DRUG DELIVERY
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2019
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IF 3.829
Zhan Tang,Lina Yin,Yawen Zhang,Wenying Yu,Qiao Wang,Zhajun Zhan
Objective: To prepare everolimus nanoformulations and increase their solubility to suit their application in the eye. Methods: The everolimus micelles was prepared by thin film dispersion method using Tween-80 (P80) and polyoxyethylene stearate (P40S) as carriers. In addition, the everolimus nanosuspension was prepared by injection method using poloxamer 407 (P407), hydroxypropyl methylcellulose (HPMC) and polyvinyl alcohol (PVA) as stabilizers. It was characterized in terms of particle size, PDI and encapsulation efficiency or drug loading. The in vitro release and in vitro rabbit scleral permeability characteristics were investigated, and the pharmacokinetics of anterior chamber drug in rabbit eyes were studied. Results: The average particle size of the micelles was (8.74 ± 0.21) nm, the encapsulation efficiency and drug loading were (90.12 ± 1.18)% and (2.14 ± 0.028)%, while the average particle size of the nanosuspension was (156.47 ± 1.10) nm, and the drug loading was (16.51 ± 0.21)%, respectively. Both in vitro release and rabbit scleral permeation models were consistent with the Higuchi equation. The pharmacokinetic experiments of aqueous humor showed that area under the curve of everolimus nanosuspension was about 3 times higher than that of micelles. Micelles could be achieved in the eye and maintained for a long time. Conclusion: The preparation of everolimus micelles or nanosuspension for eye are suitable for ocular administration and expected to be new dosage form for corneal transplantation immunological rejection or other ocular disease.
研究领域:
药剂学
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眼科医学
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药物递送系统
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高影响因子
Biomed Research International
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2021
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IF 3.411
Fengqin Wang,Hanzhong Zhang,Zhigang Cheng
EPHA2 is a member of the ephrin receptor tyrosine kinase family and is closely related to the malignant tumor progression. The effect of EPHA2 on OSCC is not clear. This study explored the role of EPHA2 and AKT/mTOR signaling pathways in Cal-27 cell invasion and migration. The expression of EPHA2 and EPHA4 in human OSCC and normal oral tissue was detected by immunohistochemistry. EPHA2-overexpressing and EPHA2-knockdown Cal-27 cells were established, and the cells were treated with an AKT inhibitor (MK2206) and mTOR inhibitor (RAD001). The expression of EPHA2 was detected by qRT-PCR, cell proliferation was evaluated by MTT assay, cell migration and invasion were examined by scratch and Transwell assay, and cell morphology and apoptosis were assessed by Hoechst 33258 staining. Western blot was performed to detect the expression of proteins related to AKT/mTOR signaling, cell cycle, and pseudopod invasion. EPHA2 and EPHA4 were highly expressed in clinical human OSCC. Overexpression of EPHA2 promoted the proliferation, migration, and invasion of Cal-27 cells, inhibited cell cycle blockage and apoptosis, and enhanced the activity of the AKT/mTOR signaling pathway. MK2206 (AKT inhibitor) and RAD001 (mTOR inhibitor) reversed the effect of EPHA2 overexpression on the biological behavior of Cal-27 cells. EPHA2 promotes the invasion and migration of Cal-27 human OSCC cells by enhancing the AKT/mTOR signaling pathway.
