The effect of long-term care insurance on healthcare utilization of middle-aged and older adults: evidence from China health and retirement longitudinal study.

BACKGROUND: As global ageing continues to increase and many countries face challenges from the growing demand for long-term care. Drawing on the experiences of developed countries, developing countries have explored their own suitable long-term care insurance and have shown strong potential for development and research prospects. However, due to their late start, relevant research is underrepresented in the global research network and still needs to be supplemented. The present study hopes to examine the effect of long-term care insurance on healthcare utilization among the middle-aged and elderly from an empirical perspective, using China as an example. METHODS: Panel data from wave 3 (2015) and wave 4 (2018) of the nationally-representative China health and retirement longitudinal study were selected to obtain a sample of 661 processing participants and 16,065 control participants after matching the policy implementation time in the first pilot cities, and quantitative analysis was conducted using difference-in-differences propensity score matching estimator method to assess the net effect of long-term care insurance on health care utilization among the middle-aged and elderly adults. RESULTS: In the matched frequency-weighted regression difference-in-differences estimator results, long-term care insurance had a negative effect on the number and costs of annual hospitalizations at the 5% significance level (key variable values of - 0.0568101 and - 1236.309, respectively) and a non-significant effect on outpatient service utilization (P > 0.05). Further exploration of the heterogeneous effect of it revealed that implementation had a more significant negative effect on hospitalization utilization for middle-aged and older people in the East and for those with higher levels of education or attended care. CONCLUSION: Long-term care insurance has played a role in controlling hospitalization costs but has not yet achieved the expected effect in controlling outpatient costs. The policy effects in terms of regional distribution and education level and care situation have been variable. The treatment plan of long-term care insurance needs to be improved, the supply of resources for long-term care services should be increased, and the promotion of long-term care insurance and health science should be given attention.

Activation and induction of antigen-specific T follicular helper cells play a critical role in recombinant SARS-CoV-2 RBD vaccine-induced humoral responses.

The role of follicular T helper (Tfh) cells in humoral response has been considered essential in recent years. Understanding how Tfh cells control complex humoral immunity is critical to developing strategies to improve the efficacy of vaccines against SARS-CoV-2 and other emerging pathogens. However, the immunologic mechanism of Tfh cells in SARS-CoV-2 receptor binding domain (RBD) vaccine strategy is limited. In this study, we expressed and purified recombinant SARS-CoV-2 RBD protein in Drosophila S2 cells for the first time and explored the mechanism of Tfh cells induced by RBD vaccine in humoral immune response. We mapped the dynamic of Tfh cell in lymph node and spleen following RBD vaccination and revealed the relationship between Tfh cells and humoral immune response induced by SARS-CoV-2 RBD vaccine through correlation analysis, blocking of IL-21 signaling pathway, and co-culture of Tfh with memory B cells. Recombinant RBD protein elicited a predominant Tfh1 and Tfh1-17 subset response and strong GC responses in spleen and lymph nodes, especially to enhanced vaccination. IL-21 secreted by Tfh cells affected the development and differentiation of B cells and played a key role in the humoral immune response. These observations will help us further understand the mechanism of protective immune response induced by COVID-19 vaccine and has guiding significance for the development of vaccines against newly emerging mutants.

Adaptive immune responses and cytokine immune profiles in humans following prime and boost vaccination with the SARS-CoV-2 CoronaVac vaccine.

