Correction: A ROS-scavenging multifunctional nanoparticle for combinational therapy of diabetic nephropathy.

Correction for 'A ROS-scavenging multifunctional nanoparticle for combinational therapy of diabetic nephropathy' by Yuna Tong et al., Nanoscale, 2020, DOI: .

Maleimide-Functionalized Liposomes for Tumor Targeting via In Situ Binding of Endogenous Albumin.

Albumin, the most abundant protein in plasma, has been widely used in drug delivery studies. Here, we developed maleimide-functionalized liposomes (Mal-Lip) that can bind to endogenous albumin to improve the tumor targeting efficiency of liposomes. Transmission electron microscopy and gel electrophoresis studies showed that albumin can bind to Mal-Lip due to the chemical coupling of the albumin thiol groups with the maleimide group. Both conventional liposomes and Mal-Lip showed minimal cytotoxicity within the tested range of lipid concentrations, indicating that the maleimide functionality did not increase the toxicity of liposomes to various cells. Mal-Lip was taken up by 4T1 cells to a greater extent than conventional liposomes, and Mal-Lip accumulated in 4T1 tumors in mice more than conventional liposomes after intravenous injection. These results suggest that the maleimide group can improve the tumor targeting efficiency of liposomes in vivo by binding to endogenous albumin in situ. However, the maleimide group also enhanced the uptake of Mal-Lip by Raw264.7 cells and shortened their time in circulation, indicating that further studies should be performed to prevent elimination of Mal-Lip by the immune system.

A ROS-scavenging multifunctional nanoparticle for combinational therapy of diabetic nephropathy.

Although synergistic therapy for diabetes mellitus has displayed significant promise for the effective treatment of diabetic nephropathy (DN), developing a simple and effective strategy to construct multifunctional nanoparticles is still a huge challenge. Moreover, the complicated pathological mechanism of DN involves various pathway dysfunctions that limit the effectiveness of a single therapeutic approach. Herein, hollow mesoporous silica nanocomposite (HMSN) particles doped with trace cerium oxide that exhibit renoprotective activity have been designed, which not only have the ability to prevent ROS-associated DN pathogenesis but also have high drug loading capacity. Interestingly, the metformin (MET) loaded multifunctional nanoparticles (MET-HMSN-CeO2) with a special size exhibited significantly increased kidney accumulation over free MET. Moreover, the cyclic conversion between Ce3+ and Ce4+ of mixed-valence ceria in our system provides the possibility for long-term ROS-scavenging activity to achieve the antioxidative effect. Then, we investigated the renoprotective effect of these nanoparticles on the streptozotocin (STZ)-induced renal injury rat model and high-glucose induced NRK-52E cell damage model. As a result, our findings demonstrated that the nanoparticles could alleviate the DN symptoms by mitigating oxidative stress, suppressing cellular apoptosis and protecting renal injury both in vitro and in vivo. The kidney deficits of DN are significantly improved after treatment with MET-HMSN-CeO2. Overall, our studies indicated that the MET-HMSN-CeO2 multifunctional nanoparticles would be a promising therapeutic candidate for DN.

Familial Exudative Vitreoretinopathy-Related Disease-Causing Genes and Norrin/ß-Catenin Signal Pathway: Structure, Function, and Mutation Spectrums.

Familial exudative vitreoretinopathy (FEVR) is a hereditary ocular disorder characterized by incomplete vascularization/abnormality of peripheral retina. Four of the identified disease-causing genes of FEVR were NDP, FZD4, LRP5, and TSPAN12, the protein coded by which were the components of the Norrin/ß-catenin signal pathway. In this review, we summarized and discussed the spectrum of mutations involving these four genes. By the end of 2017, the number of FEVR causing mutations reported for NDP, FZD4, LRP5, and TSPAN12 was, respectively, 26, 121, 58, and 40. Three most frequently reported mutations were c. 362G > A (p.R121Q) of NDP, c. 313A > G (p.M105V), and c.1282_1285delGACA (p.D428SfsX2) of FZD4. Mutations have a tendency to cluster in some "hotspots" domains which may be responsible for protein interactions.

Ethyl Vanillin Protects against Kidney Injury in Diabetic Nephropathy by Inhibiting Oxidative Stress and Apoptosis.

Diabetes-induced oxidative stress and apoptosis is regarded as a critical role in the pathogenesis of diabetic nephropathy (DN). Treating diabetes-induced kidney damage and renal dysfunction has been thought a promising therapeutic option to attenuate the development and progression of DN. In this study, we investigated the renoprotective effect of ethyl vanillin (EVA), an active analogue of vanillin isolated from vanilla beans, on streptozotocin- (STZ-) induced rat renal injury model and high glucose-induced NRK-52E cell model. The EVA treatment could strongly improve the deterioration of renal function and kidney cell apoptosis in vivo and in vitro. Moreover, treating with EVA significantly decreased the level of MDA and reactive oxygen species (ROS) and stabilized antioxidant enzyme system in response to oxidative stress by enhancing the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in vivo and in vitro. Furthermore, EVA also markedly suppressed cleaved caspase-3, Bax, and nuclear transcription factor erythroid 2-related factor (Nrf2) expression in STZ-induced rats. Therefore, these results of our investigation provided that EVA might protect against kidney injury in DN by inhibiting oxidative stress and cell apoptosis.

