Background: Emerging evidence indicates that circular RNAs (circRNAs) and m⁶A RNA methylation participate in the pathogenesis and metastasis of multiple malignancies including hepatocellular carcinoma (HCC). However, it remains undocumented how circRNAs form a feedback loop with the m⁶A modification contributing to HCC. Methods: A novel hsa_circ_0017114 (circGPR137B) was identified from three pairs of primary HCC and adjacent normal tissues by circRNA expression profiling. The association of circGPR137B and miR-4739 with clinicopathological parameters and prognosis in patients with HCC was analyzed by RT-qPCR, fluorescence in situ hybridization and TCGA cohorts. The role of circGPR137B in HCC was estimated in vitro and in vivo. RT-qPCR, western blot, m⁶A dot blot, RIP, MeRIP and dual-luciferase reporter assays were used to validate the reciprocal regulation of the feedback loop among circGPR137B, miR-4739 and m⁶A demethylase FTO. Meanwhile, the expression, function and prognosis of FTO in HCC were investigated by RT-qPCR, western blot, TCGA and rescue experiments. Results: We identified a new dramatically downregulated circGPR137B in HCC tissues, and found that downregulation of circGPR137B or upregulation of miR-4739 was associated with poor prognosis in patients with HCC. Ectopic expression of circGPR137B strikingly repressed the proliferation, colony formation and invasion, whereas knockdown of circGPR137B harbored the opposite effects. Moreover, restored expression of circGPR137B inhibited tumor growth and lung metastasis in vivo. Further investigations showed that circGPR137B, co-localized with miR-4739 in the cytoplasm, acted as a sponge for miR-4739 to upregulate its target FTO, which mediated m⁶A demethylation of circGPR137B and promoted its expression. Thus, a feedback loop comprising circGPR137B/miR-4739/FTO axis was formed. FTO suppressed cell growth and indicated favorable survival in patients with HCC. Conclusion: Our results demonstrate that circGPR137B inhibits HCC tumorigenesis and metastasis through the circGPR137B/miR-4739/FTO feedback loop. This positive feedback mechanism executed by functional coupling between a circRNA sponge and an m⁶A modification event suggests a model for epigenetics.

Objective: Undercarboxylated osteocalcin (ucOC) is one form of osteocalcin lacking full carboxylation, which plays an important role in bone homeostasis, glucose homeostasis, and energy metabolism. Our aim is to obtain the profile of serum ucOC level according to gender and age and explore its associations with bone mineral density (BMD), bone turnover markers (BTMs), and prevalence of osteopenia and osteoporosis in the Chinese population.Methods: This is a cross-sectional study with 900 subjects, composed of 431 men and 469 women. Clinical information was collected, and BMD values of the lumbar spine (L1–4), left femoral neck, and total hip were scanned. Biochemical markers including hepatic and renal function, serum calcium, serum phosphorus, procollagen type 1 N-propeptide (P1NP) β-CrossLaps of type I collagen-containing cross-linked C-telopeptide (β-CTX) intact parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHD), and ucOC were measured.Results: We found that the median ucOC level was higher in men than women [men, 2.6 ng/ml; women, 1.6 ng/ml; p < 0.001]. The profile according to age showed that ucOC levels were the lowest at the age of 40–49 years in both men [2.55 ng/ml (95% CI = 1.96–3.13 ng/ml)] and women [1.57 ng/ml (95% CI = 1.12–2.03 ng/ml)]; in patients younger than 49 years, they decreased with age; then over 50 years, they quickly increased. Furthermore, we found that a higher ucOC level was correlated with lower BMD values at the lumbar spine (men, r = −0.128, p = 0.013; women, r = −0.321, p < 0.001), femoral neck (men, r = −0.095, p = 0.062; women, r = −0.260, p < 0.001), and total hip (men, r = −0.123, p = 0.015; women, r = −0.209, p < 0.001) and higher P1NP (men, r = 0.307, p < 0.001; women, r = 0.239, p < 0.001) and β-CTX (men, r = 0.169, p = 0.001; women, r = 0.354, p < 0.001) levels in both men and women. Furthermore, we also showed that a 1 − SD increase in ucOC was associated with an odds ratio (OR) of 1.63 and 1.70 for having osteopenia or osteoporosis in men and women, respectively (men, 95% CI = 1.25–2.13, p = 0.004; women, 95% CI = 1.19–2.42, p = 0.004).Conclusions: We first revealed the profile of serum ucOC levels according to gender and age in the Chinese population and demonstrated the associations of ucOC with BMD and BTMs and the risk of prevalent osteopenia or osteoporosis. Our findings provide a clue to elucidate the function of ucOC in bone metabolism.

Objective: The present study explores the relationship between glycemic excursion and bone turnover markers. Methods: A total of 250 patients with type 2 diabetes mellitus (T2DM) (142 female and 108 male patients) were enrolled in this study. All participants underwent 72 hours of continuous glycemic monitoring to evaluate the mean amplitude of glycemic excursions (MAGE) of each person. Bone turnover markers and other biochemical data were measured for each patient. Linear regression was performed to explore the relationship between bone turnover markers and glycemic excursion. A value of P < 0.05 was considered statistically significant. Results: MAGE was negatively correlated to N-terminal propeptide of type 1 collagen (P1NP) female: [odds ratios (95% confidence interval) (OR (95% CI)), − 2.516 (− 5.389, 0.356)]; male: [− 2.895, (− 6.521, − 0.731)] and C-terminal telopeptide fragments of type-I collagen (β-CTX) female [− 0.025, (− 0.036, 0.005)]; male [− 0.043, (− 0.082, 0.003)]. MAGE was still negatively correlated with β-CTX female [− 0.036, (− 0.198, − 0.030)]; male [− 0.048, (− 0.089, − 0.007)] after adjusting for clinical data and biochemical indices. Conclusion: An independent negative relationship between glycemic excursion and bone turnover markers in patients with T2DM was identified in this study.

We confirmed the inverted U- or J-shaped association of hsCRP with SUA levels among ‘apparently healthy’ population, both cross-sectionally and longitudinally