Atherosclerosis (AS) is the main pathological basis of cardiovascular diseases. Hence, the prevention and treatment strategies of AS have attracted great research attention. As a potential probiotic, Pararabacteroides distasonis has a positive regulatory effect on lipid metabolism and bile acids (BAs) profile. Oligomeric procyanidins have been confirmed to be conducive to the prevention and treatment of AS, whose antiatherosclerotic effect may be associated with the promotion of gut probiotics. However, it remains unclear whether and how oligomeric procyanidins and P. distasonis combined (PPC) treatment can effectively alleviate high-fat diet (HFD)-induced AS. In this study, PPC treatment was found to significantly decrease atherosclerotic lesion, as well as alleviate the lipid metabolism disorder, inflammation and oxidative stress injury in ApoE^-/- mice. Surprisingly, targeted metabolomics demonstrated that PPC intervention altered the BA profile in mice by regulating the ratio of secondary BAs to primary BAs, and increased fecal BAs excretion. Further, quantitative polymerase chain reaction (qPCR) analysis showed that PPC intervention facilitated reverse cholesterol transport by upregulating Srb1 expression; In addition, PPC intervention promoted BA synthesis from cholesterol in liver by upregulating Cyp7a1 expression via suppression of the farnesoid X receptor (FXR) pathway, thus exhibiting a significant serum cholesterol-lowering effect. In summary, PPC attenuated HFD-induced AS in ApoE^-/- mice, which provides new insights into the design of novel and efficient anti-atherosclerotic strategies to prevent AS based on probiotics and prebiotics.

Our previous study has demonstrated that procyanidin A₁ (A₁) and its simulated digestive product (D-A₁) can prevent acrylamide (ACR)-induced cytotoxicity in small intestine cells. However, the potential mechanism remains poorly understood. In this study, ACR treatment was found to increase the levels of 8-hydroxy-deoxyguanine (8-OHdG) and phosphorated histone H₂AX (γH₂AX), two DNA damage markers, thereby resulting in cell cycle arrest in the G2/M phase; whereas both A₁ and D-A₁ could prevent the phosphorylation of ataxia telangiectasia mutated (ATM) and checkpoint kinase 2 (Chk2), and then regulate the expression of G2/M phase-related proteins, finally maintaining normal cell cycle progression. Moreover, A₁ and D-A₁ could increase the B cell lymphoma 2 (Bcl-2)/Bcl2-associated X (Bax) ratio and decrease the expression of cleaved caspase-3 and cleaved caspase-9 proteins to alleviate ACR-induced cell apoptosis, which might be related to the inhibition of the mitogen-activated protein kinase (MAPK) pathway. More importantly, A₁ showed no remarkable variation in inhibitory effect before and after digestion, indicating that it can endure gastrointestinal digestion and may be a promising phytochemical to alleviate ACR-induced intestinal cell damage.

Rape bee pollen has attracted increasing interests for its excellent protective effect against chemical-induced liver injury owing to its abundant polyphenols. This study aims to analyze the types and contents of phenolamides (seldom concerned) in rape bee pollen and their protective mechanism on alcoholic liver disease (ALD). Different from the previous finding that flavonoids are dominant polyphenols in bee pollen polyphenolic extract, our results demonstrated that there are only three flavonoids but 24 phenolamides in the as-prepared rape bee pollen phenolic extract (PPE). In addition, PPE was found to significantly improve the viability (from 54.9% to 84.1%, 89.2%, and 94.0%) of alcohol-induced AML12 cells and alleviate alcohol-induced cell apoptosis (from 28.5% to 22.89%, 22.0%, and 17.4%). To dissect the underlying mechanism for the protective effect of PPE against ALD, the molecular pathway was identified by RNA-seq analysis. Transcriptome data revealed that PPE may protect against ALD by decreasing inflammation, cholesterol, and fatty acid synthesis (P < 0.05). The NIAAA model was used to further evaluate the hepatoprotective effect of PPE in vivo, and the results validated that PPE could alleviate liver injury and hepatic steatosis (from 22.7% to 11.5% and 10.9%) induced by alcohol. As the dominant polyphenols in PPE, phenolamides can be a class of valuable polyphenolic compounds in bee pollen with the potential to alleviate ALD.

