BIOMATERIALS
·
2023
·
IF 14
Kui Shen,Xiaowei Li,Guanning Huang,Zhongwen Yuan,Bin Xie,Tianfeng Chen,Lizhen He
Scavenging free radicals and reducing inflammatory reaction to relieve the secondary damage are important issues in the spinal cord injury (SCI) therapeutic strategy. Nanozymes attract more attention in the drug development of SCI due to the high stability, long-lasting catalytic capacity, and multienzyme-like properties. Herein, we constructed a Rapamycin (Rapa)-loaded and hollow mesoporous Prussian blue (HMPB)-based nanozyme (RHPAzyme) to realize the combined antioxidation and anti-inflammation combination therapy of SCI. Furthermore, activated cell penetrating peptide (ACPP) is modified onto nanozyme to endow the effectively ability of lesion area-targeting. This RHPAzyme exhibits ROS scavenging capacity with the transformation of Fe 2+ /Fe 3+ valance and cyanide group of HMPB to achieve multienzyme-like activity. As expected, RHPAzyme scavenges the ROS overproduction and reduces inflammation in oxygen-glucose deprivation (OGD)-induced damage via inhibiting MAPK/AKT signaling pathway. Furtherly, RHPAzyme exhibits the combined antioxidant and anti-inflammatory activity in vivo , which can effectively alleviate neuronal damage and promote motor function recovery in SCI mice. Overall, this study demonstrates the RHPAzyme induces an effective treatment of SCI by inhibiting oxygen-mediated cell apoptosis and suppressing inflammation-induced injury, thus reduces the nervous impairment and promotes motor function recovery.
研究领域:
纳米技术
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神经科学
·
药学
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生物医学工程
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACY AND PHARMACOLOGY
·
2013
·Vol. 66
·期 4
·557-563
·
IF 2.033
Zhang Zhaoliang,Xu Lu,Chen Hao,Li Xingyi
ObjectivesAllograft rejection is the major cause of corneal graft failure. To inhibit corneal allograft rejection, rapamycin as a novel immunosuppressive agent has been discovered. However, the high water insolubility and low bioavailability of rapamycin has strongly hindered its application in the clinical setting. In this paper, we attempted to develop a novel rapamycin nano-formulation using poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCEC) nanoparticles as carrier by an emulsion evaporation method for potential application in corneal transplantation.MethodsThe solubility of rapamycin in the nano-formulation was determined and in-vitro release studies were performed. The developed rapamycin-loaded PCEC nanoparticles were further characterized by dynamic light scattering, transmission electron microscopy, X-ray diffraction and differential scanning calorimetery. Toxicity studies were performed in eye-related cell lines.Key findingsThe rapamycin in nano-formulation exhibited ∼103-fold increased solubility as compared with native rapamycin. According to the results of the in-vitro cytotoxicity assay, the developed PCEC nanoparticles did not exhibit any apparent cytotoxicity against various eye-related cell lines with PCEC nanoparticle concentrations in the range of 0.05–10 mg/ml. In-vitro release study showed that the release of rapamycin was sustained from PCEC nanoparticles over a period of 48 h.ConclusionsAll the results suggested that the developed rapamycin-loaded PCEC nanoparticles might be suitable for immunosuppression in corneal transplantation by instillation administration.
研究领域:
药剂学
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眼科医学
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生物材料学
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DOI
高影响因子
Molecular Medicine Reports
·
2018
·Vol. 18
·期 6
·5445-5454
·
IF 1.922
Yang Su,Jingxiao Lu,Pian Gong,Xianguo Chen,Chaozhao Liang,Jie Zhang
Acute kidney injury (AKI) is a clinically common and severe complication of ischemia‑reperfusion (I/R), associated with high morbidity and mortality rates, and prolonged hospitalization. Rapamycin is a type of macrolide, primarily used for anti‑rejection therapy following organ transplantation and the treatment of autoimmune diseases. Rapamycin has been identified to exert a protective effect against AKI induced by renal I/R as an autophagy inducer. However, whether rapamycin preconditioning may relieve AKI following cerebral I/R (CIR) remains to be fully elucidated. The purpose of the present study was to investigate the effects of CIR on the renal system of rats and the role of rapamycin in AKI following CIR. In the present study, a CIR model was established in Sprague‑Dawley rats via a 90‑min period of middle cerebral artery occlusion and 24 h reperfusion, and pretreatment with an intraperitoneal injection of rapamycin (dosage: 1 mg/kg; 0.5 h) prior to CIR. The levels of serum creatinine and blood urea nitrogen (BUN), and the expression of inflammation‑, apoptosis‑ and autophagy‑associated markers were subsequently measured. In addition to certain histopathological alterations to the kidney, it was identified that CIR significantly increased the levels of serum creatinine, BUN, tumor necrosis factor‑α and interleukin‑1β, and significantly induced apoptosis and autophagy. It was observed that rapamycin induced autophagy through the mammalian target of rapamycin complex 1/autophagy‑related 13/unc‑51 like autophagy activating kinase 1 signaling pathway, and that rapamycin pre‑treatment significantly improved renal function and alleviated renal tissue inflammation and cell apoptosis in rats following CIR. In conclusion, the results suggested that rapamycin may alleviate AKI following CIR via the induction of autophagy.
