Gastric cancer is a serious threat to human health. Nuclear receptor subfamily 1 group D member 1 (REV-ERBα) is a member of the nuclear hormone receptor family that regulates lipid metabolism, inflammatory responses and circadian rhythms. However, the role of REV-ERBα in the pathogenesis of human gastric cancer is unclear. The present study employed gastric cancer tissues from 74 patients and determined the association between REV-ERBα expression with clinicopathological variables and prognosis. Furthermore, the association between REV-ERBα and apoptosis in undifferentiated and moderately differentiated human gastric cancer cells was determined. It was identified that REV-ERBα expression was decreased in gastric cancer, which was positively associated with poor differentiation (P=0.009), T stage (P=0.001), Tumor-Node-Metastasis (TMN) stage (P=0.001) and lymph node metastasis (P=0.007). In the survival analysis, the 3- and 5-year survival times of patients were significantly associated with REV-ERBα expression (P=0.009 and P=0.002, respectively). Low REV-ERBα expression was associated with poor prognosis (P<0.05). Concurrently, cleaved caspase-3 expression was downregulated, whereas expression levels of Bcl-2 and the Bcl-2/Bax ratio were upregulated in gastric cancer tissues compared with normal tissues. REV-ERBα activator GSK4112 caused apoptosis in SGC-7901 and BGC-823 cell lines. REV-ERBα levels were decreased in human gastric cancer, which was associated with poor differentiation, TMN stages and poor prognosis. REV-ERBα is a potential biomarker for tumor development and prognosis, and a potential therapeutic target for gastric cancer.

Inclusion of fiber in gestation diets is a method for enhancing satiety and reducing abnormal behaviors in restricted feeding sows without providing excess energy. The purpose of this study was to use an in vitro-in vivo method to appraise the effects of two available unconventional dietary fiber resources during gestation on sows’ physio-chemical properties of diets, postprandial satiety, performance, abnormal behaviors, stress status and lactation feed intake under three different dietary treatments: control diet (CON diet), 5% resistant starch diet (RS diet), and 5% fermented soybean fiber diet (FSF diet) with a total of 78 (average parity 5) Landrace × Yorkshire sows. Results showed that swelling capacity was higher in the RS diet than in the CON or FSF diet. Meanwhile, the 48 h cumulative gas production and the final asymptotic gas volume after in vitro fermentation of gestation diets showed an increased trend (p = 0.07, p = 0.09, respectively) in the RS diet versus the CON or FSF diets. While the sows’ litter size, body weight, backfat or weaning-to-estrus interval were not affected (p > 0.05) by the three treatments during gestation, the RS group showed a decline in stillbirth number (p < 0.05) and stillbirth rate (p < 0.01) relative to the other two groups. Meanwhile, the proportion of standing was lower while the sow’s serum concentrations of PYY (peptide YY) and GLP-1 (glucagon-like peptide-1) were higher (p < 0.05) on day 70 of gestation in the RS group than in the CON or FSF group. Compared with the CON group, the RS group showed a downward tendency (p = 0.07) in the sows’ plasma cortisol concentration on day 70 of gestation. A comparison of oxidative and antioxidative indicators revealed an increase in the sows’ serum FRAP (ferric ion reducing antioxidant power) (p < 0.05) and a decrease of protein carbonyl (p < 0.05) on day 109 of gestation in the RS or FSF group versus the CON group. Overall, inclusion of 5% RS with greater swelling capacity in the gestation diet contributed to enhancing the postprandial satiety, alleviating the stress status, reducing the abnormal behaviors and thus lowering the stillbirth rate of sows.

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.

Retinoid-related orphan receptor α (RORα) is a nuclear receptor, which regulates inflammation and immune responses, lipid metabolism and circadian rhythm. Although RORα suppresses breast tumor invasion, it is unknown whether RORα is dysregulated in gastric cancer leading to cellular survival. Therefore, we hypothesize that RORα is dysfunctional in gastric carcinoma and this causes decreased apoptosis in gastric cancer cells. To test this hypothesis, we employed human gastric cancer tissues with different stages to determine RORα expression, as well as in vitro human gastric cancer cells to determine how RORα is reduced during apoptosis. We found that the expression of RORα was reduced in gastric tissues with cancer, and this correlated with increased TNM stages. The mechanisms underlying RORα reduction is due to the reduced activation of AMP-activated protein kinase (AMPK), as a selective AMPK activator AICAR increased RORα activation and level in human gastric cancer cells. Furthermore, AICAR treatment increased RORα recruitment on the promoters of tumor suppressor genes (i.e., FBXM7, SEMA3F and p21) leading to apoptosis in human gastric cancer cells. Taken together, RORα reduction occurs in gastric cancer leading to the survival of tumor cells, which is attenuated by AMPK. Therefore, both RORα and AMPK are potential targets for the intervention and therapy in gastric carcinoma.

Accumulating evidence shows a close association between various types of bile acids (BAs) and hepatocellular carcinoma (HCC), and they have been revealed to affect tumor immune response and progression mainly by regulating Farnesoid X receptor (FXR). Nevertheless, the roles of Norcholic acid(NorCA) in HCC progression remain unknown yet. In this study, herein we demonstrate that NorCA can promote HCC cell proliferation, migration and invasion through negatively regulating FXR. Additionally, NorCA can increase PD-L1 level on the surfaces of HCC cells and their exosomes, and NorCA-induced exosomes dramatically dampen the function of CD4+T cells, thereby inducing an immunosuppressive microenvironment. Meanwhile, a negative correlation between PD-L1 and FXR expression in human HCC specimens was identified, and HCC patients with FXRlowPD-L1high expression exhibit a rather dismal survival outcome. Importantly, FXR agonist (GW4064) can synergize with anti-PD-1 antibody (Ab) to inhibit HCC growth in tumor-bearing models. Taken together, NorCA can promote HCC progression and immune invasion by inhibiting FXR signaling, implying a superiority of the combination of FXR agonist and anti‐PD‐1 Ab to the monotherapy of immune checkpoint inhibitor in combating HCC. However, more well-designed animal experiments and clinical trials are warranted to further confirm our findings in future due to the limitations in our study.