Fisetin, a dietary flavonoid, promotes transintestinal cholesterol excretion through the activation of PPARδ.

Fisetin, a dietary polyphenol abundantly found in strawberries, exhibits a broad spectrum of health-promoting activities, including antihyperlipidemic effects. This study aimed to investigate the regulatory effect of fisetin on cholesterol elimination through novel transintestinal cholesterol excretion (TICE) pathway. A hypercholesterolemic mouse model and human colon epithelial cancer cell line Caco-2 were utilized to conduct the study. In hypercholesterolemic mice, fisetin (25 mg/kg) treatment reduced serum total cholesterol by 46.48% and significantly decreased lipid accumulation in the liver. Furthermore, fisetin administration led to a substantial increase in the fecal neutral sterol contents, including coprostanol, coprostanone, dihydrocholesterol, and cholesterol. Specifically, these sterol contents increased by approximately 224.20%, 151.40%, 70.40% and 50.72% respectively. The fluorescence intensity of 22-NBD-cholesterol in intestinal perfusion increased by 95.94% in fisetin group (25 mg/kg), indicating that fisetin stimulated TICE. In high cholesterol-induced Caco-2 cells, fisetin at a concentration of 30 µM reduced total cholesterol and free cholesterol by 37.21% and 45.30% respectively, stimulated cholesterol excretion, and inhibited cholesterol accumulation. Additionally, fisetin upregulated the gene and protein expression of cholesterol efflux transporters ABCG5/G8 and ABCB1, while downregulating the cholesterol uptake regulator NPC1L1. Furthermore, fisetin increased LDLR protein expression and decreased PCSK9 expression. Notably, fisetin significantly activated nuclear receptor PPARδ in Caco-2 cells. PPARδ antagonist pretreatment counteracted the regulatory effects of fisetin on TICE regulators, suggesting fisetin lowered cholesterol through enhancing TICE by activation of intestinal PPARδ. Fisetin could be used as functional dietarysupplement for eliminating cholesterol and reducing the incidence of cardiovascular diseases.

Hepatic HDAC3 Regulates Systemic Iron Homeostasis and Ferroptosis via the Hippo Signaling Pathway.

Histone deacetylases (HDACs) are epigenetic regulators that play an important role in determining cell fate and maintaining cellular homeostasis. However, whether and how HDACs regulate iron metabolism and ferroptosis (an iron-dependent form of cell death) remain unclear. Here, the putative role of hepatic HDACs in regulating iron metabolism and ferroptosis was investigated using genetic mouse models. Mice lacking Hdac3 expression in the liver (Hdac3-LKO mice) have significantly reduced hepatic Hamp mRNA (encoding the peptide hormone hepcidin) and altered iron homeostasis. Transcription profiling of Hdac3-LKO mice suggests that the Hippo signaling pathway may be downstream of Hdac3. Moreover, using a Hippo pathway inhibitor and overexpressing the transcriptional regulator Yap (Yes-associated protein) significantly reduced Hamp mRNA levels. Using a promoter reporter assay, we then identified 2 Yap-binding repressor sites within the human HAMP promoter region. We also found that inhibiting Hdac3 led to increased translocation of Yap to the nucleus, suggesting activation of Yap. Notably, knock-in mice expressing a constitutively active form of Yap (Yap K342M) phenocopied the altered hepcidin levels observed in Hdac3-LKO mice. Mechanistically, we show that iron-overload-induced ferroptosis underlies the liver injury that develops in Hdac3-LKO mice, and knocking down Yap expression in Hdac3-LKO mice reduces both iron-overload- and ferroptosis-induced liver injury. These results provide compelling evidence supporting the notion that HDAC3 regulates iron homeostasis via the Hippo/Yap pathway and may serve as a target for reducing ferroptosis in iron-overload-related diseases.

Corrigendum: A national cross-sectional study on the influencing factors of low HPV vaccination coverage in mainland China.

[This corrects the article DOI: 10.3389/fpubh.2022.1064802.].

The lipid accumulation product (LAP) association with hyperuricemic hypertension in the China Health and Nutrition Survey: A cross-sectional study.