研究领域:
药理学
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肾病学
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神经病学
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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
Materials Today Bio
·
2024
·
IF 8.7
Xue Sun,Haohao Cui,Jingfan Li,Boyuan An,Ruixing Liu,Zhihua Guo,Dandan Chu,Xingchen Geng,Bingbing Cui,Lei Zhu,Jingguo Li,Zhanrong Li
Subconjunctival fibrosis (SCF) is a common and refractory eye disease that is a serious threat to vision. The severe side effects of existing drugs and low drug bioavailability due to the ocular barrier are major challenges in SCF treatment. Hence, there is an urgent need to explore safer and more effective strategies for administering anti-SCF drugs. Herein, an injectable and adaptable hydrogel system containing the antifibrotic drug rapamycin was fabricated to address this complex need. This system possesses moderate mechanical properties, self-healing and shape-adaptive capabilities, injectability, and biosafety. It is designed to promote autophagy by modulating the PI3K/AKT/mTOR/WIPI2 pathway, thereby inhibiting SCF. In vivo experiments utilizing a rat subconjunctival injury model indicated that in situ administration of this hydrogel system effectively inhibited SCF. This system constitutes a promising method for promoting autophagy to protect against SCF, which will foster its widespread application for other fibrotic diseases.
研究领域:
眼科学
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药学
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生物材料
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DOI
PubMed
高影响因子
INFLAMMATION
·
2018
·Vol. 41
·期 4
·1384-1395
·
IF 2.884
Su Yang,Lu Jingxiao,Chen Xianguo,Liang Chaozhao,Luo Pengcheng,Qin Cong,Zhang Jie
Chronic prostatitis (CP) is a clinically common disease with high morbidity. It affects the patients’ quality of life (QoL) as well as physical and mental health seriously due to the recurring symptoms of lower urinary tract and genitalia. As the opinions about the etiology of CP are still not uniform, it is very difficult to be treated or even cured. Autophagy is a highly conserved physiological function which is widely found in eukaryotic cells. In general, cells maintain a certain level of autophagy under physiological conditions, and the basal level of autophagy can be regulated by a variety of autophagy-related genes under stress such as hunger, infection, trauma, and other circumstances. Therefore, the main purpose of this study is to investigate the role of autophagy in chronic nonbacterial prostatitis (CNP, also called CP). In this paper, we established the CNP model via hypodermic injection of 17β-estradiol and subsequently abdominal rapamycin (a common autophagy inducer) treatment based on castrated rats. Then, the expression of nuclear factor-κB (NF-κB), interleukin-1β (IL-1β), and autophagy-related markers as well as autophagosome formation in prostate tissues, peripheral blood mononuclear cells (PBMCs), and serum of rats were evaluated respectively. In addition to some histological changes in the prostate tissues, we found the levels of NF-κB and IL-1β were significantly increased in the model group, along with significantly suppressed autophagy, whereas rapamycin could reverse these effects which involved in the mTOR/ULK1/ATG13 signaling pathway. In conclusion, our results suggested that rapamycin could ameliorate hormone imbalance-induced CNP by activating autophagy.
