Hbxip is essential for murine embryogenesis and regulates embryonic stem cell differentiation through activating mTORC1.

HBXIP, also named LAMTOR5, has been well characterized as a transcriptional co-activator in various cancers. However, the role of Hbxip in normal development remains unexplored. Here, we demonstrated that homozygous knockout of Hbxip leads to embryonic lethality, with retarded growth around E7.5, and that depletion of Hbxip compromises the self-renewal of embryonic stem cells (ESCs), with reduced expression of pluripotency genes, reduced cell proliferation and decreased colony-forming capacity. In addition, both Hbxip-/- ESCs and E7.5 embryos displayed defects in ectodermal and mesodermal differentiation. Mechanistically, Hbxip interacts with other components of the Ragulator complex, which is required for mTORC1 activation by amino acids. Importantly, ESCs depleted of Ragulator subunits, Lamtor3 or Lamtor4, displayed differentiation defects similar to those of Hbxip-/- ESCs. Moreover, Hbxip-/-, p14-/- and p18-/- mice, lacking subunits of the Ragulator complex, also shared similar phenotypes, embryonic lethality and retarded growth around E7-E8. Thus, we conclude that Hbxip plays a pivotal role in the development and differentiation of the epiblast, as well as the self-renewal and differentiation of ESCs, through activating mTORC1 signaling.

Body mass index, waist circumference, and mortality in subjects older than 80 years: a Mendelian randomization study.

BACKGROUND AND AIMS: Emerging evidence has raised an obesity paradox in observational studies of body mass index (BMI) and health among the oldest-old (aged ≥80 years), as an inverse relationship of BMI with mortality was reported. This study was to investigate the causal associations of BMI, waist circumference (WC), or both with mortality in the oldest-old people in China. METHODS: A total of 5306 community-based oldest-old (mean age 90.6 years) were enrolled in the Chinese Longitudinal Healthy Longevity Survey (CLHLS) between 1998 and 2018. Genetic risk scores were constructed from 58 single-nucleotide polymorphisms (SNPs) associated with BMI and 49 SNPs associated with WC to subsequently derive causal estimates for Mendelian randomization (MR) models. One-sample linear MR along with non-linear MR analyses were performed to explore the associations of genetically predicted BMI, WC, and their joint effect with all-cause mortality, cardiovascular disease (CVD) mortality, and non-CVD mortality. RESULTS: During 24 337 person-years of follow-up, 3766 deaths were documented. In observational analyses, higher BMI and WC were both associated with decreased mortality risk [hazard ratio (HR) 0.963, 95% confidence interval (CI) 0.955-0.971 for a 1-kg/m2 increment of BMI and HR 0.971 (95% CI 0.950-0.993) for each 5 cm increase of WC]. Linear MR models indicated that each 1 kg/m2 increase in genetically predicted BMI was monotonically associated with a 4.5% decrease in all-cause mortality risk [HR 0.955 (95% CI 0.928-0.983)]. Non-linear curves showed the lowest mortality risk at the BMI of around 28.0 kg/m2, suggesting that optimal BMI for the oldest-old may be around overweight or mild obesity. Positive monotonic causal associations were observed between WC and all-cause mortality [HR 1.108 (95% CI 1.036-1.185) per 5 cm increase], CVD mortality [HR 1.193 (95% CI 1.064-1.337)], and non-CVD mortality [HR 1.110 (95% CI 1.016-1.212)]. The joint effect analyses indicated that the lowest risk was observed among those with higher BMI and lower WC. CONCLUSIONS: Among the oldest-old, opposite causal associations of BMI and WC with mortality were observed, and a body figure with higher BMI and lower WC could substantially decrease the mortality risk. Guidelines for the weight management should be cautiously designed and implemented among the oldest-old people, considering distinct roles of BMI and WC.

Spatial and Single-Cell Transcriptomics Reveals the Regional Division of the Spatial Structure of MASH Fibrosis.

