Oxidative Medicine and Cellular Longevity
·
2022
·
IF 7.31
Xinye Wang,Ran Huo,Zhongjie Liang,Congcong Xu,Tingting Chen,Jingjing Lin,Luyao Li,Wei Lin,Bingting Pan,Xiaoqin Fu,Shangqin Chen
Bronchopulmonary dysplasia (BPD) is a chronic lung disease commonly found in premature infants. Excessive inflammation and oxidative stress contribute to BPD occurrence and development. Simvastatin, as an inhibitor of HMG-CoA reductase, has been reported to have antioxidative and anti-inflammatory effects. However, its effect and possible mechanisms in hyperoxia-induced lung injury are rarely reported. In this study, in vivo and in vitro experiments were conducted to investigate whether simvastatin could ameliorate hyperoxia-induced lung injury and explore its potential mechanism. For the in vivo study, simvastatin could improve alveolar development after hyperoxic lung injury and reduce hyperoxic stress and inflammation. The in vitro study revealed that simvastatin can reduce inflammation in A549 cells after high-oxygen exposure. Simvastatin suppressed NLRP3 inflammasome activation and played anti-inflammatory and antioxidant roles by increasing KLF2 (Krüppel-like factor 2) expression. In vitro experiments also revealed that these effects of simvastatin were partially reversed by KLF2 shRNA, indicating that KLF2 was involved in simvastatin effects. In summary, our findings indicate that simvastatin could downregulate NLRP3 inflammasome activation and attenuate lung injury in hyperoxia-induced bronchopulmonary dysplasia via KLF2-mediated mechanism.
研究领域:
儿科
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肺科学
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药理学
·
炎症
·
氧化应激
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产品关联
DOI
PubMed
高影响因子
Nanomedicine-Nanotechnology Biology and Medicine
·
2020
·
IF 5.182
Zitong Qi,Cuiping Jiang,Hai Gao,Yanyan Wang,Qiqi Zhang,Wenli Zhang,Jianping Liu
Reconstituted high-density lipoproteins (rHDLs) hold promise as nanocarriers for atherosclerosis-targeted delivery, with biofunctions typified by mediating cholesterol efflux. The paradox is how rHDL offloads the delivered drugs into atherosclerotic foam cells , while simultaneously transferring cholesterol out of cells. Herein, simvastatin-loaded discoidal rHDL (ST-d-rHDL), constructed based on established paradigms, was employed to investigate its basic trafficking mechanism in foam cells. As proved, ST-d-rHDL was resecreted via lysosomal and Golgi apparatus-recycling endosome-mediated pathways following clathrin-mediated endocytosis . And the resecretion ratio reached 60% within 6-h chase with excessive ST-d-rHDLs. During the rHDL resecretion, 39% of cellular cholesterol efflux was detected, accompanied by 85% of the encapsulated cargo released intracellularly. Furthermore, the recycling rate was demonstrated to be promoted by smaller rHDL size and higher cellular lipid contents. Collectively, endocytic recycling confers the synergism in ST-d-rHDL to coordinate cholesterol efflux and intracellular drug release, providing new insights into design of biofunctional rHDL.
研究领域:
药理学
·
细胞生物学
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纳米技术
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心血管疾病
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
·
2022
·
IF 5.589
Jianhua He,Xiaoju Zhou,Fengfei Xu,Hongliang He,Shuangyan Ma,Xinyue Liu,Mengyuan Zhang,Wenli Zhang,Jianping Liu
Macrophage/foam cells and cholesterol crystals (CCs) have been regarded as the central triggers of maladaptive inflammation in atherosclerotic plaque. Despite the tremendous progress of recombinant high-density lipoprotein (rHDL) serving for targeted drug delivery to alleviate inflammation in macrophage/foam cells, the active attempt to modulate/improve its CCs dissolution capacity remains poorly explored. The untreated CCs can seriously aggravate inflammation and threaten plaque stability. Based on the superb ability of β-cyclodextrin (β-CD) to bind CCs and promote cholesterol efflux, simvastatin-loaded discoidal-rHDL (ST-d-rHDL) anchored with β-CD (βCD-ST-d-rHDL) was constructed. We verified that βCD-ST-d-rHDL specifically bound and dissolved CCs extracellularly and intracellularly. Furthermore, anchoring β-CD onto the surface of ST-d-rHDL enhanced its cholesterol removal ability in RAW 264.7 cell-derived foam cells characterized by accelerated cholesterol efflux, reduced intracellular lipid deposition, and improved cell membrane fluidity/permeability. Finally, βCD-ST-d-rHDL exerted efficient drug delivery and effective anti-inflammatory effects in macrophage/foam cells. Collectively, anchoring β-CD onto the surface of ST-d-rHDL for selective CCs dissolution, accelerated cholesterol efflux, and improved drug delivery represents an effective strategy to enhance anti-inflammatory effects for the therapy of atherosclerosis.