研究领域:
药理学
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泌尿学
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分子生物学
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炎症
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DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2026
·
IF 8.7
Lin Yang,Yan Cheng,Xinhui Zheng,Tianqi Wang,Xiaolei Zhang,Dandan He,Jitian Guan,Yue Chen,Yuanyuan Huang,Baodong Chen,Rikang Wang,Peng Liu,Renhua Wu
Background Ischemic stroke (IS) management is challenged by low drug delivery efficiency and limitations in current imaging modalities. We aimed to assemble rapamycin (RAPA), indocyanine green (ICG), epigallocatechin-3-gallate (EGCG), and Gd3+ as neuroprotective drugs, near-infrared fluorescence (NIRF) imaging agents, biomimetic coatings, and MRI agents, respectively, into a carrier-free, dual-modal imaging-guided theranostic nanoplatform (IREGd NPs) for the integrated diagnosis and therapy of IS.Methods The physicochemical properties, cytotoxicity, drug release characteristics, and cellular uptake of IREGd NPs were characterized. Therapeutic efficacy was evaluated in vitro using oxygen-glucose deprivation/reoxygenation (OGD/R) models of cell injury and in vivo in a transient middle cerebral artery occlusion (tMCAO) rat model. Outcomes included sensorimotor function, cerebral infarct volume, brain edema, neuronal apoptosis, neuroinflammation, oxidative stress, and biodistribution. The bimodal imaging properties were verified in vitro and in vivo.Results IREGd NPs demonstrated good dispersibility and stability, with a RAPA loading efficiency of 65.9 wt%, enabling enhanced MRI and NIRF imaging capabilities with a longitudinal relaxation rate of 40.18 mM−1·s−1 for precise visualization of the ischemic region and drug biodistribution. In vitro experiments confirmed effective cellular uptake and superior neuroprotective effects in OGD/R-treated cells compared with RAPA or EGCG alone. Finally, in vivo experiments in rats with tMCAO confirmed that IREGd NPs passively accumulated in the ischemic hemisphere, enabling accurate bimodal imaging and exerting neuroprotective effects, as evidenced by improved sensorimotor function, reduced cerebral infarct volume and brain edema, decreased neuronal apoptosis, and attenuated neuroinflammation and oxidative stress, outperforming individual RAPA or EGCG treatment. Histology revealed no systemic toxicity.Conclusion IREGd NPs efficiently deliver RAPA, and the neuroprotective effects are exerted by RAPA in combination with EGCG. Dual-modal imaging enables precise visualization of the ischemic region and drug biodistribution. These results suggest the translational potential of the biomimetic nanotheranostic platform for the treatment of IS.
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高影响因子
JOURNAL OF MATERIALS SCIENCE-MATERIALS IN MEDICINE
·
2026
·
IF 4.7
Hu Yuan,Wei Lijuan,Yang Haijun,Sun Jianhong,Li Donglei,Liu Qian
Wet age-related macular degeneration (Wet AMD) is a major cause of vision loss and has been linked to abnormal choroidal neovascularization (CNV). Current therapies require frequent intravitreal injections, which leads to poor patient adherence. Herein, this study was designed to investigate rapamycin-loaded chitosan-coated poly(lactic-co-glycolic acid) nanoparticles, which represent a sustained-release drug delivery system for wet AMD. The Rap@CS/PLGA NPs were synthesized using emulsion solvent evaporation, followed by coating with chitosan. The obtained Rap@CS/PLGA NPs exhibited a size of 265.9 ± 6.30 nm and encapsulation efficiency (EE) of 60.30 ± 1.20%. The drug release profile showed a biphasic pattern with reduced initial burst release (6 ± 0.6%) followed by sustained release (46 ± 4.1%) over 72 h, which indicates improved delivery control. In vitro cytotoxicity on ARPE and HUVEC cells showed minimal toxicity, with more than 85% viability at dosages up to 100 μg/mL. In vivo anti-angiogenic assays using the chick chorioallantoic membrane (CAM) model showed that the Rap@CS/PLGA group (13 ± 3 vessels) significantly reduced the vessel formation vs Rap (26 ± 2 vessels), confirming superior anti-angiogenic effects. Moreover, the laser-induced CNV mouse model, Rap@CS/PLGA NPs, significantly reduced levels of inflammatory cytokine (TNF-α and IL-6) and restored antioxidant enzyme (SOD, CAT). This showed that protection against oxidative stress in CNV-affected tissue promotes angiogenic gene expression (VEGFA, CCL2), while preserving retinal structure. These findings propose that Rap@CS/PLGA NPs can effectively and control drug delivery for wet-AMD with long-lasting efficacy. Graphical
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高影响因子
PHYTOTHERAPY RESEARCH
·
2023
·Vol. 37
·期 4
·1377-1390
·
IF 7.2
Xueyao Yang,Xin Zhao,Yanfei Liu,Yue Liu,Libo Liu,Ziyu An,Haoran Xing,Jinfan Tian,Xiantao Song
