Proteomics analysis provides novel biomarkers and therapeutic target candidates in the treatment of the Huang-Pu-Tong-Qiao formula in an AD rat mode

Background:Huang-Pu-Tong-Qiao formula(HPTQ),a traditional Chinese herbal formula,has a variety of pharmacological effects.It has been used to treat Alzheimer’s disease(AD)for decades.This study aimed to screen differentially expressed proteins in the hippocampus of AD model rats treated with HPTQ.Proteomic studies of the effects of HPTQ on AD are key to understanding the therapeutic mechanisms of HPTQ and identifying potential therapeutic targets.Methods:We hence used the isobaric tags for relative and absolute quantification(ITRAQ)approach to investigate the differentially expressed proteins in the hippocampus of AD model rats before and after HPTQ administration and to identify the potential therapeutic target proteins of HPTQ.In this study,the learning and memory abilities of AD rats were examined by the Morris water maze test.After HPTQ administration,the differentially expressed proteins in the hippocampus of AD rats were quantified and analyzed in silico.Furthermore,western blotting was used to verify the expression of related proteins.Results:The Morris water maze results showed that HPTQ could improve the learning and memory ability of AD model rats.The proteomics analysis results showed that 57 proteins were differentially expressed,of which 35 were up-regulated and 22 were down-regulated.Bioinformatics analysis indicated that proteins with altered expression after HPTQ treatment were involved in several biological processes that have the potential to exert neuroprotective effects.These included promoting the translation of ribosomes,improving the deposition of amyloid-beta(Aβ),regulating autophagy,regulating neuronal synaptic function and plasticity,and alleviating oxidative stress.Conclusion:In conclusion,we identified several potential therapeutic target proteins and related mechanistic pathways of HPTQ in the treatment of AD,laying the foundation for further investigation of the therapeutic effects of HPTQ.

Genistein suppresses the mitochondrial apoptotic pathway in hippocampal neurons in rats with Alzheimer's disease

Genistein is effective against amyloid-β toxicity, but the underlying mechanisms are unclear. We hypothesized that genistein may protect neurons by inhibiting the mitochondrial apoptotic pathway, and thereby play a role in the prevention of Alzheimer＇s disease. A rat model of Alzheimer＇s disease was established by intraperitoneal injection of D-galactose and intracerebral injection of amyloid-β peptide （25-35）. In the genistein treatment groups, a 7-day pretreatment with genistein （10, 30, 90 mg/kg） was given prior to establishing Alzheimer＇s disease model, for 49 consecutive days. Terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling assay demonstrated a reduction in apoptosis in the hippocampus of rats treated with genistein. Western blot analysis showed that expression levels of capase-3, Bax and cytochrome c were decreased compared with the model group. Furthermore, immunohistochemical staining revealed reductions in cytochrome c and Bax immunoreactivity in these rats. Morris water maze revealed a substantial shortening of escape latency by genistein in Alzheimer＇s disease rats. These findings suggest that genistein decreases neuronal loss in the hippocampus, and improves learning and memory ability. The neuroprotective effects of genistein are associated with the inhibition of the mitochondrial apoptotic pathway, as shown by its ability to reduce levels of caspase-3, Bax and cytochrome c.

Genistein protects hippocampal neurons against injury by regulating calcium/calmodulin dependent protein kinase Ⅳ protein levels in Alzheimer's disease model rats

Genistein has a neuroprotective effect in Alzheimer＇s disease, but its mechanism of action needs further clarification. Accumulating evidence suggests that excessive phosphorylation of tau protein causes production of neurofibrillary tangles, which is one of the main pathological characteristics of Alzheimer＇s disease, and tau protein can be phosphorylated by calcium/calmodulin dependent protein kinase IV （CAMK4）. After 7 days of pre-administration of genistein （90 mg/kg）, an Alzheimer＇s disease rat model was established using an intraperitoneal injection of D-galactose combined with an intracerebral injection of amyloid-β peptide （25-35）. The rat was then continu- ously administered genistein （90 mg/kg） for 42 days. The Morris water maze test, western blotting and hematoxylin-eosin staining results showed that genistein significantly decreased the escape latency and increased the number of times crossing the platform, reduced p-tau, CALM, CAMKK1 and p-CAMK4 protein levels in the hippocampus, and alleviated hippocampal neuron damage. These findings indicate that genistein may play a neuroprotective role in Alzheimer＇s disease through regulating CAMK4 to modulate tau hyperphosphorylation. Key

In vitro model of the blood-brain barrier established by co-culture of primary cerebral microvascular endothelial and astrocyte cells

Drugs for the treatment and prevention of nervous system diseases must permeate the bloodbrain barrier to take effect.In vitro models of the blood-brain barrier are therefore important in the investigation of drug permeation mechanisms.However,to date,no unified method has been described for establishing a blood-brain barrier model.Here,we modified an in vitro model of the blood-brain barrier by seeding brain microvascular endothelial cells and astrocytes from newborn rats on a polyester Transwell cell culture membrane with 0.4-μm pores,and conducted transepithelial electrical resistance measurements,leakage tests and assays for specific bloodbrain barrier enzymes.We show that the permeability of our model is as low as that of the bloodbrain barrier in vivo.Our model will be a valuable tool in the study of the mechanisms of action of neuroprotective drugs.

