The associations between modifiable risk factors and nonalcoholic fatty liver disease: A comprehensive Mendelian randomization study.

BACKGROUND AND AIMS: Early identification of modifiable risk factors is essential for the prevention of nonalcoholic fatty liver disease (NAFLD). We aimed to systematically explore the relationships between genetically predicted modifiable risk factors and NAFLD. APPROACH AND RESULTS: We applied univariable and multivariable Mendelian randomization analyses to explore the relationships between 35 modifiable risk factors and NAFLD. We also evaluated the combined results in three independent large genome-wide association studies. Genetically predicted alcohol frequency, elevated serum levels of liver enzymes, triglycerides, C-reactive protein, and obesity traits, including body mass index, waist circumference, and body fat mass, were associated with increased risks of NAFLD (all with p < 0.05). Poor physical condition had a suggestive increased risk for NAFLD (odds ratio [OR] = 2.63, p  = 0.042). Genetically instrumented type 2 diabetes (T2DM), hypothyroidism, and hypertension all increased the risk for NAFLD, and the ORs (95% confidence interval) were 1.508 (1.20-1.90), 13.08 (1.53-111.65), and 3.11 (1.33-7.31) for a 1-U increase in log-transformed odds, respectively. The positive associations of T2DM and hypertension with NAFLD remained significant in multivariable analyses. The combined results from the discovery and two replication datasets further confirmed that alcohol frequency, elevated serum liver enzymes, poor physical condition, obesity traits, T2DM, and hypertension significantly increase the risk of NAFLD, whereas higher education and high-density lipoprotein cholesterol (HDL-cholesterol) could lower NAFLD risk. CONCLUSIONS: Genetically predicted alcohol frequency, elevated serum liver enzymes, poor physical condition, obesity traits, T2DM, and hypertension were associated with an increased risk of NAFLD, whereas higher education and HDL-cholesterol were associated with a decreased risk of NAFLD.

Growth differentiation factor 15: Emerging role in liver diseases.

Growth differentiation factor 15 (GDF15) is a cell stress-response cytokine within the transforming growth factor-ß (TGFß) superfamily. It is known to exert diverse effects on many metabolic pathways through its receptor GFRAL, which is expressed in the hindbrain, and transduces signals through the downstream receptor tyrosine kinase Ret. Since the liver is the core organ of metabolism, summarizing the functions of GDF15 is highly important. In this review, we assessed the relevant literature regarding the main metabolic, inflammatory, fibrogenic, tumorigenic and other effects of GDF15 on different liver diseases, including Metabolic dysfunction-associated steatotic liver disease(MASLD), alcohol and drug-induced liver injury, as well as autoimmune and viral hepatitis, with a particular focus on the pathogenesis of MASLD progression from hepatic steatosis to MASH, liver fibrosis and even hepatocellular carcinoma (HCC). Finally, we discuss the prospects of the clinical application potential of GDF15 along with its research and development progress. With better knowledge of GDF15, increasing in-depth research will lead to a new era in the field of liver diseases.

Experimental traumatic brain injury increases epichaperome formation.

Under normal conditions, heat shock proteins work in unison through dynamic protein interactions collectively referred to as the "chaperome." Recent work revealed that during cellular stress, the functional interactions of the chaperome are modified to form the "epichaperome," which results in improper protein folding, degradation, aggregation, and transport. This study is the first to investigate this novel mechanism of protein dishomeostasis in traumatic brain injury (TBI). Male and female adult, Sprague-Dawley rats received a lateral controlled cortical impact (CCI) and the ipsilateral hippocampus was collected 24 h 1, 2, and 4 weeks after injury. The epichaperome complex was visualized by measuring HSP90, HSC70 and HOP expression in native-PAGE and normalized to monomeric protein expression. A two-way ANOVA examined the effect of injury and sex at each time-point. Native HSP90, HSC70 and HOP protein expression showed a significant effect of injury effect across all time-points. Additionally, HSC70 and HOP showed significant sex effects at 24 h and 4 weeks. Altogether, controlled cortical impact significantly increased formation of the epichaperome across all proteins measured. Further investigation of this pathological mechanism can lead to a greater understanding of the link between TBI and increased risk of neurodegenerative disease and targeting the epichaperome for therapeutics.