Studies demonstrated that Ginkgo biloba extract (GBE) played a cardioprotective role in diabetic conditions. Impaired autophagy is one of the mechanisms underlying diabetic cardiomyopathy (DCM). The effect of GBE on autophagy has been observed in several diseases; however, whether GBE can ameliorate DCM by regulating autophagy remains unclear. Here, we investigated the effect of GBE on DCM and the potential mechanisms regarding autophagy using a streptozotocin (STZ)-induced diabetic rat model and a high-glucose (HG)-stimulated H9C2 cell model. We demonstrated that GBE attenuated metabolic disturbances, improved cardiac function, and reduced myocardial pathological changes in diabetic rats. Impaired autophagy as well as dysregulation of the adenosine monophosphate-activated protein kinase/ mammalian target of the rapamycin (AMPK/mTOR) signaling pathway were observed in diabetic hearts, as evidenced by the reduced conversion of LC3B-I to LC3B-II along with excessive p62 accumulation, decreased AMPK phosphorylation, and increased mTOR phosphorylation, which could be reversed by GBE treatment. In vitro , GBE reduced the apoptosis induced by HG in H9C2 cells by activating AMPK and inhibiting mTOR to restore autophagy. However, this effect was inhibited by the AMPK inhibitor Compound C. In conclusion, the ameliorative effect of GBE on DCM might be dependent on the restoration of autophagy through modulation of the AMPK/mTOR pathway.
研究领域:
药理学
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心脏病学
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糖尿病
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CHROMATOGRAPHY A
·
2015
·
IF 4.169
Yanmei Zhang,Feng Li,Mingxia Li,Jingwu Kang
In this study, capillary electrophoresis (CE) combined with HPLC–MS/MS were used as a powerful platform for screening of inhibitors of mammalian target of rapamycin (mTOR) in natural product extracts. The screening system has been established by using 5-carboxyfluorescein labeled substrate peptide F-4EBP1, a known mTOR inhibitor AZD8055, and a small chemical library consisted of 18 natural product extracts. Biochemical screening of natural product extracts was performed by CE with laser induced fluorescence detection. The CE separation allowed a quantitative measurement of the phosphorylated product, hence the quantitation of enzymatic inhibition as well as inhibition kinetics. The hits are readily identified as long as the peak area of the phosphorylated product is reduced in comparison with the negative control. Subsequent assay-guided isolation of the active natural product extract was performed with HPLC–MS/MS to track the particular active components. The structures of the identified active components were elucidated by the molecular ions and fragmentaion information provided by MS/MS analysis. The CE-based assay method only requires minute pure compounds, which can be readily purified by HPLC. Therefore, the combination of CE and HPLC–MS/MS provides a high-throughput platform for screening bioactive compounds from the crude nature extracts. By taking the advantage of the screening system, salvianolic acid A and C in extract of Salvia miltiorrhiza were discovered as the new mTOR inhibitors.
研究领域:
药理学
·
分析化学
·
生物化学
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DOI
PubMed
高影响因子
Bioengineered
·
2022
·
IF 6.832
Meng-Hui Zhang,Jun Liu
Liver hepatocellular carcinoma (LIHC) is the most common type, comprising 75–85% of all liver malignancies. We investigated the roles of cleavage stimulation factor 2 (CSTF2) in LIHC and explored the underlying mechanisms. CSTF2 expression and its association with LIHC patient survival probability were analyzed with The Cancer Genome Atlas. CSTF2 expression in LIHC cells was assessed using western blot and quantitative real-time PCR. Alterations in CSTF2 expression were induced by cell transfection. Cell colony formation, apoptosis, proliferation, invasion, and migration were assessed using colony formation, flow cytometry, 5-ethynyl-2ʹ-deoxyuridine, and transwell assays. Pathway enrichment analysis was performed using gene set enrichment analysis (GSEA). The expression of apoptosis-, metastasis-, and pathway-associated factors was determined via western blot. The pathway rescue assay was further performed using 740Y-P or Wortmannin. CSTF2 upregulation was observed in LIHC tissues and cells. Patients with high CSTF2 expression had a lower probability of overall survival. CSTF2 overexpression enhanced colony formation, proliferation, invasion and migration, while repressing apoptosis in LIHC cells. GSEA revealed that CSTF2 was mainly enriched in the phosphatidylinositol 3′-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. Western blot analysis proved that CSTF2 overexpression activated this pathway. CSTF2 knockdown yielded the opposite effects. 740Y-P, a PI3K activator, reversed the CSTF2 knockdown-triggered effects on cell proliferation, apoptosis, invasion, and migration. Moreover, Wortmannin, a PI3K inhibitor, also reversed the CSTF2 overexpression-induced effects on cell proliferation, apoptosis, invasion, and migration. These results indicated that CSTF2 overexpression might exacerbate the malignant phenotypes of LIHC cells via activation of PI3K/AKT/mTOR pathway.
