ENVIRONMENTAL POLLUTION
·
2021
·
IF 8.071
Rili Hao,Xinyu Song,Dongxiao Sun-Waterhouse,Xintong Tan,Feng Li,Dapeng Li
Cadmium (Cd), as an environmental pollutant, can lead to nephrotoxicity. However, its nephrotoxicological mechanisms have not been fully elucidated. In this study, Cd (1.5 mg/kg body weight, gavaged for 4 weeks) was found to induce the renal damage in mice, based on indicators including Cd concentration, kidney index, serum creatinine and blood urea nitrogen levels, pro-inflammatory cytokines and their mRNA expressions, levels of Bcl-2, Bax and caspase9, and histopathological changes of the kidneys. Furthermore, Cd-caused detrimental changes through inducing inflammation and apoptosis via the miR-34a/Sirt1/p53 axis. This is the first report on the role of miR-34a/Sirt1/p53 axis in regulating Cd-caused apoptosis and nephrotoxicity in mice. The findings obtained in this study provide new insights into miRNA-based regulation of heavy metal induced-nephrotoxicity.
研究领域:
毒理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2023
·
IF 9.7
Mengjie Kong,Yan Peng,Liyan Qiu
Non-alcoholic fatty liver disease (NAFLD) is currently a common chronic liver disease worldwide. By now, however, there isn't any FDA-approved specific drug for NAFLD treatment. It has been noticed that farnesoid X receptor (FXR), miR-34a and Sirtuin1 (SIRT1) is related to the occurrence and development of NAFLD. A oligochitosan-derivated nanovesicle (UBC) with esterase responsive degradability was designed to co-encapsulate FXR agonist (obeticholic acid, OCA) and miR-34a antagomir (anta-miR-34a) into the hydrophobic membrane and the center aqueous lumen of nanovesicles, respectively, by dialysis method. The action of UBC/OCA/anta-miR-34a loop on the regulation of lipid deposition via nanovesicles was evaluated on high-fat HepG2 cells and HFD-induced mice. The obtained dual drug-loaded nanovesicles UBC/OCA/anta-miR-34a could enhance the cellular uptake and intracellular release of OCA and anta-miR-34a, leading to the reduced lipid deposition in high-fat HepG2 cells. In NAFLD mice models, UBC/OCA/anta-miR-34a achieved the best curative effect on the recovery of body weight and hepatic function. Meanwhile, in vitro and vivo experiments validated that UBC/OCA/anta-miR-34a effectively activated the expression level of SIRT1 by enhancing the FXR/miR-34a/SIRT1 regulatory loop. This study provides a promising strategy for constructing oligochitosan-derivated nanovesicles to co-deliver OCA and anta-miR-34a for NAFLD treatment. Statement of significance This study proposed a strategy to construct oligochitosan-derivated nanovesicles to co-deliver obeticholic acid and miR-34a antagomir for NAFLD treatment. Based on the FXR/miR-34a/SIRT1 action loop, this nanovesicle effectively exerted a synergetic effect of OCA and anta-miR-34a to significantly regulate lipid deposition and recover liver function in NAFLD mice.