BACKGROUND: Adaptive immune response has been thought to play a key role in SARS-CoV-2 infection. The role of B cells, CD4+T, and CD8+T cells are different in vaccine-induced immune response, thus it is imperative to explore the functions and kinetics of adaptive immune response. We collected blood samples from unvaccinated and vaccinated individuals. To assess the mechanisms contributing to protective immunity of CoronaVac vaccines, we mapped the kinetics and durability of humoral and cellular immune responses after primary and boost vaccination with CoronaVac vaccine in different timepoints. MATERIALS AND METHODS: We separate PBMC and plasma from blood samples. The differentiation and function of RBD-spcific CD4+T and CD8+T cells were analyzed by flow cytometry and ELISA. Antibodies response was analyzed by ELISA. ELISPOT analysis was perfomed to detected the RBD-spcific memory B cells. CBA analysis was performed to detected the cytokine immune profiles. Graphpad prism 8 and Origin 2021 were used for statistical analysis. RESULTS: Vaccine-induced CD4+T cell responses to RBD were more prominent than CD8+T cell responses, and characterized by a predominant Th1 and weak Th17 helper response. CoronaVac vaccine triggered predominant IgG1 antibody response and effectively recalled specific antibodies to RBD protein after booster vaccination. Robust antigen-specific memory B cells were detected (p < 0.0001) following booster vaccination and maintained at 6 months (p < 0.0001) following primary vaccination. Vaccine-induced CD4+T cells correlated with CD8+T cells (r = 0.7147, 0.3258, p < 0.0001, p = 0.04), memory B cell responses (r = 0.7083, p < 0.0001), and IgG and IgA (r = 0.6168, 0.5519, p = 0.0006, 0.003) after vaccination. In addition, vaccine induced a broader and complex cytokine pattern in plasma at early stage. CONCLUSION: Taken together, these results highlight the potential role of B cell and T cell responses in vaccine-induced long-term immunity.

Alterations in Gut Microbiota Profiles of Mice Infected with Echinococcus granulosus sensu lato Microbiota Profiles of Mice Infected with E. granulosus s.l.

OBJECTIVE: Cystic echinococcosis is a kind of parasitic disease that seriously endangers human and animal health. At present, its prevention and treatment still do not achieve the desired results. The aims of this study were to explore the effect of CE on intestinal microflora in mice. METHODS: In this study, 16S rRNA metagenome sequencing and bioinformatics were used to analyze the intestinal flora of mice infected with E. granulosus s.l. Changes in intestinal microbial community abundance were investigated and the differences in microbial populations of mice infected with E. granulosus s.l. were screened. RESULTS: Our results show that at the phylum level, nine abundant taxa were identified, the relative abundance of Firmicutes and Proteobacteria were enriched in infected mice, whereas Bacteroidetes and Patescibacteria were enriched in control mice (P < 0.01). At the class level, 13 abundant taxa were identified, the relative abundance of Bacilli was enriched in control mice, but decreased in infected mice (P < 0.01). At the order level, 15 abundant taxa were identified, the relative abundance of Lactobacillales was enriched in control mice, but decreased in infected mice (P < 0.01). At the family level, 28 abundant taxa were identified, enriched bacteria in the infected mice was Streptococcaceae, while the enriched bacteria in the control group was Lactobacillaceae (P < 0.01). At the genus level, 79 abundant taxa were identified, enriched bacteria in the infected mice was Streptococcus, while the enriched bacteria in the control group was uncultured_bacterium_f_Eggerthellaceae (P < 0.01). At the species level, 80 abundant taxa were identified, enriched bacteria in the infected mice was uncultured_bacterium_g_Streptococcus, while the enriched bacteria in the control group was uncultured_bacterium_f_Eggerthellaceae (P < 0.01). 39 KEGG pathways were identified that were differentially enriched between the infected and control mice. CONCLUSION: This study comprehensively demonstrates the differential intestinal microbiota of infected mice and analyzes the metabolic pathways related to the specific microbiota. This could provide new targets and research direction for the treatment and prevention of diseases caused by E. granulosus s.l.

Effects of NRF-1 and PGC-1α cooperation on HIF-1α and rat cardiomyocyte apoptosis under hypoxia.