OBJECTIVE: To elucidate the regional distribution of metabolic dysfunction-associated steatohepatitis (MASH) fibrosis within the liver and to identify potential therapeutic targets for MASH fibrosis. METHODS: Liver sections from healthy controls, patients with simple steatosis and MASH patients were analysed using spatial transcriptomics integrated with single-cell RNA-seq. RESULTS: Spatial transcriptomics analysis of liver tissues revealed that the fibrotic region (Cluster 9) was primarily distributed in lobules, with some fibrosis also found in the surrounding area. Integration of the single-cell-sequencing data set (GSE189175) showed a greater proportion of inflammatory cells (Kupffer cells and T cells) and myofibroblasts in MASH. Six genes, showing high- or low-specific expression in Cluster 9, namely, ADAMTSL2, PTGDS, S100A6, PPP1R1A, ASS1 and G6PC, were identified in combination with pathology. The average expression levels of ADAMTSL2, PTGDS and S100A6 on the pathological HE staining map were positively correlated with the increase in the degree of fibrosis and aligned strongly with the distribution of fibrosis. ADAMTSL2+ myofibroblasts play a role in TNF signalling pathways and in the production of ECM structural components. Pseudotime analysis indicated that in the early stages of MASH, infiltration by T cells and Kupffer cells triggers a significant inflammatory response. Subsequently, this inflammation leads to the activation of hepatic stellate cells (HSCs), transforming them into myofibroblasts and promoting the development of liver fibrosis. CONCLUSION: This study is the first to characterise lineage-specific changes in gene expression, subpopulation composition, and pseudotime analysis in MASH fibrosis and reveals potential therapeutic targets for this condition.

The function role of HIGD1A in nonalcoholic steatohepatitis from chronic hepatitis B.

BACKGROUND: Accompanied by the growing prevalence of nonalcoholic fatty liver disease (NAFLD), the coexistence of chronic hepatitis B (CHB) and NAFLD has increased. In the context of CHB, there is limited understanding of the factors that influence the development of NASH. METHODS: We enrolled CHB combined NAFLD patients who had liver biopsy and divided them to NASH vs. non-NASH groups. A whole transcriptome chip was used to examine the expression profiles of long noncoding RNAs (lncRNAs) and mRNA in biopsied liver tissues. The function analysis of HIGD1A were performed. We knocked down or overexpressed HIGD1A in HepG2.2.15 cells by transient transfection of siRNA-HIGD1A or pcDNA-HIGD1A. In vivo investigations were conducted using hepatitis B virus (HBV) transgenic mice. RESULTS: In 65 patients with CHB and NAFLD, 28 were patients with NASH, and 37 were those without NASH. After screening 582 differentially expressed mRNAs, GO analysis revealed differentially expressed mRNAs acting on nicotinamide adenine dinucleotide phosphate (NADPH), which influenced redox enzyme activity. KEGG analysis also shown that they were involved in the NAFLD signaling pathway. The function analysis revealed that HIGD1A was associated with the mitochondrion. Then, both in vivo and in vitro CHB model, HIGD1A was significantly higher in the NASH group than in the non-NASH group. HIGD1A knockdown impaired mitochondrial transmembrane potential and induced cell apoptosis in HepG2.2.15 cells added oleic acid and palmitate. On the contrary, hepatic HIGD1A overexpression ameliorated free fatty acids-induced apoptosis and oxidative stress. Furthermore, HIGD1A reduced reactive oxygen species (ROS) level by increasing glutathione (GSH) expression, but Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/Acetyl-CoA carboxylase (ACC) pathway was not involved. CONCLUSION: Both in vivo and in vitro CHB model, an upward trend of HIGD1A was observed in the NASH-related inflammatory response. HIGDIA played a protective role in cells against oxidative stress. Our data suggested that HIGD1A may be a positive regulator of NASH within the CHB context.

HBXIP induces PARP1 via WTAP-mediated m6A modification and CEBPA-activated transcription in cisplatin resistance to hepatoma.

