Search

Background: Genetic factors are increasingly being recognized as important contributors to the pathogenesis of Alzheimer's disease (AD). While the expression of most AD risk genes is enriched in microglia, which leads to microglial dysfunction and amyloid‐beta (Aβ) accumulation, emerging studies suggest that changes in the brain micro‐environment—typically changes in the levels of soluble factors—also modulate microglial functions and disease‐related pathological changes. Therefore, understanding the genetic regulation and pathogenic roles of those soluble factors in AD will help clarify the pathophysiological mechanisms of the disease. Method: We examined the changes in the level of soluble ST2 (sST2), a decoy receptor of IL‐33/ST2 signaling, in the blood and brains of patients with AD, and performed a genome‐wide association study (GWAS) for sST2 to understand its genetic regulations. Result: We showed that elevated sST2 levels are associated with more severe neurodegeneration and Aβ pathological lesions in patients with AD. Our GWAS analysis identified a genetic variant in IL1RL1 (the gene encoding sST2) that is associated with decreased sST2 levels in the blood and brain in AD. Furthermore, we demonstrated that female APOE‐ε4 carriers harboring the genetic variant exhibit decreased sST2 level and reduced risk of AD as well as decreased Aβ accumulation through enhancing microglial activation and colocalization with Aβ. Conclusion: These findings demonstrate how sST2 level in the brain milieu is modulated by a genetic variation and plays a disease‐causing role in AD through microglial clearance of Aβ, and might thus be a novel target for AD therapy. [ABSTRACT FROM AUTHOR]

A pair of unusual melibiose esters (1α/1β) and a pair of unusual raffinose esters (2α/2β), were isolated from Scrophularia ningpoensis. Structures of them were established by detailed spectroscopic analyses to be 6-O-(E)-cinnamoyl-α-d-galactopyranosyl-(1→6)-α(β)-d-glucopyranose (1α/1β) and 6-O-(E)/(Z)-cinnamoyl-α-d-galactopyranosyl-(1→6)-α-d-glucopyranosyl-(1→2)-β-d-fructofuranose (2α/2β), respectively. All these compounds were evaluated for antifouling activity against the settlement of Balanus amphitrite larvae, along with the cytotoxic effect against the proliferation of HeLa cell lines. [ABSTRACT FROM AUTHOR]

Anemoside A3 (AA3) is a natural triterpenoid glycoside isolated from the root of Pulsatilla chinensis (Bunge) Regel. We previously showed that AA3 exhibits cognitive-enhancing and neuroprotective properties. In the present study, we demonstrated that AA3 modulates inflammatory responses by regulating prostaglandin E receptor 4 signaling. Because prostaglandin E receptor 4 is involved in the pathophysiology of experimental autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis (MS), we assessed the beneficial effect of AA3 in EAE mice. AA3 treatment significantly reduced clinical severity and inflammatory infiltrates in the spinal cord of EAE mice. In vitro studies revealed that AA3 inhibited the T cell response toward the encephalitogenic epitope of myelin oligodendrocyte glycoprotein (MOG). AA3 significantly downregulated the expressions of certain Th1 and Th17 cytokines in activated T cells re-stimulated by MOG. Moreover, AA3 inhibited the activation of STAT4 and STAT3, which are the transcription factors pivotal for Th1 and Th17 lineage differentiation, respectively, in activated T cells. Pharmacological analysis further suggested that AA3 reduced Th17 cell differentiation and expansion. In conclusion, AA3 exerts an immunomodulatory effect in EAE, demonstrating its potential as a therapeutic agent for MS in humans. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a leading cause of mortality in the elderly. Genetics studies suggest that AD is polygenic in nature; thus, an individual's risk of AD can be predicted by polygenic risk score (PRS) models. Of these models, the deep learning models more accurately capture nonlinear interactions among different genetic risks and are more suitable for modeling disease polygenic risk. Method: We used the neural network‐based deep learning models to evaluate the polygenic risk of AD. Meanwhile, we examined the associations of resultant PRSs and plasma protein biomarkers for AD by regression analysis. We also identified the biological pathways that contribute to the polygenic risk using Gene Set Enrichment Analysis. Result: We found that the resultant PRSs of AD are associated with the levels of specific AD plasma protein biomarkers, including amyloid beta and p‐tau181, as well as changes in the activity of specific biological events, such as TNF‐α and cytokine‐related pathways. Conclusion: Our findings suggest that AD polygenic risk is associated with AD progression and modulates immune‐associated pathways. They also highlight the potential use of deep learning methods in investigating the underlying genetic mechanisms of AD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a leading cause of mortality in the elderly. Genetics studies have identified variants associated with AD. Moreover, Polygenic score analysis can infer the risk of developing AD solely on the basis of genotype information. Method: Whole‐genome sequencing was performed in 2 AD cohorts recruited from mainland China (n = 2,340) and Hong Kong (n = 1,009). Genotype and phenotype data were input into a neural network model that output a polygenic score. Regression analysis was subsequently conducted to examine the associations between the resultant polygenic scores and AD plasma biomarkers. Result: The resultant polygenic scores were associated with AD pathogenesis and the levels of specific AD plasma biomarkers in the Chinese population. Conclusion: The results suggest that deep‐learning methods have utility for investigating the underlying mechanisms of AD and promote the possibility of developing a genotype‐based strategy for AD risk prediction. [ABSTRACT FROM AUTHOR]

