AAPS PHARMSCITECH
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2021
·Vol. 23
·期 1
·1-13
·
IF 3.246
Wu Wenqing,Cao Wenxuan,Chen Jingbao,Cai Ye,Dong Baoqi,Chu Xiaoqin
The purpose of this study was to design an in situ liquid crystal gel (ISLG) as an ophthalmic drug delivery system for dexamethasone (DEX) to enhance its eye retention and ocular bioavailability. The in situ liquid crystal gels (ISLGs) were prepared using a phytantriol/PEG400/water (65:30:5, w/w) ternary system. Polarized light microscope (PLM), small-angle X-ray scattering (SAXS), and rheology analysis confirmed that the internal structure of the preparations was Pn3m cubic phase liquid crystal gels with pseudoplastic fluid properties. Meanwhile, in vitro release behavior of the preparations conforms to the Higuchi equation. Corneal penetration experiments showed that compared with DEX sodium phosphate eye drops, DEX-ISLGs(F2) produced a 5.45-fold increase in the P app value, indicating a significant enhancement of corneal penetration. In addition, in vivo experiments have confirmed that the ISLGs have better biocompatibility and longer retention time in the cornea. Simultaneously, corneal hydration level, eye irritation experiments, and histological observations proved the safety of the preparations. Pharmacokinetic studies have shown that the ISLG could maintain the DEX concentration in aqueous humor for at least 12 h after administration, which significantly improves the bioavailability of the drug. Collectively, these results indicated that ISLG would be a potential drug carrier for the treatment of diabetic retinopathy (DR).
研究领域:
药剂学
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眼科学
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2023
·
IF 4.8
Kai Dong,Shu-Jing Deng,Bin-Yang He,Zi-Yang Guo,Ze-Lin Guan,Xue Leng,Rui-Rui Ma,Dan-Yang Wang,Jian-Feng Xing,Cui-Yu You
Background As the first-line drug to treat ulcerative colitis (UC), long-term use of glucocorticoids (GCs) produces severe toxic and side effects. Local administration as enema can increase the local GCs concentrations and reduce systemic exposure to high oral doses by directly delivering GCs to the inflammation site in the distal colorectum. However, UC patients are often accompanied by diarrhea, leading to the short colonic residence time of GCs and failure to exert their function fully.Purpose A kind of mucoadhesive nanoparticles (NPs) loading different dexamethasone derivatives (DDs) were developed, which could attach to the positively charged inflammatory colonic mucosa through electrostatic adsorption after administered by enema, thereby improving the local concentration and achieving effective targeted therapy for UC.Methods Two DDs, dexamethasone hemisuccinate and dexamethasone phosphate, were synthesized. In NPs preparation, The core PEI-DDs NPs were built by the electrostatic adsorption of DDs and the cationic polymer polyethyleneimine (PEI). Then, the natural polyanionic polysaccharide sodium alginate (SA) was electronically coated around NPs to construct the final SA-PEI-DDs NPs, followed by the in vitro stability and release tests, in vitro and in vivo colonic mucosal adhesion tests. In the in vivo anti-UC test, the experimental colitis mice were induced by 2,4,6-trinitrobenzenesulfonic acid. The body weight and disease activity index changes were measured, and the myeloperoxidase activity, pro-inflammatory cytokines concentration, and hematoxylin and eosin staining were also investigated to evaluate the therapeutic effect of NPs.Results The structures of two DDs were demonstrated by 1H-NMR and MS. Both NPs were negatively charged and achieved high loading efficiency of DDs, while their particle sizes were significantly different. NPs showed good stability and sustained release properties in the simulated colonic environment. Moreover, the negative charge on the of NPs surface made them easier to adhere to the positively charged inflammatory colonic mucosa, thereby enhancing the enrichment and retention of DDS in the colitis site. Furthermore, the NPs exhibited better therapeutic effects than free Dex on the experimental colitis mice induced by TNBS through the enema rectal.Conclusion These results indicated the mucoadhesive NPs as a kind of novel nano-enema showed great potential to achieve efficient treatment on UC.
