QPH-FR: A Novel Quinoa Peptide Enhances Chemosensitivity by Targeting Leucine-Rich Repeat-Containing G Protein-Coupled Receptor 5 in Colorectal Cancer.

Chemoresistance is one of the difficulties in the treatment of colorectal cancer (CRC), and the enhanced stemness of tumor cells is the underlying contributing factor. Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a classical marker of CRC stem cells and can be an important potential target for CRC chemotherapy. Quinoa, a protein-rich plant, offers potential as a source of high-quality active peptides. Novelly, the study obtained quinoa protein hydrolysate (QPH) from whole quinoa grains by simulated digestion. In vivo experiments revealed that the tumor volume in the 5-FU+QPH group decreased from 145.90 ± 13.35 to 94.49 ± 13.05 mm3 in the 5-FU group, suggesting that QPH enhances the chemosensitivity of CRC. Further, the most effective peptide QPH-FR from 631 peptides in QPH was screened by activity prediction, molecular docking, and experimental validation. Mechanistically, QPH-FR competitively suppressed the formation of the LGR5/RSPO1 complex by binding to LGR5, causing RNF43/ZNRF3 to ubiquitinate the FZD receptor, thereby suppressing the Wnt/ß-catenin signaling pathway and exerting stemness inhibition. In summary, the study proposes that a novel peptide QPH-FR from quinoa elucidates the mechanism by which QPH-FR targets LGR5 to enhance chemosensitivity, providing theoretical support for the development of chemotherapeutic adjuvant drugs based on plant peptides.

Polyphenols from Foxtail Millet Improve Non-Alcoholic Fatty Liver Disease by Regulating Intestinal Microbiome in Mice.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic hepatic manifestation of metabolic dysfunction for which effective interventions are lacking. The burden of NAFLD is increasing at an alarming rate. NAFLD is frequently associated with morbidities such as dyslipidemia, type 2 diabetes mellitus and obesity, etc. The current study explored the potential role of bound polyphenols from foxtail millet (BPIS) in treating mice with NAFLD induced by a high-fat diet (HFD). The results indicated the critical role of BPIS in treating NAFLD by effectively restoring the gut microbiota in C57BL/6 mice that received a high-fat diet (HFD) for 12 weeks. At the same time, 16S rRNA analysis demonstrated that BPIS remodeled the overall structure of the gut microbiota from fatty liver diseases towards that of normal counterparts, including ten phylum and twenty genus levels. Further study found that the expression of tight junction proteins was upregulated in the BPIS-treated group. This study provides new insights into the potential NAFLD protective effects induced by polyphenols of foxtail millet.

Tumor-secreted GRP78 induces M2 polarization of macrophages by promoting lipid catabolism.

Macrophages in hypoxic regions of advanced colorectal tumors often exhibit M2-type features, but prefer oxygen-consuming lipid catabolism, which is contradictory in oxygen demand and supply. In this study, the results from bioinformatics analysis and intestinal lesions immunohistochemistry of 40 colorectal cancer patients illustrated that glucose-regulatory protein 78 (GRP78) was positively correlated with M2 macrophages. Furthermore, tumor-secreted GRP78 could enter macrophages and polarize them to M2-type. Mechanistically, entered GRP78 located in lipid droplets of macrophages, and elevated protein stabilization of adipose triglyceride lipase ATGL by interacting with it to inhibit its ubiquitination. Increased ATGL promoted the hydrolysis of triglycerides and the production of arachidonic acid (ARA) and docosahexaenoic acid (DHA). Excessive ARA and DHA interacted with PPARγ to encourage its activation, which mediated the M2 polarization of macrophages. In summary, our study showed that secreted GRP78 in the tumor hypoxic microenvironment mediated the domestication of tumor cells to macrophages and maintained tumor immunosuppressive microenvironment by promoting lipolysis, and the lipid catabolism not only provides energy for macrophages but also plays an important role in maintenance of immunosuppressive properties.

Salvianolic acid A attenuates inflammation-mediated atherosclerosis by suppressing GRP78 secretion of endothelial cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvianolic acid A (SAA) is the main active component of the classic anti-atherosclerotic drug Salvia miltiorrhiza Bunge. Inflammation-induced infiltration of monocyte/macrophages into the vascular wall is the initiating step in atherogenesis, and targeted blocking of this step may provide a promising avenue for the precise treatment of atherosclerosis. However, the effect of salvianolic acid A on macrophages is still unknown. AIM OF THE STUDY: To evaluate the effect of SAA on macrophage infiltration and the underlying mechanism of SAA against atherosclerosis. MATERIALS AND METHODS: Vascular endothelial cells were stimulated with lipopolysaccharide (LPS) to simulate the inflammatory environment, and its effect on monocyte/macrophages was evaluated. Mass spectrometry was used to identify the proteins that play a key role and further validated them. LncRNA sequencing, western blot analysis, RNA immunoprecipitation, and RNA pulldown were used to elucidate the mechanism of SAA against atherosclerosis. Finally, ApoE-/- mice were fed a high-fat diet to creat an in vivo atherosclerosis model. Secretory GRP78 content, lipid levels, plaque area, macrophage infiltration, and degree of inflammation were assessed by standard assays after 16 weeks of intragastric administration of SAA or biweekly tail vein injections of GRP78 antibody. RESULTS: After LPS stimulation, the increased secretion of GRP78 recruits circulating monocyte/macrophages and drives monocyte/macrophage adhesion and invasion into the vascular intima to promote atherosclerosis progression. Interestingly, SAA exerts anti-atherosclerosis effects by inhibiting the secretion of GRP78. Further mechanistic studies indicated that SAA upregulates the expression of lncRNA NR2F2-AS1, which reverses the abnormal localization of the KDEL receptor (KDELR) caused by inflammation. It promotes the homing of GRP78 from the Golgi apparatus to the endoplasmic reticulum rather than secreting outside the cell. CONCLUSION: SAA alleviates atherosclerosis by inhibiting GRP78 secretion via the lncRNA NR2F2-AS1-KDELR axis. The findings not only provide a new direction for the precise therapy of atherosclerosis based on secretory GRP78 but also elucidate the pharmacological mechanism of SAA against atherosclerosis, putting the foundation for further development and clinical application of SAA drugs.