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MOLECULAR MEDICINE
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2021
·Vol. 27
·期 1
·1-16
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IF 6.354
Cui Jing,Guo Yao,Wu Heshui,Xiong Jiongxin,Peng Tao
Background Gemcitabine (GEM) resistance remains a significant clinical challenge in pancreatic cancer treatment. Here, we investigated the therapeutic utility of everolimus (Evr), an inhibitor of mammalian target of rapamycin (mTOR), in targeting the Warburg effect to overcome GEM resistance in pancreatic cancer. Methods The effect of Evr and/or mTOR overexpression or GEM on cell viability, migration, apoptosis, and glucose metabolism (Warburg effect) was evaluated in GEM-sensitive (GEM sen ) and GEM-resistant (GEM res ) pancreatic cancer cells. Results We demonstrated that the upregulation of mTOR enhanced cell viability and favored the Warburg effect in pancreatic cancer cells via the regulation of PI3K/AKT/mTOR signaling. However, this effect was counteracted by Evr, which inhibited aerobic glycolysis by reducing the levels of glucose, lactic acid, and adenosine triphosphate and suppressing the expression of glucose transporter 1, lactate dehydrogenase-B, hexokinase 2, and pyruvate kinase M2 in GEM sen and GEM res cells. Evr also promoted apoptosis by upregulating the pro-apoptotic proteins Bax and cytochrome-c and downregulating the anti-apoptotic protein Bcl-2. GEM was minimally effective in suppressing GEM res cell activity, but the therapeutic effectiveness of Evr against pancreatic cancer growth was greater in GEM res cells than that in GEM sen cells. In vivo studies confirmed that while GEM failed to inhibit the progression of GEM res tumors, Evr significantly decreased the volume of GEM res tumors while suppressing tumor cell proliferation and enhancing tumor apoptosis in the presence of GEM. Conclusions Evr treatment may be a promising strategy to target the growth and activity of GEM-resistant pancreatic cancer cells by regulating glucose metabolism via inactivation of PI3K/AKT/mTOR signaling.
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Theranostics
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2021
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IF 11.556
Yiqun Xia,Jundixia Chen,Yun Yu,Fengjiao Wu,Xin Shen,Chenyu Qiu,Tingting Zhang,Lin Hong,Peisen Zheng,Rongrong Shao,Chenxin Xu,Fang Wu,Wei Chen,Congying Xie,Ri Cui,Peng Zou
Background: Cancer is a leading cause of death worldwide. Extensive research over decades has led to the development of therapies that inhibit oncogenic signaling pathways. The mammalian target of rapamycin (mTOR) signaling pathway plays an important role in the development of many cancers. Several mTOR inhibitors are approved for the treatment of cancers. However, the anticancer efficacies of mTOR inhibitor monotherapy are still limited. Methods: Western blot was used to detect the expression of indicated molecules. Thioredoxin reductase (TrxR) activity in cells was determined by the endpoint insulin reduction assay. Immunofluorescence staining was used to analyze precise location and expression of target proteins. Nude mice were used for xenograft tumor models. Results: We identified a synergistic lethal interaction of mTOR and TrxR inhibitors and elucidated the underlying molecular mechanisms of this synergism. We demonstrated that mTOR and TrxR inhibitors cooperated to induce cell death by triggering oxidative stress, which led to activation of autophagy, endoplasmic reticulum (ER) stress and c-Jun N-terminal Kinase (JNK) signaling pathway in cancer cells. Remarkably, we found that auranofin (AF) combined with everolimus significantly suppressed tumor growth in HCT116 and SGC-7901 xenograft models with no significant signs of toxicity. Conclusion: Our findings identify a promising therapeutic combination for cancer and has important implications for developing mTOR inhibitor-based combination treatments.