研究领域:
药剂学
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药理学
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纳米技术
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炎症性肠病
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DOI
PubMed
高影响因子
Pharmacology Research & Perspectives
·
2021
·Vol. 9
·期 3
·e00791
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IF 2.794
Suoli Cheng,Xueqin Liu,Fan Gong,Xiaoling Ding,Xuebing Zhou,Cuiyun Liu,Fei Zhao,Xiaoliang Li,Jiandang Shi
The pathogenesis of steroid-induced avascular necrosis of femoral head (SANFH) is complex, and there is a lack of effective early prevention method. The aim of the present study was to evaluate the effect of dexamethasone (DEX) on the biological behavior of bone marrow mesenchymal stem cells (BMSCs) and to explore the possibility of DEX in the clinical treatment of SANFH. The effect of DEX on the proliferation of BMSCs was evaluated by Counting Kit-8 assay, western blot assay, and enzyme-linked immunosorbent assay. Flow cytometry and western blot assay were performed to detect the effect of DEX on the apoptosis of BMSCs. Quantitative real-time PCR and western blot assay were performed to detect the effect of DEX on the expression of endoplasmic reticulum stress (ERS)-related genes. Immunoblotting analysis was conducted for detecting the nuclear-cytoplasmic distribution of Nrf2. DEX could significantly inhibit the proliferation of BMSCs and promote apoptosis of BMSCs. DEX could increase the expression of PERK, ATF6, and IRE1a, and induce nuclear translocation of Nrf2. The addition of ML385 could reverse the effect of DEX on BMSCs. DEX could activate the PERK-Nrf2 pathway to promote ERS and finally affect the cell proliferation and apoptosis of BMSCs.
研究领域:
药理学
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细胞生物学
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干细胞研究
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骨科
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
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2021
·
IF 9.229
Tianhua Xiao,Lei Fan,Rongtao Liu,Xingwen Huang,Shihuan Wang,Liangang Xiao,Yiyu Pang,Da Li,Jia Liu,Yonggang Min
Polyetheretherketone (PEEK) is a biocompatible polymer, but its clinical application is largely limited due to its inert surface. To solve this problem, a multifunctional PEEK implant is urgently fabricated. In this work, a dual-metal–organic framework (Zn–Mg-MOF74) coating is bonded to PEEK using a mussel-inspired polydopamine interlayer to prepare the coating, and then, dexamethasone (DEX) is loaded on the coating surface. The PEEK surface with the multifunctional coating provides superior hydrophilicity and favorable stability and forms an alkaline microenvironment when Mg2+, Zn2+, 2,5-dihydroxyterephthalic acid, and DEX are released due to the coating degradation. In vitro results showed that the multifunctional coating has strong antibacterial ability against both Escherichia coli and Staphylococcus aureus; it also improves human umbilical vein endothelial cell angiogenic ability and enhances rat bone marrow mesenchymal stem cell osteogenic differentiation activity. Furthermore, the in vivo rat subcutaneous infection model, chicken chorioallantoic membrane model, and rat femoral drilling model verify that the PEEK implant coated with the multifunctional coating has strong antibacterial and angiogenic ability and promotes the formation of new bone around the implant with a stronger bone–implant interface. Our findings indicate that DEX loaded on the Zn–Mg-MOF74 coating-modified PEEK implant with bacteriostasis, angiogenesis, and osteogenesis properties has great clinical application potential as bone graft materials.