BACKGROUND: Hypoxia is a primary inducer of cardiomyocyte injury, its significant marker being hypoxia-induced cardiomyocyte apoptosis. Nuclear respiratory factor-1 (NRF-1) and hypoxia-inducible factor-1α (HIF-1α) are transcriptional regulatory elements implicated in multiple biological functions, including oxidative stress response. However, their roles in hypoxia-induced cardiomyocyte apoptosis remain unknown. The effect HIF-1α, together with NRF-1, exerts on cardiomyocyte apoptosis also remains unclear. METHODS: We established a myocardial hypoxia model and investigated the effects of these proteins on the proliferation and apoptosis of rat cardiomyocytes (H9C2) under hypoxia. Further, we examined the association between NRF-1 and HIF-1α to improve the current understanding of NRF-1 anti-apoptotic mechanisms. RESULTS: The results show that NRF-1 and HIF-1α are important anti-apoptotic molecules in H9C2 cells under hypoxia, although their regulatory mechanisms differ. NRF-1 could bind to the promoter region of Hif1a and negatively regulate its expression. Additionally, HIF-1ß exhibited competitive binding with NRF-1 and HIF-1α, demonstrating a synergism between NRF-1 and the peroxisome proliferator-activated receptor-gamma coactivator-1α. CONCLUSION: These results indicate that cardiomyocytes can regulate different molecular patterns to tolerate hypoxia, providing a novel methodological framework for studying cardiomyocyte apoptosis under hypoxia.

Coding and Noncoding RNA Expression Profiles of Spleen CD4+ T Lymphocytes in Mice with Echinococcosis.

Cystic echinococcosis (CE) is a severe and neglected zoonotic disease that poses health and socioeconomic hazards. So far, the prevention and treatment of CE are far from meeting people's ideal expectations. Therefore, to gain insight into the prevention and diagnosis of CE, we explored the changes in RNA molecules and the biological processes and pathways involved in these RNA molecules as E. granulosus infects the host. Interferon (IFN)-γ, interleukin (IL)-2, IL-4, IL-6, IL-10, IL-17A, and tumor necrosis factor (TNF)-α levels in peripheral blood serum of E. granulosus infected and uninfected female BALB/c mice were measured using the cytometric bead array mouse Th1/Th2/Th17 cytokine kit. mRNA, microRNA (miRNA), long noncoding RNA (lncRNA), and circular RNA (circRNA) profiles of spleen CD4+ T cells from the two groups of mice were analyzed using high-throughput sequencing and bioinformatics. The levels of IFN-γ, IL-2, IL-4, IL-6, IL-10, IL-17A, and TNF-α were significantly higher in the serum of the CE mice than in control mice (P < 0.01). In total, 1,758 known mRNAs, 37 miRNAs, 175 lncRNAs, and 22 circRNAs were differentially expressed between infected and uninfected mice (|fold change| ≥ 0.585, P < 0.05). These differentially expressed molecules are involved in chromosome composition, DNA/RNA metabolism, and gene expression in cell composition, biological function, and cell function. Moreover, closely related to the JAK/STAT signaling pathways, mitogen-activated protein kinase signaling pathways, P53 signaling pathways, PI3K/AKT signaling pathways, cell cycle, and metabolic pathways. E. granulosus infection significantly increased the levels of IFN-γ, IL-2, IL-4, IL-6, IL-10, IL-17A, and TNF-α in mouse peripheral blood of mice and significantly changed expression levels of various coding and noncoding RNAs. Further study of these trends and pathways may help clarify the pathogenesis of CE and provide new insights into the prevention and treatment of this disease.

The Recombinant Eg.P29-Mediated miR-126a-5p Promotes the Differentiation of Mouse Naive CD4+ T Cells via DLK1-Mediated Notch1 Signal Pathway.

