[A retrospective analysis of 6 children with Duchenne muscular dystrophy].

OBJECTIVE: To analyze the clinical features of 6 children with Duchenne muscular dystrophy (DMD) and review related literature, and to provide a basis for early diagnosis and effective treatment of this disease. METHODS: A retrospective analysis was performed on the clinical data of 6 children with DMD who were admitted to the First Affiliated Hospital of Nanjing Medical University from January 2010 to October 2015. RESULTS: All the 6 cases were boys without a family history of DMD, and the age of diagnosis of DMD was 1.2-11.5 years. All patients had insidious onset and increases in alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, α-hydroxybutyrate dehydrogenase, creatine kinase (CK), and creatine kinase-MB, particularly CK, which was 3.3-107.2 times the normal level. Their gene detection results all showed DMD gene mutation. The gene detection results of two children's mothers showed that they carried the same mutant gene. The muscle biopsy in one case showed that the pathological changes confirmed the diagnosis of DMD. The level of CK in one case declined by 77.0% 5 days after umbilical cord blood mesenchymal stem cell transplantation. CONCLUSIONS: For boys with abnormal serum enzyme levels and motor function, DMD should be highly suspected. It should be confirmed by CK and DMD gene detection as soon as possible. And the progression of the disease could be delayed by early intervention for protecting the remaining normal muscle fibers.

Ghrelin/GHSR signaling in the lateral septum ameliorates chronic stress-induced depressive-like behaviors.

Ghrelin is a gastrointestinal hormone on feeding and metabolism regulation, and acts through its receptor-growth hormone secretagogue receptor (GHSR), which is widely distributed throughout the central nervous system. Recent studies have suggested that ghrelin plays an important role in the regulation of depression, but the underlying mechanisms remain uncertain. Lateral septum (LS) is a critical brain region in modulating depression. Therefore, we investigated the role of ghrelin/GHSR signaling in the LS on the depressive-like behaviors of mice under conditions of chronic stress by using behavioral tests, neuropharmacology, and molecular biology techniques. We found that infusion of ghrelin into the LS produced antidepressant-like responses in mice. Activation of LS GABAergic neurons was involved in the antidepressant effect of ghrelin. Importantly, GHSR was highly expressed and distributed in the LS neurons. Blockade of GHSR in the LS reversed the ghrelin-induced antidepressant-like effects. Molecular knockdown of GHSR in the LS induced depressive-like symptoms in mice. Furthermore, administration of ghrelin into the LS alleviated depressive-like behaviors induced by chronic social defeat stress (CSDS). Consistent with the neuropharmacological results, overexpression of GHSR in the LS reversed CSDS-induced depressive-like behaviors. Our findings clarify a key role for ghrelin/GHSR signaling in the regulation of chronic stress-induced depressive-like behaviors, which could provide new strategies for the treatment of depression.

Quantitative and Qualitative Parameters of DCE-MRI Predict CDKN2A/B Homozygous Deletion in Gliomas.

RATIONALE AND OBJECTIVES: Homozygous deletion (HD) of CDKN2A/B holds important prognostic value in gliomas. This study aimed to explore the predictive potential of conventional MRI characteristics combined with dynamic contrast-enhanced MRI parameters in predicting CDKN2A/B HD status in gliomas. MATERIALS AND METHODS: Preoperative MRI data of 105 patients (69 without CDKN2A/B HD, and 36 with CDKN2A/B homozygous deletion) with gliomas were retrospectively collected. Conventional MRI features and dynamic contrast-enhanced-MRI qualitative parameter time-intensity curve type, quantitative parameters Ktrans, Kep, Ve, Vp, and iAUC were obtained. Logistic regression models for prediction of CDKN2A/B HD status were constructed in all types of gliomas and both subtypes of IDH-mutant and IDH-wild gliomas. RESULTS: Multivariate analysis for all patients demonstrated that age (OR=1.103, p = 0.002) and Ktrans (OR=1.051, p < 0.001) independently predicted CDKN2A/B HD. In IDH-mutant subgroup, multivariate analysis results indicated that Ktrans (OR=1.098, p = 0.031) emerged as autonomous predictors of CDKN2A/B HD. In IDH-wild subgroup, age (OR=1.111, p = 0.002) and Ktrans (OR=1.032, p = 0.001) were independent predictors of CDKN2A/B HD according to the multivariate analysis. The areas under the receiver operating characteristic curve of the corresponding models were 0.90, 0.95 and 0.84, respectively. CONCLUSION: Ktrans can serve as valuable predictive parameters for identifying CDKN2A/B HD status in all types of gliomas and both subtypes of IDH-mutant and IDH-wild gliomas. These findings provide a foundation for precise preoperative non-invasive diagnosis and personalized treatment approaches for glioma patients.