研究领域:
材料科学
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生物医学工程
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组织工程
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DOI
PubMed
高影响因子
Nanoscale
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2021
·Vol. 13
·期 47
·20170-20185
·
IF 7.79
Yanqin Song,Muhammad Ismail,Qi Shan,Jianing Zhao,Yanping Zhu,Leiming Zhang,Yuan Du,Longbing Ling
Rheumatoid arthritis (RA) is an autoimmune inflammatory disorder that has seriously affected human health worldwide and its current management requires more successful therapeutic approaches. The combination of nanomedicines and pathophysiology into one system may provide an alternative strategy for precise RA treatment. In this work, a practical ROS-mediated liposome, abbreviated as Dex@FA-ROS-Lips that comprised synthetic dimeric thioether lipids (di-S-PC) and a surface functionalized with folic acid (FA), was proposed for dexamethasone (Dex) delivery. Incorporation with thioether lipids and a FA segment significantly improved the triggered release and improved the triggered release of cytotoxic Dex as well as the active targeting of RA, altering its overall pharmacokinetics and safety profiles in vivo. As proof, the designed Dex@FA-ROS-Lips demonstrated effective internalization by LPS-activated Raw264.7 macrophages with FA receptor overexpression and released Dex at the inflammatory site due to the ROS-triggered disassembly. Intravenous injection of this Dex@FA-ROS-Lips into adjuvant-induced arthritis (AIA) mice led to its incremental accumulation in inflamed joint tissues and significantly alleviated the cartilage destruction and joint swelling via suppression of proinflammatory cytokines (iRhom2, TNF-α and BAFF), as compared to the effect of commercial free Dex. Importantly, the Dex@FA-ROS-Lips nanoformulation showed better hemocompatibility with less adverse effects on the body weight and immune organ index of AIA mice. The anti-inflammatory mechanism of Dex@FA-ROS-Lips was further studied and it was found that it is possibly associated with the down-regulation of iRhom2 and the activation of the TNF-α/BAFF signaling pathway. Therefore, the integration of nanomedicines and the RA microenvironment using multifunctional Dex@FA-ROS-Lips shall be a novel RA treatment modality with full clinical potential, and based on the enhanced therapeutic effect, the signaling pathway of iRhom2/TNF-α/BAFF reasonably explained the mechanism of Dex@FA-ROS-Lips in anti-RA, which suggested a molecular target for RA therapy and other inflammatory diseases.
研究领域:
药理学
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纳米技术
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免疫学
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风湿病学
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产品关联
DOI
PubMed
高影响因子
Advanced Therapeutics
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2023
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IF 4.6
Honglin Jia,Qi Yang,Jiahui Hong,Rui Ding,Tao Liu,Qunfang Yang,Haiping Zheng,Qingshan Huang,Zhaowei Zhang,Xiaohong Chen,Renshan Sun,Yunlong Yu,Wenjun Shan
Maintaining the homeostasis of the skin's immune microenvironment is crucial for skin's health. In inflammatory skin conditions (like psoriasis), the immune microenvironment is dysregulated, including ROS accumulation and T cell overactivation. In addition to promoting inflammation and excessive keratinocyte proliferation, ROS upregulation in psoriasis also induces glucocorticoid resistance, which poses a significant challenge to the effectiveness of glucocorticoid treatment (e.g., dexamethasone) in psoriasis. To conquer this problem, we used epigallocatechin-3-gallate (EGCG) to eliminate ROS production in psoriasis. Application of EGCG reduced ROS levels and improved the anti-psoriasis effect of Dexamethasone (Dex) in vitro. Benefiting from the unique characteristics of microneedle for transdermal drug delivery, we construct a dissolvable microneedle (MN) patch containing EGCG and Dex (DEX/EGCG-MN), which can directly codelivery the two elements to the lesion area without stratum corneum barrier. Our MN alleviates psoriasis-like manifestations in imiquimod (IMQ)-induced psoriasis mouse model, indicated by epidermal thickness and dorsal skin signs. Besides, DEX/EGCG-MN corrected the disorder of immune cells, including innate and acquired immune cells. As a result, it mediates the balance in the skin's immune microenvironment. Meanwhile, our MN also ameliorated the hyperproliferation of keratinocytes in psoriatic lesions. We believe this approach may offer insights for further developing anti-psoriasis assays. This article is protected by copyright. All rights reserved
研究领域:
药理学
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皮肤科
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免疫学
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药物递送系统
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产品关联
DOI
高影响因子
Open Chemistry
·
2023
·Vol. 21
·期 1
·
IF 2.3
Hongmei Yu,Weiwei Liang,Yuan Sun
In this work, a novel In( iii ) coordination polymer, i.e., {[In(L)(im)(H 2 O)](H 2 O)}
n
( 1 ) was produced from the synthetic reactions in water and dimethylformamide mixed solvents and using methyl-3-hydroxy-5-carboxy-2-thiophenecarboxylic acid (H 2 L) and imidazole (Him) as the co-ligands, and then successfully loaded with dexamethasone. The injectable hydrogels were prepared from natural polysaccharide hyaluronic acid with good biocompatibility and successfully loaded with In( iii ) complex. The suppressive inhibitory effect of hydrogels toward U251 human glioma cell line viability was assessed using the Cell Counting Kit-8 assay kit, and the relatively expressed levels of the vascular endothelial growth factor signaling pathway were determined by real-time RT-PCR.
