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The extracellular domain (p75ECD) of p75 neurotrophin receptor (p75NTR) antagonizes Aβ neurotoxicity and promotes Aβ clearance in Alzheimer's disease (AD). The impaired shedding of p75ECD is a key pathological process in AD, but its regulatory mechanism is largely unknown. This study was designed to investigate the presence and alterations of naturally-occurring autoantibodies against p75ECD (p75ECD-NAbs) in AD patients and their effects on AD pathology. We found that the cerebrospinal fluid (CSF) level of p75ECD-NAbs was increased in AD, and negatively associated with the CSF levels of p75ECD. Transgenic AD mice actively immunized with p75ECD showed a lower level of p75ECD and more severe AD pathology in the brain, as well as worse cognitive functions than the control groups, which were immunized with Re-p75ECD (the reverse sequence of p75ECD) and phosphate-buffered saline, respectively. These findings demonstrate the impact of p75ECD-NAbs on p75NTR/p75ECD imbalance, providing a novel insight into the role of autoimmunity and p75NTR in AD.
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Mice , Animals , Alzheimer Disease/pathology , Receptor, Nerve Growth Factor , Amyloid beta-Peptides , Autoantibodies , Mice, TransgenicABSTRACT
Objective:To observe the effect of Puerariae Lobatae Radix on type 2 diabetes mellitus (T2DM) rats and related mechanism. Method:Ninety SD rats were divided into normal group, model group, metformin group, Puerariae Lobatae Radix high dose group, Puerariae Lobatae Radix medium dose group and Puerariae Lobatae Radix low dose group, 15 rats in each group. The rats in abnormal group were fed with high-fat and high sugar diet for 4 weeks, and then T2DM model was established by intraperitoneal injection of 40 mg·kg-1 streptozotocin (STZ). Puerariae Lobatae Radix high-dose group was intragastrically administered with 2.1 g·kg-1 of Puerariae Lobatae Radix extract powder, Puerariae Lobatae Radix medium-dose group was intragastrically administered with 1.4 g·kg-1 of Puerariae Lobatae Radix extract powder, Puerariae Lobatae Radix low-dose group was intragastrically administered with 0.7 g·kg-1 of Puerariae Lobatae Radix extract powder, 0.2 g·kg-1 of metformin hydrochloride in metformin group, distilled water once a day in normal group and model group. After 8 weeks, fasting blood glucose (FBG), glycosylated serum protein (GSP), insulin (FINS), triglyceride (TG), cholesterol (TC) were measured, and insulin resistance index （HOMA-IR） was calculated. The expression of tumor necrosis factor -α(TNF-α) was observed by immunohistochemistry. Western blot was used to detect the protein expression of glucose regulatory protein 78 （GRP78）, activated transcription factor 6 （ATF6） in pancreatic tissue. Result:Compared with normal group, the contents of FBG, GSP, TG, TC, FINS, TNF-α in model group were significantly increased (P<0.05), the HOMA-IR was significantly increased (P<0.05), the protein expressions of GRP78 and ATF6 in pancreatic tissue were significantly increased (P<0.05). Compared with model group, the contents of FBG, GSP, TG, TC, FINS and TNF-α in the metformin group and Puerariae Lobatae Radix high, medium and low dose groups were significantly decreased (P<0.05), HOMA-IR decreased significantly (P<0.05), and the expression of GRP78 and ATF6 protein in pancreatic tissue decreased significantly (P<0.05). Conclusion:Puerariae Lobatae Radix can significantly improve insulin resistance in T2DM rats, inhibit the expression of inflammatory factor TNF-α in pancreatic tissue, reduce the protein expression of GRP78 and ATF6 in pancreatic tissue.