Muscle-bone cross-talk through the FNIP1-TFEB-IGF2 axis is associated with bone metabolism in human and mouse.

Clinical evidence indicates a close association between muscle dysfunction and bone loss; however, the underlying mechanisms remain unclear. Here, we report that muscle dysfunction-related bone loss in humans with limb-girdle muscular dystrophy is associated with decreased expression of folliculin-interacting protein 1 (FNIP1) in muscle tissue. Supporting this finding, murine gain- and loss-of-function genetic models demonstrated that muscle-specific ablation of FNIP1 caused decreased bone mass, increased osteoclastic activity, and mechanical impairment that could be rescued by myofiber-specific expression of FNIP1. Myofiber-specific FNIP1 deficiency stimulated expression of nuclear translocation of transcription factor EB, thereby activating transcription of insulin-like growth factor 2 (Igf2) at a conserved promoter-binding site and subsequent IGF2 secretion. Muscle-derived IGF2 stimulated osteoclastogenesis through IGF2 receptor signaling. AAV9-mediated overexpression of IGF2 was sufficient to decrease bone volume and impair bone mechanical properties in mice. Further, we found that serum IGF2 concentration was negatively correlated with bone health in humans in the context of osteoporosis. Our findings elucidate a muscle-bone cross-talk mechanism bridging the gap between muscle dysfunction and bone loss. This cross-talk represents a potential target to treat musculoskeletal diseases and osteoporosis.

Evaluation of a mitochondrial disease criteria scoring system on mitochondrial encephalomyopathy in Chinese patients.

Due to the complicated clinical features of mitochondrial encephalomyopathy, simplified mitochondrial disease criteria (MDC) have recently been established in Europe. This study evaluated the sensitivity and specificity of this scoring system in Chinese patients. Seventy-eight patients with suspected mitochondrial encephalomyopathy were recruited to be scored by the simplified MDC and were further classified into "possible" (2-4), "probable" (5-7), or "definite" categories (≥8). Significant differences were observed between the total scores in the mitochondrial encephalomyopathy group and the other myopathy group. In the mitochondrial encephalomyopathy group, 73.5% of patients had a score above 8, whereas in the other myopathy group, the "definite" percentage was only 3.2%, suggesting the proposed MDC scoring system has a high sensitivity for diagnosis of mitochondrial encephalomyopathy in China. Moreover, there were significant differences in the clinical scores and imaging portions of the MDC, suggesting that the simplified MDC may distinguish mitochondrial disorder from other multisystem disorders to aid in early diagnosis prior to a muscle biopsy.

Development and validation of radiomics nomograms for preoperative prediction of characteristics in non-small cell lung cancer and circulating tumor cells.

