JOURNAL OF CONTROLLED RELEASE
·
2020
·
IF 7.727
Xue Yang,Fang Gao,Wenan Zhang,Huipeng Li,Xinzhi Huang,Jiajia Wei,Jiayi Bian,Ying Yang,Chenggen Qian,Minjie Sun
Invasion and metastasis of tumor cells is one of the major obstacles in cancer therapy. The process of tumor metastasis and diffusion is coordinated by multiple pathways associated with chemokine signals and migration microenvironment. In our previous work, chemokine CXC receptor 4 (CXCR4) antagonists showed significant anti-metastatic effects by blocking the CXCR4/stromal cell-derived factor-1(SDF-1) axis in pancreatic cancer and breast cancer. Here, we proposed to achieve migration chain-treatment for metastatic tumors by introducing a cell adhesion molecules CD44 inhibitor (Star miR-34a) to deprive of cell migration capability on the basis of CXCR4 antagonism (cyclam monomer , CM). Dextrin modified 1.8 k PEI with CM-end was prepared to deliver therapeutic miR-34a (named DPC/miR-34a) for efficient anti-metastasis by downregulating adhesion protein CD44 and targeting the CXCR4/SDF-1 axis. Additionally, reduced expression of the anti-apoptotic protein Bcl2 caused by miR-34a could enhance the anti-tumor efficacy of DPC/miR-34a nanoplex administration. Compared with inhibition of the CXCR4/SDF-1 axis or CD44 expression, the multidimensional therapy (DPC/miR-34a) exhibited considerable suppression of cancer cell invasion as assessed by an in vitro cell invasion assay and in vivo anti-metastasis model. Moreover, DPC/miR-34a demonstrated a superior antitumor and anti-metastatic efficacy both in lung metastatic model and orthotopic MDA-MB-231 tumor models, thus providing an efficient approach for combating metastatic tumors.
研究领域:
肿瘤学
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分子生物学
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药学
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癌症治疗
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DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY
·
2021
·Vol. 37
·期 1
·41-51
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IF 4.119
Rili Hao,Junlin Ge,Xinyu Song,Feng Li,Dongxiao Sun-Waterhouse,Dapeng Li
Cadmium (Cd) is a potent neurotoxic metal present in the environment and food. In this study, CdCl 2 (2 or 4 μM) induced cytotoxicity and neurotoxicity in PC12 cells, causing decreases in cell viability and NEP protein expression and increase in p-tau protein expression. For the first time, CdCl 2 -initiated injury was found to result from the induction of not only apoptosis but also ferroptosis, as evidenced by the increased iron content, ROS production, and mitochondrial membrane potential along with changes in the expressions of iron death-related genes (FTH1, GPX4, ASCL4, PTGS2, and NOX1) and levels of caspase9, Bax, and Bcl-2 proteins. The molecular mechanisms leading to apoptosis and ferroptosis at least included the participation of the miR-34a-5p/Sirt1 axis, in which miR-34a-5p promoted CdCl 2 -induced neurotoxicity through targeting Sirt1. Knocking out miR-34a-5p attenuated CdCl 2 -induced damage of PC12 cells, cytotoxicity and neurotoxicity. This research provides the underlying molecular mechanisms of CdCl 2 -induced damage and asserts the role of miRNAs as critical regulators.
