Rev-erbα is a nuclear receptor, which regulates circadian rhythm, inflammatory responses and lipid metabolism. We previously showed Rev-erbα reduction in human gastric cancer, which is associated with TMN stages and poor prognosis. We hypothesized that Rev-erbα modulates proliferation via glycolytic flux and the pentose phosphate pathway (PPP) in gastric cancer. Knockdown of Rev-erbα significantly increased proliferation as well as glycolytic flux and the PPP in human gastric cancer cells. These effects were reduced by a Rev-erbα agonist GSK4112 in a dose-dependent manner. Furthermore, Rev-erbα was recruited on the promoters of PFKFB3 and G6PD genes, thereby inhibiting their gene transcription. GSK4112 treatment reduced PFKFB3 and G6PD gene expression, which was not affected by BMAL1 knockdown. Pharmacological inhibition of glycolysis and the PPP using corresponding PFKFB3 and G6PD inhibitors attenuated Rev-erbα knockdown-induced proliferation in gastric cancer cells. GSK4112 treatment was not able to reduce proliferation in SGC-7901 overexpressing both PFKFB3 and G6PD genes. Both PFKFB3 and G6PD were overexpressed in patients with gastric cancer, and positively correlated with the TMN stages. The PPP and glycolysis were enhanced in gastric cancer tissues of patients with low expression of Rev-erbα compared to the patients with high expression of Rev-erbα. In conclusion, Rev-erbα reduction causes gastric cancer progression by augmenting the PPP and glycolysis.

Interleukin (IL)-35 is an anti-inflammatory cytokine that may have a protective role in atherosclerosis (AS). However, the exact role of IL-35 in the disease, and the etiology of AS, remain incompletely understood. The present study aimed to investigate whether exogenous IL-35 was able to attenuate the formation of atherosclerotic lesions in apoE−/− mice, and analyze alterations in the expression levels of forkhead box protein 3 (Foxp3) in peripheral blood and the lesions during the progression of AS. ApoE−/− mice were randomly divided into two groups that received either a basal diet (negative control group) or a high-fat diet (HFD) for 4 weeks. The HFD group was further subdivided into groups that received IL-35, atorvastatin or no treatment for 12 weeks. Diagnostic enzyme assay kits were applied for the detection of plasma lipids, and hematoxylin and eosin staining was used to analyze the severity of atherosclerotic lesions in apoE−/− mice. Immunohistochemistry and flow cytometry were performed to analyze the expression of Foxp3 in the plasma and atherosclerotic plaques. As compared with the negative control group, the plasma lipids were significantly increased, and the lesions were obviously formed, in the HFD groups. Furthermore, the area of the lesion was reduced in IL-35- and atorvastatin-treated groups, as compared with the AS control group. In addition, Foxp3 expression was upregulated in the plasma and lesions of the IL-35- and atorvastatin-treated groups, as compared with the AS control group. The present study demonstrated that IL-35 improved Treg-mediated immune suppression in atherosclerotic mice, thus suggesting that IL-35 may be a novel therapeutic target for AS.

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All-trans retinoic acid (ATRA) is a natural derivative of vitamin A that ameliorates atherosclerosis (AS) by regulating inflammatory factors. However, studies concerning the role of retinoic acid in artery endothelial function are rare. Therefore, the present study investigated its role in regulating the production of endothelin‑1 (ET‑1) and nitric oxide (NO) in rabbits with AS. The rabbits were randomly divided into 3 groups: The control group was administered an ordinary diet, while the high fat group and the ATRA drug intervention group were administered a high fat diet. After 12 weeks, the blood lipid levels of rabbits, the morphological structure of the arterial wall, the arterial intimal permeability, the activity of blood endothelial nitric oxide synthase (eNOS) and the level of plasma NO were investigated. Western blot analysis was used to detect the levels of ET‑1, eNOS and eNOS phosphorylation at Ser‑1177 (p‑eNOS), and a radioimmunoassay was performed to detect the level of ET‑1 in the plasma. It was identified that plaque formation was alleviated in the ATRA group compared with the high fat group, as revealed by hematoxylin and eosin and oil red O staining, and a similar trend was reflected in the immunofluorescence results for endothelial permeability. Western blotting demonstrated significantly decreased ET‑1 expression levels in the arterial tissue of rabbits in the ATRA group compared with the high fat group, together with increased p‑eNOS level (P<0.05), however, no difference was observed in the expression of eNOS (P>0.05). The trends observed for ET‑1 and the activity of eNOS in plasma were similar to those for arterial tissue. Therefore, the present study demonstrated that ATRA may regulate the grade of AS by the reduction of ET‑1 secretion and increased NO formation via increased phosphorylation of eNOS. ATRA provides a potential novel method for the treatment of atherosclerosis.