3‐O‐Sulfation of Heparan Sulfate Enhances Tau Interaction and Cellular Uptake

Prion‐like transcellular spreading of tau in Alzheimer's Disease (AD) is mediated by tau binding to cell surface heparan sulfate (HS). However, the structural determinants for tau–HS interaction are not well understood. Microarray and SPR assays of structurally defined HS oligosaccharides show that a rare 3‐O‐sulfation (3‐O‐S) of HS significantly enhances tau binding. In Hs3st1^?/? (HS 3‐O‐sulfotransferase‐1 knockout) cells, reduced 3‐O‐S levels of HS diminished both cell surface binding and internalization of tau. In a cell culture, the addition of a 3‐O‐S HS 12‐mer reduced both tau cell surface binding and cellular uptake. NMR titrations mapped 3‐O‐S binding sites to the microtubule binding repeat 2 (R2) and proline‐rich region 2 (PRR2) of tau. Tau is only the seventh protein currently known to recognize HS 3‐O‐sulfation. Our work demonstrates that this rare 3‐O‐sulfation enhances tau–HS binding and likely the transcellular spread of tau, providing a novel target for disease‐modifying treatment of AD and other tauopathies.     

β-secretase 1 inhibitory activity and AMP-activated protein kinase activation of Callyspongia samarensis extracts

Abstract

The methanolic extract of Callyspongia samarensis (MCS) significantly inhibited β-secretase 1 (IC₅₀ 99.82?µg/mL) in a dose-dependent manner and demonstrated a noncompetitive type of inhibition. Furthermore, it exhibited the highest AMPK activation (EC₅₀ 14.47?μg/mL) as compared with the standard, Aspirin (EC₅₀ >100?μg/mL). HPLC/ESI-MS analysis of MCS extract revealed 15 peaks, in which nine peaks demonstrated similar fragmentation pattern with the known compounds in literature and in database library: 5-aminopentanoic acid (1), 4-aminobutanoic acid (3), Luotonin A (4), (E)-3-(1H-imidazol-5-yl) prop-2-enoic acid (8), Galactosphingosine (10), D-sphingosine (11), 5,7,4′-trihydroxy-3′,5′-dimethoxyflavone (12), hydroxydihydrovolide (13), and 3,5-dibromo-4-methoxyphenylpyruvic acid (14); and 6 peaks are not identified (2, 5–7, 9, and 15). Acute oral toxicity test of MCS extract revealed that it is nontoxic, with an LD₅₀ of >2000?mg/kg. Assessment of BBB permeability of MCS extract showed that compound 15 was able to cross the BBB making it a suitable candidate for developing CNS drugs.     

Continental and Antarctic Lichens: isolation,identification and molecular modeling of the depside tenuiorin from the Antarctic lichen Umbilicaria antarctica as tau protein inhibitor

Abstract

Alzheimer´s disease (AD) is the most common form of dementia involving Aβ and tau protein. So far, AD cure remains elusive, but considering that AD progresses throughout tau pathology, which turns tau protein an appropriate target, besides tau is also included in other neurodegenerative disorders named as tauopathies. Here, we have isolated seventeen compounds belonging to six lichens species. Due to scarce of spectroscopic data of the compound 5,7-dihydroxy-6-methylphthalide, we explained their structural elucidation based on NMR data. In this study, we show that only tenuiorin from Umbilicaria antarctica inhibited 50% of tau 4R at 100?µM. Then, we shown that molecular interactions of tenuiorin with the steric zipper model of the hexapeptide ³⁰⁶VQIVYK³¹¹ were studied by docking calculations and the results suggested that tenuiorin forms both hydrogen bonds with lysine and glutamine side chains and forms several hydrophobic interactions with valine and lysine from ³⁰⁶VQIVYK³¹¹ motif.     

