Dietary Factors and Risk of Gout: A Two-Sample Mendelian Randomization Study.

BACKGROUND: Dietary intervention is the preferred approach for the prevention and clinical management of gout. Nevertheless, the existing evidence regarding the influence of specific foods on gout is insufficient. METHODS: We used two-sample Mendelian randomization for genetic prediction to analyze the relationship between the intake of more than a dozen daily food items, such as pork, beef, cheese, and poultry, and dietary macronutrient intake (fat, protein, carbohydrates, and sugar) and the risk of developing gout and elevating the serum uric acid level. Inverse-variance weighted MR analyses were used as the main evaluation method, and the reliability of the results was tested by a sensitivity analysis. RESULTS: Cheese intake was associated with lower serum uric acid levels, and tea intake (OR = 0.523, [95%CI: 0.348~0.784], p = 0.002), coffee intake (OR = 0.449, [95%CI: 0.229~0.882], p = 0.020), and dried fruit intake (OR = 0.533, [95%CI: 0.286~0.992], p = 0.047) showed a preventive effect on the risk of gouty attacks. In contrast, non-oily fish intake (ß = 1.08, [95%CI: 0.24~1.92], p = 0.012) and sugar intake (ß = 0.34, [95%CI: 0.03~0.64], p = 0.030) were risk factors for elevated serum uric acid levels, and alcohol intake frequency (OR = 1.422, [95%CI: 1.079~1.873], p = 0.012) was a risk factors for gout predisposition. CONCLUSIONS: These results will significantly contribute to the formulation and refinement of nutritional strategies tailored to patients afflicted with gout.

New sesquiterpenoids from Biscogniauxia sp.

Five new sesquiterpenoids, including a campherenane-type (1), a bergamotane-type (2), a drimane-type (3), and two bisabolane-type (5-6) sesquiterpenoids have been isolated from Biscogniauxia sp. 71-10-1-1. Their structures were determined by spectroscopic analyses, quantum chemical ECD calculations,13C chemical shifts calculations, and X-ray crystallography. This is the first report of campherenane-type and drimane-type sesquiterpenoids from Biscogniauxia. Furthermore, the anti-inflammatory assays of all compounds are evaluated, and the results showed that compounds 3 and 7 exhibited the effects against the production of the pro-inflammatory cytokine TNF-α.

Triglycerides Mediate the Influence of Body Mass Index on Non-Alcoholic Fatty Liver Disease in a Non-Obese Chinese Population with Normal Low-Density Lipoprotein Cholesterol Levels.

INTRODUCTION: Over 25% of the world's population has non-obese or lean non-alcoholic fatty liver disease (NAFLD), and the prevalence is higher than average in Asia. The present study focused on the relationship between body mass index (BMI) and non-obese NAFLD in non-overweight people in China, particularly the influence of triglycerides (TG) in the pathogenesis of non-obese NAFLD. The findings suggest new treatments for NAFLD patients with normal BMI, as well as provide an early warning system for the understanding and prevention of NAFLD in non-obese patients. METHODS: This cross-sectional study enrolled 159,959 Chinese subjects with BMI <24 kg/m2 and normal levels of low-density lipoprotein cholesterol (LDL-c). The average age was 40.21 ± 13.88 years, and males accounted for 45.7%. A total of 15,907 (9.94%) patients with NAFLD were diagnosed by ultrasonography. Biochemical indicators were measured using an automated analyzer (Abbott AxSYM). The BMI (kg/m2) was calculated from the weight (kg)/height in square meters (m2). The BMI quartile was used as the column-stratified variable to determine the baseline distribution, and logistic regression analysis was used to assess the relationship between NAFLD and its risk factors, with multiple logistic regression used to assess the relationships between BMI or TG and NAFLD and multivariate linear regression used to analyze the association between BMI and TG, while mediation analysis was used to assess the mediation effect of TG. RESULTS: After adjustment of all covariates, the odds ratios were 1.788 (95% CI: 1.749-1.829; p < 0.00001) and 1.491 (95% CI: 1.451-1.532; p < 0.00001) for the association between BMI and TG with NAFLD incidence. The multivariate linear regression coefficient of BMI and TG was ß = 0.027 (95% CI: 0.023-0.030; p < 0.00001). Mediation analysis showed that BMI contributed to 10.81% of lean NAFLD with a mediation effect of 2.98%. CONCLUSION: In a Chinese population with BMI <24 kg/m2 and normal LDL-c levels, BMI and TG were found to be independent predictors of NAFLD. The direct effect of BMI on non-obese NAFLD was 10.41%. The TG level was found to partially mediate the association.

Scribble promotes fibrosis-dependent mechanisms of hepatocarcinogenesis by p53/PUMA-mediated glycolysis.