研究领域:
药理学
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心血管疾病
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药物递送系统
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炎症
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脂质学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
VACCINE
·
2023
·
IF 5.5
Shuwen Xu,Zhiyong Wu,Gaofeng Cai,Yue Zhang,Song Peng,Lina Jiao,Zhenguang Liu,Yang Yang,Deyun Wang
Oil-in-water emulsion-based adjuvants have demonstrated acceptable safety in many disease indications, while their adjuvant activities for vaccines still need to be improved. Recently, the strategy of combining adjuvants with multiple types of immunostimulants has been shown to enhance immune responses. In this study, astragalus polysaccharides were combined with simvastatin as an immunostimulant to construct a compound O/W emulsion adjuvant. The formulations were optimized according to the OVA-specific antibody responses induced in mice. For this reason, high (5 mg/mL), medium (2.5 mg/mL), and low (1.25 mg/mL) concentrations of astragalus polysaccharides and high (10 mg/mL), medium (1 mg/mL), and low (0.1 mg/mL) concentrations of simvastatin were selected. The final optimal formulation of the immunostimulant was a high concentration of astragalus polysaccharides combined with a medium concentration of simvastatin. The optimal compound O/W emulsion adjuvant could induce effective humoral and cellular immune responses that were stronger and more stable than those induced by aluminum adjuvant and Freund's adjuvant. The OVA/HAPS-MSim-OE induced dramatically strong and persistent IgG expressions and Th1-polarized immune responses. What’s more, the highest CD4 + /CD8 + lymphocyte ratios were observed in OVA/HAPS-MSim-OE group. In addition, compound O/W emulsion adjuvant groups significantly promoted the secretion of IFN-γ and IL-6, which also indicated that the compound O/W emulsion adjuvants could induce both enhanced Th1 and Th2-mediated immune responses but prefer the Th1-mediated ones. This study would contribute to an interesting and promising direction in the development of emulsion-based adjuvants.
研究领域:
免疫学
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药学
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疫苗学
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产品关联
DOI
PubMed
高影响因子
Advanced Therapeutics
·
2023
·Vol. 6
·期 7
·2200356
·
IF 4.6
Haixia Liu,Xianxian Yao,Weichu Zhu,Jiaxin Zhang,Shuangping Ma,Daru Lu,Wuli Yang
Colorectal cancer is one of the most common causes of cancer-related deaths worldwide. Ferroptosis is a non-apoptotic form of regulated cell death that can be triggered by excessive lipid peroxidation and provides an alternative cancer treatment option. To design ferroptosis-targeted nanomedicine, a new type of nanoparticle is synthesized. The antineoplastic agent simvastatin (SIM) and specifically designed short hairpin RNA (shRNA) are co-loaded into zeolitic imidazolate framework-8 (ZIF-8) nanoparticles coated with poly(carboxybetaine methacrylate) (PCBMA). The constructed shRNA/ZIF-8@PCBMA-SIM nanoparticles effectively eliminate human colorectal carcinoma cells in vivo, showing superior cytotoxicity against tumors owing to their improved targeting ability and the high retention of antineoplastic agents delivered at tumor sites. Furthermore, SIM and shRNA downregulate the expression of ferroptosis-related enzymes 3-hydroxy-3-methylglutaryl-CoA reductase and glutathione peroxidase 4, thus, triggering ferroptosis in cancer cells. Given that SIM is already approved for clinical use, and shRNA offers high potency to downregulate the cystine/glutamate antiporter (x-CT) system protein (subunit SLC7A11), shRNA/ZIF-8@PCBMA-SIM nanoparticles show great clinical potential to treat colorectal cancer via ferroptosis. This presents an alternative therapy that addresses the limitations of chemotherapy.