HADHA alleviates hepatic steatosis and oxidative stress in NAFLD via inactivation of the MKK3/MAPK pathway.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a liver metabolic syndrome and still lacks effective treatments because the molecular mechanism underlying the development of NAFLD is not completely understood. We investigated the role of Hydroxyl CoA dehydrogenase alpha subunit (HADHA) in the pathogenesis of NAFLD. METHODS: HADHA expression was detected both in NAFLD cell and mice, and knockdown of HADHA in free fatty acids (FFA)-treated L02 or overexpression of HADHA in high fat diet (HFD)-fed mice was used to detected the influence of HADHA on hepatic steatosis, mitochondrial dysfunction, and oxidative stress by regulating of MKK3/MAPK signaling. RESULTS: Our data revealed that HADHA expression was decreased in FFA-treated L02 cells and in HFD-fed mice. Knockdown of HADHA markedly aggravated hepatic steatosis, inflammation and oxidative stress in FFA-treated L02 cells, which was associated with the activation of MKK3/MAPK signalling pathways. Moreover, oxidative stress and liver lesions were improved in NAFLD mice by upregulation of HADHA. Importantly, we demonstrated that overexpression of HADHA inhibited the expression of p-MAPK in NAFLD mice, reducing lipid accumulation and steatosis. CONCLUSION: HADHA may function as a protective factor in the progression of NAFLD by alleviating abnormal metabolism and oxidative stress by suppressing MKK3/MAPK signalling pathway activation, providing a new target for the treatment of NAFLD.

Trend analysis of dependence between rainfall and storm tides in coastal cities.

Compound flooding from rainfall and storm tides is prone to occur in coastal cities. The identification of them is essential for controlling urban flooding. First, the dependence between rainfall and storm tides is quantified by Kendall's τ, Spearman's ρ, and tail dependence coefficient. Then, a bivariate copula-based probability distribution model is built to calculate the joint and conditional probability of rainfall and storm tides. Finally, MK and SQMK methods are employed to detect the trends of the dependence and joint probability. The results show that: (1) The dependence between strong rainfall and corresponding storm tides is much higher than that of small rainfall and storm tides, and the effect of tropical cyclones may be one of the reasons. (2) The dependence between rainfall and storm tides is the largest in October and the smallest in July. More attention should be paid to the compound flooding caused by rainfall and storm tides in October for Haikou. (3) The upper tail dependence coefficient of the rainfall and storm tides is significantly greater than the lower tail dependence coefficient and exhibits a significant positive trend. The results can provide additional insights into the effect of rainfall and storm tides for coastal flood management.

Chinese Consensus Report on Family-Based Helicobacter pylori Infection Control and Management (2021 Edition).

OBJECTIVE: Helicobacter pylori infection is mostly a family-based infectious disease. To facilitate its prevention and management, a national consensus meeting was held to review current evidence and propose strategies for population-wide and family-based H. pylori infection control and management to reduce the related disease burden. METHODS: Fifty-seven experts from 41 major universities and institutions in 20 provinces/regions of mainland China were invited to review evidence and modify statements using Delphi process and grading of recommendations assessment, development and evaluation system. The consensus level was defined as ≥80% for agreement on the proposed statements. RESULTS: Experts discussed and modified the original 23 statements on family-based H. pylori infection transmission, control and management, and reached consensus on 16 statements. The final report consists of three parts: (1) H. pylori infection and transmission among family members, (2) prevention and management of H. pylori infection in children and elderly people within households, and (3) strategies for prevention and management of H. pylori infection for family members. In addition to the 'test-and-treat' and 'screen-and-treat' strategies, this consensus also introduced a novel third 'family-based H. pylori infection control and management' strategy to prevent its intrafamilial transmission and development of related diseases. CONCLUSION: H. pylori is transmissible from person to person, and among family members. A family-based H. pylori prevention and eradication strategy would be a suitable approach to prevent its intra-familial transmission and related diseases. The notion and practice would be beneficial not only for Chinese residents but also valuable as a reference for other highly infected areas.