In situ apolipoprotein E-enriched corona guides dihydroartemisinin-decorating nanoparticles towards LDLr-mediated tumor-homing chemotherapy

The therapeutic efficiency of active targeting nanoparticulate drug delivery systems(nano-DDS)is highly compromised by the plasma proteins adsorption on nanoparticles(NPs)surface,which significantly hinders cell membrane receptors to recognize the designed ligands,and provokes the off-target toxicity and rapid clearance of NPs in vivo.Herein,we report a novel dihydroartemisinin(DHA)-decorating nano-DDS that in situ specifically recruits endogenous apolipoprotein E(apoE)on the NPs surface.The apoE-anchored corona is able to prolong PLGA-PEG2000-DHA(PPD)NPs circulation capability in blood,facilitate NPs accumulating in tumor cells by the passive enhanced permeability and retention(EPR)effect and low-density lipoprotein receptor(LDLr)-mediated target transport,and ultimately improve the in vivo antitumor activity.Our findings demonstrate that the strategy of in situ regulated apoE-enriched corona ensures NPs an efficient LDLr-mediated tumor-homing chemotherapy.

基于物品综合流行性的实时推荐算法

在这个信息化时代,爆炸式增长的信息具有时效性、共享性、相对价值性的特点。为了帮助用户克服由于信息过载而带来的选择困难问题,个性化推荐应运而生。"信息老化"是信息网络发展过程中必然经历的一个过程,因此将时间因素融入到推荐算法成为必然的趋势。大多数研究时间因素的推荐算法主要集中在用户兴趣的变化或是物品近期的流行性,忽略了物品在发展过程中的综合流行性。本文以物品的综合流行性(Com PI)为研究中心,提出一种实时推荐算法。本文的主要工作有:(1)在推荐中考虑了物品在生命周期的发展阶段。(2)将时间因素加入推荐算法,建立指数型的时间权重衰减模型来合理量化时间权重。(3)将全概率模型与时间衰减模型相结合来建立物品的综合流行性模型,进而提出一种实时推荐算法,有效解决了现有算法中的"营销近视"问题。(4)将算法应用于真实数据集测试表明,本文提出的实时推荐算法具有更好的准确性、多样性和新颖性。(5)本文还研究了数据的增长特性,以及数据增长特性对于数据划分和算法性能测评的影响,提出在研究推荐算法时应该更关注具有指数增长的数据。综上所述,该算法可以有效地利用推荐系统中的时间因素来改善用户体验。此外,ComPI模型还可以帮助研究网络拓扑的演化过程,并可应用于网络相关领域。

Study on the mechanism and active components of Radix et Rhizoma Rhei in the treatment of Alzheimer's disease based on molecular docking

Objective:To explore the mechanism and active components of Radix et Rhizoma Rhei in the treatment of Alzheimer's disease(AD)based on molecular docking.Methods:22 major components of Radix et Rhizoma Rhei were screened from TCMSP and related literatures,which docked with the key targets of NLRP3/Caspase-1/GSDMD signaling pathway.NLRP3,Caspase-1,GSDMD inhibitors MCC950,ML132 and LDC7559 were used as positive control to analyze the docking results.Results:The docking results showed that the main components of Radix et Rhizoma Rhei had different degrees of binding with NLRP3,Caspase-1 and GSDMD targets,and the potential active components were mutanochrome and physciondiglucoside.Conclusion:Molecular docking predicts that the main components of Radix et Rhizoma Rhei may act on NLRP3/Caspase-1/GSDMD signaling pathway,and the active components may be mutanochrome and physciondiglucoside,which provides theoretical basis for revealing the anti-inflammatory mechanism and active components of Radix et Rhizoma Rhei in the treatment of AD.

Comparison of efficacy and safety among axitinib,sunitinib,and sorafenib as neoadjuvant therapy for renal cell carcinoma:a retrospective study

Dear editor,Renal cancer accounts for approximately 2%of all can-cer deaths worldwide,and renal cell carcinoma(RCC)is the predominant subtype[1].Radiotherapy and chemo-therapy have been found to have limited roles in the treatment of RCC.However,the treatment outcomes of metastatic RCC(mRCC)have been improved drastically since the application of molecular targeted therapeutic agents such as tyrosine kinase inhibitors(TKIs).TKIs have been gradually used for the preoperative treatment of RCC.

Synchrotron Characterisation of Ultra-Fine Grain TiB_(2)/Al-Cu Composite Fabricated by Laser Powder Bed Fusion

Isotropy in microstructure and mechanical properties remains a challenge for laser powder bed fusion(LPBF)processed materials due to the epitaxial growth and rapid cooling in LPBF.In this study,a high-strength TiB_(2)/Al-Cu composite with random texture was successfully fabricated by laser powder bed fusion(LPBF)using pre-doped TiB_(2)/Al-Cu composite powder.A series of advanced characterisation techniques,including synchrotron X-ray tomography,correlative focussed ion beam-scanning electron microscopy(FIB-SEM),scanning transmission electron microscopy(STEM),and synchrotron in situ X-ray diffraction,were applied to investigate the defects and microstructure of the as-fabricated TiB_(2)/Al-Cu composite across multiple length scales.The study showed ultra-fine grains with an average grain size of about 0.86μm,and a random texture was formed in the as-fabricated condition due to rapid solidification and the TiB_(2)particles promoting heterogeneous nucleation.The yield strength and total elongation of the as-fabricated composite were 317 MPa and 10%,respectively.The contributions of fine grains,solid solutions,dislocations,particles,and Guinier-Preston(GP)zones were calculated.Failure was found to be initiated from the largest lack-of-fusion pore,as revealed by in situ synchrotron tomography during tensile loading.In situ synchrotron diffraction was used to characterise the lattice strain evolution during tensile loading,providing important data for the development of crystal-plasticity models.