研究领域:
肿瘤学
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纳米技术
·
药学
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
International Journal of Nanomedicine
·
2026
·
IF 8.7
Zidong Wu,Kai Ma,Zixuan Wu,Xiaoyu Guo,Yuning Qu,Zheyue Zhu,Weidong Zhu,Chengxin Li,Yi Liu,Rui Ma,Pei Yang
Background Polyetheretherketone (PEEK) is a promising orthopedic implant material due to its bone-matched elastic modulus and radiolucency. However, its clinical application is limited by biological inertness and lack of antibacterial activity, which predispose to implant-associated infection (IAI) and poor osseointegration. This study developed a multifunctional coating on sulfonated PEEK (SPEEK) via polydopamine (PDA)-mediated co-delivery of simvastatin-loaded ZIF-8 nanoparticles (SIM@ZIF-8) and moxifloxacin (MOX) to address these limitations.Methods A time-programmed release coating was fabricated on SPEEK by embedding SIM@ZIF-8 within a PDA layer and surface-loading MOX onto the surface. The coating’s physicochemical properties, drug release profiles, biocompatibility, antibacterial activity, and osteogenic capacity were evaluated in vitro. Antibacterial efficacy and osseointegration were further assessed in vivo using rat subcutaneous infection and rabbit femoral defect models.Results Release profiles revealed that MOX exhibited burst release within 24 h, whereas SIM quickly reached therapeutic concentrations during the initial phase and was slowly released over five weeks, while Zn2+ from ZIF-8 was released synchronously with SIM. In vitro antimicrobial assays showed that the synergistic release of MOX and SIM exhibited potent antibacterial activity against Staphylococcus aureus and Escherichia coli, providing sustained inhibition of Staphylococcus aureus biofilms. The coating also promoted MC3T3-E1 cell adhesion, spreading, and osteogenic differentiation, as indicated by upregulated osteogenic markers (Runx2, OCN, OPN, COL1A1), enhanced matrix mineralization, and increased BMP-2 expression. In rat models, bacterial colonization on the coated surface and residual bacteria in tissues were significantly reduced. In rabbit femoral defects, sustained co-release of SIM and Zn2+ accelerated new bone formation and improved osseointegration, confirmed by micro-CT, double fluorescence labeling, and histological analysis.Conclusion This study presents a novel bioactive PEEK implant coating integrating antibacterial and osteogenic functions through a MOX/SIM@ZIF-8/PDA system. The strategy effectively combats IAI and enhances osseointegration, offering potential for clinical orthopedic applications.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Experimental and Therapeutic Medicine
·
2018
·Vol. 17
·期 1
·79-90
·
IF 1.41
Zhan‑Zhao Zhang,Hui‑Zhong Zhang,Zhi‑Yong Zhang
Repairing critical‑sized bone defects has been a major challenge for orthopedic surgeons in the clinic. The generation of functioning bone tissue scaffolds using osteogenic induction factors is a promising method to facilitate bone healing. In the present study, three‑dimensional (3D) printing of a poly(lactic‑co‑glycolic acid) (PLGA) scaffold with simvastatin (SIM) release functioning was generated by rapid prototyping, which was incorporated with collagen for surface activation, and was finally mixed with SIM‑loaded PLGA microspheres. In vitro assays with bone marrow‑derived mesenchymal stem cells were conducted. For the in vivo study, scaffolds were implanted into segmental defects created on the femurs of Sprague‑Dawley rats. At 4 and 12 weeks following surgery, X‑ray, micro‑computed tomography and histological analysis were performed in order to evaluate bone regeneration. The results demonstrated that collagen functionalization of PLGA produced better cell adhesion, while the sustained release of SIM promoted greater cell proliferation with no significant cytotoxicity, compared with the blank PCL scaffold. Furthermore, in vivo experiments also confirmed that SIM‑loaded scaffolds played a significant role in promoting bone regeneration. In conclusion, the present study successfully manufactured a 3D printing PLGA scaffold with sustained SIM release, which may meet the requirements for bone healing, including good mechanical strength and efficient osteoinduction ability. Thus, the results are indicative of a promising bone substitute to be used in the clinic.
研究领域:
骨科
·
组织工程
·
生物材料
✓ 已验证
DOI
PubMed
高影响因子
NEW JOURNAL OF CHEMISTRY
·
2015
·Vol. 40
·期 2
·1256-1262
·
IF 3.086
Xiangyu Zhang,Kaiyue Zhao,Jun Wang,Shujie Bai,Shuqing Jiao,Jie Zhang,Lian Yu
Targeting ultrasound contrast agents (UCAs) offer further opportunity to enhance the capabilities of diagnostic ultrasound imaging and controlled drug delivery to pathological tissue. In this study, simvastatin (Sim) loaded polymeric microbubbles (MBs) as UCAs were developed and targeted toward inflamed vascular endothelium to aid in the diagnosis and treatment of atherosclerosis. The polymeric shelled MBs were used to enable localized targeting of the inflamed vascular endothelium by modifying the surface of these MBs with specific antibodies. The morphology, size distribution, chemical composition and antibody conjugation efficiency of the MBs were evaluated. The gas-filled drug delivery platform described promises faster drug release, when subjected to ultrasound, compared to the drug release without ultrasound. In vivo ultrasound contrast imaging confirmed that these polymeric MBs could provide a stable acoustic enhancement and effectively identify atherosclerotic areas of plaque within the ventral aorta of rabbits. The results demonstrated that the elaboration of MBs has the potential to exhibit excellent ultrasound contrast-enhancing capabilities and provide a sufficient amount of drug to target disease sites.