研究领域:
神经科学
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毒理学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
CELL DEATH AND DIFFERENTIATION
·
2022
·Vol. 29
·期 11
·2177-2189
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IF 12.067
Yang Yang,Yuan Hongyu,Zhao Lianmei,Guo Shichao,Hu Sijun,Tian Miaomiao,Nie Yongzhan,Yu Jiarui,Zhou Chaoxi,Niu Jian,Wang Guiying,Song Yongmei
P53 mutation is an important cause of chemoresistance in colorectal cancer (CRC). The investigation and identification of the downstream targets and underlying molecular mechanism of chemoresistance induced by P53 abnormalities are therefore of great clinical significance. In this study, we demonstrated and reported for the first time that leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) is a key functional downstream factor and therapeutic target for P53 mutation-induced chemoresistance. Due to its RNA binding function, LRPPRC specifically bound to the mRNA of multidrug resistance 1 (MDR1), increasing MDR1 mRNA stability and protein expression. In normal cells, P53 induced by chemotherapy inhibited the expression of LRPPRC via miR-34a and in turn reduced the expression of MDR1. However, chemotherapy-induced P53/miR-34a/LRPPRC/MDR1 signalling pathway activation was lost when P53 was mutated. Additionally, the accumulated LRPPRC and MDR1 promoted drug resistance. Most importantly, gossypol-acetic acid (GAA) was recently reported by our team as the first specific inhibitor of LRPPRC. In CRC cells with P53 mutation, GAA effectively induced degradation of the LRPPRC protein and reduced chemoresistance. Both in vivo and in vitro experiments revealed that combination chemotherapy with GAA and 5-fluorouracil (5FU) yielded improved treatment outcomes. In this study, we reported a novel mechanism and target related to P53-induced drug resistance and provided corresponding interventional strategies for the precision treatment of CRC.
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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DOI
PubMed
高影响因子
eLife
·
2019
·
IF 7.551
Xuefei Yan,Beibei Tang,Biao Chen,Yongli Shan,Huajun Yang,Reproducibility Project: Cancer Biology,Elizabeth Iorns,Rachel Tsui,Alexandria Denis,Nicole Perfito,Timothy M Errington
As part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Li et al., 2015), that described how we intended to replicate selected experiments from the paper ‘The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44’ (Liu et al., 2011). Here we report the results. We found the microRNA, miR-34a, was expressed at twice the level in CD44+ prostate cancer cells purified from xenograft tumors (LAPC4 cells) compared to CD44- LAPC4 cells, whereas the original study reported miR-34a was underexpressed in CD44+ LAPC4 cells (Figure 1B; Liu et al., 2011). When LAPC4 cells engineered to express miR-34a were injected into mice, we did not observe changes in tumor growth or CD44 expression; however, unexpectedly miR-34a expression was lost in vivo. In the original study, LAPC4 cells expressing miR-34a had a statistically significant reduction in tumor regeneration and reduced CD44 expression compared to control (Figure 4A and Supplemental Figures 4A,B and 5C; Liu et al., 2011). Furthermore, when we tested if miR-34a regulated CD44 through binding sites in the 3’UTR we did not find a statistically significant difference, whereas the original study reported miR-34a decreased CD44 expression that was partially abrogated by mutation of the binding sites in the CD44 3’UTR (Figure 4D; Liu et al., 2011). Finally, where possible, we report meta-analyses for each result.
研究领域:
肿瘤学
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分子生物学
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癌症生物学
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DOI
PubMed
高影响因子
RSC Advances
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2016
·Vol. 6
·期 75
·70870-70876
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IF 3.289
Yan Duan,Zhen Xing,Jiebing Yang,Yudi Wang,Jiawen Chen,Yan Zhang,Wei Shi,Quanshun Li
Herein, chondroitin sulfate-functionalized polyamidoamine (CS-PAMAM) was employed as a carrier in miR-34a delivery, and the inhibition of cell proliferation and migration of pancreatic cancer was systematically evaluated, using human pancreatic carcinoma cell line MiaPaCa-2 as a model. Through confocal laser scanning microscopy, an efficient cellular uptake of CS-PAMAM/miR-34a nanoparticles has been demonstrated to be executed in a CD44-dependent manner. After the successful delivery of miR-34a, the cell proliferation could be obviously inhibited due to the activation of cell apoptosis and cell cycle arrest. Meanwhile, CS-PAMAM-mediated miR-34a delivery could realize the suppression of cell migration elucidated by wound healing and transwell migration assays. Thus, the derivative CS-PAMAM could potentially be used as an effective carrier for miR-34a delivery to achieve the tumor gene therapy.
