Cellular response toβ-amyloid neurotoxicity in Alzheimer's disease and implications in new therapeutics

β-Amyloid(Aβ)is a specific pathological hallmark of Alzheimer's disease(AD).Because of its neurotoxicity,AD patients exhibit multiple brain dysfunctions.Disease-modifying therapy(DMT)is the central concept in the development of AD thera-peutics today,and most DMT drugs that are currently in clinical trials are anti-Aβdrugs,such as aducanumab and lecanemab.Therefore,understanding Aβ's neurotoxic mechanism is crucial for Aβ-targeted drug development.Despite its total length of only a few dozen amino acids,Aβis incredibly diverse.In addition to the well-known Aβ_(1-42),N-terminally truncated,glutaminyl cyclase(QC)catalyzed,and pyroglutamate-modified Aβ(pEAβ)is also highly amyloidogenic and far more cytotoxic.The extracel-lular monomeric Aβ_(x-42)(x=1-11)initiates the aggregation to form fibrils and plaques and causes many abnormal cellular responses through cell membrane receptors and receptor-coupled signal pathways.These signal cascades further influence many cel-lular metabolism-related processes,such as gene expression,cell cycle,and cell fate,and ultimately cause severe neural cell damage.However,endogenous cellular anti-Aβdefense processes always accompany the Aβ-induced microenvironment alterations.Aβ-cleaving endopeptidases,Aβ-degrading ubiquitin-proteasome system(UPS),and Aβ-engulfing glial cell immune responses are all essential self-defense mechanisms that we can leverage to develop new drugs.This review discusses some of the most recent advances in understanding Aβ-centric AD mechanisms and suggests prospects for promising anti-Aβstrategies.

Anti-diabetic potential of apigenin,luteolin,and baicalein via partially activating PI3K/Akt/GLUT-4 signaling pathways in insulin-resistant HepG2 cells

Dietary flavonoids are abundant in natural plants and possess multiple pharmacological and nutritional activities.In this study,apigenin,luteolin,and baicalein were chosen to evaluate their anti-diabetic effect in high-glucose and dexamethasone induced insulin-resistant(IR)HepG2 cells.All flavonoids improves the glucose consumption and glycogen synthesis abilities in IR-HepG2 cells via activating glucose transporter protein 4(GLUT4)and phosphor-glycogen synthase kinase(GSK-3β).These fl avonoids signifi cantly inhibited the production of reactive oxygen species(ROS)and advanced glycation end-products(AGEs),which were closely related to the suppression of the phosphorylation form of NF-κB and P65.The expression levels of insulin receptor substrate-1(IRS-1),insulin receptor substrate-2(IRS-2)and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)pathway in IR-HepG2 cells were all partially activated by the fl avonoids,with variable effects.Furthermore,the intracellular metabolic conditions of the fl avonoids were also evaluated.

Map Reconstruction of Radio Observations with Conditional Invertible Neural Networks

In radio astronomy,the challenge of reconstructing a sky map from time ordered data is known as an inverse problem.Standard map-making techniques and gridding algorithms are commonly employed to address this problem,each offering its own benefits such as producing minimum-variance maps.However,these approaches also carry limitations such as computational inefficiency and numerical instability in map-making and the inability to remove beam effects in grid-based methods.To overcome these challenges,this study proposes a novel solution through the use of the conditional invertible neural network(cINN)for efficient sky map reconstruction.With the aid of forward modeling,where the simulated time-ordered data(TODs)are generated from a given sky model with a specific observation,the trained neural network can produce accurate reconstructed sky maps.Using the Five-hundred-meter Aperture Spherical radio Telescope as an example,cINN demonstrates remarkable performance in map reconstruction from simulated TODs,achieving a mean squared error of2.29±2.14×10^(-4)K^(2),a structural similarity index of 0.968±0.002,and a peak signal-to-noise ratio of26.13±5.22 at the 1σlevel.Furthermore,by sampling in the latent space of cINN,the reconstruction errors for each pixel can be accurately quantified.

