Thonningianin A from Penthorum chinense Pursh as a targeted inhibitor of Alzheimer's disease-related ß-amyloid and Tau proteins.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by complex pathogenesis mechanisms. Among these, ß-amyloid plaques and hyperphosphorylated Tau protein tangles have been identified as significant contributors to neuronal damage. This study investigates thonningianin A (TA) from Penthorum chinense Pursh (PCP) as a potential inhibitor targeting these pivotal proteins in AD progression. The inhibitory potential of PCP and TA on Aß fibrillization was initially investigated. Subsequently, ultra-high performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry and biolayer interferometry were employed to determine TA's affinity for both Aß and Tau. The inhibitory effects of TA on the levels and cytotoxicity of AD-related proteins were then assessed. In 3xTg-AD mice, the therapeutic potential of TA was evaluated. Additionally, the molecular interactions between TA and either Aß or Tau were explored using molecular docking. We found that PCP-total ethanol extract and TA significantly inhibited Aß fibrillization. Additionally, TA demonstrated strong affinity to Aß and Tau, reduced levels of amyloid precursor protein and Tau, and alleviated mitochondrial distress in PC-12 cells. In 3xTg-AD mice, TA improved cognition, reduced Aß and Tau pathology, and strengthened neurons. Moreover, molecular analyses revealed efficient binding of TA to Aß and Tau. In conclusion, TA, derived from PCP, shows significant neuroprotection against AD proteins, highlighting its potential as an anti-AD drug candidate.

High out-of-plane negative Poisson's ratios and strong light harvesting in two-dimensional SiS2 and its derivatives.

Two-dimensional (2D) materials with negative Poisson's ratios (NPRs) hold tremendous potential in diverse electronic devices. However, most 2D auxetic materials exhibit small out-of-plane NPRs and materials with bi-directional NPRs are rare. In this work, the SiS2 monolayer and its derivatives MX2 (M = Si, Ge, Sn and X = S, Se, Te) are systematically studied via first-principles simulation. We demonstrate that a SiS2 monolayer possesses a remarkable out-of-plane NPR with a value of -1.09 and an in-plane NPR (-0.13). Furthermore, a higher out-of-plane NPR (-1.79) can be achieved in a SnS2 monolayer by element substitution. Remarkably, SiS2 and its derivative MX2 monolayers exhibit excellent light harvesting over the ultraviolet and visible range, and the corresponding electronic properties show robustness against strains. Our results confirm that MX2 monolayers provide an ideal platform to explore auxeticity in two-dimensional limits.

Age-related self-DNA accumulation may accelerate arthritis in rats and in human rheumatoid arthritis.

The incidence of rheumatoid arthritis (RA) is increasing with age. DNA fragments is known to accumulate in certain autoimmune diseases, but the mechanistic relationship among ageing, DNA fragments and RA pathogenesis remain unexplored. Here we show that the accumulation of DNA fragments, increasing with age and regulated by the exonuclease TREX1, promotes abnormal activation of the immune system in an adjuvant-induced arthritis (AIA) rat model. Local overexpression of TREX1 suppresses synovial inflammation in rats, while conditional genomic deletion of TREX1 in AIA rats result in higher levels of circulating free (cf) DNA and hence abnormal immune activation, leading to more severe symptoms. The dysregulation of the heterodimeric transcription factor AP-1, formed by c-Jun and c-Fos, appear to regulate both TREX1 expression and SASP induction. Thus, our results confirm that DNA fragments are inflammatory mediators, and TREX1, downstream of AP-1, may serve as regulator of cellular immunity in health and in RA.

Corilagin attenuates morphine-induced BV2 microglial activation and inflammation via regulating TLR2-mediated endoplasmic reticulum stress.

Morphine-induced microglia activation and neuroinflammation have been considered as the contributors of morphine tolerance. Corilagin (Cori) has been reported to exhibit strong anti-inflammatory property. The present study aims to investigate whether and how Cori alleviates morphine-induced neuroinflammation and microglia activation. Mouse BV-2 cells were exposed to different concentrations of Cori (0.1, 1 and 10 µM) prior to morphine stimulation (200 µM). Minocycline (10 µM) acted as the positive control. Cell viability was determined by CCK-8 assay and trypan blue assay. The levels of inflammatory cytokines were determined using ELISA. IBA-1 level was examined via immunofluorescence. TLR2 expression level was examined by quantitative real-time PCR and western blot. The expression levels of corresponding proteins were measured by western blot. It was found that Cori was non-toxic to BV-2 cells but greatly inhibited morphine-induced IBA-1 expression, overproduction of pro-inflammatory cytokines, activation of NLRP3 inflammasome and endoplasmic reticulum stress (ERS), and upregulation of COX-2 and iNOS. TLR2 was negatively regulated by Cori, and could promote the activation of ERS. A high affinity between Cori and TLR2 protein was confirmed via Molecular docking investigation. Moreover, TLR2 overexpression or tunicamycin (TM), an agonist of ERS, partly abolished the inhibitory effects of Cori on morphine-induced alternations on neuroinflammation and microglial activation in BV-2 cells as above. In summary, our study suggested that Cori effectively alleviated morphine-induced neuroinflammation and microglia activation through inhibiting TLR2-mediated ERS in BV-2 cells, providing a novel potential drug to overcome morphine tolerance.

The New Application of UHPLC-DAD-TOF/MS in Identification of Inhibitors on ß-Amyloid Fibrillation From Scutellaria baicalensis.

Literary evidence depicts that aggregated ß-amyloid (Aß) leads to the pathogenesis of Alzheimer's disease (AD). Although many traditional Chinese medicines (TCMs) are effective in treating neurodegenerative diseases, there is no effective way for identifying active compounds from their complicated chemical compositions. Instead of using a traditional herbal separation method with low efficiency, we herein apply UHPLC-DAD-TOF/MS for the accurate identification of the active compounds that inhibit the fibrillation of Aß (1-42), via an evaluation of the peak area of individual chemical components in chromatogram, after incubation with an Aß peptide. Using the neuroprotective herbal plant Scutellaria baicalensis (SB) as a study model, the inhibitory effect on Aß by its individual compounds, were validated using the thioflavin-T (ThT) fluorescence assay, biolayer interferometry analysis, dot immunoblotting and native gel electrophoresis after UHPLC-DAD-TOF/MS analysis. The viability of cells after Aß (1-42) incubation was further evaluated using both the tetrazolium dye (MTT) assay and flow cytometry analysis. Thirteen major chemical components in SB were identified by UHPLC-DAD-TOF/MS after incubation with Aß (1-42). The peak areas of two components from SB, baicalein and baicalin, were significantly reduced after incubation with Aß (1-42), compared to compounds alone, without incubation with Aß (1-42). Consistently, both compounds inhibited the formation of Aß (1-42) fibrils and increased the viability of cells after Aß (1-42) incubation. Based on the hypothesis that active chemical components have to possess binding affinity to Aß (1-42) to inhibit its fibrillation, a new application using UHPLC-DAD-TOF/MS for accurate identification of inhibitors from herbal plants on Aß (1-42) fibrillation was developed.