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DOI
高影响因子
EXPERIMENTAL ANIMALS
·
2024
·
IF 2.2
Dan LI,Le WANG,Shufeng SHI,Xiaofeng DENG,Xuehan ZENG,Yunong LI,Shulin LI,Peng BAI
Acupuncture has obvious therapeutic effect on intracerebral hemorrhage (ICH). miR-34a-5p regulated by acupuncture was found to attenuate neurological deficits in ICH. However, the underlying mechanisms are unclear. Ubiquitin Like 4A (UBL4A) has not been studied in ICH. SD rats were injected with autologous blood to induce ICH and treated with Baihui-penetrating-Qubin acupuncture. Acupuncture resulted in an increase in forelimb placing test scores, and a decrease in corner test scores and brain water content of ICH rats. Histopathological examination showed that acupuncture inhibited ICH-induced inflammation, decreased damaged neurons and increased UBL4A expression. UBL4A overexpression increased cell viability, inhibited apoptosis, reduced ROS level and increased MnSOD activity, mitochondrial membrane potential and mtDNA level in rat embryonic primary cortical neurons. miR-34a-5p knockdown increased UBL4A expression, apoptosis rate and ROS level in hemin-treated neurons. Dual luciferase assays showed that miR-34a-5p bound to UBL4A. Apoptotic cells and ROS level were increased in hemin-treated neurons with UBL4A and miR-34a-5p knockdown. We firstly demonstrate the inhibitory effect of UBL4A on neuronal apoptosis, and the regulation relationship between UBL4A and miR-34a-5p. This study provides a new candidate target for ICH treatment and more basis for elucidating the molecular mechanism of acupuncture. In the future, we will conduct a deeper exploration of the effects of UBL4A on ICH.
研究领域:
神经科学
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分子生物学
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针灸
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神经病学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2023
·
IF 5.4
Chuiyang Zheng,Huan Nie,Maoxing Pan,Wen Fan,Dajin Pi,Zheng Liang,Dongdong Liu,Fengzhen Wang,Qinhe Yang,Yupei Zhang
Ethnopharmacological relevance Chaihu Shugan powder (CSP) plays an important role in the prevention and treatment of nonalcoholic fatty liver disease (NAFLD) through a variety of biological mechanisms. However, whether the mechanism involves microRNA (miRNA) regulation remains unknown. Aim of the study To investigate the effects of CSP on the miRNA expression profile of rats with NAFLD induced by high-fat diet (HFD), and to explore the mechanism of CSP in the treatment of NAFLD. Methods NAFLD rat models were established by an 8-week HFD. The therapeutic effects of CSP on NAFLD were evaluated by physiological, biochemical and pathological analysis and hepatic surface microcirculation perfusion test. MicroRNA sequencing was used to study the effect of CSP on the miRNA expression profile of NAFLD rats, and the target genes of differentially expressed (DE) miRNAs were predicted for further function enrichment analysis. Next, targets of CSP and NAFLD were collected by a network pharmacological approach, and Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis were performed for the common target genes of CSP, NAFLD and DE miRNAs, and the expression levels of key genes and proteins were verified by quantitative Real-time PCR and Western blot . Finally, a network among formula-herb-compound-miRNA-target-biological processes-disease was established to explained the complex regulation mechanism of CSP on NAFLD. Results The results showed that CSP significantly improved liver lipid accumulation, serum lipid and transaminase levels and liver surface microcirculation disturbance in HFD-induced NAFLD rats. The intervention of CSP reversed the high expression of 15 miRNAs in liver tissues induced by HFD, including miR-34a-5p, miR-146a-5p, miR-20b-5p and miR-142-3p. The results of pathway and functional enrichment analysis showed that, CSP might play an anti-NAFLD role via regulating DE miRNAs related to fatty acid metabolic process. Combined with the network pharmacological analysis, it was found that the DE miRNAs might affected the fatty acid biosynthesis pathway in the treatment of NAFLD by CSP. Molecular biology experiments have conformed the decreased the gene and protein levels of acetyl-CoA carboxylase alpha (ACACA), fatty acid synthase (FASN) and other fatty acid biosynthesis related enzymes on NAFLD rats after intervention of CSP. Conclusions CSP can significantly reduce hepatic lipid accumulation of NAFLD rat model induced by HFD, and its mechanism may be through the action of 15 miRNAs such as miR-34a-5p, miR-146a-5p, miR-20b-5p and miR-142-3p. Reduce the gene and protein expression levels of ACACA, FASN and other fatty acid biosynthesis related enzymes, thus reducing fatty acid biosynthesis. Based on an epigenetic perspective, this study explains the key anti-NAFLD mechanism of CSP via combination of microRNA sequencing and network pharmacological analysis, providing a new reference for the modernization of traditional Chinese medicine .
