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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.

Inspired by the delicate architecture of hyaline articular cartilage, we report on a biomimetic polymer hydrogel that incorporates strong intermolecular hydrogen bonding between urethane–urethane linkages as well as urethane–ester linkages. The resultant hydrogel, containing ≈75% water, can endure a compressive stress up to 56 MPa with a strain of 98%, and exhibit tunable compressive modulus (0.19–1.38 MPa), as well as toughness (3629–28290 J m–2) within a wide range. The tensile strength and elastic modulus reach as high as 0.56 and 5.5 MPa, respectively. The high stiffness and toughness enable the gel to withstand cyclic compressive loadings without fracturing. Moreover, our hydrogel mimics the extracellular matrices of cartilage and bone tissues and provides biochemical and physical cues that support the three-dimensional proliferation of chondrocytes and osteogenic differentiation of preosteoblasts.

Endometritis is a major infectious disease affecting dairy development. MicroRNAs are recognized as critical regulators of the innate immune response. However, the role and mechanism of Bta-miR-24-3p in the development of endometritis are still unclear. This study aimed to investigate the effect of Bta-miR-24-3p on the inflammatory response triggered by lipopolysaccharide (LPS) and to clarify the possible mechanism. LPS-treated bovine endometrial epithelial cells (BEECs) were cultured to investigate the role of Bta-miR-24-3p. The expression levels of Bta-miR-24-3p were downregulated, and galectin-9 (LGALS9) were measured by quantitative real-time polymerase chain reaction. The LPS-induced inflammatory response was assessed by the elevated secretion of inflammatory cytokines measured by using enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction. Activation of nuclear factor-κB (NF-κB) and TLR4 pathway was assessed by Western blot. The interaction between Bta-miR-24-3p and LGALS9 was validated by bioinformatics analysis and a luciferase reporter assay. LPS-induction in BEECs with Bta-miR-24-3p was overexpressed leads inhibition of pro-inflammatory cytokines, LGALS9 expression, and TLR4/NF-ĸB pathway deactivation. Knockdown of LGALS9 inhibited the LPS-induced inflammatory response in BEECs. LGALS9 was validated as a target of Bta-miR-24-3p. Cloned overexpression of LGALS9 failed to alter the effect of Bta-miR-24-3p on the inflammatory response in BEECs. Overall, Bta-miR-24-3p attenuated the LPS-induced inflammatory response via targeting LGALS9. The immunotherapeutic stabilisation of Bta-miR-24-3p could give a therapeutic option for endometritis and other disorders commonly associated with endometritis, suggesting a novel avenue for endometritis treatment.

Jirao Shen, Xiaohu Wu, Yayuan Yang, Yanan Lv, Xinpu Li, Xuezhi Ding, Shengyi Wang, Zuoting Yan, Yong Yan, Feng Yang, Hongsheng Li Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, People’s Republic of ChinaCorrespondence: Feng Yang; Hongsheng Li Tel +86 0391-2115262; +86 0391-2164183Email yangfeng@caas.cn; lihsheng@sina.comObjective: Streptococcus dysgalactiae is a major pathogen in bovine mastitis. The purpose of this study was to survey the prevalence, antimicrobial resistance, as well as the spread of resistance and virulence-associated gene of S. dysgalactiae.Methods: A total of 60 S. dysgalactiae strains were obtained from 830 milk samples from Holstein cows with clinical mastitis. Antimicrobial resistance was examined by the disk diffusion method. Antimicrobial resistance and virulence genes were investigated by PCR, agarose gel electrophoresis and 16S rRNA gene sequencing.Results: All isolates were resistant to tetracycline and showed a high level of resistance to aminoglycoside antibiotics, where 81.67% of the strains were multi-resistant to these ten sorts of antibiotics. In addition, the most prevalent resistance gene in S. dysgalactiae was aphA-1 (98.33%), followed by blaTEM (96.67%), ermB (83.3%), aadA1/aadA2 (78.33%) and tetL (73.33%). Totally, seven virulence genes with 25 combination patterns were detected in these isolates, and each isolates harbored at least one virulence gene. 21.67% of the isolates carried three or more virulence genes, while one strain with seven virulence-related genes and belonged to cfb+lmb+eno+napr+bca+scpB+cyl.Conclusion: These findings indicate that S. dysgalactiae isolated from clinical bovine mastitis cases in Northwest China show a variety of molecular ecology and are highly resistant to antibiotics commonly used in dairy farms. This research will help investigators better understand the pathophysiology S. dysgalactiae in bovine mastitis and choose the appropriate antibiotics to treat mastitis.Keywords: Streptococcus dysgalactiae, bovine mastitis, antimicrobial resistance, virulence gene

