Epigallocatechin gallate alleviates high-fat diet-induced hepatic lipotoxicity by targeting mitochondrial ROS-mediated ferroptosis.

Background: Non-alcoholic fatty liver disease (NAFLD) is a chronic advanced liver disease that is highly related to metabolic disorders and induced by a high-fat diet (HFD). Recently, epigallocatechin gallate (EGCG) has been regarded as a protective bioactive polyphenol in green tea that has the ability to protect against non-alcoholic fatty liver disease, but the molecular mechanism remains poorly deciphered. Ferroptosis plays a vital role in the progression of non-alcoholic fatty liver disease, but experimental evidence of ferroptosis inhibition by epigallocatechin gallate is limited. Hence, our study aimed to investigate the effect and mechanisms of epigallocatechin gallate on hepatic ferroptosis to mitigate hepatic injury in high-fat diet-fed mice. Methods: Fifty male C57BL/6 mice were fed either a standard chow diet (SCD), a high-fat diet, or a high-fat diet and administered epigallocatechin gallate or ferrostatin-1 (a ferroptosis-specific inhibitor) for 12 weeks. Liver injury, lipid accumulation, hepatic steatosis, oxidative stress, iron overload, and ferroptosis marker proteins were examined. In vitro, steatotic L-02 cells were used to explore the underlying mechanism. Results: In our research, we found that epigallocatechin gallate notably alleviated liver injury and lipid accumulation, oxidative stress, hepatic steatosis, decreased iron overload and inhibited ferroptosis in a high-fat diet-induced murine model of non-alcoholic fatty liver disease. In vitro experiments, using ferrostatin-1 and a mitochondrial reactive oxygen species (MtROS) scavenger (Mito-TEMPO), we found that epigallocatechin gallate remarkably alleviated oxidative stress and inhibited ferroptosis by reducing the level of mitochondrial reactive oxygen species in steatotic L-02 cells. Conclusion: Taken together, our results revealed that epigallocatechin gallate may exert protective effects on hepatic lipotoxicity by inhibiting mitochondrial reactive oxygen species-mediated hepatic ferroptosis. Findings from our study provide new insight into prevention and treatment strategies for non-alcoholic fatty liver disease pathological processes.

Targeting Mitochondrial ROS-Mediated Ferroptosis by Quercetin Alleviates High-Fat Diet-Induced Hepatic Lipotoxicity.

Background: The protective effect of quercetin on nonalcoholic fatty liver disease (NAFLD) has been reported, but its mechanism remains poorly understood. Recently, quercetin was reported to be capable of inhibiting ferroptosis, which is a recognized type of regulated cell death. Moreover, hepatic ferroptosis plays an important role in the progression of NAFLD, but experimental evidence is limited. Hence, our study aimed to investigate the effect of quercetin on hepatic ferroptosis in high-fat diet (HFD)-induced NAFLD and further elucidate the underlying molecular mechanism. Methods: C57BL/6J mice were fed either a normal diet (ND), an HFD, or an HFD supplemented with quercetin for 12 weeks. Hepatic lipid peroxidation, steatosis, ferroptosis and iron overload were examined. In vitro, steatotic L-02 cells was used to study the potential mechanism. Results: We found that the HFD caused lipid peroxidation, lipid accumulation and ferroptosis in the liver, which were rescued by quercetin supplementation. Consistent with the in vivo results, quercetin alleviated lipid droplet accumulation and reduced the levels of lipid reactive oxygen species (ROS) and ferroptosis in steatotic L-02 cells. Using a mitochondrial ROS (MtROS) scavenger (Mito-TEMPO) and ferroptosis specific inhibitor (Fer-1), we found that quercetin remarkably alleviated lipid droplet accumulation and lipid peroxidation by reducing MtROS-mediated ferroptosis in steatotic L-02 cells. Conclusion: Our data showed that HFD consumption induced lipid accumulation and triggered ferroptosis in liver, ultimately leading to hepatic lipotoxicity, which can be alleviated by quercetin. Findings from this study provide new insight into the mechanism by which quercetin can be used for the prevention and treatment of NAFLD.

Blood homocysteine levels in children with autism spectrum disorder: An updated systematic review and meta-analysis.