To develop and validate 3 radiomics nomograms for preoperative prediction of pathological and progression diagnosis in non-small cell lung cancer (NSCLC) as well as circulating tumor cells (CTCs). A total of 224 and 134 patients diagnosed with NSCLC were respectively gathered in 2018 and 2019 in this study. There were totally 1197 radiomics features that were extracted and quantified from the images produced by computed tomography. Then we selected the radiomics features with predictive value by least absolute shrinkage and selection operator and combined them into radiomics signature. Logistic regression models were built using radiomics signature as the only predictor, which were then converted to nomograms for individualized predictions. Finally, the performance of the nomograms was assessed on both cohorts. Additionally, immunohistochemical correlation analysis was also performed. As for discrimination, the area under the curve of pathological diagnosis nomogram and progression diagnosis nomogram in NSCLC were both higher than 90% in the training cohort and higher than 80% in the validation cohort. The performance of the CTC-diagnosis nomogram was somehow unexpected where the area under the curve were range from 60% to 70% in both cohorts. As for calibration, nonsignificant statistics (P > .05) yielded by Hosmer-Lemeshow tests suggested no departure between model prediction and perfect fit. Additionally, decision curve analyses demonstrated the clinically usefulness of the nomograms. We developed radiomics-based nomograms for pathological, progression and CTC diagnosis prediction in NSCLC respectively. Nomograms for pathological and progression diagnosis were demonstrated well-performed to facilitate the individualized preoperative prediction, while the nomogram for CTC-diagnosis prediction needed improvement.

Targeted mutation of Fas ligand gene attenuates brain inflammation in experimental stroke.

Inflammation is an important contributing mechanism in ischemic brain injury. The current study elucidates a previously unexplored role of Fas ligand (FasL) in post-stroke inflammatory responses that is independent of its well-known effect in triggering apoptosis. Focal cerebral ischemia was induced for 2 h by right middle cerebral artery occlusion (MCAO) in FasL mutant (gld) and wild-type mice. FasL mutation profoundly reduced brain damage and improved neurological performance from 6 to 72 h after ischemic stroke. The production of inflammatory cytokines in the brain was attenuated in gld mice after ischemia in the absence of dramatic change in inflammatory cell apoptosis. FasL mutation attenuated the recruitment of peripheral inflammatory cells (neutrophil) and inhibited the activation of residential glial cells (microglia and astrocyte). FasL mutation reduced CD8(+) T cells and turned the Th1/Th2 balance towards Th2 in the brain and peripheral blood after cerebral ischemia. In contrast to cerebral ischemia, the molecular and cellular inflammatory changes induced by intracerebroventricular injection of lipopolysaccharide (LPS) were also attenuated in gld mice. Moreover, the soluble FasL (sFasL) and phospho-SAPK/JNK were decreased in gld mice, suggesting that the inflammatory role of FasL in experimental stroke might relate to sFasL and the c-Jun N-terminal kinase (JNK) signaling pathway. Taken together, our data suggest a novel role of FasL in the damaging inflammatory responses associated with cerebral ischemia. Neutralization of FasL may be a novel therapeutic strategy to suppress post-stroke inflammation and improve the long-term outcomes of stroke.

CART mitigates oxidative stress and DNA damage in memory deficits of APP/PS1 mice via upregulating ß­amyloid metabolism­associated enzymes.

Alzheimer's disease (AD) is the most common form of dementia that is primarily characterized by progressive cognitive deficits. The toxicity of amyloid ß­protein (Aß) serves an important role in the progression of AD, resulting in neuronal loss via a number of possible mechanisms, including oxidative stress, mitochondrial dysfunction, energy depletion, apoptosis and neuroinflammation. Previous studies have reported that cocaine amphetamine regulated transcript (CART) treatment improves memory and synaptic structure in APP/PS1 mice. Therefore, the present study aimed to investigate whether CART served a protective role against memory deficits in AD. APP/PS1 mice were treated with CART or PBS. Spatial memory was assessed using the Morris water maze. Oxidative stress and DNA damage were compared among wild­type, APP/PS1 and CART­treated APP/PS1 mice. The mRNA and protein expression levels of Aß metabolism­associated enzymes, including neprilysin (NEP), insulin­degrading enzyme (IDE), receptor for advanced glycation end products (RAGE) and low­density lipoprotein receptor­related protein 1 (LRP­1), in the hippocampus were measured via reverse transcription­quantitative PCR and western blotting, respectively. CART improved the memory impairment of APP/PS1 mice by reducing oxidative stress, inhibiting DNA damage and protecting against mitochondrial dysfunction in the cerebral cortex and hippocampus. CART also reduced cell senescence and oxidative stress in Aß1­42­exposed primary cortical neurons in APP/PS1 mice. Moreover, CART promoted Aß degradation via modulating Aß metabolism­associated enzymes, including IDE, NEP, LRP­1 and RAGE. Collectively, the present study indicated that CART improved the learning and memory capacity of APP/PS mice, thus may have potential to serve as a novel therapeutic agent for AD.

