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Glioblastoma multiforme (GBM) is a highly lethal and aggressive tumor of the brain that carries a poor prognosis. Temozolomide (TMZ) has been widely used as a first-line treatment for GBM. However, poor brain targeting, side effects, and drug resistance limit its application for the treatment of GBM. We designed a Temozolomide-conjugated gold nanoparticle functionalized with an antibody against the ephrin type-A receptor 3 (anti-EphA3-TMZ@GNPs) for targeted GBM therapy via intranasal administration. The system can bypass the blood-brain barrier and target active glioma cells to improve the glioma targeting of TMZ and enhance the treatment efficacy, while reducing the peripheral toxicity and drug resistance. The prepared anti-EphA3-TMZ@GNPs were 46.12 ± 2.0 nm and suitable for intranasal administration, which demonstrated high safety to the nasal mucosa in a toxicity assay. In vitro studies showed that anti-EphA3-TMZ@GNPs exhibited significantly enhanced cellular uptake and toxicity, and a higher cell apoptosis ratio has been seen compared with that of TMZ (54.9 and 14.1%, respectively) toward glioma cells (C6). The results from experiments on TMZ-resistant glioma cells (T98G) demonstrated that the IC50 of anti-EphA3-TMZ@GNPs (64.06 ± 0.16 μM) was 18.5-fold lower than that of TMZ. In addition, Western blot analysis also revealed that anti-EphA3-TMZ@GNPs effectively down-modulated expression of O6-methylguanine-DNA methyltransferase and increased chemosensitivity of T98G to TMZ. The antiglioma efficacy in vivo was investigated in orthotopic glioma-bearing rats, and the results demonstrated that the anti-EphA3-TMZ@GNPs prolonged the median survival time to 42 days and increased tumor-cell apoptosis dramatically compared with TMZ. In conclusion, anti-EphA3-TMZ@GNPs could serve as an intranasal drug delivery system for efficacious treatment of GBM.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver-related morbidity and mortality disease in the world. However, no effective pharmacological treatment for NAFLD has been found. In this study, we used a high fat diet (HFD)-induced NAFLD model to investigate hepatoprotective effect of apigenin (API) against NAFLD and further explored its potential mechanism. Our results demonstrated that gavage administration of API could mitigate HFD-induced liver injury, enhance insulin sensitivity and markedly reduce lipid accumulation in HFD-fed mice livers. In addition, histological analysis showed that hepatic steatosis and macrophages recruitment in the API treatment group were recovered compared with mice fed with HFD alone. Importantly, API could reverse the HFD-induced activation of the NLRP3 inflammasome, further reduced inflammatory cytokines IL-1β and IL-18 release, accompanied with the inhibition of xanthine oxidase (XO) activity and the reduction of uric acid and reactive oxygen species (ROS) production. The pharmacological role of API was further confirmed using free fatty acid (FFA) induced cell NAFLD model. Taking together, our results demonstrated that API could protect against HFD-induced NAFLD by ameliorating hepatic lipid accumulation and inflammation. These protective effects may be partially attributed to the regulation of XO by API, which further modulated NLRP3 inflammasome activation and inflammatory cytokines IL-1β and IL-18 release. Therefore API is a potential therapeutic agent for the prevention of NAFLD.

Increasing evidence indicates that the NOD-like receptors (NLRs) family may act as critical back-up defenses and provide synergistic responses when confronted with persistent danger. However, the precise regulatory mechanism of NLRs and the contribution of NLRs to cancer are still unknown. In our previous study, we found that estrogen receptors (ERs) have a close connection with NLRs in the inflammatory response. Here, ERs are first identified as NLRs transcription regulation factors, both regulate NLRs expression and promote inflammasome co-localization. Furthermore, we identified that NLRP3 was differentially expressed in colon normal and cancer cells, selective ERα antagonist could significantly decrease pro-inflammatory cytokines expression, suppress proliferation and promote apoptosis by inhibited NLRP3 expression and inflammasome activity. In short, the research demonstrates that ERs participate in the NLR-associated signaling pathway in cancer by directly regulating NLRs. Our results provide novel insight into ERs as therapeutic targets in NLR-related inflammation and cancer.