柔性PDA薄膜阵列用于双模光学检测VOC标志物气体

本研究以亲油性的双面胶作为基底,利用滴涂二乙炔单体结合紫外光聚合来制备均匀的聚二乙炔(PDA)薄膜,通过荧光和颜色两种信号变化模式(即"双模光学检测")研究了PDA薄膜对VOC气体的响应性,发现制备的PDA薄膜在2 min内就可以实现明显的荧光和颜色变化,有效解决了目前PDA薄膜在VOC气体检测方面存在响应速度慢、薄膜均一性差等问题.此外,为解决单一PDA薄膜的交叉响应性问题,本研究制备了四种不同的基于双面胶基底的PDA薄膜,并将制备的4种PDA薄膜集成到一片PDMS薄膜基底上来构建柔性的传感阵列,利用阵列的颜色变化结合模式识别技术,实现了对8种VOC气体的快速、灵敏区分.进一步将制备的PDA薄膜阵列用于健康人、模拟糖尿病及肾病患者呼出气体中VOC标志物的辨别和分析研究,发现可以将三类人的呼出气体清晰地区分,说明了该阵列在呼气疾病诊断中的应用前景.与目前报道的PDA薄膜阵列相比,本研究中基于双面胶基底的PDA薄膜阵列具有气体响应速度快、灵敏性高、柔韧性好、制备工艺简单、成本低、易于大规模制备等优点,有望用于实VOC气体检测研究中.     

Examination of Changes in 6-minute Walk Distance and Related Factors in Patients with Perioperative Peripheral Arterial Disease

Objective: This study aimed to clarify the effects of pre- and postoperative physical function on the 6-minute walking distance (6MWD) in patients with peripheral arterial disease (PAD). Method: Forty-two elderly patients with PAD who were hospitalized for revascularization and able to walk independently were included in the study. The 6MWD, ankle brachial index (ABI), weight-bearing index (WBI), gait, and intermittent claudication distance (ICD) were measured before and after the surgery, and skeletal muscle index was measured only before surgery. Analyses were performed by comparing the pre- and postoperative values of each factor using a paired t-test. In addition, multiple regression analysis was performed with 6MWD as the dependent variable before and after surgery. Results: Postoperatively, pain disappeared in 22 patients, and ABI, ICD, 6MWD, and stride length improved significantly. ICD and stride length were extracted as factors related to 6MWD before and after surgery, and ABI, WBI, and stride length were extracted as factors related to 6MWD after surgery. Conclusion: The improvement of intermittent claudication associated with revascularization suggests a stronger influence of functional aspects on postoperative 6MWD.     

Specific Recognition of β-Galactofuranose-Containing Glycans of Synthetic Neoglycoproteins by Sera of Chronic Chagas Disease Patients

Chagas disease (CD) can be accurately diagnosed by detecting Trypanosoma cruzi in patients’ blood using polymerase chain reaction (PCR). However, parasite-derived biomarkers are of great interest for the serological diagnosis and early evaluation of chemotherapeutic efficacy when PCR may fail, owing to a blood parasite load below the method’s limit of detection. Previously, we focused on the detection of specific anti-α-galactopyranosyl (α-Gal) antibodies in chronic CD (CCD) patients elicited by α-Gal glycotopes copiously expressed on insect-derived and mammal-dwelling infective parasite stages. Nevertheless, these stages also abundantly express cell surface glycosylphosphatidylinositol (GPI)-anchored glycoproteins and glycoinositolphospholipids (GIPLs) bearing nonreducing terminal β-galactofuranosyl (β-Galf) residues, which are equally foreign to humans and, therefore, highly immunogenic. Here we report that CCD patients’ sera react specifically with synthetic β-Galf-containing glycans. We took a reversed immunoglycomics approach that entailed: (a) Synthesis of T. cruzi GIPL-derived Galfβ1,3Manpα-(CH₂)₃SH (glycan G29_SH) and Galfβ1,3Manpα1,2-[Galfβ1,3]Manpα-(CH₂)₃SH (glycan G32_SH); and (b) preparation of neoglycoproteins NGP29b and NGP32b, and their evaluation in a chemiluminescent immunoassay. Receiver-operating characteristic analysis revealed that NGP32b can distinguish CCD sera from sera of healthy individuals with 85.3% sensitivity and 100% specificity. This suggests that Galfβ1,3Manpα1,2-[Galfβ1,3]Manpα is an immunodominant glycotope and that NGP32b could potentially be used as a novel CCD biomarker.     