Results of studies on peripheral blood levels of homocysteine (Hcy) in children with autism spectrum disorder (ASD) are inconsistent, and conclusions from two previous meta-analyses on this subject published in 2012 are already outdated. Therefore, we conducted an updated systematic review and meta-analysis to quantitatively summarize the peripheral blood Hcy data in children with ASD compared with healthy controls (HC). We searched PubMed, EMBASE, PsycINFO, PsycARTICLES, Web of Science, and Cochrane Library databases from inception to September 2019 for eligible studies, with no language restriction. Using random-effects model, we computed summary statistics. Thirty-one studies (3304 participants including 1641 cases) were included. The pooled results showed that the peripheral blood Hcy levels were significantly elevated in children with ASD when compared to HC (Hedges's g = 0.56, 95% CI = 0.36 to 0.76, P < 0.001). By sensitivity analyses, we confirmed that our results were quite robust. Additionally, no publication bias was observed in this meta-analysis. In conclusion, our study support the association of increased circulating Hcy levels with ASD in children, and the involvement of Hcy in the occurrence of ASD. However, in view of the significant between-study heterogeneity, the conclusions should be interpreted cautiously and more investigation is required.

Blood biomarker levels of methylation capacity in autism spectrum disorder: a systematic review and meta-analysis.

OBJECTIVE: To compare the peripheral blood levels of methionine (Met), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), and the SAM/SAH ratio (the most core and predictive indices of cellular methylation ability) between patients with autism spectrum disorder (ASD) and control subjects. METHODS: PubMed, Embase, PsycINFO, Web of Science, and Cochrane Library were searched from inception to August 2, 2019, without language restriction. The random-effects model was used to summarize effect sizes. RESULTS: We retrieved 1,493 records, of which 22 studies met inclusion criteria. Our overall analyses revealed that individuals with ASD had significantly decreased levels of Met (22 studies; Hedges' g = -0.62; 95% confidence interval [CI]: -0.89, -0.35), SAM (8 studies; Hedges' g = -0.60; 95% CI: -0.86, -0.34), and the SAM/SAH ratio (8 studies; Hedges' g = -0.98; 95% CI: -1.30, -0.66) and significantly increased levels of SAH (8 studies; Hedges' g = 0.69; 95% CI: 0.43, 0.94). The findings of the overall analyses were quite stable after being verified by sensitivity analyses and in agreement with the corresponding outcomes of subgroup analyses. Additionally, our results from meta-analytic techniques confirmed that the effect estimates of this meta-analysis did not originate from publication bias. CONCLUSION: Individuals with ASD have substantially aberrant peripheral blood levels of Met, SAM, SAH, and the SAM/SAH ratio, which supports the association between impaired methylation capacity and ASD. Therefore, further investigations into these indices as potential biomarkers for diagnosis and therapeutic targets of ASD are warranted.

Maternal n-3 PUFAs deficiency during pregnancy inhibits neural progenitor cell proliferation in fetal rat cerebral cortex.

The aim of this study was to evaluate the in vivo impacts of maternal n-3 polyunsaturated fatty acids (PUFAs) deficiency during pregnancy on the proliferation of neural progenitor cells (NPCs) in the developing cerebral cortex of fetal rats. Our results showed that about 5 weeks of maternal dietary n-3 PUFAs deprivation resulted in a substantial n-3 PUFA deficiency in fetal rat cerebral cortex. Importantly, by two survival schemes and two quantitative methods, we found that maternal intake of n-3 PUFAs deficient diet during the gestation significantly inhibited the proliferation of NPCs in fetal rat cerebral cortex. Moreover, the decreased cortical NPCs proliferation induced by nutritional n-3 PUFAs restriction did not originate from the increased NPCs apoptosis. Finally, our observations indicated that the down-regulation of cyclin E protein might be involved in the inhibitory effects of maternal n-3 PUFAs deficient diet on the proliferation of cortical NPCs. These findings highlight the importance of maternal intake of appropriate n-3 PUFAs and deepen our understanding of the exact effects of n-3 PUFAs on mammalian brain development.

Association of maternal prenatal folic acid intake with subsequent risk of autism spectrum disorder in children: A systematic review and meta-analysis.