研究领域:
药理学
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分子生物学
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中医药
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表观遗传学
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DOI
PubMed
高影响因子
ACTA BIOCHIMICA ET BIOPHYSICA SINICA
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2020
·Vol. 52
·期 8
·821-831
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IF 2.836
He Bingnan,Wang Xia,Jin Xini,Xue Zimeng,Zhu Jianbo,Wang Caiyun,Jin Yuanxiang,Fu Zhengwei
The toxicity of synthetic pyrethroids has garnered attention, and studies have revealed that pyrethroids promote fat accumulation and lead to obesity in mice. Nevertheless, the effect of β-cypermethrin (β-CYP) on adipogenesis and its underlying mechanism remains largely unknown. In this study, mouse embryo fibroblasts 3T3-L1 cells were exposed to β-CYP, and the cell viability, intracellular reactive oxygen species (ROS) level, autophagy, and adipogenesis were assessed to investigate the roles of oxidative stress and autophagy in the toxic effects of β-CYP on adipogenesis. The results demonstrated that treatment with 100 μΜ β-CYP elevated the ROS level, decreased mitochondrion membrane potential, stimulated autophagy, and enhanced the adipogenesis induced by the mixture of insulin, dexamethasone, and 3-isobutyl-1-methylxanthine. However, co-treatment with N-acetyl-L-cysteine partially blocked the abovementioned effects of β-CYP in 3T3-L1 cells. In addition, co-treatment with rapamycin, an autophagy agonist, enhanced the inductive effect of β-CYP on adipogenesis, whereas co-treatment with 3-methyladenine blocked the enhancement of adipogenesis caused by β-CYP. Moreover, β-CYP also altered the microenvironment of 3T3-L1 cells to an adipogenesis-friendly one by reducing the extracellular expression of miR-34a, suggesting that the culture media of β-CYP-treated 3T3-L1 cells could shift macrophages to M2 type. Taken together, the data obtained in the present study demonstrated that β-CYP promoted adipogenesis via oxidative stress-mediated autophagy disturbance, and it caused macrophage M2 polarization via the alteration of miR-34a level in the microenvironment. The study demonstrated the adipogenesis-promoting effect of β-CYP and unveiled the potential mechanism.
研究领域:
毒理学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
Food & Function
·
2017
·Vol. 8
·期 12
·4496-4507
·
IF 3.247
Daorui Pang,Lijun You,Lin Zhou,Tong Li,Bisheng Zheng,Rui Hai Liu
The objective of the present study is to investigate the hepatic steatosis relieving effect of Averrhoa carambola free phenolic extract (ACF) on leptin receptor-deficient (db/db) mice and elucidate the modulation hepatic lipogenesis mechanisms. The serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) assays, accompanying hematoxylin and eosin (H&E) staining, were applied to identify the alleviation of liver histopathological changes. Serum and hepatic lipid assays, combined with oil red O staining, were used to investigate the amelioration of lipid accumulation. Further assessments by quantitative real-time PCR and western blot assays were used to elucidate the suppression of the fatty acid and triglyceride (TG) synthesis mechanisms underlying ACF protection. These results indicated that ACF treatment significantly reduced the liver TG of db/db mice (p < 0.05). The mechanisms are partly through phosphorylation of AMPK α and down-regulation of SREBP-1c expression, and further down-regulation of FAS and SCD1 (p < 0.05). In addition, the expression levels of mircoRNA-34a and mircoRNA-33, which modulate this signaling pathway, were significantly down-regulated by ACF treatment (p < 0.05). Collectively, these results revealed that ACF exhibited a potent hepatic steatosis relieving effect partly by inhibiting the signal transduction of hepatic lipogenesis.