3-Mercaptopyruvate sulfurtransferase represses tumour progression and predicts prognosis in hepatocellular carcinoma.

BACKGROUND AND: AIMS: The prognosis of hepatocellular carcinoma (HCC) remains dismal, and its molecular pathogenesis has not been completely defined. The enzyme 3-mercaptopyruvate sulfurtransferase (MPST) regulates endogenous hydrogen sulfide (H2 S) biosynthesis. However, the role of MPST in HCC has never been intensively investigated. METHODS: MPST protein expression was analysed in HCC tumour tissues and matched adjacent tissues. The effect of MPST on HCC progression was studied in vitro and in vivo. RESULTS: The mRNA and protein expression of MPST was significantly downregulated in HCC samples compared with their paired nontumour counterparts. A low MPST expression was associated with larger tumour size and a worse overall survival. Overexpression of MPST in HCC cells inhibited cell proliferation and induced apoptosis. MPST overexpression also significantly suppressed the growth of tumour xenografts in nude mice, whereas silencing MPST by intratumour delivery of siRNA substantially promoted tumour growth. Moreover, diethylnitrosamine-induced mouse HCC was aggravated by MPST gene knockout. Mechanistically, MPST suppressed the cell cycle associated with H2 S production and inhibition of the AKT/FOXO3a/Rb signalling pathway in HCC development. In addition, MPST expression negatively correlated with that of pRb in HCC specimens and the combination of these two parameters is a more powerful predictor of poor prognosis. CONCLUSIONS: MPST may function as a tumour suppressor gene that plays an essential role in HCC proliferation and liver tumorigenesis. It is a candidate predictor of clinical outcome in patients with HCC and may be used as a biomarker and intervention target for new therapeutic strategies.

Deficiency in the anti-apoptotic protein DJ-1 promotes intestinal epithelial cell apoptosis and aggravates inflammatory bowel disease via p53.

Parkinson disease autosomal recessive, early onset 7 (PARK7 or DJ-1) is involved in multiple physiological processes and exerts anti-apoptotic effects on multiple cell types. Increased intestinal epithelial cell (IEC) apoptosis and excessive activation of the p53 signaling pathway is a hallmark of inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD). However, whether DJ-1 plays a role in colitis is unclear. To determine whether DJ-1 deficiency is involved in the p53 activation that results in IEC apoptosis in colitis, here we performed immunostaining, real-time PCR, and immunoblotting analyses to assess DJ-1 expression in human UC and CD samples. In the inflamed intestines of individuals with IBD, DJ-1 expression was decreased and negatively correlated with p53 expression. DJ-1 deficiency significantly aggravated colitis, evidenced by increased intestinal inflammation and exacerbated IEC apoptosis. Moreover, DJ-1 directly interacted with p53, and reduced DJ-1 levels increased p53 levels both in vivo and in vitro and were associated with decreased p53 degradation via the lysosomal pathway. We also induced experimental colitis with dextran sulfate sodium in mice and found that compared with DJ-1-/- mice, DJ-1-/-p53-/- mice have reduced apoptosis and inflammation and increased epithelial barrier integrity. Furthermore, pharmacological inhibition of p53 relieved inflammation in the DJ-1-/- mice. In conclusion, reduced DJ-1 expression promotes inflammation and IEC apoptosis via p53 in colitis, suggesting that the modulation of DJ-1 expression may be a potential therapeutic strategy for managing colitis.

SeP is elevated in NAFLD and participates in NAFLD pathogenesis through AMPK/ACC pathway.

Nonalcoholic fatty liver disease (NAFLD) is prevalent chronic liver diseases with unknown mechanism and no curative treatment. Hepatokines have demonstrated importance in NAFLD but, role of selenoprotein P (SeP) in NAFLD is unknown. A total of 79 patients with NAFLD and 79 healthy controls were included in this case-control study. SeP is elevated in patients with NAFLD. With elevating level of SeP, NAFLD prevalence, and detecting rate increases. As NAFLD aggravated, serum SeP increases. Correlation analysis demonstrates that SeP is positively associated with NAFLD risk factors including body mass index, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, and serum uric acid. Both NAFLD in vivo and in vitro models, SeP protein level is higher in liver. Small interfering RNA of SEPP1 inhibited TG accumulation by activating adenosine monophosphate activated protein kinase/acetyl-CoA carboxylase (AMPK/ACC), and overexpression of SEPP1 aggravated lipid accumulation and inhibited AMPK/ACC phosphorylation. SeP expression is activated in NAFLD and exacerbated NAFLD through AMPK/ACC, providing insight into new diagnostic, therapeutic target in NAFLD.