Protective effect of ethyl vanillin against Aß-induced neurotoxicity in PC12 cells via the reduction of oxidative stress and apoptosis.

Increased aggregation of ß-amyloid (Aß) peptides induces oxidative stress, which is considered a major contributor in the development of Alzheimer's disease (AD). Prevention of Aß-induced neurotoxicity is proposed as a possible modality for treatment of AD. The present study aimed to elucidate possible effects of ethyl vanillin (EVA), an analog of vanillin isolated from vanilla beans, on the Aß1-42-induced oxidative injury in PC12 cells. EVA restrained the decrease in PC12 cell viability and apoptosis induction caused by treatment with Aß1-42. In addition, EVA markedly alleviated intracellular lipid peroxidation as demonstrated by malondialdehyde levels and reactive oxygen species production in Aß1-42-treated PC12 cells. In addition, the reduction in the activity levels of the antioxidative enzymes superoxide dismutase, catalase and glutathione peroxidase was detected in Aß1-42-treated PC12 cells. This effect was partially reversed by treatment with EVA. Furthermore, the results indicated that EVA attenuated Aß1-42-induced caspase-3 activation and the increase noted in the apoptosis regulator Bcl-2/apoptosis regulator Bax ratio of PC12 cells. These results indicated that EVA could be used as an efficient and novel agent for the prevention of neurodegenerative diseases via inhibition of oxidative stress and cell apoptosis.

Sucrose Acetate Isobutyrate as an In situ Forming Implant for Sustained Release of Local Anesthetics.

OBJECTIVE: In this study, an injectable Sucrose Acetate Isobutyrate (SAIB) drug delivery system (SADS) was designed and fabricated for the sustained release of Ropivacaine (RP) to prolong the duration of local anesthesia. METHODS: By mixing SAIB, RP, and N-methyl-2-pyrrolidone, the SADS was prepared in a sol state with low viscosity before injection. After subcutaneous injection, the pre-gel solution underwent gelation in situ to form a drug-released depot. RESULT: The in vitro release profiles and in vivo pharmacokinetic analysis indicated that RP-SADS had suitable controlled release properties. Particularly, the RP-SADS significantly reduced the initial burst release after subcutaneous injection in rats. CONCLUSION: In a pharmacodynamic analysis of rats, the duration of nerve blockade was prolonged by over 3-fold for the RP-SADS formulation compared to RP solution. Additionally, RP-SADS showed good biocompatibility in vitro and in vivo. Thus, the SADS-based depot technology is a safe drug delivery strategy for the sustained release of local anesthetics with long-term analgesia effects.

Shikonin Protects PC12 Cells Against ß-amyloid Peptide-Induced Cell Injury Through Antioxidant and Antiapoptotic Activities.

Excessive accumulation of ß-amyloid (Aß) is thought to be a major causative factor in the pathogenesis of Alzheimer's disease (AD). Pretreating Aß-induced neurotoxicity is a potential therapeutic approach to ameliorate the progression and development of AD. The present study aimed to investigate the neuroprotective effect of shikonin, a naphthoquinone pigment isolated from the roots of the traditional Chinese herb Lithospermum erythrorhizon, on Aß1-42-treated neurotoxicity in PC12 cells. Pretreating cells with shikonin strongly improved cell viability, decreased the malondialdehyde and reactive oxygen species (ROS) content, and stabilized the mitochondrial membrane potential in Aß1-42-induced PC12 cells. In addition, shikonin strongly improved the response of the antioxidant system to ROS by increasing the levels of superoxidedismutase, catalase and glutathione peroxidase. Furthermore, shikonin has the ability to reduce proapoptotic signaling by reducing the activity of caspase-3 and moderating the ratio of Bcl-2/Bax. These observations indicate that shikonin holds great potential for neuroprotection via inhibition of oxidative stress and cell apoptosis.

The protective effect of shikonin on renal tubular epithelial cell injury induced by high glucose.

Hyperglycemia-induced oxidative stress is thought to play a critical role in the pathogenesis of diabetic nephropathy (DN). Treating high-glucose (HG)-induced proximal tubule injury has become a patential therapeutic option to attenuate the onset and progression of DN. The present study aimed to investigate the renoprotective effect of shikonin, the chief active compound extracted from the roots of the traditional Chinese herb Lithospermum erythrorhizon, on HG-induced cytotoxicity in NRK-52E cells. Treating cells with HG significantly reduce cell viability while also significantly increasing content of reactive oxygen species (ROS). Treating the cells with shikonin improved these changes induced by HG. Shikonin strongly stabilized mitochondrial membrane potential in HG-induced NRK-52E cells. In addition, treatment with shikonin upregulated antioxidant system in response to ROS by increasing levels of SOD and CAT. Furthermore, shikonin also strongly decreased the levels of activated caspase-3, Bax and p-GSK-3ß while increased the p-AKT level. These findings provide that the renoprotective effects of shikonin against HG-induced cytotoxicity in NRK-52E cells may be mediated in inhibiting oxidative stress through activating of the AKT signalling pathway.