Exploring the Alzheimer's disease neuroepigenome: recent advances and future trends

Exploring the Alzheimer's disease neuroepigenome:recent advances and future trends:Alzheimer's disease (AD)is a chronic neurodegenerative disease and the most common cause of dementia.After decades of ongoing efforts by scientists,many hallmarks of AD,such as amyloid-β Aβ and tau pathologies.

DRP1 deficiency induces mitochondrial dysfunction and oxidative stress-mediated apoptosis during porcine oocyte maturation

Background: Environmental pollution induces oxidative stress and apoptosis in mammalian oocytes, which can cause defects in reproduction;however, the molecular regulation of oxidative stress in oocytes is still largely unknown. In the present study, we identified that dynamin-related protein 1(DRP1) is an important molecule regulating oocyte mitochondrial function and preventing oxidative stress/apoptosis. DRP1 is a member of the dynamin GTPase superfamily localized at the mitochondrial-endoplasmic reticulum interaction site, where it regulates the fission of mitochondria and other related cellular processes.Results: Our results show that DRP1 was stably expressed during different stages of porcine oocyte meiosis, and might have a potential relationship with mitochondria as it exhibited similar localization. Loss of DRP1 activity caused failed porcine oocyte maturation and cumulus cell expansion, as well as defects in polar body extrusion.Further analysis indicated that a DRP1 deficiency caused mitochondrial dysfunction and induced oxidative stress,which was confirmed by increased reactive oxygen species levels. Moreover, the incidence of early apoptosis increased as detected by positive Annexin-V signaling.Conclusions: Taken together, our results indicate that DRP1 is essential for porcine oocyte maturation and that a DRP1 deficiency could induce mitochondrial dysfunction, oxidative stress, and apoptosis.

儿童腺样体肥大的诊断与筛查技术进展现状

本文介绍了腺样体肥大的一般临床表现,尤其是对儿童发育的不良影响,简述了腺样体肥大诊断方法技术路线的发展历程,着重回顾各种诊断技术的应用,并比较分析其优缺点。腺样体扁桃体肥大的诊断方法较为多样,目前应用最广泛的头颅侧位片定量测量;随着技术的进步,能提供三维特征的锥形束CT(CBCT)和磁共振成像(MRI)也逐渐走进临床医生的视野,如何充分利用这些三维信息是目前研究的关注点之一;除此之外,超声、面部摄影等无创检查手段也取得了不错的诊断效果。随着计算机技术的发展,人工智能辅助诊断也是目前的研究热点之一,与传统手段相比,人工智能自动诊断速度显著提高,准确度也在不断提高。

Seasonal change of circulating leptin associated with testicular activities of the wild ground squirrels(Citellus dauricus)

The purpose of this study was to explore the variations in the circulating leptin concentrations of the wild ground squirrels in relation to seasonal changes in testicular activities.Hematoxylin-eosin staining showed all types of elongated spermatids and spermatogenic cells existed in the testis in April,while the primary spermatocytes and spermatogonia were most advanced stages of germ cells in June.In addition,the primary spermatocytes,secondary spermatocytes,and spermatogonia were most advanced stages of germ cells in September.The highest circulating leptin concentration was consistent with the maximum body weight results from accumulation of adipose tissue in September.The mRNA expression level of leptin receptor(Ob-R)and STAT3 was lowest in June,raised in September,and remained increased in April.Ob-R and STAT3 were stronger staining in the Leydig cells in July.Moreover,the concentrations of testosterone(T)showed the maximum values in April,the minimum values in June,and significant increases in September.Furthermore,it is worth noting that the levels of T increased with the mRNA levels of Ob-R,STAT3,StAR,and testicular steroidogenic enzymes(3β-HSD,P450c17,and P450scc).Moreover,RNA-seq analyses of testis during the different periods showed that a total of 4209 genes were differ-entially expressed genes(DEGs);further analysis revealed that DEGs related with the Jak/STAT pathways and reproduction were altered.Taken together,the results suggested that the leptin regulated testicular function through the Jak/STAT pathways and testicular steroidogenic factor expressions.