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To evaluate whether the polygenic profile modifies the development of sporadic Alzheimer's disease (sAD) and pathological biomarkers in cerebrospinal fluid (CSF), 462 sAD patients and 463 age-matched cognitively normal (CN) controls were genotyped for 35 single-nucleotide polymorphisms (SNPs) that are significantly associated with sAD. Then, the alleles found to be associated with sAD were used to build polygenic risk score (PRS) models to represent the genetic risk. Receiver operating characteristic (ROC) analyses and the Cox proportional hazards model were used to evaluate the predictive value of PRS for the sAD risk and age at onset. We measured the CSF levels of Aβ42, Aβ42/Aβ40, total tau (T-tau), and phosphorylated tau (P-tau) in a subgroup (60 sAD and 200 CN participants), and analyzed their relationships with the PRSs. We found that 14 SNPs, including SNPs in the APOE, BIN1, CD33, EPHA1, SORL1, and TOMM40 genes, were associated with sAD risk in our cohort. The PRS models built with these SNPs showed potential for discriminating sAD patients from CN controls, and were able to predict the incidence rate of sAD and age at onset. Furthermore, the PRSs were correlated with the CSF levels of Aβ42, Aβ42/Aβ40, T-tau, and P-tau. Our study suggests that PRS models hold promise for assessing the genetic risk and development of AD. As genetic risk profiles vary among populations, large-scale genome-wide sequencing studies are urgently needed to identify the genetic risk loci of sAD in Chinese populations to build accurate PRS models for clinical practice.
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Objective: To investigate the mechanism of Shenling Baizhu San (SLBZS) in treating dextra sulfate sodium (DSS)-induced inflammatory bowel disease (IBD) mice and its relationship with autophagy. Method: SPF BALB/c mice were randomly divided into control group,model group,mesalazine group,low,medium and high-dose SLBZS groups,and autophagy inducer rapamycin group.The IBD mice were fed with 5% DSS in their drinking water for 7 days,and the control mice received only water.SLBZS groups were given SLBZS at doses of 3,6,12 g·kg-1·d-1, positive group was given mesalazine sustained release granules at the dose of 2 g·kg-1·d-1, rapamycin group was given rapamycin at the dose of 4 mg·kg-1·d-1, and control mice was given the same volume of normal saline by gavage.The mice weight,stool occult blood in stool,score of disease activity (DAI),pathological examination of intestinal mucosal lesions integral were observed after 7 days. interleukin(IL)-8 and IL-10 in serum were detected by enzyme\|linked immuno sorbent assay(ELISA), vascular tissue samples were prepared for the detection of tumor neorosis factor-(TNF-α) and IL-1β, and transmission electron microscope and Western blot were used to detect the formation of autophagosomes and the level of autophagy. Result: The body mass decrease, the colon length, disease activity scoring, and histological scoring of SLBZS group were better than those of DSS group. Compared with control group, the level of IL-10 decreased, while the level of IL-8 increased obviously (Pα expressions significantly up-regulated(PPPα expressions(PConclusion: Shenling Baizhu San can significantly inhibit the IBD by regulating autophagy and suppressing inflammation.
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Objective:To investigate the effect of Shenling Baizhu San on inflammatory bowel disease (IBD) induced by 5% dextran sodium sulfate (DSS) in mice by regulating autophagy of intestinal epithelial cells. Method:The 84 BALB/c mice were randomly divided into 7 groups with 12 mice in each group. In addition to the normal group, 5% DSS was freely drunk for 7 days to induce acute inflammatory bowel disease. In the treatment group, high, medium and low doses of shenlingbaishu powder (12,6,3 g·kg-1·d-1), mesalazine (2 g·kg-1·d-1) and autophagy inducer rapamycin (4 mg·kg-1·d-1) were given by gavage. Hematoxylin-eosin (HE) staining was used to observe the morphological changes of colon tissues in mice. The autophagosome formation of intestinal epithelial cells was detected by transmission electron microscopy. Western blot was used to detect the ratio of autophagy related protein LC3-Ⅱ/LC3-Ⅰ, phosphatidylinositol-3kinase (PI3K), mammalian target of rapamycin (mTOR), ubiquitin-binding protein-1 (p62), Beclin1 phosphorylation, ULK1, 4EBP protein expression. Result:Compared with normal group, model group mice colonic mucosa epithelial cells are widely missed, most incomplete glands, change in colitis, LC3-Ⅱ content decreased significantly (PPPPPConclusion:The effect of Shenling Baizhu San on DSS-induced IBD is related to the regulation of the phosphorylation of PI3K, mTOR and p62 proteins in the autophagy pathway of intestinal epithelial cells.