Poly (ADP-ribose) polymerase 1 (PARP1) is a DNA-binding protein that is involved in various biological functions, including DNA damage repair and transcription regulation. It plays a crucial role in cisplatin resistance. Nevertheless, the exact regulatory pathways governing PARP1 have not yet been fully elucidated. In this study, we present evidence suggesting that the hepatitis B X-interacting protein (HBXIP) may exert regulatory control over PARP1. HBXIP functions as a transcriptional coactivator and is positively associated with PARP1 expression in tissues obtained from hepatoma patients in clinical settings, and its high expression promotes cisplatin resistance in hepatoma. We discovered that the oncogene HBXIP increases the level of PARP1 m6A modification by upregulating the RNA methyltransferase WTAP, leading to the accumulation of the PARP1 protein. In this process, on the one hand, HBXIP jointly activates the transcription factor ETV5, promoting the activation of the WTAP promoter and further facilitating the promotion of the m6A modification of PARP1 by WTAP methyltransferase, enhancing the RNA stability of PARP1. On the other hand, HBXIP can also jointly activate the transcription factor CEBPA, enhance the activity of the PARP1 promoter, and promote the upregulation of PARP1 expression, ultimately leading to enhanced DNA damage repair capability and promoting cisplatin resistance in hepatoma. Notably, aspirin inhibits HBXIP, thereby reducing the expression of PARP1. Overall, our research revealed a novel mechanism for increasing PARP1 abundance, and aspirin therapy could overcome cisplatin resistance in hepatoma.

Oncoprotein LAMTOR5-mediated CHOP silence via DNA hypermethylation and miR-182/miR-769 in promotion of liver cancer growth.

C/EBP homologous protein (CHOP) triggers the death of multiple cancers via endoplasmic reticulum (ER) stress. However, the function and regulatory mechanism of CHOP in liver cancer remain elusive. We have reported that late endosomal/lysosomal adapter, mitogen-activated protein kinase and mTOR activator 5 (LAMTOR5) suppresses apoptosis in various cancers. Here, we show that the transcriptional and posttranscriptional inactivation of CHOP mediated by LAMTOR5 accelerates liver cancer growth. Clinical bioinformatic analysis revealed that the expression of CHOP was low in liver cancer tissues and that its increased expression predicted a good prognosis. Elevated CHOP contributed to destruction of LAMTOR5-induced apoptotic suppression and proliferation. Mechanistically, LAMTOR5-recruited DNA methyltransferase 1 (DNMT1) to the CpG3 region (-559/-429) of the CHOP promoter and potentiated its hypermethylation to block its interaction with general transcription factor IIi (TFII-I), resulting in its inactivation. Moreover, LAMTOR5-enhanced miR-182/miR-769 reduced CHOP expression by targeting its 3'UTR. Notably, lenvatinib, a first-line targeted therapy for liver cancer, could target the LAMTOR5/CHOP axis to prevent liver cancer progression. Accordingly, LAMTOR5-mediated silencing of CHOP via the regulation of ER stress-related apoptosis promotes liver cancer growth, providing a theoretical basis for the use of lenvatinib for the treatment of liver cancer.

Identifying an AML Prognostic Model Using 10 Marker Genes from Single-Cell Transcriptome and Bulk Transcriptome Analysis.

Fanconi anemia (FA) is the predominant hereditary syndrome of bone marrow failure (BMF), distinguished by impairments in DNA repair mechanisms. The deficiency in the FANC pathway, which governs DNA repair and replication rescue, results in aberrant responses to DNA damage in individuals with FA. The objective of this study is to examine the involvement of the FANC core complex in BMF and ascertain nucleolar homeostasis-related genes by conducting transcriptome analysis on primary hematopoietic stem cells obtained from FA patients with FANCA and FANCC variants. In the present study, we analyzed scRNA-seq data obtained from both healthy donors and individuals diagnosed with FA in order to investigate the phenomenon of cell-cell communication. Through the implementation of trajectory analysis, the differentiation pathways of several progenitor cell types, such as HSC cells transitioning into LMPP, N, M, B-prog, and E cells, were elucidated. Moreover, by scrutinizing the inferred interactions, notable disparities in cell-cell communication were observed between FA patients and their healthy counterparts. Our analysis has unveiled heightened interactions involving TNFSF13B, MIF, IL16, and COL4A2 in patients with FA. Furthermore, we have developed a prognostic model for predicting the outcome of acute myeloid leukemia (AML) which has exhibited remarkable predictive precision, with an AUC exceeding 0.83 at the 3- and 5-year intervals following the baseline assessment. In summary, the prognostic model that has been developed provides a valuable instrument for forecasting outcomes of AML by utilizing the genes identified through both single-cell and bulk transcriptome analyses.

