Quercetin‐3‐O‐Glucuronide Alleviates Cognitive Deficit and Toxicity in Aβ_1‐42‐Induced AD‐Like Mice and SH‐SY5Y Cells

Abstract

Scope Alzheimer's disease (AD) is characterized by amyloid‐β (Aβ) related imbalance, Tau‐hyperphosphorylation, and neuroinflammation, in which Aβ and neuroinflammation can induce brain insulin resistance (IR). Gut microbiome disorder is correlated with inflammation in AD. As of yet, there are no effective treatments clinically. Thus, it is focused on the potential benefit of quercetin‐3‐O‐glucuronide (Q3G), a pharmacologically active flavonol glucuronide, on AD treatment by regulating brain IR and the gut microbiome. Methods and results AD mice model built through intracerebroventricular injection of Aβ1‐42 and AD cell model developed through the SH‐SY5Y cell line and Aβ1‐42 are used to explore the protective effects of Q3G on AD. Neurobehavioral test, brain insulin signaling pathway, and high‐throughput pyrosequencing of 16S rRNA are assessed. Data show that Q3G attenuates neuroinflammation and brain IR in Aβ1‐42‐injected mice and relieves apoptosis in Aβ1‐42‐treated SH‐SY5Y cells by interrupting the downstream insulin signaling. Q3G ameliorates Aβ accumulation and Tau phosphorylation, restores CREB and BDNF levels in the hippocampus , and reverses Aβ1‐42‐induced cognitive impairment. Besides, Q3G restores Aβ1‐42‐induced reduction of short‐chain fatty acids (SCFAs) and gut microbiota dysbiosis. Conclusion Q3G can alleviate brain IR through directly acting on the brain or modulating the gut‐brain axis, ultimately to relieve Aβ1‐42‐induced cognitive dysfunction.

CX3CL1 Derived from Bone Marrow Mesenchymal Stem Cells Inhibits Aβ1-42-Induced SH-SY5Y Cell Pathological Damage through TXNIP/NLRP3 Signaling Pathway

“…SH-SY5Y cells were grouped as follows: control, A β , A β +MSC, A β +MSC-NC-ov, and A β +MSC-CX3CL1-ov. An AD cell model was built via treating SH-SY5Y with 20 μ M A β 1-42 [ 29 ], while the control group was administrated with phosphate buffer saline (PBS) with an equal amount. Moreover, SH-SY5Y cells in A β +MSC, A β +MSC-NC-ov, and A β +MSC-CX3CL1-ov groups were coincubated with BMSCs, BMSCs transfected with NC-ov, and BMSCs transfected with CX3CL1-ov, respectively.…”

Hesperidin Preferentially Stimulates Transient Receptor Potential Vanilloid 1, Leading to NO Production and Mas Receptor Expression in Human Umbilical Vein Endothelial Cells

“…Metabolic conjugates of hesperidin and its aglycone, hesperetin, such as sulfated and glucuronided forms during the absorption process, , may be another issue to be considered for TRPV1-mediated NO production of hesperidin when it is orally administered. The reports regarding vasorelaxant and neuroprotective bioactivity induced by sulfated and glucuronided forms of polyphenols, in which sulfation of ferulic acid (a phenolic acid) caused an enhancement of vasorelaxation power of contracted vessels compared to intact form, also provided us speculation that the conjugated forms of hesperidin may exert physiological potentials in the body system. Thus, to further demonstrate structural factors of flavonoids showing preferential TRPV1 stimulation, an in silico analysis of the TRPV1-hesperetin (or its conjugates) complex, using e.g., a CHARMM-GUI-aided molecular dynamics simulation in a virtual phospholipid membrane must be performed in a future study.…”

Roles of traditional chinese medicine regulating neuroendocrinology on AD treatment

“…Quercetin-3-o-glucuronide (Q3G), a flavonol Glucuronide, also has similar down-regulation of JNK/c-Jun pathway. In addition, Q3G can also regulate intestinal microbiome ecological imbalance, alleviates cerebral insulin resistance and improves cognitive dysfunction through intestinal brain axis ( 132 ). Magnolol also has been proved to have a similar effect on reducing apoptosis and regulating intestinal microbes ( 140 ).…”

“…Insulin-degrading enzyme(IDE) and enkephalinase(NEP) have strong ability to degrade insulin and Aβ42, which are associated with neurodegeneration in Alzheimer’s disease ( 132 ). EGCG can inhibit NEP expression in astrocytes by activating extracellular signal-regulated kinase (ERK) and phosphoinositol 3-kinase (PI3K) ( 38 , 165 ).…”