研究领域:
药理学
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分子生物学
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肝病学
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Wenjie Duan,Qian Shen,Linjie Ju,Zhongxi Huang,Jiaying Geng,Qiong Wu,Changmin Yu,Jifu Wei
Triple-negative breast cancer (TNBC) is a subtype of breast cancer that carries the worst prognosis and lacks specific therapeutic targets. To achieve accurate “cargos” delivery at the TNBC site, we herein constructed a novel biomimetic nano-Trojan horse integrating chemotherapy with gene therapy for boosting TNBC treatment. Briefly, we initially introduce the diselenide-bond-containing organosilica moieties into the framework of mesoporous silica nanoparticles (MONs), thereby conferring biodegradability to intratumoral redox conditions in the obtained MONSe. Subsequently, doxorubicin (Dox) and therapeutic miR-34a are loaded into MONSe, thus achieving the combination of chemotherapy and gene-therapy. After homologous tumor cell membrane coating, the ultimate homologous tumor cell-derived biomimetic nano-Trojan horse (namely, MONSe@Dox@miR-34a@CM) can selectively enter the tumor cells in a stealth-like fashion. Notably, such a nanoplatform not only synergistically eradicated the tumor but also inhibited the proliferation of breast cancer stem-like cells (BCSCs) in vitro and in vivo. With the integration of homologous tumor cell membrane-facilitated intratumoral accumulation, excellent biodegradability, and synergistic gene-chemotherapy, our biomimetic nanocarriers hold tremendous promise for the cure of TNBC in the future.
研究领域:
肿瘤学
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纳米技术
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药学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2022
·
IF 5.988
Zhou Jing,Li Lisha,Pan Xinyao,Wang Jing,Qi Qing,Sun Hongmei,Li Chuyu,Wang Ling
Objective: To explore the effect and mechanisms of a traditional Chinese quadri-combination therapy [Bushen, Yiqi, Lixue and Yangtai (BYLY)] in treating recurrent spontaneous abortion (RSA).Methods: A clinical trial was conducted to study the effect of BYLY on RSA. Pharmacological network analysis and UPLC-Q/TOF-mass spectrometry (MS) were applied to investigate the key active component in BYLY and potential targets. Cellular experiments based on former results were performed to examine the mechanism of BYLY in the treatment of RSA.Results: Four hundred and eighty participants enrolled in the clinical trial. The results showed that, compared with the use of BYLY or duphaston alone, a combination of duphaston and BYLY could decrease the early abortion rate in RSA (p < 0.001). Network pharmacological analysis indicated that BYLY contained 132 active components and 146 core targets, and the quercetin maybe the key effective component. In vitro experiments found that pretreatment of quercetin at the correct concentration (2 μM) prevented hypoxia-induced viability and proliferation reduction, and apoptosis and mitochondrial dysfunction. Furthermore, quercetin could modulate mitochondrial fission/fusion balance in trophoblasts, and specifically decrease the expression of Drp1 by regulating miR-34a-5p.Conclusion: BYLY could improve pregnancy outcomes of RSA, based on multi-components and multi-targets. The protective effect of quercetin on trophoblasts, through decreasing Drp1 expression via regulating miR-34a-5p, might be one possible effective mechanism.
研究领域:
中医
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药理学
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妇产科学
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分子生物学
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临床试验
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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）