Danon disease: a case report and literature review.

BACKGROUND: Danon disease (DD) is a rare x-linked dominant multisystemic disorder with a clinical triad of severe cardiomyopathy, skeletal myopathy, and mental retardation. It is caused by a defect in the lysosomal-associated membrane protein-2 (LAMP2) gene, which leads to the formation of autophagic vacuoles containing glycogen granule deposits in skeletal and cardiac muscle fibers. So far, more than 50 different mutations in LAMP2 have been identified. CASE PRESENTATION: Here, we report an 18-year-old male patient who was hospitalized for heart failure. Biopsy of the left lateral femoral muscle revealed scattered autophagic vacuoles in the muscle fibers with increased glycogen. Next generation sequencing (NGS) was used to detect gene mutations of the proband sample and a novel frameshift mutation (c.1052delG) has been identified in exon 8 of LAMP2, which leads to truncation of the protein. CONCLUSION: We found a novel frameshift mutation, a hemizygous mutation (c.1052delG) in exon 8 of LAMP2, identified as presenting the hypertrophic cardiomyopathy (HCM) phenotype. Genetic analysis is the gold standard for the diagnosis of DD and is essential to determine appropriate treatment strategies and to confirm the genetic risk of family members.

Inhibition of p22phox Suppresses Epithelial Ovarian Cancer Cell Proliferation and Tumorigenesis.

The aim of this study was to investigate the biological role and molecular mechanism of p22phox in epithelial ovarian cancer. Immunohistochemistry was employed to determine the p22phox expression level in epithelial ovarian cancer tissues. The effects of p22phox on epithelial ovarian cancer cell proliferation, tumorigenesis, and chemosensitivity were evaluated by CCK-8, EdU assay, colony formation and apoptosis assays in vitro and by mouse experiments in vivo. Immunoprecipitation analyses were utilized to explore the potential mechanisms of p22phox mediated downstream signaling, and RT-PCR and western blot were used to confirm the relevance. P22phox expression could be detected in epithelial ovarian cancer tissues and normal fallopian epithelial cells. Silencing p22phox suppressed epithelial ovarian cancer cell proliferation and colony formation capacity in vitro, and inhibited the tumor growth in nude mice bearing the A2780 xenograft in vivo. Mechanistic investigations showed that p22phox regulated proteasome ubiquitination and subsequent proteasome-dependent degradation of p53 in A2780 and U87 cells in vitro. Furthermore, knockdown of p22phox significantly increased the chemosensitivity of A2780 cells to cisplatin or paclitaxel. These results suggested that p22phox as a pivotal oncogene during epithelial ovarian cancer carcinogenesis and p22phox inhibition might be a potential therapeutic strategy for epithelial ovarian cancer.

Clinical manifestations and acid alpha-glucosidase mutation characterisation of a cohort of patients with late-onset Pompe disease in eastern China.