Liver xenotransplantation (LXT) is greatly impeded by severe thrombocytopenia, anemia, and coagulopathy. Hepatic phagocytic cells are thought to play an important role in LXT-induced thrombocytopenia and anemia. In this study, we investigated whether the lack of recipient CD47-donor SIRPα interaction, which is known to induce xenograft rejection by macrophages, exacerbates platelet and RBC depletion following LXT. We first addressed this question in the absence of anti-donor immune responses using a syngeneic mouse liver transplantation (LT) model. Neither wild-type (WT) nor CD47KO B6 mice developed thrombocytopenia following LT from WT B6 donors. Although a moderate decline in RBCs was detected following LT, there was no significant difference in RBC counts between WT and CD47KO recipients. Because mouse CD47 is cross-reactive with rat SIRPα, we then compared thrombocytopenia and anemia between WT and CD47KO mice following rat LXT. Unlike syngeneic mouse LT, significant thrombocytopenia and anemia were detected following rat LXT. However, the severities of both platelet and RBC depletions were comparable between WT and CD47KO recipients. Furthermore, WT and CD47KO recipients showed a similar extent of early platelet activation. Our results indicate that CD47-SIRPα signaling does not significantly affect the loss of platelets or RBCs following LXT, suggesting that the limited cross-reactivity between recipient CD47 and donor SIRPα is not a significant risk factor for LXT-induced thrombocytopenia and anemia.

Affine registration can fit the non-rigid deformation of slices effectively, and it is widely used in volume reconstruction of biological tissue. But most of the existing affine registration methods are registered in a given sequence, which results in the accumulation of errors. In this paper, a global optimized affine registration method is proposed, which can be used in volume reconstruction. To eliminate the cumulative error, the affine transformation of all images is estimated simultaneously based on an energy function. A soft penalty on affine transformation is added to restrict the shearing of images. Experiments show that our method provides a more reliable registration result compared with sequential affine registration. It can solve the problems caused by the accumulation of errors. The registration result fits the deformation of slices well and preserves the rigidity of images.

Key Clinical Message Twelve days after birth, the child was admitted to hospital because of “poor response, lethargy, and poor appetite for 6 days” and developed into coma immediately. The ventilator is required. The urine had significant maple syrup odor. After different diagnosis, she was diagnosed with classical maple syrup urine disease.

Purpose The present study analyzed the appearances of optical coherence tomography angiography (OCTA) in patients with central serous chorioretinopathy (CSC) based on fluorescein angiography (FA) and indocyanine green angiography (ICGA). Method In the current case series, 54 eyes of 50 patients diagnosed as CSC were evaluated retrospectively. OCTA, FA, and ICGA were performed on each patient. Two trained observers examined the OCTA images independently to confirm and compare the choriocapillary appearance with that on FA/ICGA. Also, the leakage of vessels on FA, perfusion of choroidal blood flow on ICGA, blood flow density, and vascular morphology on OCTA, as well as, the effect of serous retinal detachment (SRD) on imaging were observed. Furthermore, the image findings of contralateral eyes were included. Results 47/54 eyes (corresponding to 43 patients in 50 patients) were finally diagnosed with CSC that presented a leakage on FA and dilated vessels on ICGA, and the corresponding areas could be recognized on OCTA. However, in some of the cases (15 eyes, 31.9%), a portion of the leakage lesion on FA did not overlap completely with that on OCTA. On the OCTA B-scan, six eyes did not show a choriocapillary flow signal under subretinal fluid (SRF) with a median SRD height of 485 µm, despite the dilated vessels on ICGA. Approximately, 21 contralateral eyes without SRD and leakage presented dilated vessels on ICGA; however, only 13 eyes could be recognized on OCTA. In addition, seven eyes presented CSC on FA/ICGA but manifested explicit abnormal vascularization beneath the retinal pigment epithelium (RPE) on OCTA. Conclusion FA/ICGA remains the gold standard for the diagnosis of CSC and cannot be completely replaced by OCTA. However, in some cases displaying hot-spots CNV, OCTA can contribute toward a definite diagnosis. The SRD height may exert a shielding effect on the choriocapillary flow signals on OCTA. Lasers Surg. Med. 50:987-993, 2018. © 2018 Wiley Periodicals, Inc.

