The deubiquitinase USP7 regulates oxidative stress through stabilization of HO-1.

Heme oxygenase-1 (HO-1) is an inducible heme degradation enzyme that plays a cytoprotective role against various oxidative and inflammatory stresses. However, it has also been shown to exert an important role in cancer progression through a variety of mechanisms. Although transcription factors such as Nrf2 are involved in HO-1 regulation, the posttranslational modifications of HO-1 after oxidative insults and the underlying mechanisms remain unexplored. Here, we screened and identified that the deubiquitinase USP7 plays a key role in the control of redox homeostasis through promoting HO-1 deubiquitination and stabilization in hepatocytes. We used low-dose arsenic as a stress model which does not affect the transcriptional level of HO-1, and found that the interaction between USP7 and HO-1 is increased after arsenic exposure, leading to enhanced HO-1 expression and attenuated oxidative damages. Furthermore, HO-1 protein is ubiquitinated at K243 and subjected to degradation under resting conditions; whereas when after arsenic exposure, USP7 itself can be ubiquitinated at K476, thereafter promoting the binding between USP7 and HO-1, finally leading to enhanced HO-1 deubiquitination and protein accumulation. Moreover, depletion of USP7 and HO-1 inhibit liver tumor growth in vivo, and USP7 positively correlates with HO-1 protein level in clinical human hepatocellular carcinoma (HCC) specimens. In summary, our findings reveal a critical role of USP7 as a HO-1 deubiquitinating enzyme in the regulation of oxidative stresses, and suggest that USP7 inhibitor might be a potential therapeutic agent for treating HO-1 overexpressed liver cancers.

Household cooking oil type and risk of oral micronucleus frequency in Chinese nonsmokers.

Household animal fat has been linked to increased incidence of cancers compared with vegetable fat. However, few epidemiological studies have associated these two cooking oil types with precancerous genotoxic effects, such as occurrence of micronuclei (MN). This study aimed to explore the association between oral MN frequency and household cooking oil type and whether the association can be attributed to polycyclic aromatic hydrocarbons (PAHs). We collected information about individual cooking oil use, measured genotoxic effects by MN tests and urinary PAHs metabolites (OHPAHs) in 245 nonsmokers. The associations between household cooking oil type and MN frequency and OHPAHs were analyzed using generalized linear models (GLMs) and logistic regression models, evaluating odds ratios and coefficient (95% confidence intervals) (ORs, 95% Cls; ß, 95% Cls). The odds of animal fat consumers, rather than vegetable fat consumers, was positively associated with higher MN frequency (OR = 1.94, P < 0.05). The associations were discovered in participants only using kitchen ventilation (OR = 2.04, P < 0.05). Animal fat consumers had higher total OHPAHs than vegetable fat consumers (1.58 ± 0.22 mg/mol, Cr vs 1.20 ± 0.12 mg/mol, Cr; P = 0.028). Significant correlations were observed between total OHPAHs quartiles and increased MN frequency (ß = 0.38, P-trend = 0.026). After stratifying by household cooking oil type, sensitivity analyses showed that the positive association between total OHPAHs quartiles and increased MN frequency was only observed in animal fat consumers (ß = 0.61, P-trend = 0.030). In conclusion, usage of household animal fat was associated with an increased odds of oral MN frequency in Chinese nonsmokers and the odds correlated with increased PAHs exposure. This finding supplemented evidence associating cooking oil type with genotoxic effects and explained its association with PAHs exposure.

High-Temperature Soup Foods in Plastic Packaging Are Associated with Phthalate Body Burden and Expression of Inflammatory mRNAs: A Dietary Intervention Study.

Plastic packaging material is widely used to package high-temperature soup food in China, but this combination might lead to increased exposure to phthalates. The health effects and potential biological mechanisms have not been well studied. This study aimed to examine urinary phthalate metabolites and the expression of inflammatory cytokines in the blood before, during, and after a "plastic-packaged high-temperature soup food" dietary intervention in healthy adults. The results showed that compared with those in the preintervention period, urinary creatinine-adjusted levels of monomethyl phthalate (MMP), mono-n-butyl phthalate (MBP), mono-isobutyl phthalate (MIBP), and total phthalate metabolites in the intervention period were significantly higher, with increases of 71.6, 41.8, 38.8, and 29.8% for MMP, MBP, MIBP, and the total phthalate metabolites, respectively. After intervention, the mean levels of IL-1ß, IL-4, and TNF-α mRNA increased by 19.0, 21.5, and 25.0%, respectively, while IL-6 and IFN-γ mRNA decreased by 24.2 and 32.9%, respectively, when compared with the preintervention period. We also observed that several phthalates were associated with the mRNA or protein expression of IL-8, TNF-α, and IL-10. Therefore, consumption of plastic-packaged high-temperature soup food was linked to increased phthalate exposure and might result in significant changes in mRNA expression of several inflammatory cytokines.