We investigated the treatment of experimental autoimmune encephalomyelitis (EAE) in mice with Niaspan, an agent used to elevate high-density lipoprotein (HDL). EAE mice were treated with Niaspan starting on the immunization or clinical onset day. Neurological functional recovery was significantly increased in the Niaspan treated mice (100 mg/kgbw) compared to the controls. Inflammatory infiltrates were significantly reduced in the Niaspan treatment group compared to the EAE controls. HDL level, intact myelin area, newly formed oligodendrocytes, regenerating axons, gene and protein levels of sonic hedgehog (Shh)/Gli1 were significantly increased in the Niaspan treated mice compared to EAE controls. These data indicate that Niaspan treatment improved functional recovery after EAE, possibly, via reducing inflammatory infiltrates and demyelination areas, and stimulating oligodendrogenesis and axonal regeneration. Niaspan-mediated activation of Shh/Gli1 pathway may promote functional recovery post-EAE.

Hemodynamic abnormality and disruption of white matter (WM) integrity are significant components in the pathophysiology of multiple sclerosis (MS) lesions. However, the roles of stratified lesions with distinct degrees of hemodynamic and structural injury in disease states remain to be explored. We tested the hypothesis that hemodynamic and structural impairment, as assessed by cerebral blood volume (CBV) and fractional anisotropy (FA), respectively, characterizes the extent of tissue injury, and the load of lesion with substantial tissue destruction would reflect the disease status and therefore, would be related to clinical disability.

Amplification of the C19MC oncogenic miRNA cluster and high LIN28 expression has been linked to a distinctly aggressive group of cerebral CNS-PNETs (group 1 CNS-PNETs) arising in young children. In this study, we sought to evaluate the diagnostic specificity of C19MC and LIN28, and the clinical and biological spectra of C19MC amplified and/or LIN28+ CNS-PNETs. We interrogated 450 pediatric brain tumors using FISH and IHC analyses and demonstrate that C19MC alteration is restricted to a sub-group of CNS-PNETs with high LIN28 expression; however, LIN28 immunopositivity was not exclusive to CNS-PNETs but was also detected in a proportion of other malignant pediatric brain tumors including rhabdoid brain tumors and malignant gliomas. C19MC amplified/LIN28+ group 1 CNS-PNETs arose predominantly in children <4 years old; a majority arose in the cerebrum but 24 % (13/54) of tumors had extra-cerebral origins. Notably, group 1 CNS-PNETs encompassed several histologic classes including embryonal tumor with abundant neuropil and true rosettes (ETANTR), medulloepithelioma, ependymoblastoma and CNS-PNETs with variable differentiation. Strikingly, gene expression and methylation profiling analyses revealed a common molecular signature enriched for primitive neural features, high LIN28/LIN28B and DNMT3B expression for all group 1 CNS-PNETs regardless of location or tumor histology. Our collective findings suggest that current known histologic categories of CNS-PNETs which include ETANTRs, medulloepitheliomas, ependymoblastomas in various CNS locations, comprise a common molecular and diagnostic entity and identify inhibitors of the LIN28/let7/PI3K/mTOR axis and DNMT3B as promising therapeutics for this distinct histogenetic entity.

No head-to-head clinical trials have been published comparing guanfacine extended release (GXR) and atomoxetine (ATX): two nonstimulants approved for the treatment of attention-deficit/hyperactivity disorder (ADHD). However, other study designs or methods could be used to indirectly compare these two medications. Matching-adjusted indirect comparison (MAIC) is a recent methodology that utilizes individual patient data (IPD) from clinical trials for one treatment and published aggregate data from another treatment to estimate the relative efficacy of both, providing rapid, reliable comparative efficacy results.

High yield and quality determine the commercial potential of rice variety. Brown rice rate (BRR) is a key factor ensuring grain yield and quality in rice. So far, there were few reports about the genes that directly controlled the BRR in rice. Therefore, dissecting the genetic mechanism of the BRR genes can facilitate improving effective rice supply or edible grain yield.