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Journal of Materials Chemistry B
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2023
·Vol. 11
·期 20
·4464-4474
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IF 7
Xiaoqian Jiang,Xinxin Xu,Hua Kuang,Liqiang Liu,Liguang Xu,Aihua Qu,Chuanlai Xu
Tacrolimus is a macrolide immunosuppressant widely used in organ transplantation. Due to the narrow treatment window, therapeutic drug monitoring of the clinical application of tacrolimus is necessary. In this study, a carboxyl group introduced at the hydroxyl or carbon positions of tacrolimus was used to couple with carrier protein to synthesize complete antigens. After screening different immunogens and coating antigens, a highly-sensitive and specific monoclonal antibody (mAb) 4C5 was obtained, with a half inhibitory concentration (IC50) value of 0.26 ng mL−1 determined by indirect competitive enzyme-linked immunosorbent assay (ic-ELISA). A colloidal gold-based immunochromatographic strip (CG-ICS) was established to monitor tacrolimus in human whole blood based on the mAb 4C5. Through visual observation, it was found that the visual limit of detection (vLOD) and cut-off value of qualitative detection were 1.0 and 20.0 ng mL−1, respectively. The calculated LOD (cLOD) value of quantitative detection was 0.16 ng mL−1, and the linear range was 0.48–7.57 ng mL−1. In addition, the results of the CG-ICS for analyzing real positive samples of human whole blood were basically consistent with those of LC-MS/MS. Therefore, the CG-ICS was suitable for rapid and accurate clinical monitoring of tacrolimus.
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Virulence
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2024
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IF 5.5
Xin Wang,Feiyang Pu,Xuanye Yang,Xili Feng,Jiayou Zhang,Kai Duan,Xuanxuan Nian,Zhongren Ma,Xiao-Xia Ma,Xiao-Ming Yang
Influenza A virus (IAV) poses threat to patients receiving immunosuppressive medications since they are more susceptible to infection with severe symptoms, and even death. Understanding the direct effects of immunosuppressants on IAV infection is critical for optimizing immunosuppression in these patients who are infected or at risk of influenza virus infection. We profiled the effects of ten immunosuppressants, explored the antiviral mechanisms of immunosuppressants and demonstrated the combination effects of immunosuppressants with the antiviral drug oseltamivir in IAV-infected cell models. We found that mycophenolic acid (MPA) strongly inhibited viral RNA replication via depleting cellular guanosine pool. Treatment with 6-Thioguanine (6-TG) promoted viral protein degradation through proteasomal pathway. Filgotinib blocked mRNA splicing of matrix protein 2, resulting in decreased viral particle assembly. Furthermore, combined treatment with immunosuppressants and oseltamivir inhibited IAV viral particle production in an additive or synergic manner. Our results suggest that MPA, 6-TG and filgotinib could be the preferential choices for patients who must take immunosuppressants but at risk of influenza virus infection.
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RARE METALS
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2025
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IF 11
Qi Liu-Jie,Zhang Zhao-Qi,Iqbal Mujahid,Wang Fei,Li Jing-An,Guan Shao-Kang
Drug-eluting magnesium (Mg) alloy stents have a slower degradation rate and lower restenosis rate compared with uncoated stents, demonstrating good clinical efficacy. However, the release of anti-hyperplasia drugs from coatings delays endothelial tissue repair, thus leading to late stent thrombosis. To address these issues, a dual self-healed coating with various biological properties was fabricated on magnesium fluoride/polydopamine (MgF 2 /PDA)-treated Mg alloys by spraying-assisted layer-by-layer (LBL) self-assembly of chitosan (CS), gallic acid (GA), and 3-aminobenzeneboronic acid-modified hyaluronic acid (HA-ABBA). The LBL coating, approximately 1.50 μm thick, exhibited a uniform morphology with good adhesion strength (~ 1065 mN). The annual corrosion rate ( P i ) of LBL samples was ~ 1400 times slower than that of the Mg substrate, due to the physical barrier function provided by MgF 2 /PDA layers and the dual self-healed ability of LBL layers. The rapid self-healing ability (with a healing period of ~ 4 h under dynamic/static conditions) resulted from the synergistic interplay between the recombination of diverse chemical bonds within the LBL coating and the coordination of LBL-released GA with Mg 2+ , as corroborated by computer simulations. Compared with the drug-eluting coatings, the LBL sample demonstrated substantial advantages in anti-oxidation, anti-denaturation of fibrinogen, anti-platelet adhesion, anti-inflammation, anti-hyperplasia, and promoted-endothelialization. These benefits effectively address the limitations associated with drug-eluting coatings. Graphical abstract
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危险品化学品经营许可证（带存储）