研究领域:
药学
·
分子生物学
·
肝病学
·
纳米技术
✓ 已验证
DOI
PubMed
高影响因子
ONCOLOGY REPORTS
·
2023
·Vol. 49
·期 5
·1-14
·
IF 4.2
Chuanzhuo Wang,He Xin,Guangxin Yan,Zhaoyu Liu
Colorectal cancer (CRC) is an aggressive tumor, whose development is considered to be modulated by certain long non‑coding RNAs (lncRNAs). Therefore, the aim of the present study was to investigate the regulatory mechanism of lncRNA NONHSAG028908.3 on CRC. Data from The Cancer Genome Atlas (TCGA) database revealed that NONHSAG028908.3 was increased in CRC tissues compared with normal tissues (P<0.001). The results of reverse transcription‑quantitative PCR indicated that NONHSAG028908.3 was upregulated in four types of CRC cells compared with that in NCM460, a normal colorectal cell line. MTT, BrdU, and flow cytometric assays were applied to evaluate CRC cell growth. The migratory and invasive abilities of CRC cells were detected using wound healing and Transwell assays. Silencing of NONHSAG028908.3 inhibited proliferation, migration, and invasion of CRC cells. A dual‑luciferase reporter assay demonstrated that NONHSAG028908.3 served as a sponge to combine with microRNA (miR)‑34a‑5p. MiR‑34a‑5p suppressed the aggressiveness of CRC cells. The effects induced by NONHSAG028908.3 knockdown were partly reversed by inhibition of miR‑34a‑5p. Furthermore, miR‑34a‑5p, a target of NONHSAG028908.3, modulated aldolase, fructose‑bisphosphate A (ALDOA) expression in a negative feedback manner. Suppression of NONHSAG028908.3 notably decreased ALDOA expression, which was rescued via silencing of miR‑34a‑5p. Moreover, suppression of ALDOA revealed the inhibitory action on CRC cell growth and migration. In summary, the data of the present study indicate that NONHSAG028908.3 may positively regulate ALDOA via sponging miR‑34a‑5p, thereby promoting malignant activities in CRC.
研究领域:
癌症生物学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Polymer Chemistry
·
2014
·Vol. 6
·期 11
·1952-1960
·
IF 5.368
Hanmei Li,Hao Jiang,Mengnan Zhao,Yao Fu,Xun Sun
An amphiphilic cationic graft polymer polyethylenimine-cystamine-poly(ε-caprolactone) (PSSP) with intracellular redox potential-responsive cleavable ability was synthesized for the first time by coupling poly(ε-caprolactone) (PCL) to polyethylenimine (PEI) via a bio-cleavable disulfide linkage. PSSP based micelles, which can degrade in the intracellular reducing environment, were developed as smart non-viral gene vectors for enhanced miR-34a delivery. The PSSP/miR-34a complexes showed effective and stable miRNA condensation with a narrow particle size of around 120 nm. The gel retardation assay showed that PSSP micelles could protect miRNA from RNase and achieve intracellular release of miRNA in the reducing environment. Compared with PEI-25k, PSSP revealed comparable transfection efficiencies in the B16F10 cell with less cytotoxicity. The B16F10 cell treated with PSSP/miR-34a complexes showed a significantly higher cell apoptosis than the PEI-25k/miR-34a complexes. These encouraging results indicated that PSSP may possess promising potential as a smart non-viral gene vector with low cytotoxicity, intracellular redox potential to trigger miRNA release and high transfection efficiency.
研究领域:
生物材料
·
基因治疗
·
药剂学
✓ 已验证
DOI
高影响因子
Frontiers in Bioengineering and Biotechnology
·
2024
·
IF 4.3
Fangling Li,Dongdong Cao,Lixia Yao,Wenyi Gu,Zhiyong Liu,Dongmei Li,Lin Cui
Kaposi’s sarcoma-associated herpesvirus (KSHV) can infect a variety of cells and cause malignant tumors. At present, the use of microRNA (miRNA) for anti-KSHV is a promising treatment strategy, but the instability and non-specific uptake of miRNA still limit its use in the treatment of KSHV. In the present study, we constructed a nano-drug delivery system employing chemical grafting and electrostatic adsorption to solve the problems of easy degradation and low cell uptake of miRNA during direct administration. This nano-drug delivery system is to graft 4-carboxyphenylboric acid (PBA) and lauric acid (LA) onto polyethylenimine (PEI) through amidation reaction, and then prepare cationic copolymer nanocarriers (LA-PEI-PBA). The drug-carrying nanocomplex LA-PEI-PBA/miR-34a-5p was formed after further electrostatic adsorption of miR-34a-5p on the carrier and could protect miR-34a-5p from nuclease and serum degradation. Modification of the drug-carrying nanocomplex LA-PEI-PBA/miR-34a-5p by targeted molecule PBA showed effective uptake, increase in the level of miR-34a-5p, and inhibition of cell proliferation and migration in KSHV-infected cells. In addition, the drug-carrying nanocomplex could also significantly reduce the expression of KSHV lytic and latent genes, achieving the purpose of anti-KSHV treatment. In conclusion, these cationic copolymer nanocarriers with PBA targeting possess potential applications in nucleic acid delivery and anti-KSHV therapy.