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Objective:To investigate the effect of Buyang Huanwu Tang in resisting lipopolysaccharide (LPS)-induced macrophage activation and autophagy through phosphatidylinositol 3-kinase/protein kinase B/mammalian rapamycin target protein (PI3K/Akt/mTOR) signaling pathway. Method:The cell counting kit-8 (CCK-8) method was used to screen out the optimal LPS concentration for inducing the activity of RAW264.7 macrophages. RAW264.7 macrophages were treated separately with PI3K blocker 3-methyladenine(3-MA) (5 mmol·L-1), Akt blocker MK2206 (5 μmol·L-1), mTOR blocker Rapamycin (10 μmol·L-1), Beclin1 blocker Spautin-1 (5 μmol·L-1), different doses of Buyang Huanwu Tang serum (5%, 10%, 20%) and the optimum concentration of LPS for 24 h. The concentrations of inflammatory factors interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in RAW264.7 macrophages were detected by enzyme-lined immunosorbent assay(ELISA). Western blot was used to detect the expression levels of phosphorylated PI3K, phosphorylated Akt, phosphorylated mTOR protein, microtubule light chain protein 3 (LC3), ubiquitin-binding protein 1 (p62) and Beclin-1. The autophagy flow of RAW264.7 cells was detected by transfection with autophagy double-labeled adenovirus. Result:Results of CCK-8 showed the highest cell viability when 10 mg·L-1 LPS was applied. The concentrations of IL-1β, IL-6 and TNF-α in the model group were significantly higher than those in the blank group (PPβ, IL-6 and TNF-α (PPPPPPPPConclusion:Buyang Huanwu Tang can resist LPS-induced macrophages activation and autophagy, inhibit macrophage inflammatory response, regulate PI3K/Akt/mTOR signaling pathway, and inhibit the excessive occurrence of autophagy.
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Alzheimer's disease (AD), the most common type of dementia, is becoming a major challenge for global health and social care. However, the current understanding of AD pathogenesis is limited, and no early diagnosis and disease-modifying therapy are currently available. During the past year, significant progress has been made in clinical research on the diagnosis, prevention, and treatment of AD. In this review, we summarize the latest achievements, including diagnostic biomarkers, polygenic hazard score, amyloid and tau PET imaging, clinical trials targeting amyloid-beta (Aβ), tau, and neurotransmitters, early intervention, and primary prevention and systemic intervention approaches, and provide novel perspectives for further efforts to understand and cure the disease.
Subject(s)
Animals , Humans , Alzheimer Disease , Diagnosis , Therapeutics , Biomarkers , Blood , Biomedical Research , Methods , Disease Progression , Magnetic Resonance ImagingABSTRACT
OBJECTIVE: To investigate the effects of Buyanghuanwu decoction on preventing atherosclerosis induced by Hey in rats in vivo. METHODS: The model of atherosclerosis in rats was induced by intragastric gavage of Hey. The intervention group was administered Buyanghuanwu decoction (5, 10, 20 g · kg-1 · d-1). After 8 weeks treatment, the area of atherosclerotic plaques, blood vessel walls and their ratio, and ROS contention in the aorta were analyzed. The positive cell ratio of NF-κB P65 in vascular was detected by immunohistochemistry, and the expression of I-κBα was determined by Western-blotting. RESULTS: The rats in the model group showed evident AS lesions which had significant difference with others groups. Compared with control group, the ROS content of model group was elevated (P < 0.01), the I-κBα protein in the vascular tissue was significantly reduced, and NF-κB was significantly activated. Different doses of Buyanghuanwutang decoction could decrease ROS content (P < 0.01), improve I-κBα protein and inhibit the activation of NF-κB. CONCLUSION: Buyanghuanwutang decoction can prevent atherosclerosis induced by Hcy via inhibiting NF-κB-dependent pathway. Copyright 2012 by the Chinese Pharmaceutical Association.