研究领域:
生物医学工程
·
药学
·
超声成像
·
药物递送系统
·
心血管疾病
✓ 已验证
产品关联
DOI
高影响因子
Journal of Materials Chemistry B
·
2020
·Vol. 8
·期 7
·1496-1506
·
IF 5.344
Jianhua He,Yun Yang,Xiaoju Zhou,Wenli Zhang,Jianping Liu
Targeting drug delivery to macrophage/foam cells is challenged owing to the poor cell permeability and fluidity resulting from the massive accumulation of intracellular cholesterol in atherosclerosis (AS). Discoidal reconstituted high-density lipoprotein (d-rHDL) has been well regarded as a potential drug delivery system for AS by virtue of its plaque-targeting and cholesterol removal abilities, while the latter is compromised by the high activation energy of cholesterol efflux. It is reported that a low concentration of β-cyclodextrin (β-CD) can function as a cholesterol shuttle to promote cholesterol efflux from cells to the extracellular acceptors (cholesterol sink, such as HDL particles), but it is still unknown whether the combination of β-CD with a drug-loaded d-rHDL can function as a shuttle/sink model to promote the remodeling and drug release of the d-rHDL carrier after accelerating the cholesterol efflux. Furthermore, it is interesting to investigate whether enhanced cholesterol efflux can improve the cellular drug uptake by restoring the permeability and fluidity of the cell membrane. Here, simvastatin-loaded d-rHDL (ST-d-rHDL) was combined with different concentrations of β-CD. Compared with ST-d-rHDL alone, the cholesterol removal ability of ST-d-rHDL combined with 0.5 mM of β-CD increased by 31-fold after incubation for 6 h and the cumulative drug release of ST-d-rHDL increased by two-fold during the initial 1 h in an acellular mimetic system. In macrophage/foam cells, 0.5 mM of β-CD showed superior promoting effects in the cholesterol removal ability and remodeling of ST-d-rHDL compared to 0.1 mM of β-CD. The high concentration of β-CD at 2 mM displayed a low efficiency for accelerating cholesterol efflux, which might function as a cholesterol sink rather than a cholesterol shuttle. Moreover, the permeability and fluidity of the cell membrane were improved by combining 0.5 mM of β-CD with ST-d-rHDL, which exhibited an enhanced cellular drug uptake and inhibiting effect on the intracellular lipid deposition and secretion of inflammatory cytokine. Collectively, combination of β-CD and ST-d-rHDL as a shuttle/sink model could enhance cholesterol efflux and drug uptake to suppress inflammation in macrophage/foam cells.
研究领域:
药学
·
心血管疾病
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOACTIVE AND COMPATIBLE POLYMERS
·
2017
·
IF 1.31
Fengzhe Wang,Xuan Liu,Longbao Feng,Qiyu Zhu,Shina Yan,Rui Guo
The development of nanomedicine has provided advanced treatment opportunities for many diseases. Simvastatin, a widely used anti-lipidaemic drug, has potential for the treatment of orthopaedic diseases. However, the clinical application of simvastatin is limited because of its hydrophobicity and lack of distribution in osseous tissue. In this study, an amphiphilic nanoparticle, poly(d,l-lactide-co-glycolide)–poly(ethyleneglycol)–poly(d,l-lactide-co-glycolide), was synthesised to improve the biocompatibility of simvastatin. The haemocompatibility of the poly(d,l-lactide-co-glycolide)–poly(ethyleneglycol)–poly(d,l-lactide-co-glycolide) copolymer was investigated through its aggregation, morphology and lysis of human red blood cells, along with its impact on the clotting function according to the activated partial thromboplastin time, prothrombin time and thromboelastographic assays. The results demonstrated that the poly(d,l-lactide-co-glycolide)–poly(ethyleneglycol)–poly(d,l-lactide-co-glycolide) copolymer with a concentration lower than 10 mg/mL had little impact on the aggregation, morphology or lysis of red blood cells, or on blood coagulation. Therefore, the copolymer may be a strong alternative candidate as an effective and safe drug carrier.
研究领域:
生物材料学
·
药剂学
·
医学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）