研究领域:
药学
·
分子生物学
·
纳米技术
·
病毒学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2019
·Vol. 7
·期 4
·1632-1642
·
IF 5.251
Zheyu Song,Xiao Liang,Yudi Wang,Haobo Han,Jiebing Yang,Xuedong Fang,Quanshun Li
In the present research, a tumor-targeted gene carrier, PPP, was constructed through the modification of phenylboronic acid onto the surface of a polyamidoamine dendrimer, and then miR-34a delivery was employed as a model to evaluate its anti-tumor efficacy. The carrier PPP was identified to possess favorable miR-34a binding and condensation ability and meanwhile protect miR-34a against nuclease degradation. Through confocal laser scanning microscopy and flow cytometry analysis, PPP-mediated cellular uptake of miR-34a was found to proceed through a sialic acid-dependent endocytosis pathway and the nanoparticles could achieve endosome/lysosome escape within 6 h. Further, an anti-proliferative effect could be obtained after PPP/miR-34a transfection through the induction of cell apoptosis. Meanwhile, the inhibition of migration and invasion could be realized through blocking the Notch-1 signaling pathway after PPP/miR-34a treatment. Finally, PPP possessed acceptable safety and inhibited in vivo tumor growth through the in situ apoptosis of tumor sites, which relied on the specific tumor-targeting ability and long circulation time in the blood. In summary, the derivative PPP could be potentially utilized as an efficient carrier for miR-34a delivery to achieve an anti-tumor response in clinical use.
研究领域:
癌症研究
·
分子生物学
·
基因治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2024
·Vol. 25
·期 5
·2932
·
IF 4.9
Fangling Li,Dongdong Cao,Wenyi Gu,Dongmei Li,Zhiyong Liu,Lin Cui
Kaposi’s sarcoma-associated herpesvirus (KSHV) can cause a variety of malignancies. Ganciclovir (GCV) is one of the most efficient drugs against KSHV, but its non-specificity can cause other side effects in patients. Nucleic acid miR-34a-5p can inhibit the transcription of KSHV RNA and has great potential in anti-KSHV therapy, but there are still problems such as easy degradation and low delivery efficiency. Here, we constructed a co-loaded dual-drug nanocomplex (GCV@ZIF-8/PEI-FA+miR-34a-5p) that containsGCVinternally and adsorbs miR-34a-5p externally. The folic acid (FA)-coupled polyethyleneimine (PEI) coating layer (PEI-FA) was shown to increase the cellular uptake of the nanocomplex, which is conducive to the enrichment of drugs at the KSHV infection site.GCVand miR-34a-5p are released at the site of the KSHV infection through the acid hydrolysis characteristics of ZIF-8 and the “proton sponge effect” of PEI. The co-loaded dual-drug nanocomplex not only inhibits the proliferation and migration of KSHV-positive cells but also decreases the mRNA expression level of KSHV lytic and latent genes. In conclusion, this co-loaded dual-drug nanocomplex may provide an attractive strategy for antiviral drug delivery and anti-KSHV therapy.
研究领域:
药理学
·
纳米技术
·
病毒学
·
分子生物学
·
治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2015
·
IF 4.152
Shaojun Liang,Yan Duan,Zhen Xing,Haobo Han,Aijun Zhang,Li Li,Yan Yang,Quanshun Li
Chondroitin sulfate was chemically conjugated to PEI25K through Michael addition to construct a non-viral gene carrier CS-PEI, and then the carrier was employed in miR-34a delivery to achieve the inhibition of cell proliferation and migration, using prostate tumor cell PC-3 as a model. The nanoparticle from CS-PEI and miR-34a at a mass ratio of 10 was prepared with particle size and zeta potential of 170.7 nm and +42.2 mV, respectively. Flow cytometry and fluorescence microscopy revealed that CS-PEI could efficiently induce the cellular uptake of miR-34a in a CD44-mediated endocytosis manner. Through CS-PEI-mediated miR-34a transfection, obvious cell apoptosis was observed with early apoptotic cells of 47.49%, and meanwhile the activation of caspase-3, -8 and -9, and decreased expression level of Bcl-2 were detected. Moreover, wound healing assay showed that CS-PEI/miR-34a transfection could inhibit the cell migration. Overall, CS-PEI is potentially employed as a promising tumor-targeting system for miR-34a delivery in tumor gene therapy.