BACKGROUND AND OBJECTIVES: Previous studies have explored the relationship between lipid accumulation product (LAP) and hypertension or hyperuricemia. However, the association between LAP and hypertension with hyperuricemia (HWH) is inconclusive. Therefore, we aimed to evaluate the association between LAP and HWH. METHODS AND STUDY DESIGN: A total of 7897 participants aged 18 to 75 years from the 2009 wave of the China Health and Nutrition Survey were included in this study. General linear regression models were built to assess the association of LAP with systolic blood pressure (SBP), diastolic blood pressure (DBP), and uric acid (UA) concentrations. Logistic regression models were used to estimate the association between LAP and HWH risk, restricted cubic splines (RCS) were used to analyze the dose-response relationship between them. RESULTS: The prevalence of HWH was significantly higher in men (7.63%) than in women (1.99%) (X2=142; p<0.001). After adjustment for potential confounders, LAP scores were positively correlated with SBP, DBP, and UA concentrations in both genders (all p-trend <0.01). Compared with participants in the lowest quartile of LAP, those in the highest quartile had a higher risk of HWH [OR (95% CI)=12.2 (7.22-20.5) for men, OR (95% CI)=14.5 (3.50- 60.2) for women]. The RCS results suggested a nonlinear relationship between the continuous change of LAP and HWH risk after adjustment for confounding factors in each gender (p for nonlinearity <0.001). CONCLUSIONS: Our findings suggest that higher LAP scores was strongly associated with greater HWH risk in Chinese adults.

Influencing Factors and Improvement Path of Academic Engagement among College Students in the Context of Epidemic Prevention and Control.

OBJECTIVE: The implementation of online teaching in the context of epidemic prevention and control has had an impact on the learning engagement of college students to some extent. This study aims to investigate the mechanisms that influence perceived social support and health behaviors on learning engagement, so as to make college students more focused on their studies by improving their physical and mental health as well as their ability to perceive social support. METHODS: A total of 538 college students from Henan Province, China, were studied using the Perceived Social Support Scale, Health Behavior Scale and Learning Engagement Scale, and the data were analyzed by IBM SPSS Amos 26.0 software (IBM SPSS Inc., Chicago, IL, USA). RESULTS: (1) The level of health behavior among college students was positively correlated with perceived social support ability (ß = 0.289, p < 0.001); both perceived social support and health behaviors predicted college students' learning engagement significantly (ß = 0.200, p < 0.01; ß = 0.406, p < 0.001). (2) College students' perceived social support partially mediated the relationship between health behaviors and learning engagement. CONCLUSION: One of the main ways to improve college students' learning engagement is to improve their health behavior and perceived social support. This study contributes to a better understanding of the relationships between health behaviors and learning engagement, as well as to the development of interventions to improve learning engagement among college students.

Metagenomic insight of corn straw conditioning on substrates metabolism during coal anaerobic fermentation.

Increasing methane production from anaerobic digestion of coal is challenging. This study shows that the combined fermentation of coal and corn straw greatly enriched the substrates available to microorganisms. This was mainly manifested in the increased types and abundance of organic matter in the fermentation liquid, which enhanced methane production by 61%. Metagenomic analysis showed that the addition of corn straw enriched the abundance of Methanosarcina in the combined fermentation system and promoted the complementary advantages of the microorganisms. At the same time, the abundance of genes that convert glucose into acetic acid (K00927, K01689, K01905, etc.) in the combined fermentation system increased, which is conducive to acidification process and biomethane production. In addition, there were the two key methanogenic pathways, namely aceticlastic (57.1%-63.5%) and hydrogenotrophic (23.4%-25.1%) methanogenesis, identified in the single coal fermentation system and the combined coal and corn straw fermentation system. Combined fermentation enhanced the hydrogenotrophic and methylotrophic methanogenic pathways by increasing the gene abundance of K00200 (methane production from CO2 and oxidation of coenzyme M to CO2), K00440 (participates in the binding to other known physiological receptors with hydrogen as a donor), and K00577 (methyltransferase).

A national cross-sectional study on the influencing factors of low HPV vaccination coverage in mainland China.

Background: HPV vaccine can block the infection of high-risk human papillomavirus and is an important measure to effectively reduce the incidence of cervical cancer and precancerous lesions. However, the HPV vaccination rate is still low in China. There are many factors. Therefore, it is important to study the influencing factors to provide basis for promoting the formulation of vaccination strategies. Methods: This study used a multi-stage sampling method to conduct a face-to-face questionnaire survey on women in different regions of China. The new general self-efficacy scale was used to measure the self-efficacy of the respondents. The short form of family health scale measured their family health. The t-test and binary Logistic regression analysis were used to screen the influencing factors of HPV vaccination. Restricted cubic spline model was used to analyze the influence trend of self-efficacy and family health on HPV vaccination rate. Results: (1) The HPV vaccination rate was low, especially in the ≤18 group. The place of residence, capita household income/month, individual self-efficacy and family health had a significant impact on HPV vaccination. (2) The restricted cubic spline model showed that self-efficacy positively promoted HPV vaccination, the correlation strength was statistically significant (χ2 =27.64, P<0.001) and non-linear (χ2 = 12.49, P = 0.0004); The poor family health hindered HPV vaccination, and the association strength was statistically significant (χ2 = 47.81, P < 0.001) and non-linear (χ2 = 9.96, P = 0.0016). Conclusion: It is necessary to strengthen the health education of HPV vaccination knowledge in the population to eliminate the hesitancy of vaccination. Free HPV vaccination strategies should be developed and encourage people of appropriate age to receive as early as possible. Self-efficacy and family health should be enhanced to increase HPV vaccination rate, so as to achieve the goal of reducing the incidence of cervical cancer and protecting women's health.