CCN6 improves hepatic steatosis, inflammation, and fibrosis in non-alcoholic steatohepatitis.

BACKGROUND AND AIMS: CCN6 is a secretory protein with functions of maintaining mitochondrial homeostasis and anti-oxidative stress; and yet, whether it is involved in the pathogenesis of non-alcoholic steatohepatitis (NASH) is still obscure. We investigated the role and mechanism of CCN6 in the development of NASH. METHODS: Human liver tissue samples were collected to detect the expression profile of CCN6. High-fat-high-cholesterol (HFHC) and methionine choline-deficient (MCD) diet were applied to mice to establish NASH animal models. Liver-specific overexpression of CCN6 was induced in mice by tail vein injection of adeno-associated virus (AAV), and then the effect of CCN6 on the course of NASH was observed. Free fatty acid (FFA) was applied to HepG2 cells to construct the cell model of steatosis, and the effect of CCN6 was investigated by knocking down the expression of CCN6 through small interfering RNA (siRNA) transfection. RESULTS: We found that CCN6 expression was significantly downregulated in the liver of NASH. We confirmed that liver-specific overexpression of CCN6 significantly attenuated hepatic steatosis, inflammation response and fibrosis in NASH mice. Based on RNA-seq analysis, we revealed that CCN6 significantly affected the MAPK pathway. Then, by interfering with apoptosis signal-regulating kinase 1 (ASK1), we identified the ASK1/MAPK pathway pairs as the targets of CCN6 action. CONCLUSIONS: CCN6 protects against hepatic steatosis, inflammation response and fibrosis by inhibiting the activation of ASK1 along with its downstream MAPK signalling. CCN6 may be a potential therapeutic target for the treatment of NASH.

Sorafenib triggers ferroptosis via inhibition of HBXIP/SCD axis in hepatocellular carcinoma.

Sorafenib, which inhibits multiple kinases, is an effective frontline therapy for hepatocellular carcinoma (HCC). Ferroptosis is a form of iron-dependent programmed cell death regulated by lipid peroxidation, which can be induced by sorafenib treatment. Oncoprotein hepatitis B X-interacting protein (HBXIP) participates in multiple biological pro-tumor processes, including growth, metastasis, drug resistance, and metabolic reprogramming. However, the role of HBXIP in sorafenib-induced ferroptotic cell death remains unclear. In this study, we demonstrated that HBXIP prevents sorafenib-induced ferroptosis in HCC cells. Sorafenib decreased HBXIP expression, and overexpression of HBXIP blocked sorafenib-induced HCC cell death. Interestingly, suppression of HBXIP increased malondialdehyde (MDA) production and glutathione (GSH) depletion to promote sorafenib-mediated ferroptosis and cell death. Ferrostatin-1, a ferroptosis inhibitor, reversed the enhanced anticancer effect of sorafenib caused by HBXIP silencing in HCC cells. Regarding the molecular mechanism, HBXIP transcriptionally induced the expression of stearoyl-CoA desaturase (SCD) via coactivating the transcriptional factor ZNF263, resulting in the accumulation of free fatty acids and suppression of ferroptosis. Functionally, activation of the HBXIP/SCD axis reduced the anticancer activity of sorafenib and suppressed ferroptotic cell death in vivo and in vitro. HBXIP/SCD axis-mediated ferroptosis can serve as a novel downstream effector of sorafenib. Our results provide new evidence for clinical decisions in HCC therapy.