Design,Synthesis, and Structure–Activity Relationship Study of Potent MAPK11 Inhibitors

Huntington’s disease (HD) is a rare single-gene neurodegenerative disease, which can only be treated symptomatically. Currently, there are no approved drugs for HD on the market. Studies have found that MAPK11 can serve as a potential therapeutic target for HD. Regrettably, no MAPK11 small molecule inhibitors have been approved at present. This paper presents three series of compounds that were designed and synthesized based on the structure of skepinone-L, a known MAPK14 inhibitor. Among the synthesized compounds, 13a and 13b, with IC₅₀ values of 6.40 nM and 4.20 nM, respectively, displayed the best inhibitory activities against MAPK11. Furthermore, the structure–activity relationship (SAR) is discussed in detail, which is constructive in optimizing the MAPK11 inhibitors for better activity and effect against HD.     

铁过量与人体健康

综述了机体铁储存过多与某些疾病之间的关系,包括:铁过量与肝脏疾病、心血管病、肿瘤、肾损伤、高血压等有关。铁过量主要是由于病理过程和通过各种途径进入人体的铁量增加。过量的铁在失控条件下,引起细胞成分的明显损伤,导致组织炎症和多器官的纤维化。因为铁是自由基反应的催化剂,可引起过氧化作用或细胞膜脂质和细胞内化合物的交联反应,致细胞老化或死亡。     

A New Series of Aryloxyacetic Acids Endowed with Multi-Target Activity towards Peroxisome Proliferator-Activated Receptors (PPARs), Fatty Acid Amide Hydrolase (FAAH), and Acetylcholinesterase (AChE)

A new series of aryloxyacetic acids was prepared and tested as peroxisome proliferator-activated receptors (PPARs) agonists and fatty acid amide hydrolase (FAAH) inhibitors. Some compounds exhibited an interesting dual activity that has been recently proposed as a new potential therapeutic strategy for the treatment of Alzheimer’s disease (AD). AD is a multifactorial pathology, hence multi-target agents are currently one of the main lines of research for the therapy and prevention of this disease. Given that cholinesterases represent one of the most common targets of recent research, we decided to also evaluate the effects of our compounds on the inhibition of these specific enzymes. Interestingly, two of these compounds, (S)-5 and 6, showed moderate activity against acetylcholinesterase (AChE) and even some activity, although at high concentration, against Aβ peptide aggregation, thus demonstrating, in agreement with the preliminary dockings carried out on the different targets, the feasibility of a simultaneous multi-target activity towards PPARs, FAAH, and AChE. As far as we know, these are the first examples of molecules endowed with this pharmacological profile that might represent a promising line of research for the identification of novel candidates for the treatment of AD.     

A review of computational modeling and deep brain stimulation: applications to Parkinson's disease

Biophysical computational models are complementary to experiments and theories, providing powerful tools for the study of neurological diseases. The focus of this review is the dynamic modeling and control strategies of Parkinson's disease (PD). In previous studies, the development of parkinsonian network dynamics modeling has made great progress. Modeling mainly focuses on the cortex-thalamus-basal ganglia (CTBG) circuit and its sub-circuits, which helps to explore the dynamic behavior of the parkinsonian network, such as synchronization. Deep brain stimulation (DBS) is an effective strategy for the treatment of PD. At present, many studies are based on the side effects of the DBS. However, the translation from modeling results to clinical disease mitigation therapy still faces huge challenges. Here, we introduce the progress of DBS improvement. Its specific purpose is to develop novel DBS treatment methods, optimize the treatment effect of DBS for each patient, and focus on the study in closed-loop DBS. Our goal is to review the inspiration and insights gained by combining the system theory with these computational models to analyze neurodynamics and optimize DBS treatment.