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Objective To explore the prognostic value of pediatric critical illness score(PCIS)and pediatric risk of mortality score(PRISMⅢ)and the accuracy for evaluating the state of children with acute respiratory distress syndrome(ARDS).Methods Seventy-one cases hospitalized children from 29 days to 14 years old of Hebei ARDS cooperation group were selected during the 13 months between 2005 and 2006.All cases were confirmed according to ARDS diagnostic standard.For prospective studies,the patients were scored simultaneously with PCIS and PRISMⅢ at different times:when the patients entered PICU,when the patients were in the worst situation in PICU,when the patients were diagnosed as ARDS and when ARDS was serious.The data were performed by using Logistic regression etc.Results Values of Logistic regression were P
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<p><b>OBJECTIVE</b>To evaluate the value of C-reactive protein (CRP) to diagnostic test in elderly patients with infections.</p><p><b>METHODS</b>C-reactive protein were investigated in 142 elderly patients with infections and 216 elderly patients without. CRP 7 - 20, 21 - 40 and 41 - 60 mg/L were stratified, the index of diagnostic test counted.</p><p><b>RESULTS</b>Concentrations of CRP in patients with different diseases were upper respiratory tract infection 36.9 mg/L +/- 28.9 mg/L, acute bronchitis 30.1 mg/L +/- 28.1 mg/L, pneumonia 55.9 mg/L +/- 32.9 mg/L, urinary infection 49.0 mg/L +/- 27.6 mg/L and enteritis 39.3 mg/L +/- 35.6 mg/L. They were all higher than those in control group (5.2 mg/L +/- 2.9 mg/L, P < 0.001). Stratified analysis disclosed that the specificity of CRP was 83.3% - 99.0% for diagnostic infection disease. The positive likelihood ratio (LR) of 7 - 20, 21 - 40 and 41 - 60 mg/L were 3.6, 27.0 and 128.0, respectively.</p><p><b>CONCLUSION</b>C-reactive protein was an important marker to diagnose elderly patients with infections.</p>
Subject(s)
Aged , Female , Humans , Male , Middle Aged , Biomarkers , C-Reactive Protein , Diagnostic Tests, Routine , Pneumonia , Diagnosis , Respiratory Tract Infections , Diagnosis , Urinary Tract Infections , DiagnosisABSTRACT
Vascular-resided bacterial and fungal diseases have caused a great deal of yield loss and quality reduction in crop production world-wide. For genetic engineering of crops resistant to these diseases, it is disirable to have a strong and vascular-specific promoter. This article reviews the progress in identification of vascular-specific promoters and its function. To date, roughly twenty vascular-specific promoters have been documented. The cis-elements and motifs have been studied in detail for the promoters of bean phenylalanine ammonia lyase (PAL2), bean glycine-rich protein (grp 1.8) and Arabidopsis profilin2 (pfn2) in particular.The motif of vs-1 (CATGCTCCGTTGGATGTGGAAGACAGCA) found in grp 1.8 promoter was a cis-element that specificically bind to a transcription activation factor VSF-1 protein (one of the bZIP proteins). Mutation of vs-1 prevented it from binding to VSF-1 that resulted in abolishing the vascular-specific expresson of gus gene. Motifs of AC-I and AC-II found in PAL2 promoter were also found to be essential for vascular-specific expression. In our laboratory we have dissected pfn2 promoter into three domains (A, B, C) through 5'-deletion analysis. In this promoter we have identified two core sequences of ACGT that is commonly found in the binding sites of bZIP protein, the most abundent transcription factor existed in plants. In additon, the pfn2 promoter also contains an AC- I like sequence (CCACCTAC) that is similar to the AC- I motif (CCCACCTACC) found in PAL2 promoter. These promoters and cis-elements may have a wide range of potential applications to the genetic improvement of crops resistant to vascular diseases.
Subject(s)
Gene Expression Regulation, Plant , Genetics , Physiology , Phenylalanine Ammonia-Lyase , Genetics , Plant Proteins , Genetics , Promoter Regions, Genetic , Genetics , Regulatory Sequences, Nucleic Acid , GeneticsABSTRACT
The paper introduces four kinds of 2450 MHz antennas including noninsulted (bare), insulated-open-tip (I.O.T.), dipole-type and sleeve invasive microwave ones. The comparison between the antennas' hyperthermia performances in the muscle tissue phantom made by specific absorption rate (SAR) shows that the sleeve antenna is the best. It has a bigger heating range and a changeless shape and is independent of the inserting depth.