Cystic echinococcosis (CE) is a zoonotic parasitic disease spread worldwide caused by Echinococcus granulosus (Eg), which sometimes causes serious damage; however, in many cases, people are not aware that they are infected. A number of recombinant vaccines based on Eg are used to evaluate their effectiveness against the infection. Our previous report showed that recombinant Eg.P29 (rEg.P29) has a marvelous immunoprotection and can induce Th1 immune response. Furthermore, data of miRNA microarray in mice spleen CD4+ T cells showed that miR-126a-5p was significantly elevated 1 week after immunization by using rEg.P29. Therefore, in this perspective, we discussed the role of miR-126a-5p in the differentiation of naive CD4+ T cells into Th1/Th2 under rEg.P29 immunization and determined the mechanisms associated with delta-like 1 homolog (DLK1) and Notch1 signaling pathway. One week after P29 immunization of mice, we found that miR-126a-5p was significantly increased and DLK1 expression was decreased, while Notch1 pathway activation was enhanced and Th1 response was significantly stronger. The identical conclusion was obtained by overexpression of mmu-miR-126a-5p in primary naive CD4+ T cells in mice. Intriguingly, mmu-miR-126a-5p was significantly raised in serum from mice infected with protoscolex in the early stages of infection and markedly declined in the late stages of infection, while has-miR-126-5p expression was dramatically reduced in serum from CE patients. Taken together, we show that miR-126a-5p functions as a positive regulator of Notch1-mediated differentiation of CD4+ T cells into Th1 through downregulating DLK1 in vivo and in vitro. Hsa-miR-126-5p is potentially a very promising diagnostic biomarker for CE.

Beyond emotion: online takeaway food consumption is associated with emotional overeating among Chinese college students.

BACKGROUND: Online takeaway food has become very popular in China. However, the potential effects of online takeaway food consumption on eating behaviours among individuals during the transition stage from adolescence to young adulthood have not yet been assessed. OBJECTIVE: This study aimed to examine the effects of takeaway food consumption on emotional overeating behaviour among college students. METHODS: Data were collected from 1450 college students from six universities in Anhui, China. The frequency of emotional overeating during the past 4 weeks was assessed by the emotional overeating questionnaire (EOQ). Data on the frequency of online takeaway food consumption and other potential risk factors at the individual, interpersonal, physical environment, and macro-system levels were assessed by questionnaire. Multilevel linear regression analyses were employed to explore the association between takeaway food consumption and emotional overeating behaviour. RESULTS: Compared to those who consumed online takeaway food less than 1 day per week, participants who consumed this food 4-5 days per week and participants who consumed this food 6-7 days per week had significantly higher EOQ scores (ß = 0.14, p < 0.05 and ß = 0.67, p < 0.001, respectively). More frequent consumption was associated with higher EOQ scores (p for trend < 0.001). CONCLUSION: A higher frequency of takeaway food consumption was associated with an elevated risk of emotional overeating among college students independent of personal emotional status and other potential confounders at the interpersonal, physical environmental and macro-system levels. LEVEL OF EVIDENCE: Level V; cross-sectional descriptive study.

Metabolic profiling of liver and faeces in mice infected with echinococcosis.

BACKGROUND: Echinococcosis is a severe zoonotic parasitic disease which severely affects the health of the hosts. The diagnosis of echinococcosis depends mainly on imaging examination. However, the patient is often in the late stage of the disease when the symptoms appear, thus limiting the early diagnosis of echinococcosis. The treatment and prognosis of the patients are hampered because of long-term asymptomatic latency. Metabolomics is a new discipline developed in the late 1990s. It reflects a series of biological responses in pathophysiological processes by demonstrating the changes in metabolism under the influence of internal and external factors. When the organism is invaded by pathogens, the alteration in the characteristics of metabolites in cells becomes extremely sensitive. Here, we used a metabolomics approach involving liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) to determine the molecular mechanism of cystic echinococcosis (CE) and to develop an effective method for CE diagnosis. METHODS: Twenty 8-week-old female BALB/c mice were divided into normal and Echinococcus granulosus infection groups. To develop the E. granulosus infection model, mice were infected with protoscoleces. Six weeks later, the abdomens of the mice showed significant bulging. An LC-MS/MS system-based metabolomics approach was used to analyse the liver and faeces to reveal the metabolic profiles of mice with echinococcosis. RESULTS: We found that the metabolism of nucleotides, alkaloids, amino acids, amides, and organic acids in mice is closely interrelated with E. granulosus infection. In the liver, the metabolic pathways of tyrosine and tryptophan biosynthesis; phenylalanine, valine, leucine and isoleucine biosynthesis; and phenylalanine metabolism were notably associated with the occurrence and development of hydatid disease, and in the faeces, pantothenate and CoA biosynthesis are thought to be closely associated with the development of CE. CONCLUSION: The metabolomics approach used in this study provides a reference for a highly sensitive and specific diagnostic and screening method for echinococcosis.

lncRNA028466 regulates Th1/Th2 cytokine expression and associates with Echinococcus granulosus antigen P29 immunity.