研究领域:
药学
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肿瘤学
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材料科学
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产品关联
DOI
高影响因子
Acta Biomaterialia
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2022
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IF 10.633
Yifan Li,Qiangwei Liang,Liyue Zhou,Yongjing Cao,Jiayu Yang,Juan Li,Jinxia Liu,Jiawei Bi,Yanhua Liu
The signaling cascade between nuclear factor-kappa B (NF-κB) and hypoxia-inducible factor-1α (HIF-1α) can be activated by proinflammatory M1 macrophages in rheumatoid arthritis (RA), which produces reactive oxygen species (ROS) and enhances M1 macrophage polarization, thus aggravating the development of RA. Therefore, an ROS-responsive artesunate prodrug micellar nanosystem for co-delivery of dexamethasone (DEX/HA-TK-ART micelles , abbreviated as DEX/HTA) was developed for synergistic inhibition of the HIF-1α/NF-κB cascade to regulate ROS scavenging and macrophage repolarization in RA combination therapy. DEX/HTA micelles displayed prolonged circulation in blood and efficiently co-delivered ART&DEX in the inflamed joints of adjuvant-induced arthritis (AIA) rats; moreover, they were specifically recognized and internalized into M1 macrophages through CD44 receptor-mediated endocytosis . ROS-responsive co-released ART&DEX then exerted a synergistic action to efficiently perform ROS scavenging and repolarization of M1 to M2 macrophages by inhibition of the HIF-1α/NF-κB cascade. The intravenous administration of DEX/HTA micelles into AIA rat models significantly alleviated inflammatory cell infiltration and repaired cartilage injury in the joint. Collectively, our study highlights the therapeutic potential of DEX/HTA micelles for treating RA through synergistic inhibition of the HIF-1α/NF-κB signaling cascade to regulate ROS scavenging and macrophage repolarization. Statement of significance An ROS-responsive artesunate (ART) prodrug micellar nanosystem for co-delivering dexamethasone (DEX), abbreviated as DEX/HA-TK-ART micelle, was developed for synergistic cascade regulation of the HIF-1α/NF-κB pathway on ROS scavenging and macrophage repolarization in combination therapy for rheumatoid arthritis. The well-designed nanosystem showed prolonged circulation in blood and superior ART&DEX accumulation in the inflamed joints of AIA rats; moreover, the micelles were specifically internalized into M1 macrophages and co-released ART&DEX, subsequently leading to inhibition of the HIF-1α/NF-κB pathway for ROS scavenging and macrophage repolarization, thus generating synergistic anti-inflammatory effects in RAW 264.7 cells and AIA rats. The HIF-1α/NF-κB cascade regulation on ROS scavenging and macrophage repolarization based on ART&DEX combination with smart nanotechnology could serve as a promising approach for rheumatoid arthritis therapy.