GCSF deficiency attenuates nonalcoholic fatty liver disease through regulating GCSFR-SOCS3-JAK-STAT3 pathway and immune cells infiltration.

Granulocyte colony stimulating factor (GCSF) is a cytokine with immunomodulation effects. However, little is known about its role in metabolic diseases. In the current study, we aimed to explore the role of GCSF in nonalcoholic fatty liver disease (NAFLD). Male GCSF-/- mice were used to investigate the function of GCSF in vivo after high-fat diet (HFD). Primary hepatocytes were used for evaluating the function of GCSF in vitro. Liver immune cells were isolated and analyzed by flow cytometry. Our results showed that GCSF administration significantly increased serum triglyceride (TG) levels in patients. Circulating GCSF was markedly elevated in HFD-fed mice. GCSF-/- mice exhibited alleviated HFD-induced obesity, insulin resistance, and hepatic steatosis. Extra administration of GCSF significantly aggravated palmitic acid (PA)-induced lipid accumulation in primary hepatocytes. Mechanically, GCSF could bind to granulocyte colony stimulating factor receptor (GCSFR) and regulate suppressors of cytokine signaling 3, Janus kinase, signal transducer and activator of transcription 3 (SOCS3-JAK-STAT3) pathway. GCSF also enhanced hepatic neutrophils and macrophages infiltration, thereby modulating NAFLD. These findings suggest that GCSF plays an important regulatory role in NAFLD and may be a potential therapeutic target for NAFLD.NEW & NOTEWORTHY We found GCSF was involved in lipid metabolism and NAFLD development. GCSF administration increased serum triglyceride levels in patients. GCSF deficiency alleviated HFD-induced insulin resistance and hepatic steatosis in mice. GCSF could directly act on hepatocytes through GCSFR-SOCS3-JAK-STAT3 pathway, and regulate the infiltration of immune cells into the liver to indirectly modulate NAFLD. Our finding indicates that GCSF may provide new strategies for the treatment of NAFLD.

A meta-analysis on the diagnostic performance of magnetic resonance imaging and transient elastography in nonalcoholic fatty liver disease.

BACKGROUND: Noninvasive methods have been used for the assessment of hepatic steatosis in patients with nonalcoholic fatty liver disease (NAFLD). The aim was to assess the efficacy and accuracy of both magnetic resonance imaging(MRI) and transient elastography(TE) for the evaluation of hepatic steatosis. MATERIALS AND METHODS: The PubMed, Cochrane Library, Embase, MEDLINE and Web of Science databases were searched to retrieve studies examining the accuracy of MRI-proton density fat fraction(PDFF) and TE-controlled attenuation parameter(CAP) for evaluating the grading of steatosis(S0-S3) diagnosed by liver biopsy in NAFLD. We compared the sensitivity, specificity, hierarchical summary receiver operating characteristic curves(HSROC) and clinical utility of these methods. RESULTS: Twenty-four articles with a total of 2979 patients with NAFLD were included. The steatosis distribution was 8.1%/35.1%/32.2%/24.6% for S0/S1/S2/S3. For the diagnostic accuracy of MRI-PDFF, the HSROCs were 0.97 for ≥S1, 0.91 for ≥S2 and 0.90 for ≥S3. For the diagnostic accuracy of TE-based CAP, the HSROCs were 0.85 for ≥S1, 0.83 for ≥S2 and 0.79 for ≥S3. Following a 'positive' measurement (over the threshold value) for ≥S1, the corresponding post-test probabilities of PDFF and CAP for the presence of steatosis were 82% and 61%, respectively, when the pretest probability was 24%. If the values were below these thresholds ('negative' results), the post-test probabilities were 3% and 7%. CONCLUSION: MRI-PDFF and TE-CAP both provide highly accurate noninvasive approaches for quantifying and staging hepatic steatosis in NAFLD. Compared with TE-CAP, MRI-PDFF is significantly more accurate for evaluating dichotomized grades of steatosis.