BACKGROUND: A number of studies have explored the link of antenatal folic acid (FA) intake with autism spectrum disorder (ASD) in children, with inconsistent findings. Therefore, we conducted a systematic review and meta-analysis of relevant studies to elucidate the actual association between maternal FA intake during the prenatal period and the risk of ASD in offspring. METHODS: PubMed, EMBASE, PsycINFO, Scopus, Web of Science, and Cochrane Library were searched up to June 7, 2018, without language restriction. The random-effects model was applied to summarize results. The adjusted odds ratios (ORs) and hazard ratios (HRs) were pooled separately. RESULTS: Eight observational studies (a total of 13 reports; 840,776 children and 7127 cases) were included. FA intake was mainly estimated from self-report of mothers or available databases. The results of overall analysis from 6 studies (9 reports) combined by OR and 2 studies (4 reports) presenting HR showed that the likelihoods of ASD in offspring whose mothers were prenatally exposed to FA did not vary significantly compared with those in offspring of mothers without such exposure (OR = 0.91, 95% CI: 0.73-1.13 and HR = 0.66, 95% CI: 0.38-1.17, respectively). Further analysis revealed that the primary outcome of the meta-analysis was stable regardless of the study design, and not unduly affected by any single report. Additionally, no publication bias was observed, and the findings of overall analysis were in agreement with those of subgroup analyses. CONCLUSIONS: This study does not provide support for the association between maternal FA intake during the prenatal period and the reduced risk of ASD in children. However, in view of the types and limited number of studies in the literature, more investigation is needed to confirm the findings of this meta-analysis.

Maternal multivitamin supplementation is associated with a reduced risk of autism spectrum disorder in children: a systematic review and meta-analysis.

Several studies have explored the link of antenatal multivitamin supplementation with autism spectrum disorder (ASD) in offspring, but the findings are inconsistent. The purpose of the current study was to perform a systematic review and meta-analysis of published studies to evaluate the actual association between maternal multivitamin supplementation during the prenatal period and the risk of ASD in children. PubMed, EMBASE, PsycINFO, Web of Science, and Cochrane Library were searched up to August 26, 2018. The random-effects model was used to calculate the pooled results. The adjusted risk ratios (RRs) were used as the common measure of association among studies. Sensitivity and subgroup analyses were also conducted. A total of 5 articles (9 independent trials; 231 163 children encompassing 4459 cases) were included. The results of overall analysis showed that the likelihood of ASD in offspring whose mothers used multivitamin supplements during the prenatal period was significantly reduced compared with that in offspring of mothers without such supplementation (RR, 0.62; 95% CI, 0.45-0.86; P = .003). Additionally, the primary outcome of the meta-analysis was quite robust after being verified by sensitivity analyses and no publication bias was found. Furthermore, the findings of overall analysis were generally consistent with those of subgroup analyses. In conclusion, this meta-analysis supports a protective association between maternal multivitamin supplementation during the prenatal period and the subsequent risk of ASD in children. Further investigation is needed and should address the constituent(s) contributing to the protective effect of multivitamin on ASD risk and the underlying molecular mechanisms.

Green Tea Polyphenols Attenuate High-Fat Diet-Induced Renal Oxidative Stress through SIRT3-Dependent Deacetylation.

Fifty male Wistar rats were fed a standard chow diet or a high-fat (HF) diet, and different concentrations of green tea polyphenols (GTPs) (0.8, 1.6, and 3.2 g/L) were administered in the drinking water. We found that the malondialdehyde (MDA) level in the HF diet group was significantly higher than that in the control (CON) group (P<0.05). Decreased peroxisome proliferator-activated receptor (PPAR)-α and sirtuin 3 (SIRT3) expression, and increased manganese superoxide dismutase (MnSOD) acetylation levels were also detected in the HF diet group (P<0.05). GTP treatment upregulated SIRT3 and PPARα expression, increased the pparα mRNA level, reduced the MnSOD acetylation level, and decreased MDA production in rats fed a HF diet (P<0.05). No significant differences in total renal MnSOD and PPAR-γ coactivator-1α (PGC1-α) expression were detected. The reduced oxidative stress detected in kidney tissues after GTP treatment was partly due to the higher SIRT3 expression, which was likely mediated by PPARα.