Effects of Daily Raspberry Consumption on Immune-Metabolic Health in Subjects at Risk of Metabolic Syndrome: A Randomized Controlled Trial.

Consumption of red raspberries has been reported to exert acute beneficial effects on postprandial glycemia, insulinemia, triglyceridemia, and cytokine levels in metabolically disturbed subjects. In a two-arm parallel-group, randomized, controlled trial, 59 subjects with overweight or abdominal obesity and with slight hyperinsulinemia or hypertriglyceridemia were randomized to consume 280 g/day of frozen raspberries or to maintain their usual diet for 8 weeks. Primary analyses measured metabolic differences between the groups. Secondary analyses performed with omics tools in the intervention group assessed blood gene expression and plasma metabolomic changes following the raspberry supplementation. The intervention did not significantly affect plasma insulin, glucose, inflammatory marker concentrations, nor blood pressure. Following the supplementation, 43 genes were differentially expressed, and several functional pathways were enriched, a major portion of which were involved in the regulation of cytotoxicity, immune cell trafficking, protein signal transduction, and interleukin production. In addition, 10 serum metabolites were found significantly altered, among which ß-alanine, trimethylamine N-oxide, and bioactive lipids. Although the supplementation had no meaningful metabolic effects, these results highlight the impact of a diet rich in raspberry on the immune function and phospholipid metabolism, thus providing novel insights into potential immune-metabolic pathways influenced by regular raspberry consumption.

Black Raspberries Suppress Colorectal Cancer by Enhancing Smad4 Expression in Colonic Epithelium and Natural Killer Cells.

Innate immune cells in the tumor microenvironment have been proposed to control the transition from benign to malignant stages. In many cancers, increased infiltration of natural killer (NK) cells associates with good prognosis. Although the mechanisms that enable NK cells to restrain colorectal cancer (CRC) are unclear, the current study suggests the involvement of Smad4. We found suppressed Smad4 expression in circulating NK cells of untreated metastatic CRC patients. Moreover, NK cell-specific Smad4 deletion promoted colon adenomas in DSS-treated ApcMin/+ mice and adenocarcinomas in AOM/DSS-treated mice. Other studies have shown that Smad4 loss or weak expression in colonic epithelium associates with poor survival in CRC patients. Therefore, targeting Smad4 in both colonic epithelium and NK cells could provide an excellent opportunity to manage CRC. Toward this end, we showed that dietary intervention with black raspberries (BRBs) increased Smad4 expression in colonic epithelium in patients with FAP or CRC and in the two CRC mouse models. Also, benzoate metabolites of BRBs, such as hippurate, upregulated Smad4 and Gzmb expression that might enhance the cytotoxicity of primary human NK cells. Of note, increased levels of hippurate is a metabolomic marker of a healthy gut microbiota in humans, and hippurate also has antitumor effects. In conclusion, our study suggests a new mechanism for the action of benzoate metabolites derived from plant-based foods. This mechanism could be exploited clinically to upregulate Smad4 in colonic epithelium and NK cells, thereby delaying CRC progression.

Suppression of nuclear factor-kappa B and mitogen-activated protein kinase signalling pathways by goshonoside-F5 extracted from Rubi Fructus.

Rubi Fructus, a traditional Chinese medicine, was considered as an anti-inflammatory agent in folk medicine. In the present study, we investigated the signalling pathways involved in the anti-inflammatory effects of goshonoside-F5 (GF5), isolated from Rubi Fructus, in peritoneal macrophages and examined its therapeutic effect in a mouse endotoxic shock model. GF5 decreased NO and PGE2 production in LPS-stimulated macrophages (IC50=3.84 and 3.16µM). This effect involved the suppression of NOS-2 and COX-2 gene expression at the transcriptional level. Examination of the effects of GF5 on NF-κB signalling demonstrated that it inhibits the phosphorylation of IκB-α and IκB-ß, blocking their degradation and the nuclear translocation of the NF-κB p65 subunit. Moreover, inhibition of MAPK signalling was also observed, and phosphorylation of p38 and JNK was suppressed in the presence of GF5. Inflammatory cytokines, including IL-6 and TNF-α, were down-regulated by this compound after activation with LPS (IC50=17.04 and 4.09µM). Additionally, GF5 (30 and 90mg/kg, i.p.) significantly reduced the circulating cytokine levels (IL-6 and TNF-α) and increased survival in a mouse model of endotoxemia. These results show that GF5 significantly inhibits the pro-inflammatory response induced by LPS, both in vitro and in vivo. Our results provide a strong pharmacological basis for further understanding the potential therapeutic role of GF5 in inflammatory disease and shed new light on the bioactivity of ent-labdane diterpene glucoside.