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Targeting Nicotinamide adenine dinucleotide (NAD) metabolism has emerged as a promising anti-cancer strategy; we aimed to explore the health benefits of boosting NAD levels with nicotinamide riboside (NR) on hepatocellular carcinoma (HCC). We established three in vivo tumor models, including subcutaneous transplantation tumor model in both Balb/c nude mice (xenograft), C57BL/6J mice (allograft), and hematogenous metastatic neoplasm in nude mice. NR (400 mg/kg bw) was supplied daily in gavage. In-situ tumor growth or noninvasive bioluminescence were measured to evaluate the effect of NR on the HCC process. HepG2 cells were treated with transforming growth factor-β (TGF-β) in the absence/presence of NR in vitro. We found that NR supplementation alleviated malignancy-induced weight loss and metastasis to lung in nude mice in both subcutaneous xenograft and hematogenous metastasis models. NR supplementation decreased metastasis to the bone and liver in the hematogenous metastasis model. NR supplementation also significantly decreased the size of allografted tumors and extended the survival time in C57BL/6J mice. In vitro experiments showed that NR intervention inhibited the migration and invasion of HepG2 cells triggered by TGF-β. In summary, our results supply evidence that boosting NAD levels by supplementing NR alleviates HCC progression and metastasis, which may serve as an effective treatment for the suppression of HCC progression.

ObjectivesThe study aimed to explore the relationship of thyroid function and resistance indices with subsequent risk of gestational diabetes (GDM).DesignThis was a longitudinal study embedded in the Huizhou Birth Cohort.MethodsA total of 2,927 women of singleton pregnancy were recruited from January to October of 2019. Thyroid central resistance indices were evaluated by Thyroid Feedback Quartile-Based index (TFQI), Thyrotrophy T4 Resistance Index (TT4RI), and TSH Index (TSHI) based on plasma-free thyroxine (FT4) and thyroid-stimulating hormone (TSH) levels during the first half of pregnancy. Thyroid peripheral sensitivity was assessed by free triiodothyronine (FT3) to FT4 ratio (FT3/FT4), a proxy of deiodinase activity. GDM was diagnosed between 24 and 28 weeks of gestation by a standardized 75 g oral glucose tolerance test. Multivariable linear and logistic regression was applied to examine the associations of thyroid markers with GDM risk.ResultsFT3 and FT3/FT4 were positively associated with both fasting and post-load glucose levels, while TSH, TSHI, TT4RI, and TFQI were negatively associated with 1 and 2 h post-load glucose levels. Compared with the lowest quartile, GDM risk in the highest quartile increased by 44% [odds ratio (OR) = 1.44; 95%CI, 1.08–1.92; ptrend = 0.027] for FT3 and 81% (OR = 1.81; 95%CI, 1.33–2.46; ptrend < 0.001) for FT3/FT4, while it lowered by 37% (OR = 0.63; 95%CI, 0.47–0.86; ptrend = 0.002] for TSHI, 28% for TT4RI (OR = 0.72; 95%CI, 0.54–0.97; ptrend = 0.06), and 37% for TFQI (OR = 0.63; 95%CI, 0.46–0.85; ptrend < 0.001).ConclusionsThis longitudinal study indicated that higher FT3 and FT3/FT4 and lower central thyroid resistance indices were associated with increased risk of GDM.

Background: Nicotinamide riboside (NR) is a nicotinamide adenine dinucleotide (NAD+) precursor which is present in foods such as milk and beer. It was reported that NR can prevent obesity, increase longevity, and promote liver regeneration. However, whether NR can prevent ethanol-induced liver injuries is not known. This study aimed to explore the effect of NR on ethanol induced liver injuries and the underlying mechanisms. Methods: We fed C57BL/6 J mice with Lieber-DeCarli ethanol liquid diet with or without 400 mg/kg·bw NR for 16 days. Liver injuries and SirT1-PGC-1α-mitochondrial function were analyzed. In in vitro experiments, HepG2 cells (CYP2E1 over-expressing cells) were incubated with ethanol ± 0.5 mmol/L NR. Lipid accumulation and mitochondrial function were compared. SirT1 knockdown in HepG2 cells were further applied to confirm the role of SirT1 in the protection of NR on lipid accumulation. Results: We found that ethanol significantly decreased the expression and activity of hepatic SirT1 and induced abnormal expression of enzymes of lipid metabolism in mice. Both in vivo and in vitro experiments showed that NR activated SirT1 through increasing NAD+ levels, decreased oxidative stress, increased deacetylation of PGC-1α and mitochondrial function. In SirT1 knockdown HepG2 cells, NR lost its ability in enhancing mitochondrial function, and its protection against lipid accumulation induced by ethanol. Conclusions: NR can protect against ethanol induced liver injuries via replenishing NAD+, reducing oxidative stress, and activating SirT1-PGC-1α-mitochondrial biosynthesis. Our data indicate that SirT1 plays an important role in the protection of NR against lipid accumulation and mitochondrial dysfunctions induced by ethanol. Keywords: Alcoholic liver disease, NAD+, Nicotinamide Riboside, SirT1, Oxidative stress, Mitochondrial biosynthesis

Cyanidin-3-O-β-glucoside (Cy-3-G) has protective properties in many diseases. Whether Cy-3-G has protective effects on alcohol induced liver injuries remains uncertain. In our study, mice were fed with a high fat high cholesterol diet (HFC) plus ethanol for 12 weeks. Cy-3-G supplementation reversed the liver damage induced by alcohol. In vitro studies, Cy-3-G restored the intracellular energy status of LX-2 cells and inhibited the activation of LX-2 cells induced by ethanol plus palmitate. The protective effect of Cy-3-G is via the increase of AMPK phosphorylation and autophagy. In conclusion, Cy-3-G ameliorated chronic alcoholic liver injuries, possibly by improving energy metabolic status. Specifically, liver fibrosis was protected by Cy-3-G via inhibiting the activation of stellate cells, which was mediated partially by AMPK/autophagy signaling pathway.