Long-term fine particular exposure and incidence of frailty in older adults: findings from the Chinese Longitudinal Healthy Longevity Survey.

BACKGROUND: The association between fine particular matter (PM2.5) and frailty is less studied, and the national burden of PM2.5-related frailty in China is unknown. OBJECTIVE: To explore the association between PM2.5 exposure and incident frailty in older adults, and estimate the corresponding disease burden. DESIGN: Chinese Longitudinal Healthy Longevity Survey from 1998 to 2014. SETTING: Twenty-three provinces in China. SUBJECTS: A total of 25,047 participants aged ≥65-year-old. METHODS: Cox proportional hazards models were performed to evaluate the association between PM2.5 and frailty in older adults. A method adapted from the Global Burden of Disease Study was used to calculate the PM2.5-related frailty disease burden. RESULTS: A total of 5,733 incidents of frailty were observed during 107,814.8 person-years follow-up. A 10 µg/m3 increment of PM2.5 was associated with a 5.0% increase in the risk of frailty (Hazard Ratio = 1.05, 95% confidence interval = [1.03-1.07]). Monotonic, but non-linear exposure-response, relationships of PM2.5 with risk of frailty were observed, and slopes were steeper at concentrations >50 µg/m³. Considering the interaction between population ageing and mitigation of PM2.5, the PM2.5-related frailty cases were almost unchanged in 2010, 2020 and 2030, with estimations of 664,097, 730,858 and 665,169, respectively. CONCLUSIONS: This nation-wide prospective cohort study showed a positive association between long-term PM2.5 exposure and frailty incidence. The estimated disease burden indicated that implementing clean air actions may prevent frailty and substantially offset the burden of population ageing worldwide.

Leisure Activities, Genetic Risk, and Frailty: Evidence from the Chinese Adults Aged 80 Years or Older.

INTRODUCTION: About half of adults aged ≥80 years suffer from frailty. Exercise is considered effective in preventing frailty but may be inapplicable to adults aged ≥80 years due to physical limitations. As an alternative, we aimed to explore the association of leisure activities with frailty and identify potential interaction with established polygenic risk score (PRS) among adults aged ≥80 years. METHODS: Analyses were performed in a prospective cohort study of 7,471 community-living older adults aged ≥80 years who were recruited between 2002 and 2014 from 23 provinces in China. Leisure activity was assessed using a seven-question leisure activity index and frailty was defined as a frailty index ≥0.25 using a validated 39-item health-related scale. The PRS was constructed using 59 single-nucleotide polymorphisms associated with frailty in a subsample of 2,541 older adults. Cox proportional hazards models were used to explore the associations of leisure activities, PRS with frailty. RESULTS: The mean age of participants was 89.4 ± 6.6 years (range: 80-116). In total, 2,930 cases of frailty were identified during 42,216 person-years of follow-up. Each 1 unit increase in the leisure activity index was associated with 12% lower risk of frailty (hazard ratio: 0.88 [95% confidence interval, 0.85-0.91]). Participants with high genetic risk (PRS >2.47 × 10-4) suffered from 26% higher risk of frailty. Interaction between leisure activity and genetic risk was not observed. CONCLUSION: Evidence is presented for the independent association of leisure activities and genetic risk with frailty. Engagement in leisure activities is suggested to be associated with lower risk of frailty across all levels of genetic risk among adults aged ≥80 years.

A highly sensitive method (supercritical fluid chromatography coupled with ion mobility mass spectrometry) for determination of multiple compounds in radix curcumae.

A highly sensitive method was developed for simultaneously separating and identifying multiple compounds in radix curcumae. The determination of these compounds was achieved by combining supercritical fluid chromatography with drift tube ion mobility quadrupole time-of-flight MS. Related parameters were optimized: the RX-SIL column was used as the stationary phase, methanol was selected as the organic modifier, back pressure was 120 bar, back temperature was 60°C, the mobile phase flow rate was 1.75 mL/min, the makeup solvent was 0.2% formic acid/methanol with a flow rate of 0.7 mL/min. Under optimal conditions, multipolar compounds were separated. Furthermore, these compounds were identified by the values of collision sectional areas. The established method was verified by related parameters and exhibited good linearity, sensitivity, precision and accuracy. It could be extended to analyze other curcuminoids and sesquiterpenoids in natural products.