BACKGROUND: Pompe disease is a rare, progressive, and life-threatening autosomal recessive disorder. In its late-onset form, the disease is primarily characterised by mild progressive proximal limb and respiratory muscle weakness. Mutations in the acid alpha-glucosidase (GAA) gene cause lysosomal enzyme GAA to be significantly reduced or missing altogether, for which supplementation can be given through enzyme replacement therapy. METHODS: Fourteen patients diagnosed with late-onset Pompe disease (LOPD) in the First Affiliated Hospital of Nanjing Medical University from 2017 to 2021 were enrolled. GAA activity was measured based on enzymatic activity in dried blood spots, and next-generation sequencing was used to detect mutations in the GAA gene. The impacts of novel missense variants were determined by five different prediction algorithms. The structural figures of novel variants and their wide types were processed with PyMOL. RESULTS: The study included 14 patients with LOPD (male-to-female ratio, 1:1) from eastern China. The median age at symptom onset and diagnosis was 15.0 years (7-36 years) and 21.5 years (8-47 years), respectively. The median diagnostic delay from onset was 3.0 years (0-22 years). Proximal muscle weakness was the first prominent symptom in 8 patients, while the other 6 patients experienced respiratory failure, chest congestion and asthma, and scoliosis. The most frequent mutation of the GAA gene was c.2238G>C (p.W746C), which was observed at an allele frequency of 14.3% (4/28) and in 28.6% of patients (4/14). Four novel variants potentially related to the pathogenicity of LOPD were found: c.1299G>C (p.Q433H), c.1409A>G (p.N470S), c.2242delG (p.E748Rfs*16), and c.2832delA (p.E945Sfs*78). CONCLUSIONS: The c.2238G>C (p.W746C) mutation was the most common mutation in 14 patients with LOPD from eastern China. This study has identified four novel variants in patients with LOPD. Predicting the pathogenicity of these novel variants may increase the understanding of the genetic mutation spectrum in LOPD. Our findings may also improve recognition of the characteristics of Chinese patients with LOPD.

Ghrelin improves muscle function in dystrophin-deficient mdx mice by inhibiting NLRP3 inflammasome activation.

AIMS: Immuno-inflammation contributes to the pathogenesis of Duchenne muscular dystrophy (DMD), characterized by progressive muscle degeneration and weakness. The nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is crucial for initiating innate immunity. Ghrelin is a circulating hormone that exerts anti-inflammatory activity in several inflammatory diseases. However, the role of ghrelin in DMD and underlying mechanism are still unstated. Therefore, we investigated the effect and potential mechanism of ghrelin on muscle morphology and muscular function of mdx mice, a mouse model of DMD. MAIN METHODS: 4-Week-old male mdx mice were injected intraperitoneally with ghrelin (100 µg/kg of body weight/day) or saline for 4 weeks. Then, muscle performance was evaluated by behavioral tests. Skeletal muscles samples were collected and relevant parameters were measured by using histopathological analysis and molecular biology techniques both in mdx muscles and primary myoblasts. KEY FINDINGS: Ghrelin significantly improved motor performance, alleviated muscle pathology and decreased inflammatory cell infiltration in mdx mice. Importantly, ghrelin dramatically inhibited NLRP3 inflammasome activation and reduced the production of mature IL-1ß both in dystrophic muscles and in lipopolysaccharide (LPS)-primed primary myoblasts induced by the NLRP3 inflammasome activator benzylated ATP (BzATP). Furthermore, the inhibition of NLRP3 inflammasome by ghrelin was partly mediated by the suppression of JAK2-STAT3 and p38 MAPK signaling pathway. SIGNIFICANCE: Our findings reveal that ghrelin suppresses muscle inflammation and ameliorates disease phenotype through inhibition of NLRP3 inflammasome activation and the production of IL-1ß in mdx mice, which suggests new therapeutic potential of ghrelin in DMD.

Mitochondrial dysfunction and cerebral metabolic abnormalities in patients with mitochondrial encephalomyopathy subtypes: Evidence from proton MR spectroscopy and muscle biopsy.