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.

Vacuum-drying and freeze-drying were adopted to improve the catalytic activity of Ce0.5Pr0.5O2 for soot combustion. The specific surface area and pore volume of the as-prepared Ce0.5Pr0.5O2 were greatly increased compared to the counterpart using the common drying method. Furthermore, the redox performance and the oxidation ability for soot were enhanced, as demonstrated by H2-TPR and soot-TPR. Thus, lower combustion temperatures and higher intrinsic activity were obtained. This work demonstrated that simply changing the drying process of precipitates can be served as a paradigm to improve the structure and catalytic performance.

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.

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.

Aims To investigate the clinicopathological features and outcomes of adefovir dipivoxil (ADV)-related renal impairment in Chinese patients. Materials and methods Clinical, pathological, and follow-up data from 15 patients with ADV-related renal impairment were studied. Proximal renal tubular dysfunction (PRTD) was defined by the presence of at least two of the following four abnormalities: hypophosphatemia, hypouricemia, nondiabetic glucosuria, and proteinuria. Results All patients were treated for 3 - 15 (mean 6.7) years with daily ADV of 10 mg. Renal impairment manifested as PRTD (12, 80%), elevated serum creatinine (12, 80%), and hematuria (2, 13.3%). Mild to moderate tubulointerstitial injury primarily affecting the proximal tubules by light microscopy, and enlarged, dysmorphic mitochondria with loss and disorientation of cristae by electron microscope were identified in all of our cases. Four patients had pathological evidence of IgA nephropathy. The phosphorus, serum uric acid, and creatinine levels were normalized after ADV cessation in 66.7% (8/12) of affected patients, 27.3% (3/11) of affected patients, and 25% (3/12) of affected patients, respectively; proteinuria was eliminated in 7 of 13 affected patients (53.8%); and glucosuria and hematuria both disappeared in all affected patients. These abnormalities had hardly any recovery, and even aggravated with new-onset glucosuria, new-onset hematuria in 3 patients who replaced ADV with tenofovir. Conclusion Nephrotoxicity developed in patients undergoing long-term ADV treatment and was partially reversible after drug cessation. Tubulointerstitial lesions and heteromorphic mitochondria were the predominant pathological changes. Patients with ADV-induced renal impairment should replace ADV with other antiviral agents other than tenofovir. .

A nanorod-like KTi8O16 catalyst was successfully prepared by combustion method and applied for removing hazardous diesel soot. The cryptomelane structure of KTi8O16 is confirmed by X-ray powder diffraction (XRD). The straight and smooth crystalline nanorods with the diameter of 180 nm are identified by transmission electron microscopy (TEM) and (200) facet is observed to be preferentially exposed. K cations are not freely present in cryptomelane structure of KTi8O16 derived from X-ray absorption fine-structure (XAFS) results, possibly due to the confinement or interaction of K with Ti element. By temperature-programmed oxidation (TPO) experiments, its catalytic soot combustion performance was evaluated, with T 10 and T m of 435°C and 511°C, which are decreased by 19°C and 45°C respectively compared with pure anatase TiO2. K+ species are deduced to serve as the active sites in the catalytic soot oxidation reaction, which are confined in the channels of the nanorod-like KTi8O16.