The Effects of Early-Life Stress on Liver Transcriptomics and the Protective Role of EPA in a Mouse Model of Early-Life-Stress-Induced Adolescent Depression.

Early-life stress (ELS) was found to increase the risk of adolescent depression, and clinical evidence indicated that eicosapentaenoic acid (EPA) was decreased in patients with adolescent depression, but the underlying mechanisms are unclear. Here, we utilized an ELS model of maternal separation with early weaning to explore the protective role of EPA in adolescent depression. We found that that ELS induced depression-like behavior rather than anxiety-like behavior in adolescent mice. RNA-sequencing results showed that ELS changed the transcription pattern in the liver, including 863 upregulated genes and 971 downregulated genes, especially those related to the biosynthesis of unsaturated fatty acids metabolism in the liver. Moreover, ELS decreased the expression of the rate-limiting enzymes, fatty acid desaturases 1/2 (FADS1/2), involved in the biosynthesis of EPA in the liver. Additionally, ELS reduced the levels of EPA in the liver, serum, and hippocampus, and EPA administration improved depression-like behavior-induced by ELS. Our results provide transcriptomic evidence that ELS increases the risk of adolescent depression by reducing the synthesis of unsaturated fatty acids in the liver, especially EPA, and suggest that supplementation with EPA should be investigated as a potential treatment for adolescent depression.

The modulation of PD-L1 induced by the oncogenic HBXIP for breast cancer growth.

Programmed death ligand-1 (PD-L1)/PD-1 checkpoint extensively serves as a central mediator of immunosuppression. A tumor-promoting role for abundant PD-L1 in several cancers is revealed. However, the importance of PD-L1 and how the PD-L1 expression is controlled in breast cancer remains obscure. Here, the mechanisms of controlling PD-L1 at the transcription and protein acetylation levels in promoting breast cancer growth are presented. Overexpressed PD-L1 accelerates breast cancer growth in vitro and in vivo. RNA-seq uncovers that PD-L1 can induce some target genes affecting many cellular processes, especially cancer development. In clinical breast cancer tissues and cells, PD-L1 and HBXIP are both increased, and their expressions are positively correlated. Mechanistic exploration identifies that HBXIP stimulates the transcription of PD-L1 through co-activating ETS2. Specifically, HBXIP induces PD-L1 acetylation at K270 site through interacting with acetyltransferase p300, leading to the stability of PD-L1 protein. Functionally, depletion of HBXIP attenuates PD-L1-accelerated breast tumor growth. Aspirin alleviates breast cancer via targeting PD-L1 and HBXIP. Collectively, the findings display new light into the mechanisms of controlling tumor PD-L1 and broaden the utility for PD-L1 as a target in breast cancer therapy.

Recent advances on discovery of enzyme inhibitors from natural products using bioactivity screening.

The essence of enzymes is to keep the homeostasis and balance of humans by catalyzing metabolic responses and modulating cells. Suppression of an enzyme slows the progress of some diseases, making it a therapeutic target. Therefore, it is important to develop enzyme inhibitors by proper bioactivity screening strategies for the future treatment of some major diseases. In this review, we summarized the recent (2015-2020) applications of several screening strategies (electrophoretically mediated microanalysis, enzyme immobilization, affinity chromatography, and affinity ultrafiltration) in finding enzyme inhibitors from certain species of bioactive natural compounds of plant origin (flavonoids, alkaloids, phenolic acids, saponins, anthraquinones, coumarins). At the same time, the advantages and disadvantages of each strategy were also discussed, and the future possible development direction in enzyme inhibitor screening has been prospected. To sum up, it is expected to help readers select suitable screening strategies for enzyme inhibitors and provide useful information for the study of the biological effects of specific kinds of natural products.