Causal association of childhood obesity with cancer risk in adulthood: A Mendelian randomization study.

In observational studies of children and adolescents, higher body weight has been associated with distinct disease outcomes, including cancer, in adulthood. Therefore, we performed a two-sample Mendelian randomization (MR) study to evaluate the causal effect of childhood obesity on long-term cancer risk. Single-nucleotide polymorphisms associated with higher childhood body mass index (BMI) from large-scale genome-wide association studies were used as genetic instruments. Summary-level data for 24 site-specific cancers were obtained from UK Biobank. We found that a 1-SD increase in childhood BMI (kg/m2 ) was significantly associated with a 60% increase in risk of pancreatic cancer (odds ratio [OR]: 1.60; 95% confidence interval [CI]: 1.12-2.28; P < 0.01) and a 47% increase in risk of esophageal cancer (OR: 1.47; 95% CI: 1.09-1.97; P < 0.01) in adults. In contrast, there was an inverse association of genetic predisposition to childhood obesity with throat (OR: 0.46; 95% CI: 0.27-0.79; P < 0.01) and breast cancer (OR: 0.77; 95% CI: 0.64-0.94; P < 0.01) in adult life. For the other 20 cancers studied, no statistically significant association was observed. Our MR analyses found causal effects of childhood obesity on several cancers. Maintaining a healthy weight should be emphasized during childhood and adolescence to prevent cancer risk later in life.

[Progress on epigenetic regulation of iron homeostasis].

Iron homeostasis plays an important role for the maintenance of human health. It is known that iron metabolism is tightly regulated by several key genes, including divalent metal transport-1(DMT1), transferrin receptor 1(TFR1), transferrin receptor 2(TFR2), ferroportin(FPN), hepcidin(HAMP), hemojuvelin(HJV) and Ferritin H. Recently, it is reported that DNA methylation, histone acetylation, and microRNA (miRNA) epigenetically regulated iron homeostasis. Among these epigenetic regulators, DNA hypermethylation of the promoter region of FPN, TFR2, HAMP, HJV and bone morphogenetic protein 6 (BMP6) genes result in inhibitory effect on the expression of these iron-related gene. In addition, histone deacetylase (HADC) suppresses HAMP gene expression. On the contrary, HADC inhibitor upregulates HAMP gene expression. Additional reports showed that miRNA can also modulate iron absorption, transport, storage and utilization via downregulation of DMT1, FPN, TFR1, TFR2, Ferritin H and other genes. It is noteworthy that some key epigenetic regulatory enzymes, such as DNA demethylase TET2 and histone lysine demethylase JmjC KDMs, require iron for the enzymatic activities. In this review, we summarize the recent progress of DNA methylation, histone acetylation and miRNA in regulating iron metabolism and also discuss the future research directions.

Transferrin Receptor 1 Regulates Thermogenic Capacity and Cell Fate in Brown/Beige Adipocytes.

Iron homeostasis is essential for maintaining cellular function in a wide range of cell types. However, whether iron affects the thermogenic properties of adipocytes is currently unknown. Using integrative analyses of multi-omics data, transferrin receptor 1 (Tfr1) is identified as a candidate for regulating thermogenesis in beige adipocytes. Furthermore, it is shown that mice lacking Tfr1 specifically in adipocytes have impaired thermogenesis, increased insulin resistance, and low-grade inflammation accompanied by iron deficiency and mitochondrial dysfunction. Mechanistically, the cold treatment in beige adipocytes selectively stabilizes hypoxia-inducible factor 1-alpha (HIF1α), upregulating the Tfr1 gene, and thermogenic adipocyte-specific Hif1α deletion reduces thermogenic gene expression in beige fat without altering core body temperature. Notably, Tfr1 deficiency in interscapular brown adipose tissue (iBAT) leads to the transdifferentiation of brown preadipocytes into white adipocytes and muscle cells; in contrast, long-term exposure to a low-iron diet fails to phenocopy the transdifferentiation effect found in Tfr1-deficient mice. Moreover, mice lacking transmembrane serine protease 6 (Tmprss6) develop iron deficiency in both inguinal white adipose tissue (iWAT) and iBAT, and have impaired cold-induced beige adipocyte formation and brown fat thermogenesis. Taken together, these findings indicate that Tfr1 plays an essential role in thermogenic adipocytes via both iron-dependent and iron-independent mechanisms.