AIMS: Accumulated evidence indicates that cerebral metabolic features, evaluated by proton magnetic resonance spectroscopy (1 H-MRS), are sensitive to early mitochondrion dysfunction associated with mitochondrial encephalomyopathy (ME). The metabolite ratios of lactate (lac)/Cr, N-acetyl aspartate (NAA)/creatine (Cr), total choline (tCho)/Cr, and myoinositol (mI)/Cr are measured in the infarct-like lesions by 1 H-MRS and may reveal metabolic changes associated with ME. However, the application of this molecular imaging technique in the investigation of the pathology of ME subtypes is unknown. METHODS: In this study, cerebral metabolic features of pathologically diagnosed ME cases, that is, 19 mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); nine chronic progressive external ophthalmoplegia (CPEO); and 23 healthy controls, were investigated using 1 H-MRS. Receiver operating characteristics (ROC) analysis was used to evaluate the diagnostic power of the cerebral metabolites. Histochemical evaluation was carried out on muscle tissues derived from biopsy to assess the abnormal mitochondrial proliferation. The association between cerebral metabolic and mitochondrial cytopathy was examined by correlation analysis. RESULTS: Patients with MELAS or CPEO exhibited a significantly higher Lac/Cr ratio and a lower NAA/Cr ratio compared with controls. The ROC curve of Lac/Cr ratio indicated prominent discrimination between MELAS or CPEO and healthy control subjects, whereas the NAA/Cr ratio may present diagnostic power in the distinction of MELAS from CPEO. Lower NAA/Cr ratio was associated with higher Lac/Cr in MELAS, but not in CPEO. Furthermore, higher ragged-red fibers (RRFs) percentages were associated with elevated Lac/Cr and reduced NAA/Cr ratios, notably in MELAS. This association was not noted in the case of mI/Cr ratio. CONCLUSIONS: Mitochondrial cytopathy (lactic acidosis and RRFs on muscle biopsy) was associated with neuronal viability but not glial proliferation, notably in MELAS. Mitochondrial neuronopathy and neuronal vulnerability are considered significant causes in the pathogenesis of MELAS, particularly with regard to stroke-like episodes.

Correction: Cerebral Glioma Grading Using Bayesian Network with Features Extracted from Multiple Modalities of Magnetic Resonance Imaging.

[This corrects the article DOI: 10.1371/journal.pone.0153369.].

Cerebral Glioma Grading Using Bayesian Network with Features Extracted from Multiple Modalities of Magnetic Resonance Imaging.

Many modalities of magnetic resonance imaging (MRI) have been confirmed to be of great diagnostic value in glioma grading. Contrast enhanced T1-weighted imaging allows the recognition of blood-brain barrier breakdown. Perfusion weighted imaging and MR spectroscopic imaging enable the quantitative measurement of perfusion parameters and metabolic alterations respectively. These modalities can potentially improve the grading process in glioma if combined properly. In this study, Bayesian Network, which is a powerful and flexible method for probabilistic analysis under uncertainty, is used to combine features extracted from contrast enhanced T1-weighted imaging, perfusion weighted imaging and MR spectroscopic imaging. The networks were constructed using K2 algorithm along with manual determination and distribution parameters learned using maximum likelihood estimation. The grading performance was evaluated in a leave-one-out analysis, achieving an overall grading accuracy of 92.86% and an area under the curve of 0.9577 in the receiver operating characteristic analysis given all available features observed in the total 56 patients. Results and discussions show that Bayesian Network is promising in combining features from multiple modalities of MRI for improved grading performance.

High cytochrome c oxidase expression links to severe skeletal energy failure by (31)P-MRS spectroscopy in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.

AIMS: The purpose of this study was to evaluate the energy metabolism and mitochondrial function in skeletal muscle from patients with Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) or chronic progressive external ophthalmoplegia (CPEO) using phosphorus magnetic resonance spectroscopy ((31)P-MRS), to determine whether abnormally increasing cytochrome c oxidase (COX), as detected in muscle biopsy, could be a cause for MELAS. METHODS: (31)P-MRS was performed on the quadriceps femoris muscle of 12 healthy volunteers and 11 patients diagnosed as MELAS or CPEO by muscle biopsy and genetic analysis. All subjects experienced a state of rest, 5-min exercise, and 5-min recovery protocol in a supine position. RESULTS: Compared to CPEO, MELAS patients typically exhibited COX-positive ragged-red fibers (RRFs) as well as strongly SDH-positive blood vessels (SSVs). However, based on (31)P-MRS results, MELAS showed a higher inorganic phosphate (Pi)/phosphocreatine (PCr) ratio and lower ATP/PCr ratio during exercise and delayed Pi/PCr and ATP/PCr recovery to normal. CONCLUSIONS: This study suggests that high COX expression contributes to severe skeletal energy failure by (31)P-MRS spectroscopy in MELAS.

