BackgroundExtracellular accumulation of amyloid β-peptide (Aβ) is one of pathological hallmarks of Alzheimer’s disease (AD) and contributes to the neuronal loss. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) stress-inducible neurotrophic factor. Many groups, including ours, have proved that MANF rescues neuronal loss in several neurological disorders, such as Parkinson’s disease and cerebral ischemia. However, whether MANF exerts its protective effect against Aβ neurotoxicity in AD remains unknown.MethodsIn the present study, the characteristic expressions of MANF in Aβ1–42-treated neuronal cells as well as in the brains of APP/PS1 transgenic mice were analyzed by immunofluorescence staining, qPCR, and Western blot. The effects of MANF overexpression, MANF knockdown, or recombination human MANF protein (rhMANF) on neuron viability, apoptosis, and the expression of ER stress-related proteins following Aβ1–42 exposure were also investigated.ResultsThe results showed the increased expressions of MANF, as well as ER stress markers immunoglobulin-binding protein (BiP) and C/EBP homologous protein (CHOP), in the brains of the APP/PS1 transgenic mice and Aβ1–42-treated neuronal cells. MANF overexpression or rhMANF treatment partially protected against Aβ1–42-induced neuronal cell death, associated with marked decrease of cleaved caspase-3, whereas MANF knockdown with siRNA aggravated Aβ1–42 cytotoxicity including caspase-3 activation. Further study demonstrated that the expressions of BiP, ATF6, phosphorylated-IRE1, XBP1s, phosphorylated-eIF2α, ATF4, and CHOP were significantly downregulated by MANF overexpression or rhMANF treatment in neuronal cells following Aβ1–42 exposure, whereas knockdown of MANF has the opposite effect.ConclusionsThese findings demonstrate that MANF may exert neuroprotective effects against Aβ-induced neurotoxicity through attenuating ER stress, suggesting that an applicability of MANF as a therapeutic candidate for AD.Electronic supplementary materialThe online version of this article (10.1186/s12974-019-1429-0) contains supplementary material, which is available to authorized users.
Self-healing hydrogels based on degradable resources have developed rapidly in the past decade due to their extensive bioapplications with biosecurity. In this research, a new kind of cellulose-based selfhealing hydrogel with bio-degradability is constructed through boronic ester linkage. The carboxyethyl cellulose-graft-phenylboronic acid (CMC-B(OH) 2 ) was synthesized through condensation reaction conveniently and then hydrogels were prepared with dynamic boronic ester cross-linking. The chemical structures, microscopic morphologies, mechanical and self-healing properties of the hydrogels were investigated intensively through Fourier transform infrared (FT-IR) spectroscopy, rheological, SEM and tensile testing. The hydrogels formed instantly without any additional catalyst and exhibit excellent selfhealing ability with good mechanical properties. Moreover, the hydrogels were applied for controlled release of doxorubicin (DOX$HCl) and showed a successive slow release profile. Importantly, the hydrogel exhibited excellent biocompatibility and show potential applications in controlled drug delivery, 3D cell culture and tissue engineering.
Tumor-targeting multifunctional liposomes simultaneously loaded with magnetic iron oxide nanoparticles (MIONs) as a magnetic resonance imaging (MRI) contrast agent and anticancer drug, mitoxantrone (Mit), were developed for targeted cancer therapy and ultrasensitive MRI. The gonadorelin-functionalized MION/Mit-loaded liposome (Mit-GML) showed significantly increased uptake in luteinizing hormone–releasing hormone (LHRH) receptor overexpressing MCF-7 (Michigan Cancer Foundation-7) breast cancer cells over a gonadorelin-free MION/Mit-loaded liposome (Mit-ML) control, as well as in an LHRH receptor low-expressing Sloan-Kettering HER2 3+ Ovarian Cancer (SK-OV-3) cell control, thereby leading to high cytotoxicity against the MCF-7 human breast tumor cell line. The Mit-GML formulation was more effective and less toxic than equimolar doses of free Mit or Mit-ML in the treatment of LHRH receptors overexpressing MCF-7 breast cancer xenografts in mice. Furthermore, the Mit-GML demonstrated much higher T2 enhancement than did Mit-ML controls in vivo. Collectively, the study indicates that the integrated diagnostic and therapeutic design of Mit-GML nanomedicine potentially allows for the image-guided, target-specific treatment of cancer.
Objective
To establish the age‐specific centiles of serum anti‐müllerian hormone (AMH) levels in Chinese women, and to explore the use of multiples of median (MoM) AMH levels for the diagnosis of polycystic ovary syndrome (PCOS).
Design
An observational study.
Setting
University‐affiliated hospitals and community clinics.
Population
We included 3137 healthy women aged 20–44 years recruited prospectively or who had archived serum samples from previous research projects. Another validation cohort of 751 women with PCOS as well as ovulatory controls, which was a convenient sample of women attending for infertility or menstrual disorders, was also studied.
Methods
The serum samples were assayed for AMH by the automated Access AMH assay.
Main outcome measures
Age‐specific reference ranges were constructed on the primary cohort with the Lambda‐Mu‐Sigma method. The MoM AMH of each subject in the validation cohort was calculated.
Results
Centile curves of serum AMH level against age were established. MoM AMH was significantly higher in women with PCOS than in controls (P < 0.05). The area under the ROC curve was 0.852 (95% confidence interval [CI] 0.825–0.877) (P < 0.0001) for discriminating women with PCOS from ovulatory controls by MoM AMH.
Conclusions
We established a set of year‐by‐year age‐specific reference ranges of serum AMH levels in Chinese women. The MoM AMH derived from this set of reference ranges is a promising tool to replace antral follicle count in the diagnosis of PCOS.
Tweetable abstract
A set of age‐specific reference ranges of AMH levels was established in Chinese women. Multiples of median AMH may be used to diagnose PCOS.
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