Non-enzymatic glycation reaction in food can produce diet‑derived advanced glycation end products (dAGEs), which have potential health risks. Thus, it is of great significance to find efficient substances to improve the negative effects induced by dAGEs on human health. This study investigated the intervening effects of peanut skin procyanidins (PSP) on the dAGEs-induced oxidative stress and systemic inflammation in experimental mice model. Results showed that the accumulation of AGEs in serum, liver, and kidney was significantly increased after mice were fed dAGEs (P < 0.05). The expression of RAGE was also significantly increased in liver and kidney (P < 0.05). PSP could not only effectively reduce the accumulation of AGEs in serum, liver and kidney of mice, but also reduce the expression of RAGE in liver and kidney of mice. And the levels of pro-inflammatory cytokines IL-6, TNF-α, and IL-1β in serum of mice were significantly decreased (P < 0.05), while the levels of anti-inflammatory factor IL-10 were increased, and the inflammatory injury in mice was improved. In addition, the levels of SOD, GSH and CAT in liver and kidney of mice were increased (P < 0.05), and the level of MDA was decreased (P < 0.05), which enhanced the antioxidant capacity of mice in vivo, and improved the oxidative damage of liver and kidney. Molecular docking technique was used to confirm that the parent compound of procyanidins and its main metabolites, such as 3-hydroxyphenylacetic acid, could interact with RAGE, which might inhibit the activation of NF-κB, and ultimately reduce oxidative stress and inflammation in mice.

Our previous study has revealed that procyanidin A₁ (A₁) and its simulated digestive product (D-A₁) can alleviate acrylamide (ACR)-induced intestine cell damage. However, the underlying mechanism remains unknown. In this study, we elucidated the molecular mechanism for A₁ and D-A₁ to alleviate ACR-stimulated IPEC-J2 cell damage. ACR slightly activated nuclear factor erythroid 2-related factor 2 (Nrf2) signaling and its target genes, but this activation could not reduce intestine cell damage. A₁ and D-A₁ could alleviate ACR-induced cell damage, but the effect was abrogated in cells transiently transfected with Nrf2 small interfering RNA (siRNA). Further investigation confirmed that A₁ and D-A₁ interacted with Kelch-like ECH-associated protein 1 (Keap1), which boosted the stabilization of Nrf2, subsequently promoted the translocation of Nrf2 into the nucleus, and further increased the expression of antioxidant proteins, thereby inhibiting glutathione (GSH) consumption, maintaining redox balance and eventually alleviating ACR-induced cell damage. Importantly, there was no difference between A₁ and D-A₁ treated groups, indicating that A₁ can tolerate gastrointestinal digestion and may be a potential compound to limit the toxicity of ACR.

Obesity is associated with numerous metabolic disorders, and dietary polyphenols have been confirmed to have beneficial effects on the metabolism in obesity. However, the effect of 3-(3’,4’-dihydroxyphenyl)propanoic acid (DHPA) and 3’,4’-dihydroxyphenylacetic acid (DHAA), two main metabolites of dietary polyphenols, on obesity remains poorly understood. In this study, DHPA and DHAA were found to alleviate obesity, as well as regulate insulin resistance, lipid metabolism, and oxidative stress response in high-fat diet (HFD)mice. Surprisingly, the 16S rRNA sequencing and UHPLC-Q-TOF/MS demonstrated that DHPA and DHAA only slightly disturbed the intestinal microbiome, but significantly altered the urine metabolome of HFD mice mainly by regulating pentose and glucuronate interconversion, tyrosine metabolism, pentose phosphate and tricarboxylic acid (TCA) cycle as indicated by metabolic pathway analysis based on Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Correlation analysis revealed that the differential metabolites are strongly associated with body weight, blood glucose, insulin level, and superoxide dismutase (SOD) enzyme activity. Our results revealed that DHPA and DHAA exert their anti-obesity effect by regulating important metabolites in the glucose, lipid and tyrosine metabolism pathways.