BACKGROUND: Cystic echinococcosis (CE) is a parasitic disease that is caused by Echinococcus granulosus (Eg). The recombinant Echinococcus granulosus antigen P29 (rEg.P29) was shown to confer effective immunity to sheep and mice during E. granulosus secondary infection in our previous study. In this study, we sought to investigate the ability of long noncoding RNA 028466 (lncRNA028466) as a regulator for the protective immunity mediated by rEg.P29 vaccination and to study the effects of lncRNA028466 on CD4+T cell differentiation in mice spleen. METHODS: Female BALB/c mice were divided into two groups and were vaccinated subcutaneously with rEg.P29 antigen and PBS as a control (12 mice each group). Following prime-boost vaccination, CD4+T, CD8+T, and B cells from the spleen were isolated by flow cytometry. Quantitative real-time PCR (qRT-PCR) was performed to measure the expression of lncRNA028466 in these three kinds of cells. Then, lncRNA028466 was overexpressed and knocked down in naive CD4+T cells, and Th1 and Th2 cytokine expression was detected. qRT-PCR, western blot, and ELISA were performed to evaluate the production of IFN-γ, IL-2, IL-4, and IL-10, and flow cytometry was performed to detect the differentiation of Th1 and Th2 subgroups. RESULTS: lncRNA028466 was significantly decreased after the second week of immunization with rEg.P29 antigen. The proportion of CD4+ T cells was increased after rEg.P29 immunization. Overexpression of lncRNA028466 facilitated the production of IL-4, IL-10 and suppressed the production of IFN-γ, IL-2. Furthermore, after transfection with siRNA028466, IL-2 production was facilitated and IL-10 production was suppressed in naive CD4+ T cells. CONCLUSIONS: Immunization with rEg.P29 downregulated the expression of lncRNA028466, which was related to a higher Th1 immune response and a lower Th2 immune response. Our results suggest that lncRNA028466 may be involved in rEg.P29-mediated immune response by regulating cytokine expression of Th1 and Th2.

Screening, construction, and serological identification of the diagnostic antigen molecule EG-06283 for the diagnosis of Echinococcus granulosus.

Several strategies exist to prevent and control echinococcosis, a global parasitic disease. However, most treatments are ineffective and adverse effects are common. Therefore, we aimed to screen protoscolex antigen molecules of Echinococcus granulosus to identify a diagnostic biomarker for hydatid disease. Published E. granulosus transcriptome sequencing data were analyzed to screen for antigen molecules that are highly expressed in protoscoleces but not in oncospheres. The membrane protein EG-06283 (annotated as Frizzled-4) was selected from 16 antigens, and its gene fragment was subjected to codon optimization and synthesis. rEG-06283 expression was induced in the pET-24a/EG-06283/BL21 strain; subsequently, the protein was purified and subcutaneously injected into ICR mice at weeks 0, 2, 4, and 6. Blood sampling occurred periodically to quantify serum immunoglobulin G (IgG) levels via enzyme-linked immunosorbent assays (ELISA). Immunogenicity was determined by western blot assays using sera from normal mice and mice with secondary hydatid infections. The antigen's immune reactivity and diagnostic value were validated using sera of patients with hydatid disease. ELISA results confirmed that the antigen molecule induced specific IgG production in mice, resulting in significantly higher levels than those in the adjuvant and control groups (P < 0.05). The western blot results indicated that the protein was recognized by antibodies in the sera of mice with hydatid infection and the antisera of immunized mice. Quantification of protein levels in the sera of patients with hydatid disease significantly differed from levels in healthy participants (P < 0.05). These results indicate that rEG-06283 is a potential diagnostic antigen for E. granulosus infections.