Lactoferrin functionalized PEG-PLGA nanoparticles of shikonin for brain targeting therapy of glioma.

Shikonin (SHK) is a highly liposoluble naphthoquinone pigment has recently been investigated as a potential antiglioma agent. However, shikonin shows several limitations like poor aqueous solubility, short half-life and non-selective biodistribution. Herein, we have developed a nanoparticles (NPs) prepared from PEG-PLGA using an emulsion solvent evaporation method. Nanoparticle surfaces were modified by coating with lactoferrin (Lf) to improve the crossing of the blood brain barrier and targeting of glioma cells via receptor-mediated path-ways. X-ray powder diffraction and differential scanning calorimetry analysis revealed the amorphous nature of SHK encapsulated within the NPs. Moreover, the drug-loaded NPs exhibit narrow size distribution and high encapsulation efficiency. The in vitro release experiments of the NPs exhibited sustained release for more than 72h. When compared to free SHK and SHK/NPs, in vivo study demonstrated higher brain concentration of SHK, indicating a significant effect of Lf coated NPs on brain targeting. Accordingly, these findings provide evidence for the potential of Lf-modified NPs as a targeted delivery system for brain glioblastomas treatment.

Up-Regulation of MicroRNA-133a Inhibits the MEK/ERK Signaling Pathway to Promote Cell Apoptosis and Enhance Radio-Sensitivity by Targeting EGFR in Esophageal Cancer In Vivo and In Vitro.

This study aims to explore how microRNA-133a (miR-133a) affects cell apoptosis and radio-sensitivity by targeting EGFR via regulating MEK/ERK pathway in esophageal cancer (EC). A total of 358 EC patients were selected and assigned into the resistant and sensitive groups. Human EC KYSE 150 cell line was assigned into the blank, negative control (NC), miR-133a mimic, miR-133a inhibitors, si-EGFR, miR-133a inhibitors + si-EGFR groups after transfection. MiR-133a and EGFR mRNA expressions were detected by qRT-PCR and EGFR, MEK/ERK pathway-related protein expressions were detected by Western blotting. The radio-sensitivity and cell apoptosis were testified by clone formation and flow cytometry. MiR-133a was up-regulated but EGFR was down-regulated in the sensitive group than in the resistant group. Compared with the blank and NC groups, the miR-133a mimic and si-EGFR groups exhibited increased cell apoptosis rate but decreased EGFR, p-MEK1/2, and p-ERK1/2 protein expressions; while opposite trend was observed in the miR-133a inhibitors group. Compared with the miR-133a inhibitors group, the miR-133a inhibitors + si-EGFR group presented reduced cell survival rate, EGFR, p-MEK1/2, and p-ERK1/2 protein expressions but increased cell apoptosis rate. These results indicated that miR-133a could inhibit the MEK/ERK pathway to promote cell apoptosis and enhance radio-sensitivity by targeting EGFR in EC. J. Cell. Biochem. 118: 2625-2634, 2017. © 2017 Wiley Periodicals, Inc.

Ischemia-reperfusion induces renal tubule pyroptosis via the CHOP-caspase-11 pathway.

The apoptotic or necrotic death of renal tubule epithelial cells is the main pathogenesis of renal ischemia-reperfusion-induced acute kidney injury (AKI). Pyroptosis is a programmed cell death pathway that depends on the activation of the caspase cascade and IL-1 cytokine family members. However, the role of pyroptosis in AKI induced by ischemia-reperfusion remains unclear. In this study, we found that the levels of the pyroptosis-related proteins, including caspase-1, caspase-11, and IL-1ß, were significantly increased after 6 h of renal ischemia-reperfusion injury (IRI) and peaked at 12 h after IRI. Enhanced pyroptosis was accompanied by elevated renal structural and functional injury. Similarly, hypoxia-reoxygenation injury (HRI) also induced pyroptosis in renal tubule epithelial NRK-52E cells, which was characterized by increased pore formation and elevated lactate dehydrogenase release. In addition, obvious upregulation of the endoplasmic reticulum (ER) stress biomarkers glucose-regulated protein 78 and C/EBP homologous protein (CHOP) preceded the incidence of pyroptosis in cells treated with IRI or HRI. Pretreatment with a low dose of tunicamycin, an inducer of ER stress, relieved IRI-induced pyroptosis and renal tissue injury. Silencing of CHOP by small interfering RNA significantly decreased HRI-induced pyroptosis of NRK-52E cells, as evidenced by reduced caspase-11 activity and IL-1ß generation. Therefore, we conclude that pyroptosis of renal tubule epithelial cells is a key event during IRI and that CHOP-caspase-11 triggered by overactivated ER stress may be an essential pathway involved in pyroptosis.