The regulation of acetylation and stability of HMGA2 via the HBXIP-activated Akt-PCAF pathway in promotion of esophageal squamous cell carcinoma growth.

High-mobility group AT-hook 2 (HMGA2) is an architectural transcription factor that plays essential roles in embryonic development and cancer progression. However, the mechanism of HMGA2 regulation remains largely uncharacterized. Here, we demonstrate that HMGA2 can be modulated by hepatitis B X-interacting protein (HBXIP), an oncogenic transcriptional coactivator, in esophageal squamous cell carcinoma (ESCC). HMGA2 expression was positively associated with HBXIP expression in clinical ESCC tissues, and their high levels were associated with advanced tumor stage and reduced overall and disease-free survival. We found that oncogenic HBXIP could posttranslationally upregulate HMGA2 protein level in ESCC cells. HBXIP induced HMGA2 acetylation at the lysine 26 (K26), resulting in HMGA2 protein accumulation. In this process, HBXIP increased the acetyltransferase p300/CBP-associated factor (PCAF) phosphorylation and activation via the Akt pathway, then PCAF directly interacted with HMGA2, leading to HMGA2 acetylation in the cells. HMGA2 K26 acetylation enhanced its DNA binding capacity and blocked its ubiquitination and then inhibited proteasome-dependent degradation. Functionally, HBXIP-stabilized HMGA2 could promote ESCC cell growth in vitro and in vivo. Strikingly, aspirin suppressed ESCC growth by inhibiting HBXIP and HMGA2. Collectively, our findings disclose a new mechanism for the posttranslational regulation of HMGA2 mediated by HBXIP in ESCC.

The extent and nature of television food and non-alcoholic beverage advertising to children during chinese New Year in Beijing, China.

BACKGROUND: Exposure to food and non-alcoholic beverage advertisements (F&B ads) on television, which can affect children's nutrition knowledge, food consumption, diet quality, and purchasing preferences, is one aspect of the obesogenic environment. This aspect has been well-studied and assessed in many countries. In China, however, only few studies have been done in earlier years and all of them were focus on regular days. This study aimed to assess the extent and nature of F&B ads on television (TV) during the public holiday directed towards children aged 4-14 years in Beijing. METHOD: Top 3 channels viewed by children aged 4-14 years in Beijing were selected by TV viewership data, survey, and expert consultation. Each channel was recorded for 7 days (24 h) during the public holiday of the Chinese New Year in 2019. F&B ads were coded and analyzed following the adapted food promotion module of INFORMAS protocol. Three nutrient profile models were used to classify F&B ads as healthy or unhealthy F&B ads. RESULTS: Of the 10,082 ads in 504-hour recorded programs, 42.9% were F&B ads. The hourly average ads and F&B ads per channel were 19.8 (SD 15.32) and 8.6 (SD 9.84), while that was higher on the national children's channel (17.15, SD 12.25) than other channels (p < 0.05). Of F&B ads classified with the three nutrient profile models, more than 55% were unhealthy for children. The categories most frequently advertised were savory snacks, milk drinks, nonpermitted milk drinks, cakes/sweet biscuits, and beverages. Unhealthy F&B ads were more likely to use promotional characters, brand benefit claims, and health claims than permitted F&B ads (p < 0.05). CONCLUSIONS: Children in Beijing were exposed to a high proportion of unhealthy F&B ads during the Chinese New Year holiday. Our findings support the need to assess and regulate TV F&B ads marketing for children.

Ligand fishing based on bioaffinity ultrafiltration for screening xanthine oxidase inhibitors from citrus plants.