MiR-374b-5p Regulates T Cell Differentiation and Is Associated with rEg.P29 Immunity.

Cystic echinococcosis (CE) is a zoonotic disease caused by Echinococcus granulosus (Eg) infection. Our previous study confirmed that recombinant Eg.P29 (rEg.P29) could protect against echinococcus granulosus secondary infection in sheep and mice. The aim of the study was to investigate the association between immunoprotection of rEg.P29 vaccine and mmu-miR-374b-5p (miR-374b-5p) and study the immunity influence of miR-374b-5p on CD4+ T cells in mice spleen. MiR-374b-5p level was significantly increased after the second-week and the fourth week of vaccination with rEg.P29. Overexpression of miR-374b-5p increased IFN-γ, IL-2, IL-17A mRNA levels and decreased IL-10 mRNA levels in CD4+ T cells. Moreover, the inhibition of miR-374b-5p decreased IFN-γ and IL-17A and increased IL-10 mRNA levels in CD4+ T cells; this was further confirmed by the flow cytometry. The vaccination of rEg.P29 enhanced miR-374b-5p expression that was associated with a higher Th1 and Th17 immune response, a lower IL-10 mRNA production with miR-374b-5p overexpression, a lower Th1 immune response, and a higher IL-10 mRNA levels with miR-374b-5p inhibitions. To sum up, these data suggest that miR-374b-5p may participate in rEg.P29 immunity by regulating Th1 and Th17 differentiation.

Homocysteine activates autophagy by inhibition of CFTR expression via interaction between DNA methylation and H3K27me3 in mouse liver.

Elevated homocysteine (Hcy) levels have been reported to be involved in liver injury, and autophagy plays an important role in normal hepatic physiology and pathophysiology, but the mechanism underlying Hcy regulated autophagy is currently unknown. In this study, CBS+/- mice were fed with regular diet for 12 weeks to establish a hyperhomocysteinemia (HHcy) model and HL-7702 cells were treated with Hcy, we found that Hcy increases autophagy and aggravates liver injury by downregulation of cystic fibrosis transmembrane conductance regulator (CFTR) expression in vivo and in vitro. Overexpression of CFTR inhibited the formation of autophagosomes and the expression of autophagy-related proteins BECN1, LC3-II/I and Atg12, while the expression of p62 increased in Hcy-treated hepatocytes and CBS+/- mice injected with lentivirus expressing CFTR. Further study showed that CFTR expression is regulated by the interaction of DNA methyltransferase 1 (DNMT1) and enhancer of zeste homolog 2 (EZH2), which, respectively, regulate DNA methylation and histone H3 lysine 27 trimethylation (H3K27me3). In conclusion, our study showed that Hcy activates autophagy by inhibition of CFTR expression via interaction between H3K27me3 and DNA methylation in the mouse liver. These findings provide new insight into the mechanism of Hcy-induced autophagy in liver injury.

Reciprocal Regulation Between miR-148a/152 and DNA Methyltransferase 1 Is Associated with Hyperhomocysteinemia-Accelerated Atherosclerosis.