Leukocyte cell-derived chemotaxin 2 promotes the development of nonalcoholic fatty liver disease through STAT-1 pathway in mice.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD), whose pathogenesis remains unelucidated, has become an increasingly prevalent disease globally requiring novel treatment strategies. This study aims to explore the role of leukocyte cell-derived chemotaxin 2 (LECT2), one of the known hepatokines, in the development of NAFLD. METHODS: The serum LECT2 level was evaluated in patients with NAFLD and male C57BL/6 mice fed a high-fat diet (HFD) for 8 weeks. Tail intravenous injection of adeno-associated virus that contained Lect2 short hairpin RNA or Lect2 overexpression plasmid was administered to mice to inhibit or increase hepatic Lect2 expression. Hepatic steatosis was evaluated by histological staining with haematoxylin and eosin and Oil Red O, and also by quantitative hepatic triglyceride measurements. RNA-seq was performed to discover the specific targets of LECT2 on NAFLD. RESULTS: Serum and hepatic LECT2 levels were elevated in NAFLD patients and HFD-fed mice. Inhibition of hepatic Lect2 expression alleviated HFD-induced hepatic steatosis and inflammation, whereas hepatic overexpression of Lect2 aggravated HFD-induced hepatic steatosis and inflammation. RNA-seq and bioinformatical analysis suggested that the signal transducers and activators of transcription-1 (STAT-1) pathway might play an indispensable role in the interaction between LECT2 and NAFLD. A STAT-1 inhibitor could reverse the accumulation of hepatic lipids caused by Lect2 overexpression. CONCLUSION: LECT2 expression is significantly elevated in NAFLD. LECT2 induces the occurrence and development of NAFLD through the STAT-1 pathway. LECT2 may be a potential therapeutic target for NAFLD.

Insulin-like growth factor binding protein 1 ameliorates lipid accumulation and inflammation in nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: Insulin-like growth factor binding protein 1 (IGFBP1) is recently proved to be associated with glucose regulation and insulin resistance. However, little is known about its direct impact on nonalcoholic fatty liver disease (NAFLD). This study aims to investigate the effect and potential mechanism of IGFBP1 in NAFLD. METHODS: We first measured the expression level of IGFBP1 in NAFLD patients, mice, and cells. Then in in vivo study, C57BL/6 mice were fed with a methionine/choline-deficient (MCD) diet for 4 weeks to establish the model of NAFLD. And for the last 2 weeks, the mice were injected intraperitoneally with vehicle or recombinant mouse IGFBP1 0.015 mg/kg/d. The L02 cells were treated with free fatty acids (FFA) or palmitate acids (PA) and recombinant IGFBP1 for 48 h. Integrin-linked kinase (ILK) inhibitor and small interfering RNA were used to explore the potential interactions between IGFBP1 and integrin ß1 (ITGB1). RESULTS: The expression of IGFBP1 was increased in NAFLD patients, mice, and cells. IGFBP1 treatment significantly ameliorated lipid accumulation and hepatic injury in MCD-fed mice. IGFBP1 downregulated hepatic lipogenesis and upregulated lipid ß-oxidation. In addition, IGFBP1 attenuated the nuclear factor-kappa B (NF-κB) and extracellular regulated protein kinases (ERK) signaling pathways. In vitro, we proved that IGFBP1 relieved FFA-induced lipid accumulation via interacting with ITGB1 and alleviated inflammation by inhibiting NF-κB and ERK signaling pathways. CONCLUSIONS: IGFBP1 treatment significantly ameliorated hepatic steatosis by interacting with ITGB1 and suppressed inflammation by inhibiting NF-κB and ERK signaling pathways. Therefore, IGFBP1 might be a potential therapeutic target for NAFLD.