研究领域:
药学
·
分子生物学
·
癌症研究
·
基因治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Nano Materials
·
2023
·
IF 5.9
Fangling Li,Dongdong Cao,Wenyi Gu,Lin Cui,Zhongpeng Qiu,Zhiyong Liu,Dongmei Li,Xuhong Guo
Kaposi’s sarcoma-associated herpesvirus (KSHV) infection can cause a range of malignancies. The use of microRNA (miRNA) to combat viruses and inhibit tumor development has received increasing attention. However, it is difficult for free miRNA to enter into cells directly and to degrade easily. Therefore, the miRNA therapy alone often fails to achieve the expected effect. The selection of an appropriate delivery system for effective miRNA delivery and anti-KSHV is rarely considered. In this study, a β-cyclodextrin-grafted polyethylenimine (β-CD-PEI) was prepared by the chemical synthesis method, and folic acid was further coupled to a nanocarrier (β-CD-PEI-FA). Gel electrophoresis retardation experiments showed that β-CD-PEI-FA could combine with miR-34a-5p to form a drug-carrying nanocomplex β-CD-PEI-FA/miR-34a-5p, which effectively protected miR-34a-5p from serum and nuclease degradation. The particle size and potential were 203.13 ± 0.41 nm and 27.02 ± 0.72 mV, respectively, which were suitable for endocytosis. The cytotoxicity of the vector to KSHV-positive cells BCBL-1 and SK-RG cells was detected by the CCK-8 assay, which proved that the vector had good biosafety in vitro. Further cell experiments showed that β-CD-PEI-FA/miR-34a-5p not only had the ability to transport miR-34a-5p but also accelerated the G2-phase process of BCBL-1 and SK-RG cells and inhibited the proliferation of KSHV-infected cells. Most importantly, it can significantly reduce the expression levels of KSHV genes ORF26, K8.1A, and LANA. Therefore, the nanocarriers may be a promising antiviral drug delivery system with potential applications in the anti-KSHV therapy.
研究领域:
药学
·
分子生物学
·
病毒学
·
癌症研究
·
纳米技术
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2024
·Vol. 28
·期 13
·e18527
·
IF 4.3
Maomao Miao,Mengying Li,Yunjie Sheng,Peijian Tong,Yang Zhang,Dan Shou
Infected bone defects (IBDs) are the common condition in the clinical practice of orthopaedics. Although surgery and anti-infective medicine are the firstly chosen treatments, in many cases, patients experience a prolonged bone union process after anti-infective treatment. Epimedium-Curculigo herb pair (ECP) has been proved to be effective for bone repair. However, the mechanisms of ECP in IBDs are insufficiency. In this study, Effect of ECP in IBDs was verified by micro-CT and histological examination. Qualitative and quantitative analysis of the main components in ECP containing medicated serum (ECP-CS) were performed. The network pharmacological approaches were then applied to predict potential pathways for ECP associated with bone repair. In addition, the mechanism of ECP regulating LncRNA MALAT1/miRNA-34a-5p/SMAD2 signalling axis was evaluated by molecular biology experiments. In vivo experiments indicated that ECP could significantly promote bone repair. The results of the chemical components analysis and the pathway identification revealed that TGF-β signalling pathway was related to ECP. The results of in vitro experiments indicated that ECP-CS could reverse the damage caused by LPS through inhibiting the expressions of LncRNA MALAT1 and SMAD2, and improving the expressions of miR-34a-5p, ALP, RUNX2 and Collagen type І in osteoblasts significantly. This research showed that ECP could regulate the TGF-β/SMADs signalling pathway to promote bone repair. Meanwhile, ECP could alleviate LPS-induced bone loss by modulating the signalling axis of LncRNA MALAT1/miRNA-34a-5p/ SMAD2 in IBDs.