In this work, we developed an unexplored enzyme-responsive core-shell nanogel via the assembly of hydrogelators at the surface of silicon nanoparticles. The immobilized carboxylesterase at the surface of silicon nanoparticles can catalyse precursors into hydrogelators, self-assembling around the surface of silicon nanoparticles owing to its surface confinement effect. These novel phenomena can be confirmed by observation of their morphology and increased diameters through scanning electron microscopy, transmission electron microscopy and dynamic light scattering. Moreover, these resulting core-shell nanogels can achieve controlled growth of the gel layer by means of changing the concentrations of precursors. Because of their good biocompatibility, these nanogels can realize applications in enzyme-specific drug delivery as nanocarriers.

The incidence of congenital hypothyroidism (CH) in newborn infants ranges from 1 in 3,000 to 1 in 4,000. Previous studies have indicated the neuroprotective role of microRNA (miR)-124-3p, however the expression and role of miR-124-3p in CH remain unclear. Therefore, the present study was performed to investigate the role and precise molecular mechanism of miR-124-3p in CH. Propylthiouracil (50 mg/day) was injected into the stomach of pregnant rats from gestational day 15 until parturition in order to establish a thyroid hypofunction model. Newborn rats were divided into the following four groups: The control group; the thyroid hypofunction group; the miR-124-3p mimic group; and the miR-124-3p negative control group. Reverse transcription-quantitative polymerase chain reaction indicated that miR-124-3p was significantly decreased in the hippocampus of the thyroid hypofunction group compared with the control group. Bioinformatics software was used to predict mRNA targets recognized by miR-124-3p and the programmed cell death protein 6 (PDCD6) 3′ untranslated region (UTR) was demonstrated to exhibit the seed sequence of miR-124-3p. The interaction between miRNA-124-3p and PDCD6 was then verified using a dual-luciferase reporter assay system. PDCD6 expression was significantly increased in the hippocampus of rats with CH compared with the control group. Flow cytometry was performed to investigate the effects of miR-124-3p on neuronal cell apoptosis and the results indicated that the apoptosis rate in the thyroid hypofunction group was significantly increased compared with the control group; this increase was reversed by transfection with miR-124-3p mimics. Western blot analysis was used to detect the levels of cleaved poly [ADP-ribose] polymerase (PARP), full-length PARP, caspase-3, B cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax) proteins. The results indicated that the expression of cleaved PARP, caspase-3 and Bax protein were significantly increased and the expression of full-length PARP and Bcl-2 protein was significantly decreased compared with the control group. These effects were reversed by miRNA-124-3p mimic transfection. Taken together, the results of the present study demonstrate that miRNA-124-3p serves a protective role in CH via targeting PDCD6.

The accumulation of starch in cereal endosperm is a key process that determines crop yield and quality. Research has reported that sucrose and abscisic acid (ABA) synergistically regulate the synthesis of crop starch. However, little is known about the molecular mechanisms behind this synergistic effect. In this study, the effect of sucrose and ABA on starch synthesis in maize endosperm was investigated. The starch content, the ADP-Glc pyrophosphorylase (AGPase) concentration, and the expression of AGPase-encoding genes were found to be enhanced slightly by sucrose or ABA alone, but were elevated significantly by the co-treatment of sucrose and ABA. Truncation analysis of the Bt2 promoter via transient expression in maize endosperm showed that the promoter region (-370/-186) is involved in sucrose response, and that an adjacent region (-186/-43) responds to ABA. The synergistic induction of sucrose and ABA on Bt2 promoter activity requires interaction with both of these regions. Interestingly, removal of the sucrose-responsive region (-370 to -186) abolishes ABA responsiveness in the Bt2 promoter, even in the presence of ABA-responsive region (-186 to -43). This study provides novel insights into the regulatory mechanisms that underlie the synergistic regulation of starch synthesis and grain filling from sucrose and ABA in cereal endosperm.