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DOI
PubMed
高影响因子
NEUROREPORT
·
2021
·Vol. 32
·期 11
·925-935
·
IF 1.837
Hu Jijun,Chen Xueling,Cheng Jie,Kong Fanli,Xia Hui,Wu Jiang
Unveiling the etiology and the underlying mechanism of neuropathic pain, a poorly treated disease, is essential for the development of effective therapies. This study aimed to explore the role of mammalian target of rapamycin (mTOR) signaling in autophagy-mediated neuropathic pain.
We established a spared nerve injury (SNI) model in adult male SD rats by ligating the common peroneal nerve and tibial, with the distal end cutoff. The paw withdrawal threshold (PWT) and C/A-fiber evoked field potentials were determined by electrophysiologic tests at day 0 (before operation),
day 7 and day 14 postoperation, and SNI significantly increased field potentials (P < 0.05). Immunohistochemistry and western blots using spinal cord tissues showed that the expressions of GluR1, GluR2, Beclin-1, p62, mTOR and 4EBP1 were significantly
increased after SNI (all P < 0.05), whereas the expressions of LC3 and LAMP2 were significantly decreased after SNI (all P < 0.05). Rapamycin efficiently counteracted the effect of SNI and restored the phenotypes to the level comparable to the
sham control. In conclusion, rapamycin inhibits C/A-fiber-mediated long-term potentiation in the SNI rat model of neuropathic pain, which might be mediated by activation of autophagy signaling and downregulation of GluRs expression.
研究领域:
神经科学
·
药理学
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疼痛研究
·
自噬
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Yanhui Wang,Huayu Fu,Bangqi Huang,Ziyang Liang,Yijun Shen,Yulan Wang,Jun Wu,Yi Zhao
The kidney’s abundant mitochondrial content and substantial oxygen requirements make it particularly vulnerable to a series of detrimental events following ischemia/reperfusion (I/R). These events encompass oxidative stress, mitochondrial impairment, depletion of adenosine triphosphate (ATP), and inflammation, cumulatively leading to acute kidney injury (AKI). Currently, no approved therapy beyond supportive care is available for AKI. While numerous studies have focused on neutralizing pre-existing reactive oxygen species (ROS) to mitigate AKI, insufficient attention has been paid to addressing the root causes of ROS. Here, we prepared Rapamycin (Rapa)-loaded hollow mesoporous Prussian blue nanoparticles (HMPB-Rapa) and grafted injured renal-targeted hyaluronic acid (HA) onto HMPB-Rapa (HA-HMPB-Rapa), which effectively scavenge pre-existing ROS and the source (massive damaged mitochondria) through the dual function of HMPB carrier and Rapa, thus preventing the further burst of ROS. In the I/R-induced AKI rat model, a single-dose of HA-HMPB-Rapa 6 h after I/R injury effectively inhibited oxidative stress and inflammation, protected renal cells from apoptotic damage, as well as ultimately restored renal function, and attenuated pathological changes. Mechanistically, HA-HMPB-Rapa cleared damaged mitochondria by activating the pro-mitophagy signaling pathway (PINK-1/Parkin-P62-LC3), cutting off the conduction in the intrinsic apoptotic pathway mediated by the Bax-Cyt-c-Cleaved Casp-3 signaling axis, and reduced the expression of renal tubular marker kidney injury molecule-1. HA-HMPB-Rapa represents an exciting new avenue for the treatment of diseases related to I/R-induced injury.
研究领域:
纳米技术
·
药学
·
肾病学
·
分子生物学
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治疗学
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产品关联
DOI
高影响因子
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