This study aims to construct a 3D structure of the avian major histocompatibility complex (MHC)-β2M complex through homology modelling technology, perform molecular docking of the predicted infectious bronchitis virus (IBV) S1 protein potential epitope peptide Sp6 (NQFYIKLT) and the avian MHC-β2M complex, and demonstrate the interactive mechanism between Sp6 and MHC using molecular dynamical simulations. The peptide Sp6 and the non-related peptide NP89-97 (PKKTGGPIY) were used to stimulate in vitro recombinant plasmid (pCAGGS-S1) avian splenic lymphocytes. Flow cytometric results show that CD8(+) T lymphocytes reproduce stimulated by the Sp6 and the nonrelated peptide proliferate by 34.8% and 2.6%, respectively. Meanwhile, fluorescent quantitative PCR results show that the secretion of IFN-γ in avian splenic lymphocytes increases after Sp6 stimulation. These data suggest that Sp6 can induce the activated avian lymphocytes in vitro to produce CTL, which is the CTL epitope in IBV S1.

Human umbilical tissue-derived cells (hUTC) represent an attractive cell source and a potential technology for neurorestoration and improvement of functional outcomes following stroke. Male Wistar rats were subjected to a transient middle cerebral artery occlusion (tMCAo) and were intravenously administered hUTC (N = 11) or vehicle (N = 10) 48 hrs after stroke. White matter and vascular reorganization was monitored over a 12-week period using MRI and histopathology. MRI results were correlated with neurological functional and histology outcomes to demonstrate that MRI can be a useful tool to measure structural recovery after stroke. MRI revealed a significant reduction in the ventricular volume expansion and improvement in cerebral blood flow (CBF) in the hUTC treated group compared to vehicle treated group. Treatment with hUTC resulted in histological and functional improvements as evidenced by enhanced expression of vWF and synaptophysin, and improved outcomes on behavioral tests. Significant correlations were detected between MRI ventricular volumes and histological lesion volume as well as number of apoptotic cells. A positive correlation was also observed between MRI CBF or cerebral blood volume (CBV) and histological synaptic density. Neurological functional tests were also significantly correlated with MRI ventricular volume and CBV. Our data demonstrated that MRI measurements can detect the effect of hUTC therapy on the brain reorganization and exhibited positive correlation with histological measurements of brain structural changes and functional behavioral tests after stroke. MRI ventricular volumes provided the most sensitive index in monitoring brain remodeling and treatment effects and highly correlated with histological and functional measurements.

Human umbilical tissue-derived cells (hUTC) are a promising source of cells for regenerative treatment of stroke. In this study, we tested the efficacy of hUTC in experimental stroke and whether multiple injections of hUTC provide additional therapeutic benefits as compared to a single injection.

Obesity in women of reproductive age is not only associated with numerous adverse maternal and fetal effects prenatally but also exerts a negative influence on female fertility. The aim of this study was to investigate the situation of prepregnant obesity in Shanghai and explore the impact of prepregnant obesity on gestational weight gain as well as other pregnancy outcomes. A prospective hospital-based pregnant women cohort was established in Shanghai since January 2015. All pregnant women who were registered and expected to deliver in this hospital were included in the cohort. Nearly one fourth of pregnant women in Shanghai were overweight/obese and the prevalence of overweight/obesity was more common among women with advancing age (P < .001). Women prepregnancy overweight/obesity was associated with 3.5-fold higher risk of excessive gestational weight gain (odds ratio, OR 3.58; 95% confidence interval, CI, 2.82-4.55; P < .001). Women prepregnancy BMI was statistically related to pregnancy outcomes as macrosomia (OR 2.24; 95% CI, 1.55-3.23; P < .001), cesarean delivery (OR 2.04; 95% CI, 1.60-2.62; P < .001), maternal complications (OR 1.53; 95% CI, 1.18-1.98; P < .001). Prepregnancy obesity is associated with a much higher risk of excessive gestational weight gain and pregnancy outcomes in Shanghai. Further interventions targeting maternal obesity, especially prepregnancy obesity are required.

The Soybean (Glycine max) leghemoglobin c2 (LegHb) gene was introduced into Pichia pastoris yeast for sustainable production of a heme-carrying protein, for organoleptic use in plant-based meat. The potential allergenicity and toxicity of LegHb and 17 Pichia host-proteins each representing ≥1% of total protein in production batches are evaluated by literature review, bioinformatics sequence comparisons to known allergens or toxins, and in vitro pepsin digestion.