BACKGROUNDS AND AIMS: Liver cancer is the sixth most common type of cancer and the fifth leading cause of cancer mortality worldwide. Scribble has been shown to function as a neoplastic tumor suppressor gene in most tumors. Our previous studies reported that down-regulation or mislocalization of Scribble was sufficient to initiate mammary tumorigenesis and NSCLC. Recently, it was reported that Scribble was highly expressed in hepatocellular carcinoma (HCC). We aim to study how it was up-regulated and the contradictory role of Scribble in HCC. METHODS AND RESULTS: Using a mouse model of carbon tetrachloride (CCl4)-induced liver fibrosis system, we showed that Scribble was over-expressed and which may protect the mice against hepatic fibrosis. Unexpectedly, we found out the potential for Scribble to act as a tumor driver at the advanced stage of N-nitrosodiethylamine (DEN) plus CCl4 induced HCC mice model in vivo. In addition, we observed even higher expression of Scribble in HCC tumors harboring elevated levels of wild-type p53. Most importantly, nuclear translocated Scribble could interact with p53, which lead to enhanced stability and transcriptional activity of p53. Mechanistically, our data suggested that Scribble might drive HCC progression by promoting metabolic regulation of p53 through p53-upregulated modulator of apoptosis (PUMA)-mediated Warburg effect. CONCLUSIONS: Our data identified the molecular basis of hepatic fibrosis-specific gene expression of polarity gene, such as Scribble. Interestingly, with the progression from fibrosis to cirrhosis to HCC, its nuclear translocation promoted a wild-type p53-mediated cancer metabolic switch and tumor progression in HCC. Taken together, we demonstrated that Scribble was up-regulated and served a protective role in liver fibrosis, while also apparently acting as a tumor driver in fibrosis-dependent hepatocarcinogenesis.

Multimolecular characteristics and role of BRCA1 interacting protein C-terminal helicase 1 (BRIP1) in human tumors: a pan-cancer analysis.

BACKGROUND: The aberrant expression of BRIP1 was associated with several cancers; however, the panoramic picture of BRIP1 in human tumors remains unclear. This study aims to explore the pan-cancerous picture of the expression of BRIP1 across 33 human cancers. METHODS: Based on the data from TCGA and GTEx, a series of bioinformatic analyses were applied to systematically explore the genetic landscape and biologic function of BRIP1 in 33 human tumors. RESULTS: We observed prognosis-related differential BRIP1 expressions between various carcinomas and the corresponding normal tissues. "Basal transcription factors," "homologous recombination," "nucleotide excision repair," and DNA metabolism pathways may play a role in the functional mechanisms of BRIP1. Patients with uterine corpus endometrial carcinoma presented with the highest alteration frequency of BRIP1 (nearly 10%). Single-nucleotide and copy number variations of BRIP1 were noticed in multiple cancers, and the expression of BRIP1 is significantly regulated by copy number variation in breast invasive carcinoma and lung squamous cell carcinoma. BRIP1 expression is negatively correlated with the DNA methylation levels in many tumors and is associated with the activation of apoptosis, cell cycle, DNA damage response, and inhibition of hormone ER and RNS/MARK signaling pathways. Moreover, a positive correlation was observed between BRIP1 expression and the immune infiltration levels of cancer-associated fibroblasts and CD8+ T cells in lung adenocarcinoma. CONCLUSION: Our pan-cancer analysis of BRIP1 provides a valuable resource for understanding the multimolecular characteristics and biological function of BRIP1 across human cancers.

Enhanced anticancer effect of MAP30-S3 by cyclosproin A through endosomal escape.

Cyclosporin A (CsA) is a calcium antagonist and can enhance the efficacy of some protein drugs, but its mechanism remains unknown. In this study, MAP30, a ribosome-inactivating protein reported to have apoptotic effects on cancer cells, was fused with S3, an epidermal growth factor receptor (EGFR)-targeting peptide. In addition, CsA was used to investigate whether it can further promote the apoptotic effects of S3 fused MAP30 (MAP30-S3). Our result showed that the internalization of FITC-labeled MAP30-S3 was increased significantly by S3 in HeLa cells. Unexpectedly, MAP30-S3 only showed a minor decrease in the viability of EGFR-overexpressing cancer cells, including HeLa, SMMC-7721, and MGC803 (IC50>5 µmol/l). However, 2 µmol/l CsA significantly increased the cytotoxicity of MAP30-S3, especially for HeLa cells (IC50=40.3 nmol/l). In comparison, CsA did not further decrease the cytotoxicity of MAP30-S3 on MRC-5, an EGFR low-expressing cell line from normal lung tissue, indicating that CsA did not affect the cancer-targeting specificity of MAP30-S3. Our results also showed that CsA further increased the apoptotic activity of MAP30-S3 in HeLa cells. CsA could promote the endosomal escape of FITC-MAP30-S3 with a diffused pattern in the cytoplasm. Five endocytic inhibitors were used to investigate the cellular uptake mechanism of MAP30-S3, and the results showed that the endosomal escape-enhancing effect of CsA on MAP30-S3 may be associated with the clathrin-dependent endocytic pathways. Our study suggested that CsA could be a novel endosomal escape enhancer to potentiate the intracellular release of anticancer protein drugs, resulting in their improved therapeutic efficacy.