The treatment efficacy of adding prokinetics to PPIs for gastroesophageal reflux disease: a meta-analysis.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common gastrointestinal disorder. Proton pump inhibitors (PPIs) are first-line drugs for GERD. For those who fail to respond to PPIs, adding prokinetics to PPIs is recommended and several trials have been conducted to evaluate the efficacy of prokinetic-PPI combination therapy. METHODS: A systematic literature search was performed using PubMed and the Cochrane Library databases before February 2019 for randomized controlled trials (RCTs), which compared the efficacy of prokinetics plus PPI treatment with that of PPI monotherapy. Relevant studies were examined and data were extracted independently by two investigators. The risk ratios (RRs) with 95% CIs were used to evaluate the responder rate, and standard mean differences (SMDs) or mean differences (MDs) with 95% CIs were used for symptom score changes. Statistical heterogeneity was evaluated by the I2 statistic. Either a fixed-effect or a random-effect model was established for calculating the pooled data. RESULTS: A total of 14 studies, comprising 1,437 patients were ultimately included in the meta-analysis. The pooled analysis showed that compared to PPI monotherapy, addition of prokinetics to PPI did not elevate the rate of endoscopic responders (RR = 0.996, 95% CI 0.929 - 1.068, p = 0.917), but improved symptom response (RR = 1.185, 95% CI 1.042 - 1.348, p = 0.010). Additionally, the combined therapy achieved a greater symptom relief than monotherapy both in FSSG and GERD-Q subgroups (MD = - 2.978, 95% CI - 3.319 to - 2.638, p < 0.001; MD = - 0.723, 95% CI - 0.968 to - 0.478, p < 0.001). CONCLUSIONS: Adding prokinetics to PPIs achieves symptomatic improvement compared to PPI monotherapy, thus can enhance life quality of GERD patients. However, the combined treatment seems to have no significant effect on mucosal healing.

Light-to-Moderate Alcohol Consumption Is Associated With Increased Risk of Type 2 Diabetes in Individuals With Nonalcoholic Fatty Liver Disease: A Nine-Year Cohort Study.

OBJECTIVE: This study explored the association between light-to-moderate alcohol consumption (LMAC) and risk of type 2 diabetes mellitus (T2DM) in individuals with nonalcoholic fatty liver disease (NAFLD). METHODS: A 9-year cohort study was performed among Chinese men who underwent their annual health checkups between 2009 and 2018. NAFLD was diagnosed based on abdominal ultrasound with exclusion of excess alcohol intake and other causes of liver disease. Logistic regression and Cox proportional regression analyses were applied to identify the risk of prevalent and incident T2DM. RESULTS: Of the 7,079 participants enrolled, 243 had T2DM at baseline and 630 developed T2DM during the 45,456 person-years follow-up. Both at the baseline and by the end of the follow-up, LMAC was associated with a decreased risk of prevalent T2DM in NAFLD-free participants but with a significantly increased risk in patients with NAFLD. LMAC was also associated with a decreased risk of incident T2DM in NAFLD-free participants. The adjusted hazard ratios (95% confidence interval) of incident T2DM were 0.224 (0.115-0.437) and 0.464 (0.303-0.710) for NAFLD-free light drinkers and NAFLD-free moderate drinkers, respectively. Nondrinking, light-drinking, and moderate-drinking patients with NAFLD all showed significantly increased risks of incident T2DM. Compared with NAFLD-free nondrinkers, the adjusted hazard ratios (95% confidence interval) of incident T2DM were 1.672 (1.336-2.092), 2.642 (1.958-3.565), and 2.687 (2.106-3.427) for nondrinking, light-drinking, and moderate-drinking patients with NAFLD, respectively. DISCUSSION: LMAC decreased the risks of prevalent and incident T2DM in NAFLD-free participants. LMAC, however, was associated with an increased risk of T2DM in patients with NAFLD (ClinicalTrials.gov number: NCT03847116).

Long noncoding RNA FLRL2 alleviated nonalcoholic fatty liver disease through Arntl-Sirt1 pathway.