研究领域:
骨科
·
药理学
·
分子生物学
·
信号转导
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2017
·
IF 6.319
Wenqi Chen,Yong Liu,Xiao Liang,Yu Huang,Quanshun Li
Chondroitin sulfate (CS) was modified on a polyamidoamine dendrimer (PAMAM) through Michael addition to construct a tumor-targeted carrier CS-PAMAM for miR-34a delivery. The derivative CS-PAMAM was demonstrated to achieve an efficient cellular uptake of miR-34a in a CD44-dependent endocytosis way and further facilitate the endosomal escape of miR-34a after 4 h. Through the miR-34a delivery, obvious inhibition of cell proliferation could be detected which was attributed to the enhancement of cell apoptosis and cell cycle arrest , and meanwhile the cell migration and invasion has been observed to be inhibited. Finally, the intravenous injection of CS-PAMAM/miR-34a formulation into mice bearing human lung adenocarcinoma cell A549 xenografts could efficiently inhibit the tumor growth and induce the tumor apoptosis owing to the enhanced accumulation of miR-34a in tumor tissue. Overall, CS-PAMAM is potential to be used as a tumor-targeted oligonucleotide carrier for achieving tumor gene therapy. Statement of Significance The cationic dendrimer PAMAM was modified by chondroitin sulfate (CS) through Michael addition to construct a tumor-targeted carrier CS-PAMAM for miR-34a delivery. The introduction of CS could achieve an efficient cellular uptake and intracellular transfection of miR-34a in a CD44-dependent endocytosis manner. The miR-34a delivery could execute the anti -proliferation activity by simultaneously inducing cell apoptosis and cell cycle arrest, and also the anti -migration activity. The CS-PAMAM-mediated systemic delivery of miR-34a showed significant inhibition of tumor growth and induction of tumor apoptosis using a mice model of subcutaneously implanted tumors.
研究领域:
药学
·
分子生物学
·
癌症研究
·
纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2022
·
IF 5.714
Yaojian Rao,Junjie Li,Ruofei Qiao,Jinxin Luo,Yan Liu
Background Both Tetramethylpyrazine (TMPZ) and Astragaloside IV (AGS-IV) can ameliorate neuronal apoptosis and neuroinflammation in CNS diseases. This study revolves around the underlying mechanism of TMPZ and AGS-IV in spinal cord injury (SCI)-associated neuropathic pain (NP). Materials and methods An in-vivo NP model was constructed in Sprague-Dawley (SD) rats via SCI. qRT-PCR was employed to detect OIP5-AS1 and miR-34a. The paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) of the rats were evaluated. Neuronal apoptosis in the spinal cord of rats was examined by Nissl staining and TUNEL staining. The interactions between OIP5-AS1 and miR-34a as well as miR-34a and Sirt1 were investigated through dual luciferase assay and RIP assay. The protein expressions of Bad, Bax, Caspase-3, iNOS, COX2, NF-κB, and Sirt1 were examined by western blot. Results TMPZ and AGS-IV combination relieved behavioral symptoms of neuropathic pain in the SCI rat model, enhanced the levels of OIP5-AS1 and Sirt1, and lowered the profile of miR-34a. OIP5-AS1 downregulation weakened the neuroprotective function of TMPZ and AGS-IV in SCI rats and reversed their anti-inflammatory and anti-apoptotic effects on LPS-elicited primary spinal cord neurons. miR-34a was identified as a target of OIP5-AS1. Upregulated miR-34a partly abated the protective functions of TMPZ and AGS-IV in primary spinal cord neurons. Additionally, miR-34a targeted and repressed Sirt1, thus activating the NF-κB pathway and inflammatory reactions. Sirt1 inhibition reduced the protective effects mediated by OIP5-AS1. Conclusion TMPZ and AGS-IV ameliorate SCI-elicited NP via the OIP5-AS1/miR-34a/Sirt1/NF-κB pathway.
研究领域:
神经科学
·
药理学
·
分子生物学
·
神经病学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）