Human urinary kallidinogenase suppresses cerebral inflammation in experimental stroke and downregulates nuclear factor-kappaB.

The purpose of this study is to investigate the possible mechanism and the neuroprotective effect of human urinary kallidinogenase (HUK) in cerebral ischemia. The mouse middle cerebral artery occlusion (MCAO) model was used. Mice were treated with HUK (20 PNAU/g per day, intravenous) or saline as control, from the beginning of reperfusion to 72 h. Neurological deficits, infarct size, and BWC were measured at 6, 24, 48, and 72 h after MCAO, respectively. Pathological changes of brain were observed by TUNEL assay. Inflammatory factors were measured by real-time PCR and western blotting. Activation of MAPKs, Akt, and nuclear factor-kappaB (NF-kappaB) was detected by western blotting. Our results indicated that HUK significantly improved neurofunction, decreased infarct size, and suppressed edema, as well as inflammatory mediators as compared with the vehicle group. Furthermore, HUK inhibited the NF-kappaB pathway and activated the MAPK/ERK pathway in this neuroprotection.

Altered expression of Abeta metabolism-associated molecules from D-galactose/AlCl(3) induced mouse brain.

Cerebral deposition of amyloid-beta peptide (Abeta) is a critical feature of Alzheimer's disease (AD). Either aluminium trichloride (Al) or D-galactose (D-gal) induces Abeta overproduction in rat or mouse brain and has been used to produce models of aging and AD. Here it is shown that mice treated with Al plus D-gal represent a good model of AD with altered expression of Abeta metabolism-associated molecules. The work shows that Al/D-gal causes memory impairment and high Abeta levels in the cortex (Co) and hippocampus (Hi). Then, we found that beta-site APP cleavage enzyme 1 (BACE1) was increased in mouse Co and Hi. Al or Al plus D-gal suppressed mRNA of the low-density lipoprotein receptor-related protein 1(LRP1). D-gal also decreased the LRP expression in Hi, but not in Co. However, Al/D-gal did not affect the receptor for advanced glycation end products (RAGE) expression in mouse brains. Furthermore, Al/D-gal reduced the expression of neprilysin (NEP), but not the insulin degrading enzyme (IDE). This study indicates that Al/D-gal affects the expression of Abeta metabolism-associated molecules that are responsible for Abeta deposition during AD, suggesting that this mouse model can be a useful model for studying the mechanisms and biomarkers of AD and for drug screening.

Trichostatin A enhances OGD-astrocyte viability by inhibiting inflammatory reaction mediated by NF-kappaB.

In this study we investigate the protective effects of Trichostatin A (TSA) on astrocyte injury after oxygen-glucose deprivation (OGD) and further explore its possible protective mechanisms of inhibiting inflammatory reaction mediated by nuclear factor-kappaB (NF-kappaB). In the in vitro model of astrocyte OGD, TSA treatment was used at different doses and time points before deprivation. Astroglial viability was determined by MTT assay. Then tumor necrosis factor-alpha, interleukin-1beta (IL-1beta), and IL-6 mRNA were measured by RT-PCR. Furthermore, the expression of phosphorylated p65, mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (ERK), MAPK/c-Jun N-terminal (JNK) and MAPK/p38 was assayed by Western blot. The results showed that TSA at the five doses (12.5, 25, 50, 100, and 200 ng/ml) significantly enhanced the astrocytes viability by 25.3%, 46.1%, 37.5%, 34.9%, and 22% of the vehicle, respectively. The level of TNF-alpha, IL-1beta and IL-6 mRNA in astrocytes was increased after OGD and down-regulated by TSA (p<0.05). In addition, the phosphorylation p65 was markedly activated in the astrocytes after OGD compared to the control (p<0.05). TSA inhibited phosphorylation of p65 but did not affect the MAPK pathway. Our results suggest that TSA protects astrocytes from damage after OGD by the inhibition of the inflammatory reaction and this protection is at least partially through the suppression of phosphorylation of NF-kappaB p65.