Waterborne viruses frequently cause disease outbreaks and existing strategies to remove such viral pathogens often involve harsh or energy‐consuming water treatment processes. Here, a simple, efficient, and environmentally friendly approach is reported to achieve highly selective disinfection of specific viruses with living engineered biofilm materials. As a proof‐of‐concept, Escherichia coli biofilm matrix protein CsgA was initially genetically fused with the influenza‐virus‐binding peptide (C5). The resultant engineered living biofilms could correspondingly capture virus particles directly from aqueous solutions, disinfecting samples to a level below the limit‐of‐detection for a qPCR‐based detection assay. By exploiting the surface‐adherence properties of biofilms, it is further shown that polypropylene filler materials colonized by the CsgA‐C5 biofilms can be utilized to disinfect river water samples with influenza titers as high as 1 × 107 PFU L−1. Additionally, a suicide gene circuit is designed and applied in the engineered strain that strictly limits the growth of bacterial, therefore providing a viable route to reduce potential risks confronted with the use of genetically modified organisms. The study thus illustrates that engineered biofilms can be harvested for the disinfection of pathogens from environmental water samples in a controlled manner and highlights the unique biology‐only properties of living substances for material applications., A simple, efficient, and environmentally friendly approach to achieve highly selective disinfection of specific viruses with living engineered biofilm materials from virus‐polluted water is reported. The engineered biofilms can disinfect influenza virus from contaminated water to a level below the limit‐of‐detection for a qPCR‐based detection assay, thus protecting mammalian cells against virus infections efficiently.

1093 Background: Anthracyclines are associated with cardiotoxicity and myelosuppression in breast cancer (BC) patients. A new drug delivery system, liposomal preparation has shown higher anti-cancer effect and lower toxicity due to modified drug release and particle shape. This trial aimed to evaluate the efficacy and safety of Lipo-MIT in ABC. Methods: This is a randomized, open label, active-controlled, single-center, phase II clinical trial. Eligible patients were randomized in a ratio of 1:1 to receive Lipo-MIT or mitoxantrone hydrochloride injection (MIT) intravenously. The dosage was 20 mg/m2 for Lipo-MIT and 14 mg/m2 for MIT, once every four weeks (i.e., one treatment cycle). The primary endpoint was objective response rate(ORR). The secondary endpoints were progression free survival (PFS) and safety. Results: From Oct 2015 through Jul 2017, 60 patients were randomized to Lipo-MIT group (n = 30) or MIT group (n = 30). The Median (Q1,Q3) age was 56.0 (41.0,62.0) years in Lipo-MIT group and 54.5 (44.0,62.0) years in MIT group. Nineteen patients in Lipo-MIT group and 23 in MIT group received < 4 cycles of treatment, 11 patients in Lipo-MIT group and 7 in MIT group were treated for 4 or more cycles. When Lipo-MIT group was compared with MIT group, ORR was 13.3% (4/30) and 6.7% (2/30), disease control rate (PR+SD) was 50% (15/30) and 30% (9/30), median PFS was 2.30 (95% CI: 1.74-3.91) and 1.86 (95% CI: 1.74-2.40) months ( P> 0.05). Lipo-MIT showed significantly lower incidence of all-grade white blood cell decreased (86.7% vs 96.7%), neutrophil count decreased (80.0% vs 96.7%), conjugated bilirubin increased (53.3% vs 56.7%), aspartate aminotransferase increased (40.0% vs 53.3%), and troponin T increased (3.3% vs 36.7%) than MIT, but higher incidence of anemia (76.7% vs 46.7%), skin hyperpigmentation (66.7% vs 3.3%), and platelet count decreased (56.7% vs 53.3%) than MIT. Conclusions: Lipo-MIT provided numerically better ORR, DCR, and PFS than MIT in ABC. Lower incidence of troponin T increased might suggest lower cardiotoxicity of Lipo-MIT. It is worthwhile to further explore the clinical utility of Lipo-MIT in ABC. Clinical trial information: NCT02596373 .

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.

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.

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.