Dongsheng Ji,Jiahui Zhang,Jihai Liang,Zhi-Shu Huang,Bing Shu,Ding Li
Alzheimer's disease (AD) is a severe neurodegenerative disorder characterized by abnormal metabolism of β-amyloid (Aβ) precursor proteins and neuronal apoptosis, ultimately leading to cognitive dysfunction. The pathogenesis of AD is complex, and current single-target therapies are not effective in preventing the rapid progression of AD, which highlights the urgent need for developing multi-target drugs. In this study, a series of compounds were synthesized through a multi-targeting ligand strategy. After extensive screening and evaluation, we found a lead compound B14 , which showed excellent dual targeting ability for effectively alleviating neuronal apoptosis and oxidative stress damage of AD. In our molecular and cellular level experiments, B14 could target and stabilize the i-motif structure formed on the BCL-2 promoter to upregulate BCL-2 expression, which could also bind to Aβ and inhibit its deposition. In the Aβ 1-42 -induced cell model, B14 could maintain mitochondrial function and number, regulate intracellular reactive oxygen species (ROS) and Ca 2+ metabolism disorders, and effectively reduce Aβ 1-42 -induced apoptosis. Further studies showed that B14 also exhibited good ability to cross the blood-brain barrier (BBB), which significantly improved learning memory and cognitive deficits, reduced brain Aβ plaques, alleviated inflammation and restored oxidative stress markers in APP/PS1 mice. Our findings provide an innovative strategy of dual targeting BCL-2 promoter i-motif for transcriptional regulation and Aβ aggregation synergistically for mitigating AD pathologies. B14 represents a promising multi-target lead compound with a good potential for further development for AD treatment.
Bei Hua Kang,Zhong Feng Gao,Na Li,Yan Shi,Nian Bing Li,Hong Qun Luo
Silver ions have been widely applied to many fields and have harmful effects on environments and human health. Herein, a label-free optical sensor for Ag + detection is constructed based on thiazole orange (TO) as a fluorescent probe for the recognition of i-motif DNA structure change at neutral pH. Ag + can fold a C-rich single stranded DNA sequence into i-motif DNA structure at neutral pH and that folding is reversible by chelation with cysteine (Cys). The DNA folding process can be indicated by the fluorescence change of TO, which is non-fluorescent in free molecule state and emits strong fluorescence after the incorporation with i-motif DNA. Thus, a rapid, sensitive, and selective method for the detection of Ag + and Cys is developed with a detection limit of 17 and 280 nM, respectively. It is worth noting that the mechanism underlying the increase of the fluorescence of thiazole orange in the presence of i-motif structure is explained. Moreover, a fluorescent DNA logic gate is successfully designed based on the Ag + /Cys-mediated reversible fluorescence changes. The proposed detection strategy is label-free and economical. In addition, this system shows a great promise for i-motif/TO complex to analyze Ag + in the real samples.
Background Differentiation of telomere length is of vital importance because telomere length is closely related with several deadly diseases such as cancer. Additionally, G-quadruplex and i-motif formation in telomeric DNA have been shown to act as a negative regulator of telomere elongation by telomerase in vivo and are considered as an attractive drug target for cancer chemotherapy. Results In this assay, Ag nanoclusters templated by hyperbranched polyethyleneimine (PEI–Ag NCs) are designed as a new novel resonance Rayleigh scattering (RRS) probe for sensitive differentiation of telomere length and monitoring special motifs (G-quadruplex and i-motif). In this assay, free PEI–Ag NC probe or DNA sequence alone emits low intensities of RRS, while the formation of PEI–Ag NCs/DNA complexes yields greatly enhanced RRS signals; however, when PEI–Ag NCs react with G-quadruplex or i-motif, the intensities of RRS exhibit slight changes. At the same concentration, the enhancement of RRS signal is directly proportional to the length of telomere, and the sensitivity of 64 bases is the highest with the linear range of 0.3–50 nM (limit of detection 0.12 nM). On the other hand, due to the conversion of telomere DNA molecules among multiple surrounding conditions, a DNA logic gate is developed on the basis of two chemical input signals (K + and H + ) and a change in RRS intensity as the output signal. Conclusion Our results indicate that PEI–Ag NCs can serve as a novel RRS probe to identify DNA length and monitor G-quadruplex/i-motif through the different increasing degrees of RRS intensity. Meanwhile, the novel attributes of the nanoprobe stand superior to those involving dyes or labeled DNA because of no chemical modification, low cost, green, and high efficiency.
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