Based on the knowledge that poly(sialic acid) is a critical element for tumour development and that the receptors for its monomer are expressed on neutrophils, which play important roles in the progression and invasion of tumours, a poly(sialic acid)-p-octadecylamine conjugate (PSA-p-ODA) was synthesised and used to modify the surface of liposomal pixantrone (Pix-PSL) to improve the delivery of Pix to peripheral blood neutrophils (PBNs). The liposomes were fabricated using a remote loading technology via a pH gradient, and were then assessed for particle size, encapsulation efficiency, in vitro release, in vitro cytotoxicity, and pharmacokinetics. Simultaneously, in vitro and in vivo cellular uptake studies demonstrated that Pix-PSL provided an enhanced accumulation of Pix in PBNs. An in vivo study showed that the anti-tumour activity of Pix-PSL was superior to that of other formulations, probably owing to the efficient targeting of PBNs by Pix-PSL, after which PBNs containing Pix-PSL (Pix-PSL/PBNs) in the circulatory system are recruited by the tumour microenvironment. These findings suggest that PSA-p-ODA-decorated liposomal Pix may provide a neutrophil-mediated drug delivery system (DDS) for the eradication of tumours, and thus represents a promising approach for the tumour targeting of chemotherapeutic treatments.

Insulin resistance in the brain is a pathological mechanism that is shared between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). Although aberrant expression and phosphorylation of insulin receptor substrate 1 (IRS-1) contribute to insulin resistance, the underlying mechanism remains elusive. In this study, we used several approaches, including adeno-associated virus-based protein overexpression, immunoblotting, immunoprecipitation, immunohistochemistry, and in situ proximal ligation assays, to investigate the function of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) in IRS-1 regulation and the downstream insulin signaling in neurons. We found that DYRK1A overexpression up-regulated IRS-1 expression by slowing turnover of the IRS-1 protein. We further observed that DYRK1A directly interacted with IRS-1 and phosphorylated IRS-1's multiple serine residues. Of note, DYRK1A and IRS-1 were coordinately up-regulated in the prefrontal cortex of db/db mice brain. Furthermore, DYRK1A overexpression ameliorated chronic high insulin-induced insulin resistance in SH-SY5Y cells as well as in primary rat neurons. These findings suggest that DYRK1A protects against insulin resistance in the brain by elevating IRS-1 expression.

Despite the recent advances in the acute stroke care, treatment options for long-term disability are limited. RPh201 is a botany-derived bioactive compound that has been shown to exert beneficial effects in various experimental models of neural injury. The present study evaluated the effect of delayed RPh201 treatment on long term functional recovery after stroke.

The death of mature oligodendrocytes (OLs) which are the sole myelinating cells of the central nervous system (CNS), leads to demyelination and functional deficits. Currently, there is lack of effective remyelination therapies for patients with demyelinating diseases. MicroRNAs (miRNAs) mediate OL function. We hypothesized that miR-146a, by inactivating interleukin-1 receptor-associated kinase 1 (IRAK1), promotes differentiation of oligodendrocyte progenitor cells (OPCs) and thereby enhances remyelination. To test this hypothesis, a demyelination model induced by a cuprizone (CPZ) diet was employed, in which C57BL/6J mice were fed with a CPZ diet for 5weeks. After termination of CPZ diet, the mice were randomly treated with continuous infusion of miR-146a mimics or mimic controls into the corpus callosum for 7days. Compared to the mimic control, infusion of miR-146a mimics facilitated remyelination assessed by increased myelin basic proteins in the corpus callosum, which was associated with augmentation of newly generated mature OLs. Infusion of miR-146a mimics also substantially elevated miR-146a levels in the corpus callosum and fluorescently tagged miR-146a mimics were mainly detected in OPCs. Western blot and double immmunofluorescent staining analysis showed that the miR-146a treatment considerably reduced IRAK1 protein levels and the number of IRAK1-positive cells, respectively. Collectively, these data indicate that exogenous miR-146a enhances remyelination, possibly by promoting OPCs to differentiate into myelinated OLs via targeting IRAK1.

Henoch-Schönlein purpura nephritis (HSPN) is the principal cause of morbidity and mortality in children with Henoch-Schönlein purpura (HSP). However, the criteria for risk assessment currently used is not satisfactory. The urine proteome may provide important clues to indicate the development of HSPN.

