BackgroundNicotinamide 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.MethodsWe 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.ResultsWe 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.ConclusionsNR 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.

Efficacy of EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, to treat human non-small cell lung cancers (NSCLCs) with activating mutations in EGFR is not persistent due to drug resistance. Reprogramming in energy (especially glucose) metabolism plays an important role in development and progression of acquired resistance in cancer cells. We hypothesize that glucose metabolism in EGFR-TKI sensitive HCC827 cells and erlotinib-resistant sub-line of HCC827 (which we name it as erlotinib-resistant 6, ER6 cells in this study) is different and targeting glucose metabolism might be a treatment strategy for erlotinib-resistant NSCLCs. In this study, we found increased glucose uptakes, significant increase in glycolysis rate and overexpression of glucose transporter 1 in ER6 cells compared to its parental cells HCC827. We also found AKT and autophagy of ER6 cells were more activated than HCC827 cells after glucose starvation. Combining glucose deprivation and AKT or autophagy inhibitor could synergize and overcome the acquired resistance against EGFR-targeted therapy for NSCLCs. Our data suggest that the combinations of inhibitors of AKT or autophagy together with glucose deprivation could be novel treatment strategies for NSCLC with acquired resistance to targeted therapy.

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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.

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