Zearalenone (ZEA) can widely contaminate crops and agricultural products. The ingestion of ZEA-contaminated food or feed affects the integrity and functions of the intestines. In this study, we aimed to find the potential protective mechanism against ZEA ingestion. We found that ZEA induced cell death in IPEC-J2 cells. Meanwhile, the cytoprotective autophagy was activated in ZEA-treated cells. Further studies demonstrated that a p38/MAPK inhibitor down-regulated autophagy and increased cell death compared to those of the controls. Furthermore, ZEA could induce the accumulation of ROS, and eliminating ROS with NAC resulted in a decline in cell death, p38/MAPK phosphorylation, and the expression of LC3-II compared to those of ZEA-group. In addition, cytochrome P450 reductase (CYPOR) was significantly increased in ZEA-treated cells compared to that in the controls, and an inhibitor of CYPOR decreased ROS levels and mitigated cell death compared to those of the ZEA-group. More importantly, we found that blocking both p38/MAPK signalling and autophagy could enhance CYPOR expression and elevate ROS levels. Overall, our study indicated that the p38/MAPK pathway could activate protective autophagy in response to the CYPOR-dependent oxidative stress that was induced by ZEA in IPEC-J2 cells.

AGPase catalyzes a key rate-limiting step that converts ATP and Glc-1-p into ADP-glucose and diphosphate in maize starch biosynthesis. Previous studies suggest that AGPase is modulated by redox, thermal and allosteric regulation. However, the phosphorylation of AGPase is unclear in the kernel starch biosynthesis process. Phos-tagTM technology is a novel method using phos-tagTM agarose beads for separation, purification, and detection of phosphorylated proteins. Here we identified phos-tagTM agarose binding proteins from maize endosperm. Results showed a total of 1733 proteins identified from 10,678 distinct peptides. Interestingly, a total of 21 unique peptides for AGPase sub-unit Brittle-2 (Bt2) were identified. Bt2 was demonstrated by immunoblot when enriched maize endosperm protein with phos-tagTM agarose was in different pollination stages. In contrast, Bt2 would lose binding to phos-tagTM when samples were treated with alkaline phosphatase (ALP). Furthermore, Bt2 could be detected by Pro-Q diamond staining specifically for phosphorylated protein. We further identified the phosphorylation sites of Bt2 at Ser10, Thr451, and Thr462 by iTRAQ. In addition, dephosphorylation of Bt2 decreased the activity of AGPase in the native gel assay through ALP treatment. Taking together, these results strongly suggest that the phosphorylation of AGPase may be a new model to regulate AGPase activity in the starch biosynthesis process.

In this study, the mitochondrial damage effect and mechanism of zearalenone (ZEA) in swine small intestine IPEC-J2 cells in vitro were comprehensively characterized. The analyses revealed that ZEA at high doses (8 and 7 μg/mL) can significantly increase P < 0.05 the malondialdehyde levels and decrease antioxidant enzymes activities after 48 h of exposure. Meanwhile, the reactive oxygen species (ROS) accumulation increased in high dose ZEA-treated groups after 2 h treatment, but decreased due to the ROS-induced mitochondrial damage and the caused cell apoptosis after 48 h of high does ZEA treatment. Moreover, the decreasing of mitochondrial membrane potential (MMP; ΔΨ) in high dose ZEA exposure was observed in line with the increasing ROS production in mitochondria. Results suggest that ZEA exposure can induce mitochondrial damage by reducing antioxidant enzyme activities, accumulation of ROS, and decreasing MMP. The mitochondrial damage had a dramatic concentration–effects relationship with ZEA.