Citrus plants are valuable medicinal plants with abundant flavonoids content in the parts of fruits and peels, which exhibit potential hypouricemic effect. In the present study, a ligand fishing assay was performed based on bio-affinity ultrafiltration for rapidly screening and identifying xanthine oxidase inhibitors from citrus plants. Under the optimal experimental conditions, five potential ligands were fished out when xanthine oxidase acted as the targeted protein. Subsequently, the chemical structures of all five compounds were identified by quadrupole time-of-flight mass spectrometry. Among them, hesperidin and naringin were confirmed as high-efficiency xanthine oxidase inhibitors. The half maximal inhibitory concentration values of hesperidin and naringin were 0.15 and 1.82 µM, respectively. Compared with the clinical antigout drug, allopurinol (half maximal inhibitory concentration = 8.03 µM), lower half maximal inhibitory concentration values indicated higher enzyme inhibitory activity. The Lineweaver-Burk plots indicated that the two compounds inhibited xanthine oxidase in a noncompetitive manner. The results demonstrate that the bioaffinity ultrafiltration method is a powerful tool for screening out xanthine oxidase inhibitors from natural products.

Cucurbituril and zwitterionic surfactant-based matrix solid-phase dispersion microextraction to simultaneously determine terpenoids from Radix Curcumae.

A rapid, efficient, and environmentally friendly matrix solid-phase dispersion microextraction was established to determine and quantify terpenoids in Radix Curcumae using ultra-high-performance liquid chromatography with a diode array detector. Various parameters affecting the extraction were investigated in detail, such as the grinding time, amount of adsorbent, type and concentration of elution solvent, and pH. The optimization of single-factor and response surface methodology was performed to confirm the best conditions in this procedure. The final optimized conditions were obtained by applying 70 mg of cucurbituril as adsorbent, 149 s as the optimum grinding time, and 228 mM of 3-(N,N-dimethylpalmitylammonio)propanesulfonate aqueous solution (pH 6.5) as the optimal elution solvent. The validated method showed a satisfactory linear range of 0.10-10 µg/mL for curdione and furanodiene, 0.01-10 µg/mL for isocurcumenol and germacrone, and 0.05-10 µg/mL for furanodienone, while the correlation coefficients ranged from 0.9945 to 0.9970. The recoveries of the investigated analytes at two spiked concentration levels (0.1 and 1.0 µg/mL) ranged from 96.53 to 104.60%. In addition, this method displayed acceptable reproducibility (relative standard deviation ≤ 3.66%). The results showed that the newly proposed matrix solid-phase dispersion microextraction method was successfully applied to analyze curdione, isocurcumenol, furanodienone, germacrone and furanodiene in Radix Curcumae samples.

Clinical features of hepatitis B patients at immune-tolerance phase with basal core promoter and/or precore mutations.

Little data exist on basal core promoter/precore (BCP/PC) mutations in chronic hepatitis B (CHB) patients at the immune-tolerance (IT) phase. We studied consecutive treatment-naïve, CHBe-antigen (HBeAg)-positive patients who had undergone liver biopsy and genotyping. Those in the IT phase or immune-clearance (IC) phase were enrolled for comparison of the frequency of BCP/PC mutations and their clinical presentations. Subgroup analyses for the IT group were also performed between patients with and without mutations, and IC patients between fibrosis stages ≤2 vs fibrosis >2. Among 301 patients enrolled, 88/301 (29.24%) and 213/301 (70.76%) were at the IT and IC phase, respectively. The frequency of BCP/PC mutations in IT phase was significantly lower than those in IC phase (15.91% vs 64.79%, P < .001). The BCP mutation only was significantly more frequent than the PC mutation in both groups and also in all IC subgroups. IT patients with BCP/PC mutations had significantly higher quantitative anti-HBc levels compared with those of patients with wild-type virus (P < .05). They also had significantly lower mean levels of alanine transaminase, aspartate transaminase, total bilirubin and qAnti-HBc compared with those of IC patients (all P < .05). Additionally, they were significantly younger in mean age, had higher platelet count, higher levels of HBV DNA and surface antigen, as well as higher frequency of genotype B than those of IC patients with fibrosis >2 (all P < .05). BCP/PC mutations were found in IT patients with CHB. They had distinct clinical characteristics when compared with patients with wild-type or at IC phase. Further studies are needed to understand their natural history and treatment outcomes.