Nonalcoholic fatty liver disease (NAFLD), which has an unknown pathogenesis and lacks a curative treatment, is becoming more prevalent. A previous long noncoding RNA (lncRNA) profiling analysis revealed a potential role for fatty liver-related lncRNA 2 (FLRL2) in the pathogenesis of NAFLD. To further understand the role of FLRL2 in NAFLD and explore its therapeutic value, both in vivo and in vitro NAFLD models were constructed. Small interfering RNA and small hairpin RNA interference and adenovirus transfection were adopted to manipulate the expressions of FLRL2, aryl-hydrocarbon receptor nuclear translocator-like (Arntl), and sirtuin 1 (Sirt1) expression. Steatosis was evaluated through histologic staining with hematoxylin and eosin and oil red O and also by quantitative triglyceride measurements. FLRL2 is a widely distributed nuclear lncRNA that is down-regulated in NAFLD. Overexpression of FLRL2 resolved steatosis, lipogenesis, inflammation, and endoplasmic reticulum (ER) stress in NAFLD, and down-regulation of FLRL2 resulted in the opposite effects. Sequence analysis demonstrated that FLRL2 was located in the intronic region of the Arntl gene, and a luciferase assay showed transcriptional activation of the Arntl gene upon FLRL2 overexpression. A similar expression pattern and synergistic effect of Arntl manipulation was observed in NAFLD in vitro. Inhibition of Arntl partially reversed the steatosis amelioration induced by FLRL2 overexpression. Downstream Sirt1 was also inhibited in NAFLD and influenced by both FLRL2 and Arntl. In NAFLD mice, FLRL2 enhancement alleviated steatosis, activated the Arntl-Sirt1 axis, and inhibited lipogenesis, ER stress, and inflammation, providing preliminary evidence of the benefits of FLRL2-mediated gene therapy in NAFLD.-Chen, Y., Chen, X., Gao, J., Xu, C., Xu, P., Li, Y., Zhu, Y., Yu, C. Long noncoding RNA FLRL2 alleviated nonalcoholic fatty liver disease through Arntl-Sirt1 pathway.

Cost-Effectiveness Analysis of Helicobacter pylori Eradication Therapy for Prevention of Gastric Cancer: A Markov Model.

BACKGROUND: Helicobacter pylori (H. pylori) eradication can reduce the prevalence of gastric cancer. However, whether H. pylori eradication therapy should be performed in infected patients, especially in asymptomatic cases, is still controversial. AIMS: The aims of this study were to determine whether H. pylori screening and eradication could prevent gastric cancer in a cost-effective way, and further whether eradication therapy should be administered to asymptomatic individuals. METHODS: Cost-effectiveness analysis was performed using a Markov model. We established two groups, each with 10,000 hypothetical Chinese individuals at the age of 40 years. Clinical outcomes and cost of H. pylori eradication were compared between the eradication and control groups. RESULTS: There was a lower morbidity with gastric cancer in the eradication group than in the control group, which was most significant after running the model for 15 years. The eradication group experienced an average of 34.64 quality-adjusted life years (QALYs) per person, and the average cost was US $1706.52 per person. The control group exhibited an average of 32.63 QALYs per person, and the average cost was US $2045.10 per person. The cost-effectiveness analysis showed that eradication saved $1539 per LY per person and $168.45 per QALY per person. CONCLUSIONS: H. pylori screening and eradication therapy effectively reduces the morbidity of gastric cancer and cancer-related costs in asymptomatic infected individuals. Therefore, we believe that H. pylori eradication can prevent gastric cancer in a cost-effective way.

Nitrogen removal and microbial communities of a completely autotrophic nitrogen removal over nitrite (CANON) sequencing batch biofilm reactor (SBBR) at different inorganic carbon (IC) concentrations.