The pharmacological interventions aimed at activating pathways inducing chondrocyte autophagy or reversing extracellular matrix degradation may be promising approaches for the management of osteoarthritis (OA). Evidence exists suggesting that sirtuin 1 (SIRT1) is involved in the pathogenesis of OA. The present study aimed to explore the regulatory role and downstream mechanisms of SIRT1 in OA. Bioinformatics predictions identified downstream factors phosphatase and tensin homolog (PTEN) and epidermal growth factor receptor (EGFR) in OA. We validated poorly expressed SIRT1 and EGFR and highly expressed PTEN in cartilage tissues of OA patients. OA was induced in vitro by exposing human primary chondrocytes to IL-1β and in vivo by destabilization of the medial meniscus (DMM) in a mouse model. SIRT1 knockdown was found to augment IL-1β-stimulated inflammation and chondrocyte metabolic imbalance. Knockdown of SIRT1 diminished PTEN acetylation and then enhanced PTEN expression. PTEN inactivation decreased EGFR ubiquitination and promoted EGFR expression by destabilizing the EGFR-Cbl complex, which in turn inhibited extracellular matrix degradation in cartilage tissues and activated chondrocyte autophagy. In the DMM mouse model, knockdown of SIRT1 inhibited chondrocyte autophagy, promoted metabolic imbalance, thus accelerating osteoarthritic process. In conclusion, SIRT1 represses the ubiquitination of EGFR by down-regulating PTEN, inhibits extracellular matrix degradation and activates chondrocyte autophagy, thereby performing an OA-alleviating role.

Vascular Dementia (VaD) refers to dementia caused by cerebrovascular disease and/or reduced blood flow to the brain and is the second most common form of dementia after Alzheimer's disease. We previously found that in middle-aged rats subjected to a multiple microinfarction (MMI) model of VaD, treatment with AV-001, a Tie2 receptor agonist, significantly improves short-term memory, long-term memory, as well as improves preference for social novelty compared to control MMI rats. In this study, we tested the early therapeutic effects of AV-001 on inflammation and glymphatic function in rats subjected to VaD.

Immunotherapy has revolutionized the landscape of cancer treatment. However, single immunotherapy only works well in a small subset of patients. Combined immunotherapy with antitumor synergism holds considerable potential to boost the therapeutic outcome. Nevertheless, the synergistic, additive or antagonistic antitumor effects of combined immunotherapies have been rarely explored. Herein, we established a novel combined cancer treatment modality by synergizing p21-activated kinase 4 (PAK4) silencing with immunogenic phototherapy in engineered extracellular vesicles (EVs) that were fabricated by coating M1 macrophage-derived EVs on the surface of the nano-complex cores assembled with siRNA against PAK4 and a photoactivatable polyethyleneimine. The engineered EVs induced potent PAK4 silencing and robust immunogenic phototherapy, thus contributing to effective antitumor effects in vitro and in vivo. Moreover, the antitumor synergism of the combined treatment was quantitatively determined by the CompuSyn method. The combination index (CI) and isobologram results confirmed that there was an antitumor synergism for the combined treatment. Furthermore, the dose reduction index (DRI) showed favorable dose reduction, revealing lower toxicity and higher biocompatibility of the engineered EVs. Collectively, the study presents a synergistically potentiated cancer treatment modality by combining PAK4 silencing with immunogenic phototherapy in engineered EVs, which is promising for boosting the therapeutic outcome of cancer immunotherapy.

Despite genomic simplicity, recent studies have reported at least 3 major atypical teratoid rhabdoid tumor (ATRT) subgroups with distinct molecular and clinical features. Reliable ATRT subgrouping in clinical settings remains challenging due to a lack of suitable biological markers, sample rarity, and the relatively high cost of conventional subgrouping methods. This study aimed to develop a reliable ATRT molecular stratification method to implement in clinical settings.

Functional recovery after brain injury in animals is improved by marrow stromal cells (MSC) which stimulate neurite reorganization. However, MRI measurement of neurite density changes after injury has not been performed. In this study, we investigate the feasibility of MRI measurement of neurite density in an animal model of traumatic brain injury (TBI) with and without MSC treatment.