Exogenous Plant gma-miR-159a, Identified by miRNA Library Functional Screening, Ameliorated Hepatic Stellate Cell Activation and Inflammation via Inhibiting GSK-3β-Mediated Pathways

Abstract

Plant-derived exogenous microRNAs (miRNAs) regulate human physiological functions by blocking the translation of target mRNAs. Although several computational approaches have been developed to elucidate the interactions of cross-species miRNAs and their targets in mammals, the number of verified plant miRNAs is still limited, and the biological roles of most exogenous plant miRNAs remain unknown. Methods: A miRNA mimic library-based phenotypic screening, which contained 8394 plant mature miRNAs published in the official database miRbase, was performed to identify more novel bioactive plant miRNAs for the prevention of hepatic fibrosis. Inhibition of candidates for the activation of hepatic stellate cells (HSCs) and the underlying mechanisms were evaluated in TGF-β1-and PDGF-exposed HSC models. The protective effects of the candidates against CCl 4 -induced liver fibrosis were evaluated in a mouse model. Results: Among the 8394 plant mature miRNAs reported in the official database miRBase, five candidates were found to effectively inhibit the differentiation of HSCs. gma-miR-159a (miR159a) exerted the strongest inhibitory activities on both TGF-β1-and PDGF-induced HSC activation and proliferation by inhibiting the GSK-3β-mediated NF-κB and TGF-β1 pathways. Moreover, miR159a was mainly accumulated in the liver after intravenous injection, and it reduced CCl 4 -induced hepatic fibrosis and inflammation in mice. Conclusion:Results indicated that miR159a has the therapeutic potential for preventing hepatic fibrosis. This study provides a novel strategy for achieving natural nucleic acid drugs.

Alfalfa Xeno-miR168b Target CPT1A to Regulate Milk Fat Synthesis in Bovine Mammary Epithelial Cells

“…In this study, xeno-miRNAs were detected in the blood and milk of both high-fat-milk and low-fat-milk dairy cows, which demonstrated that xeno-miRNAs could be absorbed into the tissues of dairy cows. This was consistent with previous studies that demonstrated direct uptake of plant miRNAs into animals without special treatment [ 4 , 10 , 27 , 28 , 29 ]. The expression levels of xeno-miRNAs in blood and milk were statistically different in dairy cows within the same group (high-fat group or low-fat group), which might have been related to their variable intake and/or metabolic traits of individual dairy cows.…”

“…There are several classic examples of cross-kingdom regulation by miRNAs. For example, miR159a from soybean can inhibit NF-κB and TGF-β1 signaling in mice, which helps prevent hepatic fibrosis [ 3 , 4 ]. Another notable example is the ability of miR2911 in the decoction of honeysuckle to inhibit the replication of the influenza A virus, and it could also inhibit SARS-CoV-2 replication and accelerate the negative conversion of infected patients [ 5 , 6 ].…”

The role of microRNAs in neurodegenerative diseases: a review

“…When exogenous miRNAs enter the human body, they seem to act similarly to endogenous miRNAs, participating in the host body’s management of life activities. By suppressing GSK3β-mediated NF-κB and transforming growth factor beta 1 (TGF-β1) pathways, soybean-derived gma-miR159a improves hepatic stellate cell activation and lowers inflammation (Yu et al 2021 ). Moreover, cross-kingdom gene regulation by miRNAs has initiated the hot topic of the potential function of miRNAs on human or mice gene expression after oral administration.…”

Advances in Bioactivity of MicroRNAs of Plant-Derived Exosome-Like Nanoparticles and Milk-Derived Extracellular Vesicles

“…Such miRNAs include miR-124a, which can directly target MCP-1 mRNA; miR-21, miR-let7, miR-146a, miR-146b, miR-126, miR-155, and miR-199a, which intervene with the downstream inflammatory mediators of TLR, IL-1, and NF-κB. , However, Rai et al found that miR-155 can promote B cell lymphoma, which has been correlated with milk consumption . In addition, Yu et al reported that plant gma-miR-159a effectively alleviated liver inflammation in TGF-β1- and PDGF-induced hepatic stellate cell (HSC)- and CCl 4 -induced hepatic fibrosis mouse models, primarily through inhibiting the GSK-3β-mediated NF-κB and TGF-β1 pathways. Xu et al researched the effect of orally administered oat-derived ELNs (O-ELNs) on alcohol-induced brain inflammation.…”

“…61,62 However, Rai et al 63 found that miR-155 can promote B cell lymphoma, which has been correlated with milk consumption. 64 In addition, Yu et al 65 reported that plant gma-miR-159a effectively alleviated liver inflammation in TGF-β1and PDGF-induced hepatic stellate cell (HSC)-and CCl 4induced hepatic fibrosis mouse models, primarily through inhibiting the GSK-3β-mediated NF-κB and TGF-β1 pathways. Xu et al 66 the induction of multiple diseases, such as Alzheimer's and type 2 diabetes.…”