In this study, the completely autotrophic nitrogen removal over nitrite (CANON) process was initiated in a sequencing batch biofilm reactor (SBBR). Then the reactor was operated under different IC/N ratios. The total inorganic nitrogen removal efficiency (TINRE) at IC/N ratios of 0.75, 1.0, 1.25, 1.5 and 2.0 were 37.0 ± 11.0%, 58.9 ± 10.2%, 73.9 ± 3.2%, 73.6 ± 1.8% and 72.6 ± 2.0%, respectively. The suitable range of IC/N ratio in this research is 1.25-2.0. The poor nitrogen removal performance at IC/N ratio of 0.75 was due to the lack of growth substrate for AnAOB and low pH simultaneously; at IC/N ratio of 1.0 this was because the substrate concentration was insufficient for fully recovering the AnAOB activities. Microbial analysis indicated that Nitrosomonas, Nitrospira and Candidatus Brocadia were the main ammonium oxidation bacteria (AOB), nitrite oxidation bacteria (NOB) and anammox bacteria (AnAOB), respectively. In addition, at IC ratios of 1.25 or higher, denitrification was promoted with the rise of IC/N ratio, which might be because the change of IC concentrations caused cell lysis of microorganisms and provided organic matter for denitrification.

MiR-542-3p controls hepatic stellate cell activation and fibrosis via targeting BMP-7.

There has been an increasing number of studies about microRNAs as key regulators in the development of hepatic fibrosis. Here, we demonstrate that miR-542-3p can promote hepatic fibrosis by downregulating the expression of bone morphogenetic protein 7 (BMP-7), which is known to antagonize transforming growth factor ß1 (TGFß1)-mediated fibrogenesis effect. The expression of miR-542-3p is increased in activated hepatic stellate cells (HSCs). Downregulation of MiR-542-3p by antisense inhibitors can inhibit HSCs activation markers, including α-smooth muscle actin (α-SMA) and collagen as well as TGFß signaling pathways. MiR-542-3p was significantly upregulated in carbon tetrachloride (CCl4 )-induced hepatic fibrosis in mice, and downregulation of miR-542-3p by lentivirus could prevent the development of hepatic fibrosis. In addition, miR-542-3p can directly bind to the 3'-untranslated region of BMP-7 mRNA, indicating that its profibrotic effect appears to be caused by its inhibition of BMP-7. Our results suggest that downregulation of miR-542-3p prevents liver fibrosis both in vitro and in vivo, highlighting its potential as a novel biomarker or therapeutic target for hepatic fibrosis.

Alcohol Consumption and the Risk of Gastroesophageal Reflux Disease: A Systematic Review and Meta-analysis.

AIMS: Epidemiologic evidence on alcohol consumption increasing the risk of gastroesophageal reflux disease (GERD) is contradictory. This study aimed to investigate the correlation between alcohol consumption and GERD by a meta-analysis of observational studies. SHORT SUMMARY: Gastroesophageal reflux disease (GERD) is a prevalent disease, and the incidence is rising. We conducted a meta-analysis of observational studies, indicating that there was a significant association between alcohol consumption and the risk of GERD. This finding provides important implications for the prevention and control of GERD. METHODS: Two investigators retrieved relevant studies on PubMed, Cochrane and EMBASE, respectively. The summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by random effects model to assess the association. Heterogeneity was quantified using the Q statistic and I2. Subgroup analysis, publication bias and sensitivity analysis were also conducted. RESULTS: Twenty-six cross-sectional studies and three case-control studies were included in the meta-analysis. The pooled random effects OR was 1.48 (95%CI, 1.31-1.67; I2 = 88.8%), in comparison between drinkers and non-/occasional drinkers. For reflux esophagitis and non-erosive reflux disease, two subtypes of GERD, the ORs were 1.78 (95%CI, 1.56-2.03; I2 = 87.5%) and 1.15 (95%CI, 1.04-1.28; I2 = 0.3%), respectively. In addition, the pooled OR for drinkers who drank <3-5 times or days per week was 1.29 (95%CI, 1.14-1.46; I2 = 35.5%), while for those who drank more frequently, the OR was 2.12 (95%CI, 1.63-2.75; I2 = 55.1%). Dose-response analysis showed a linear association between alcohol consumption and GERD (Pfornonlinearity=0.235). The pooled OR for a 12.5 g/day increment of alcohol was 1.16 (95%CI, 1.07-1.27; P = 0.001). CONCLUSIONS: This meta-analysis provides evidence for a potential association between alcohol drinking and the risk of GERD. The increase in alcohol consumption and frequency showed a stronger association with GERD.