研究领域:
药理学
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纳米技术
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炎症
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风湿病学
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE
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2024
·
IF 3.3
Xi-you Li,Xiao-yuan Gu,Xiao-min Li,Jian-gang Yan,Xin-liang Mao,Qin Yu,Yu-lan Du,Hiroshi Kurihara,Chang-Yu Yan,Wei-xi Li
BACKGROUND Carnosine, a natural bioactive dipeptide derived from meat muscle, possesses strong antioxidant properties. Dexamethasone, widely employed for treating various inflammatory diseases, raises concerns regarding its detrimental effects on bone health. This study aimed to investigate the protective effects of carnosine against dexamethasone-induced oxidative stress and bone impairment, along with its underlying mechanisms, utilizing chick embryos and a zebrafish model in vivo , as well as MC3T3-E1 cells in vitro . RESULTS Our findings revealed that carnosine effectively mitigated bone injury in dexamethasone-exposed chick embryos, accompanied by reduced oxidative stress. Further investigation demonstrated that carnosine alleviated impaired osteoblastic differentiation in MC3T3-E1 cells and zebrafish by suppressing the excessive production of reactive oxygen species (ROS) and enhancing the activity of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPX). Moreover, mechanistic studies elucidated that carnosine promoted the expression and nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2), thereby facilitating the transcription of its downstream antioxidant response elements, including heme oxyense-1 (HO-1), glutamate cysteine ligase modifier (GCLM), and glutamate cysteine ligase catalytic (GCLC) to counteract dexamethasone-induced oxidative stress. CONCLUSION Overall, this study underscores the potential therapeutic efficacy of carnosine in mitigating oxidative stress and bone damage induced by dexamethasone exposure, shedding light on its underlying mechanism of action by activating the NRF2 signaling pathway. © 2024 Society of Chemical Industry.
研究领域:
药理学
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生物化学
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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
HORMONE AND METABOLIC RESEARCH
·
2020
·Vol. 52
·期 10
·755-763
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IF 2.562
Wenge Zhang,Yu Qiao,Fulei Qi,Qingyi Shen,Ruqian Zhao,Xiaojing Yang
Zinc-α2-glycoprotein (ZAG), as an adipokine, plays an important role inlipid metabolism. However, its influence on whole gene expression profile inadipose tissue is not known. Under stress condition, how ZAG affects the lipidmetabolism is also unclear. Therefore, in this study ZAG systemic knockout (KO)mice were used as a model to reveal the genes expression profile in visceral fattissues of ZAG KO mice and wild-type mice by genome-wide microarray screening.Then dexamethasone (DEX) was used to explore the effect of ZAG deletion on bodyfat metabolism under stress. Our results showed that 179 genes weredifferentially expressed more than 1.5 times between ZAG KO mice and wild typemice, of which 26 genes were upregulated dramatically and 153 genes weresignificantly downregulated. Under DEX simulated stress, ZAG systemic knockoutin vivo resulted in a markedly decrease of triglycerides (TG) and nonesterifiedfatty acid (NEFA) content in in plasma. Similarly, for lipid catabolism, ZAG KOled to a significant increase of phosphorylated HSL (p-HSL) protein and a risingtendency of adipose triglyceride lipase (ATGL) protein relative to those of theDEX group. For lipid anabolism, fatty acid synthase (FAS) and adiponectinprotein expression in visceral fat rose notably in ZAG KO mice after DEXtreatment. In conclusion, ZAG knockout can affect the gene expression profile ofadipose tissue, reduce elevated TG and NEFA levels in plasma, and alter lipidmetabolism under DEX treatment. These findings provide new insights into themechanism of lipid metabolic disorders in response to stress.