Ferroptosis as a target for protection against cardiomyopathy.

Heart disease is the leading cause of death worldwide. A key pathogenic factor in the development of lethal heart failure is loss of terminally differentiated cardiomyocytes. However, mechanisms of cardiomyocyte death remain unclear. Here, we discovered and demonstrated that ferroptosis, a programmed iron-dependent cell death, as a mechanism in murine models of doxorubicin (DOX)- and ischemia/reperfusion (I/R)-induced cardiomyopathy. In canonical apoptosis and/or necroptosis-defective Ripk3-/-, Mlkl-/-, or Fadd-/-Mlkl-/- mice, DOX-treated cardiomyocytes showed features of typical ferroptotic cell death. Consistently, compared with dexrazoxane, the only FDA-approved drug for treating DOX-induced cardiotoxicity, inhibition of ferroptosis by ferrostatin-1 significantly reduced DOX cardiomyopathy. RNA-sequencing results revealed that heme oxygenase-1 (Hmox1) was significantly up-regulated in DOX-treated murine hearts. Administering DOX to mice induced cardiomyopathy with a rapid, systemic accumulation of nonheme iron via heme degradation by Nrf2-mediated up-regulation of Hmox1, which effect was abolished in Nrf2-deficent mice. Conversely, zinc protoporphyrin IX, an Hmox1 antagonist, protected the DOX-treated mice, suggesting free iron released on heme degradation is necessary and sufficient to induce cardiac injury. Given that ferroptosis is driven by damage to lipid membranes, we further investigated and found that excess free iron accumulated in mitochondria and caused lipid peroxidation on its membrane. Mitochondria-targeted antioxidant MitoTEMPO significantly rescued DOX cardiomyopathy, supporting oxidative damage of mitochondria as a major mechanism in ferroptosis-induced heart damage. Importantly, ferrostatin-1 and iron chelation also ameliorated heart failure induced by both acute and chronic I/R in mice. These findings highlight that targeting ferroptosis serves as a cardioprotective strategy for cardiomyopathy prevention.

HDAC1 Governs Iron Homeostasis Independent of Histone Deacetylation in Iron-Overload Murine Models.

AIMS: Iron-overload disorders are common and could lead to significant morbidity and mortality worldwide. Due to limited treatment options, there is a great need to develop novel strategies to remove the excess body iron. To discover potential epigenetic modulator in hepcidin upregulation and subsequently decreasing iron burden, we performed an epigenetic screen. The in vivo effects of the identified compounds were further tested in iron-overload mouse models, including Hfe-/-, Hjv-/-, and hepatocyte-specific Smad4 knockout (Smad4fl/fl;Alb-Cre+) mice. RESULTS: Entinostat (MS-275), the clinical used histone deacetylase 1 (HDAC1) inhibitor, was identified the most potent hepcidin agonist. Consistently, Hdac1-deficient mice also presented higher hepcidin levels than wild-type controls. Notably, the long-term treatment with entinostat in Hfe-/- mice significantly alleviated iron overload through upregulating hepcidin transcription. In contrast, entinostat showed no effect on hepcidin expression and iron levels in Smad4fl/fl;Alb-Cre+ mice. Further mechanistic studies revealed that HDAC1 suppressed expression of hepcidin through interacting with SMAD4 rather than deacetylation of SMAD4 or histone-H3 on the hepcidin promoter. INNOVATION: The findings uncovered HDAC1 as a novel hepcidin suppressor through complexing with SMAD4 but not deacetylation of either histone 3 or SMAD4. In addition, our study suggested a novel implication of entinostat in treating iron-overload disorders. CONCLUSIONS: Based on our results, we conclude that entinostat strongly activated hepcidin in vivo and in vitro. HDAC1 could serve as a novel hepcidin suppressor by binding to SMAD4, effect of which is independent of BMP/SMAD1/5/8 signaling. Antioxid. Redox Signal. 28, 1224-1237.