MicroRNA-132 in the Adult Dentate Gyrus is Involved in Opioid Addiction Via Modifying the Differentiation of Neural Stem Cells

MicroRNA-132(miR-132), a small RNA that regulates gene expression, is known to promote neurogenesis in the embryonic nervous system and adult brain.Although exposure to psychoactive substances can increase miR-132 expression in cultured neural stem cells(NSCs)and the adult brain of rodents, little is known about its role in opioid addiction. So, we set out to determine the effect of miR-132 on differentiation of the NSCs and whether this effect is involved in opioid addiction using the rat morphine self-administration(MSA) model. We found that miR-132 overexpression enhanced the differentiation of NSCs in vivo and in vitro. Similarly, speci?c overexpression of miR-132 in NSCs of the adult hippocampal dentate gyrus(DG) during the acquisition stage of MSA potentiated morphine-seeking behavior. These ?ndings indicate that miR-132 is involved in opioid addiction,probably by promoting the differentiation of NSCs in the adult DG.

Novel phthalimides regulating PD-1/PD-L1 interaction as potential immunotherapy agents

Programmed cell death 1(PD-1)/programmed cell death ligand 1(PD-L1)have emerged as one of the most promising immune checkpoint targets for cancer immunotherapy.Despite the inherent advantages of small-molecule inhibitors over antibodies,the discovery of small-molecule inhibitors has fallen behind that of antibody drugs.Based on docking studies between small molecule inhibitor and PD-L1 protein,changing the chemical linker of inhibitor from a flexible chain to an aromatic ring may improve its binding capacity to PD-L1 protein,which was not reported before.A series of novel phthalimide derivatives from structure-based rational design was synthesized.P39 was identified as the best inhibitor with promising activity,which not only inhibited PD-1/PD-L1 interaction(IC_(50)=8.9 nmol/L),but also enhanced killing efficacy of immune cells on cancer cells.Co-crystal data demonstrated that P39 induced the dimerization of PD-L1 proteins,thereby blocking the binding of PD-1/PD-L1.Moreover,P39 exhibited a favorable safety profile with a LD_(50)>5000 mg/kg and showed significant in vivo antitumor activity through promoting CD8^(+)T cell activation.All these data suggest that P39 acts as a promising small chemical inhibitor against the PD-1/PD-L1 axis and has the potential to improve the immunotherapy efficacy of T-cells.

Overcoming Mycobacterium tuberculosis through small molecule inhibitors to break down cell wall synthesis

Mycobacterium tuberculosis(MTB) utilizes multiple mechanisms to obtain antibiotic resistance during the treatment of infections. In addition, the biofilms, secreted by MTB, can further protect the latter from the contact with drug molecules and immune cells. These self-defending mechanisms lay a formidable challenge to develop effective therapeutic agents against chronic and recurring antibiotictolerant MTB infections. Although several inexpensive and effective drugs(isoniazid, rifampicin, pyrazinamide and ethambutol) have been discovered for the treatment regimen, MTB continues to cause considerable morbidity and mortality worldwide. Antibiotic resistance and tolerance remain major global issues, and innovative therapeutic strategies are urgently needed to address the challenges associated with pathogenic bacteria. Gratifyingly, the cell wall synthesis of tubercle bacilli requires the participation of many enzymes which exclusively exist in prokaryotic organisms. These enzymes, absent in human hepatocytes, are recognized as promising targets to develop anti-tuberculosis drug. In this paper, we discussed the critical roles of potential drug targets in regulating cell wall synthesis of MTB. And also, we systematically reviewed the advanced development of novel bioactive compounds or drug leads for inhibition of cell wall synthesis, including their discovery, chemical modification, in vitro and in vivo evaluation.