DNA methyltransferase 1 (DNMT1) and miRNAs are both important regulators of gene expression that have been implicated in the pathogenesis of atherosclerosis. This study was designed to elucidate the potential interaction between DNMT1 and miRNAs in the context of hyperhomocysteinemia (HHcy)-related atherosclerosis. In the aorta of ApoE-/- mice fed a high methionine diet, increased expression of miR-148a/152, with decreased DNMT1 mRNA and protein levels, was detected. Similar changes were observed in cultured foam cells stimulated with homocysteine. When miR-148a/152 was overexpressed using viral vectors, DNMT1 expression was suppressed, whereas the expression of adipose differentiation-related protein (ADRP) was enhanced, and the contents of total cholesterol (TC) and cholesteryl ester (CE) were increased in cultured foam cells. Conversely, downregulation of miR-148a/152 led to elevated DNMT1 expression, reduced ADRP expression, and lowered contents of TC and CE. The luciferase reporter assay verified that DNMT1 is a target gene for miR-148a/152 and overexpression of DNMT1 can partially reverse the miR-148a/152-induced lipid accumulation in foam cells. Meanwhile, we observed that DNMT1 overexpression enhanced DNA methylation and reduced miR-148a/152 expression. Our data showed reciprocal regulation between miR-148a/152 and DNMT1 in foam cells, which likely plays a critical role in HHcy-related atherosclerosis.

miR-34a Targets HDAC1-Regulated H3K9 Acetylation on Lipid Accumulation Induced by Homocysteine in Foam Cells.

Hyperhomocysteinemia (HHcy) promotes atherogenesis by modification of histone acetylation patterns and regulation of miRNA expression while the underlying molecular mechanisms are not well known. In this study, we investigated the effects of homocysteine (Hcy) on the expression of histone deacetylase 1 (HDAC1) and tested our hypothesis that Hcy-induced atherosclerosis is mediated by increased HDAC1 expression, which is regulated by miR-34a. The expression of HDAC1 increased and acetylation of histone H3 at lysine 9 (H3K9ac) decreased in the aorta of ApoE-/- mice fed with high methionine diet, whereas miR-34a expression was inhibited. Over-expression of HDAC1 inhibited H3K9ac level and promoted the accumulation of total cholesterol, free cholesterol, and triglycerides in the foam cells. Furthermore, up-regulation of miR-34a reduced HDAC1 expression and inhibited the accumulation of total cholesterol (TC), free cholesterol (FC), and triglycerides (TG) in the foam cells. These data suggest that HDAC1-related H3K9ac plays a key role in Hcy-mediated lipid metabolism disorders, and that miR-34a may be a novel therapeutic target in Hcy-related atherosclerosis. J. Cell. Biochem. 118: 4617-4627, 2017. © 2017 Wiley Periodicals, Inc.

Folate Protects Hepatocytes of Hyperhomocysteinemia Mice From Apoptosis via Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-Activated Endoplasmic Reticulum Stress.

Folate deficiency is a known risk factor for liver injury; however, the underlying mechanism remains unclear. In this study, we employed a high homocysteine-induced liver injury model of Apolipoprotein E-deficient (ApoE-/- ) mice fed high-methionine diet and found that high homocysteine induced endoplasmic reticulum (ER) stress and liver cell apoptosis by downregulation of cystic fibrosis transmembrane conductance regulator (CFTR) expression; observations that were attenuated with supplementation of dietary folate. The regulation on CFTR expression was mediated by CFTR promoter methylation and trimethylation of lysine 27 on histone H3 (H3K27me3). Mechanistically, folate inhibited homocysteine-induced CFTR promoter methylation and H3K27me3, which resulted in upregulation of CFTR expression, and reduced ER stress and liver cell apoptosis. Further study showed that folate inhibited the expression of DNA methyltransferase 1 and enhancer of zeste homolog 2, downregulated the cellular concentrations of S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) and upregulated the SAM/SAH ratio, leading to the inhibition of Hcy-induced DNA hypermethylation and H3K27me3 in CFTR promoter. In conclusion, our results provide insight into the protective role of folate in homocysteine-induced ER stress and liver cell apoptosis through the regulation of CFTR expression. J. Cell. Biochem. 118: 2921-2932, 2017. © 2017 Wiley Periodicals, Inc. HIGHLIGHTS: Folate protects hepatocytes of hyperhomocysteinemia mice from apoptosis. Folate alleviates Hcy-induced hepatocyte apoptosis. Folate inhibits Hcy-induced ER stress via upregulation of CFTR expression in hepatocytes. Folate inhibits Hcy-induced methylation of CFTR promotor and H3K27me3.