研究领域:
分子生物学
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内分泌学
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代谢学
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基因组学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Xiaolin Xie,Haikang Fu,Zhixuan Ai,Ziwei Huang,Wenwen Tan,Qingfeng Xie,Yuhong Liu,Yucui Li,Jiannan Chen,Xiaobo Yang,Ziren Su,Zhengquan Lai,Jianhui Xie
Ethnopharmacological relevance Coptidis Rhizome (CR), a cornerstone medicinal herb, is routinely used to treat metabolic diseases for centuries in China. However, the potential mechanism has not been completely elucidated. Preceding investigation has reported that berberine in CR can bind to hemoglobin (Hb) and utilize erythrocyte-Hb self-assembly drug delivery system to significantly upregulate HO-1 expression. Aim of the study This study was designed in a pioneering endeavor to explore the therapeutic potential and underlying mechanism of CR in dexamethasone- and fructose-induced glycolipid metabolism disorders (GLD) rat models. Material and methods The major elements of CR were identified by high performance liquid chromatograph (HPLC). Dexamethasone- and fructose-induced rat GLD model was constructed. Glucolipid metabolism, oxidative status, and insulin sensitivity were investigated. Histopathological, transcriptomic, in silico simulations, immunofluorescence, immunohistochemistry, and Western blotting analyses were performed to gain further mechanism insight. Results HPLC analysis revealed that berberine, palmatine, coptisine, epiberberine, and jatrorrhizine were detected in CR, with berberine as the most abundant. Administration of CR favorably regulated the organ indexes, and significantly improved glucose metabolism by decreasing the FBG and GSP levels along with improved OGTT. CR promoted insulin sensitivity by suppressing the increased levels of FINS, HOMA-IR and ISI, and concomitantly improving ITT. Furthermore, CR normalized lipid metabolism by decreasing the elevated TG, TC and LDL-C levels. Additionally, CR effectively ameliorated histopathological deterioration in pancreatic and hepatic tissues and reduced serum ALT and AST activities. CR also ameliorated oxidative stress by remarkably lowering hepatic ROS fluorescence intensity and serum MDA content, whereas enhancing SOD and CAT enzymatic activity, and T-AOC level. Hepatic transcriptomics analysis revealed the oxidative stress-related gene HMOX1 encoding HO-1 and AMPK pathway critically involved in the therapeutic effect of CR. Furthermore, CR was found to significantly up-regulate the protein expression levels of HO-1, NQO1 and p-AMPK. On the other hand, in silico simulations indicated that strong van der Waals forces interaction between these alkaloids and HO-1. Notably, CR exhibited potent HO-1 agonistic activity comparable to the HO-1 inducer hemin, as manifested by enhanced HMOX1 mRNA level, HO-1 expression level, cytoplasmic HO-1 fluorescence intensity, carbon monoxide production, and reduced heme level, which were the markers of erythrocyte metabolism. Administration of CR or hemin significantly improved fasting glycemia, blood fat, insulin sensitivity, and antioxidant capacity. Nevertheless, these effects were observably reversed by the HO-1 inhibitor zinc protoporphyrin (ZnPP). Conclusion CR effectively ameliorated insulin resistance, hyperglycemia, and dyslipidemia, and its mechanism of action may be at least partially, mediated through HO-1 activation via erythrocyte metabolic regulation. This study provided further evidences for the historical use of CR in the therapy of metabolic diseases. These results highlighted the potential of CR as a novel HO-1 agonist for the development of innovative treatments for GLD.
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DOI
PubMed
高影响因子
Frontiers in Bioengineering and Biotechnology
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2021
·
IF 5.89
Wu Xiaodong,Li Pengpeng,Cheng Jian,Xu Qiang,Lu Beiji,Han Conghui,Huo Weiling
Objective: Osteoarthritis (OA) is a common subtype of arthritis. To date, treatment of OA focuses primarily on alleviating pain and improving joint function. The lack of a vascular system within synovial joints and the rapid removal of agents due to synovial exchange hinder continuous delivery of OA drugs. However, these obstacles are being addressed by promising nanoscale drugs.Methods: We synthesize and assemble a hydrogen peroxide [H2O2, belongs to the category of active oxygen species (ROS)]-sensitive nanomicelle, which is loaded with the anti-inflammation drug dexamethasone and chondrogenic differentiation factor cartilage-derivedmor-phogeneticprotein-1. The micelle can induce bone marrow mesenchymal stem cells to repair cartilage while inhibiting joint inflammation.Results: The prepared nanoparticles were of uniform size and displayed an obvious core-shell structure. Under H2O2 stimulation, the shell layer could be removed gradually. The drug-loaded micelle effectively inhibited proliferation of activated macrophages, induced macrophage apoptosis with an anti-inflammatory effect, and caused the BMSCs to differentiate into chondrocytes.Conclusion: This work provides an experimental and theoretical basis for further development of a drug-loaded micelle in the healing of osteoarthritis.
研究领域:
药学
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生物医学工程
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骨科
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纳米技术
✓ 已验证
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）