wang,Kai-Yan Xu,Qing-Shan Wang,Shi-Wu Chen
The PI3K/AKT/mTOR signaling pathway is one of the most common abnormal activation pathways in tumor cells, and has associated with multiple functions such as tumor cell growth, proliferation, migration, invasion, and tumor angiogenesis. Here, a series of 3-amino-1 H -indazole derivatives were synthesized, and their antiproliferative activities against HT-29, MCF-7, A-549, HepG2 and HGC-27 cells were evaluated. Among them, W24 exhibited the broad-spectrum antiproliferative activity against four cancer cells with IC 50 values of 0.43–3.88 μM. Mechanism studies revealed that W24 inhibited proliferation by affecting the DNA synthesis, induced G 2 /M cell cycle arrest and apoptosis by regulating Cyclin B1, BAD and Bcl-xL, meanwhile induced the change of intracellular ROS and mitochondrial membrane potential in HGC-27 cells. Moreover, W24 inhibited the migration and invasion of HGC-27 cells by decreasing EMT pathway related proteins and reducing the mRNA expression levels of Snail, Slug and HIF-1α. Furthermore, W24 displayed low tissue toxicity profile and good pharmacokinetic properties in vivo . Therefore, 3-amino-1 H -indazole derivatives might serve as a new scaffold for the development of PI3K/AKT/mTOR inhibitor and anti-gastric cancer reagent.
研究领域:
肿瘤学
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药理学
·
化学
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细胞生物学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
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