Fully functionalized pyranuloses derived from Achmatowicz rearrangement (AR) are versatile building blocks in organic synthesis. However, access to trans-2,6-dihydropyrans from pyranuloses remains underexplored. Herein, we report a new two-step trans arylation of AR products to access 2,6-trans-dihydropyranones. This new trans-arylation method built on numerous plausible, but unsuccessful, direct arylation reactions, including Ferrier-type and Tsuji- Trost-type reactions, was finally enabled by an unprecedented, highly regioselective γ-deoxygenation of AR products by using Zn/HOAc and a diastereoselective Heck-Matsuda coupling. The synthetic utility of the reaction was demonstrated in the first asymmetric total synthesis of (-)-musellarins A-C and 12 analogues in 11-12 steps. The brevity and efficiency of our synthetic route permitted preparation of enantiomerically pure musellarins and analogues (>20 mg) for preliminary cytotoxicity evaluation, which led us to identify two analogues with three-to-six times greater potency than the musellarins as promising new leads. [ABSTRACT FROM AUTHOR]

Twenty nine novel spiroketal derivatives related to the rubromycins were evaluated for their anti-telomerase activity using the real-time quantitative telomeric repeat amplification protocol assay. The parent compound γ-rubromycin exhibited the highest potency against human telomerase activity within the series. Modification of the spiroketal motif by the introduction of heteroatoms and substituents at different positions produced analogues with varying bioactivity. Variation at the isocoumarin subunit of the title compound resulted in weaker activity, indicative of its importance in telomerase inhibition. [ABSTRACT FROM AUTHOR]

Oleanolic acid (3β-hydroxy-olea-12-en-28-oic acid) is a natural pentacyclic triterpenoic acid found in many fruits, herbs and medicinal plants. In the past decade, increasing evidence has suggested that oleanolic acid exhibits inhibitory activities against different types of cancer including skin cancer and colon cancer, but not leukemia. We report here that a derivative of oleanolic acid, olean-12-eno[2,3-c] [1], [2], [5]oxadiazol-28-oic acid (designated OEOA) effectively blocks the proliferation of human leukemia cells. OEOA significantly reduces cell proliferation without inducing cell death in three types of leukemia cell lines, including K562, HEL and Jurket. Moreover, exposure of K562 cells to OEOA results in G1 cell cycle arrest, with a concomitant induction of cyclin-dependent kinase inhibitor p27 and downregulation of cyclins and Cdks that are essential for cell cycle progression. Interestingly, OEOA also enhances erythroid differentiation in K562 cells through suppressing the expression of Bcr-Abl and phosphorylation of Erk1/2. These findings identify a novel chemical entity for further development as therapeutics against leukemia. [ABSTRACT FROM AUTHOR]

One of the pathological hallmarks of Alzheimer's disease (AD) is deposition of extracellular amyloid-β(Aβ) peptide, which is generated from the cleavage of amyloid precursor protein (APP). Accumulation of Aβ is thought to associate with the progressive neuronal death observed in AD. However, the precise signaling mechanisms underlying the action of Aβ in AD pathophysiology are not completely understood. Here, we report the involvement of the transcription factor signal transducer and activator of transcription 3 (STAT3) in mediating Aβ-induced neuronal death. We find that tyrosine phosphorylation of STAT3 is elevated in the cortex and hippocampus of APP/PS1 transgenic mice. Treatment of cultured rat neurons with Aβ or intrahippocampal injection of mice with Aβ both induces tyrosine phosphorylation of STAT3 in neurons. Importantly, reduction of either the expression or activation of STAT3 markedly attenuates Aβ-induced neuronal apoptosis, suggesting that STAT3 activation contributes to neuronal death after Aβ exposure. We further identify Tyk2 as the tyrosine kinase that acts upstream of STAT3, as Aβ-induced activation of STAT3 and caspase-3-dependent neuronal death can be inhibited in tyk2&-/- neurons. Finally, increased tyrosine phosphorylation of STAT3 is also observed in postmortem brains of AD patients. Our observations collectively reveal a novel role of STAT3 in Aβ-induced neuronal death and suggest the potential involvement of Tyk2/STAT3 signaling in AD pathophysiology. [ABSTRACT FROM AUTHOR]

Members of the X11/Mint family of multidomain adaptor proteins are composed of a divergent N terminus, a conserved PTB domain and a pair of C-terminal PDZ domains. Many proteins can interact with the PDZ tandem of X11 proteins, although the mechanism of such interactions is unclear. Here we show that the highly conserved C-terminal tail of X11α folds back and inserts into the target-binding groove of the first PDZ domain. The binding of this tail occludes the binding of other target peptides. This autoinhibited conformation of X11 requires that the two PDZ domains and the entire C-terminal tail be covalently connected to form an integral structural unit. The autoinhibited conformation of the X11 PDZ tandem provides a mechanistic explanation for the unique target-binding properties of the protein and hints at potential regulatory mechanisms for the X11–target interactions. [ABSTRACT FROM AUTHOR]

Background: Although blood transcriptome has emerged as a powerful resource for studying human diseases, the changes in the blood transcriptome of Alzheimer's disease (AD) patients are poorly understood. Method: We conducted transcriptome profiling of 422 participants (208 normal controls and 214 patients with AD) from the Hong Kong Chinese population. WGCNA (weighted correlation network analysis) was performed to construct a co‐expression network to identify modules associated with AD and AD‐associated biomarkers. Result: Co‐expression modules exerting significant association with AD and AD plasma biomarkers (e.g., Aβ and NFL) were identified. Pathway enrichment analysis suggested their possible involvement in specific biological pathways. Motif analysis further revealed the potential mechanisms that driving the observed blood transcriptomic changes observed in AD. Conclusion: The co‐expression network analysis of the AD blood transcriptome changes may facilitate a better understanding of AD progression, as well as the identification of potential targets for disease intervention and monitoring. [ABSTRACT FROM AUTHOR]

The article presents chemical reactions for highly trans-selective arylation of achmatowicz rearrangement products by reductive γ-deoxygenation and Heck--Matsuda reaction.