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The Combination of Two Bioactive Constituents, Lactoferrin and Linolenic Acid, Inhibits Mouse Xenograft Esophageal Tumor Growth by Downregulating Lithocholyltaurine and Inhibiting the JAK2/STAT3-Related Pathway.

ABSTRACT: The addition of lactoferrin and three unsaturated fatty acids, oleic acid, docosahexaenoic acid (DHA), and linolenic acid, to dairy products was approved in recent years. Research into the biological activities of lactoferrin and these three unsaturated fatty acids has revealed anti-inflammatory, antiviral, antioxidant, antitumor, antiparasitic, and antibiotic effects. However, investigations and comparisons of lactoferrin + oleic acid/DHA/linolenic acid combinations in an esophageal cancer cell model and in xenograft tumor models have not been extensively reported, and the related mechanism of these combinations remains elusive. In the present study, the effects of lactoferrin and the three fatty acids on KYSE450 cell viability, migration, and invasion were investigated to choose the proper doses and effective combination in vitro. A tumor-bearing nude mouse model was established to investigate the role of selected combinations in inhibiting esophageal tumor formation in vivo. Metabonomics detection and data analysis were performed to screen special metabolites and related pathways, which were validated by western blotting. The results demonstrated that lactoferrin, the three unsaturated fatty acids, and their combinations inhibited the viability, migration, and invasion of KYSE450 cells and induced apoptosis and the lactoferrin + linolenic acid combination exhibited the strongest activity in suppressing KYSE450 tumor formation in vivo. The lactoferrin + linolenic acid combination inhibited phosphorylation in the JAK2/STAT3-related pathway by downregulating the special metabolite lithocholyltaurine, thereby suppressing formation of KYSE450 tumors.

SUBMITTER: Li H

PROVIDER: S-EPMC7450510 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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The Combination of Two Bioactive Constituents, Lactoferrin and Linolenic Acid, Inhibits Mouse Xenograft Esophageal Tumor Growth by Downregulating Lithocholyltaurine and Inhibiting the JAK2/STAT3-Related Pathway.

Li Huiying H Yao Qianqian Q Min Li L Huang Shengnan S Wu Haoming H Yang Huaigu H Fan Linlin L Wang Jiaqi J Zheng Nan N

ACS omega 20200811 33

The addition of lactoferrin and three unsaturated fatty acids, oleic acid, docosahexaenoic acid (DHA), and linolenic acid, to dairy products was approved in recent years. Research into the biological activities of lactoferrin and these three unsaturated fatty acids has revealed anti-inflammatory, antiviral, antioxidant, antitumor, antiparasitic, and antibiotic effects. However, investigations and comparisons of lactoferrin + oleic acid/DHA/linolenic acid combinations in an esophageal cancer cell ...[more]

PMID: 32875209

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Project description:BackgroundNonalcoholic steatohepatitis (NASH), a common cause of liver-related morbidity and mortality worldwide, is characterized by inflammation and hepatocellular injury. Our research focuses on lipoprotein-associated phospholipase A2 (Lp-PLA2), an inflammation-related biomarker that has recently garnered interest in the context of NASH due to its potential roles in disease pathogenesis and progression.MethodsWe established a NASH mouse model using a high-fat diet (HFD) and treated it with sh-Lp-PLA2 and/or rapamycin (an mTOR inhibitor). Lp-PLA2 expression in NASH mice was detected by qRT-PCR. Serum levels of liver function parameters and inflammatory cytokines were detected using corresponding assay kits. We examined pathological changes in liver using hematoxylin-eosin, oil red O, and Masson staining, and observed autophagy through transmission electron microscopy. The protein levels of Lp-PLA2, mTOR, light chain 3 (LC3) II/I, phosphorylated Janus kinase 2 (p-JAK2)/JAK2, and phosphorylated signal transducer and activator of transcription 3 (p-STAT3)/STAT3 were determined by western blotting. Kupffer cells extracted from C57BL/6J mice were treated to replicate NASH conditions and treated with sh-Lp-PLA2, rapamycin, and/or a JAK2-inhibitor to further verify the roles and mechanisms of Lp-PLA2 in NASH.ResultsOur data indicate an upregulation of Lp-PLA2 expression in HFD-induced NASH mice. Silencing Lp-PLA2 in NASH mice reduced liver damage and inflammation markers (aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC), triglycerides (TG), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6)), while increasing IL-10 levels, an anti-inflammatory cytokine. Additionally, Lp-PLA2 silencing decreased lipid and collagen accumulation and promoted autophagy. The beneficial effects of sh-Lp-PLA2 on NASH were enhanced by rapamycin. Furthermore, Lp-PLA2 silencing resulted in the downregulation of the expression of p-JAK2/JAK2 and p-STAT3/STAT3 in NASH mice. Similar results were observed in Kupffer cells treated under NASH conditions; Lp-PLA2 silencing promoted autophagy and repressed inflammation, effects which were potentiated by the addition of rapamycin or a JAK2-inhibitor.ConclusionOur findings suggest that silencing Lp-PLA2 promotes autophagy via deactivating the JAK2/STAT3 signaling pathway, thereby restraining NASH progression. This highlights the potential therapeutic value of targeting Lp-PLA2, adding a new dimension to our understanding of NASH pathogenesis and treatment strategies.

Dataset Information

The Combination of Two Bioactive Constituents, Lactoferrin and Linolenic Acid, Inhibits Mouse Xenograft Esophageal Tumor Growth by Downregulating Lithocholyltaurine and Inhibiting the JAK2/STAT3-Related Pathway.

Publications

The Combination of Two Bioactive Constituents, Lactoferrin and Linolenic Acid, Inhibits Mouse Xenograft Esophageal Tumor Growth by Downregulating Lithocholyltaurine and Inhibiting the JAK2/STAT3-Related Pathway.

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