Causal relationship between key genes and metabolic dysfunction-associated fatty liver disease risk mediated by immune cells: A Mendelian randomization and mediation analysis.

AIM: Non-invasive diagnostics for metabolic dysfunction-associated fatty liver disease (MAFLD) remain challenging. We aimed to identify novel key genes as non-invasive biomarkers for MAFLD, elucidate causal relationships between biomarkers and MAFLD and determine the role of immune cells as potential mediators. MATERIALS AND METHODS: Utilizing published transcriptome data of patients with biopsy-proven MAFLD, we applied linear models for microarray data, least absolute shrinkage and selector operation (LASSO) regressions and receiver operating characteristic (ROC) curve analyses to identify and validate biomarkers for MAFLD. Using the expression quantitative trait loci database and a cohort of 778 614 Europeans, we used Mendelian randomization to analyse the causal relationships between key biomarkers and MAFLD. Additionally, mediation analysis was performed to examine the involvement of 731 immunophenotypes in these relationships. RESULTS: We identified 31 differentially expressed genes, and LASSO regression showed three hub genes, IGFBP2, PEG10, and P4HA1, with area under the receiver operating characteristic (AUROC) curve of 0.807, 0.772 and 0.791, respectively, for identifying MAFLD. The model of these three genes had an AUROC of 0.959 and 0.800 in the development and validation data sets, respectively. This model was also validated using serum-based enzyme-linked immunosorbent assay data from MAFLD patients and control subjects (AUROC: 0.819, 95% confidence interval: 0.736-0.902). PEG10 was associated with an increased MAFLD risk (odds ratio = 1.106, p = 0.032) via inverse variance-weighted analysis, and about 30% of this risk was mediated by the percentage of CD11c + CD62L- monocytes. CONCLUSIONS: The MAFLD panels have good diagnostic accuracy, and the causal link between PEG10 and MAFLD was mediated by the percentage of CD11c + CD62L- monocytes.

Machine learning algorithms based on proteomic data mining accurately predicting the recurrence of hepatitis B-related hepatocellular carcinoma.

BACKGROUND AND AIM: Over 10% of hepatocellular carcinoma (HCC) cases recur each year, even after surgical resection. Currently, there is a lack of knowledge about the causes of recurrence and the effective prevention. Prediction of HCC recurrence requires diagnostic markers endowed with high sensitivity and specificity. This study aims to identify new key proteins for HCC recurrence and to build machine learning algorithms for predicting HCC recurrence. METHODS: The proteomics data for analysis in this study were obtained from the Clinical Proteomics Tumor Analysis Consortium (CPTAC) database. We analyzed different proteins based on cases with or without recurrence of HCC. Survival analysis, Cox regression analysis, and area under the ROC curves (AUROC > 0.7) were used to screen for more significant differential proteins. Predictive models for HCC recurrence were developed using four machine learning algorithms. RESULTS: A total of 690 differentially expressed proteins between 50 relapsed and 77 non-relapsed hepatitis B-related HCC patients were identified. Seven of these proteins had an AUROC > 0.7 for 5-year survival in HCC, including BAHCC1, ESF1, RAP1GAP, RUFY1, SCAMP3, STK3, and TMEM230. Among the machine learning algorithms, the random forest algorithm showed the highest AUROC values (AUROC: 0.991, 95% CI 0.962-0.999) for identifying HCC recurrence, followed by the support vector machine (AUROC: 0.893, 95% Cl 0.824-0.956), the logistic regression (AUROC: 0.774, 95% Cl 0.672-0.868), and the multi-layer perceptron algorithm (AUROC: 0.571, 95% Cl 0.459-0.682). CONCLUSIONS: Our study identifies seven novel proteins for predicting HCC recurrence and the random forest algorithm as the most suitable predictive model for HCC recurrence.

Resveratrol Attenuates Aß25-35 Caused Neurotoxicity by Inducing Autophagy Through the TyrRS-PARP1-SIRT1 Signaling Pathway.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of ß-amyloid peptide (Aß) and loss of neurons. Resveratrol (RSV) is a natural polyphenol that has been found to be beneficial for AD through attenuation of Aß-induced toxicity in neurons both in vivo and in vitro. However, the specific underlying mechanisms remain unknown. Recently, autophagy was found to protect neurons from toxicity injuries via degradation of impaired proteins and organelles. Therefore, the aim of this study was to determine the role of autophagy in the anti-neurotoxicity effect of RSV in PC12 cells. We found that RSV pretreatment suppressed ß-amyloid protein fragment 25-35 (Aß25-35)-induced decrease in cell viability. Expression of light chain 3-II, degradation of sequestosome 1, and formation of autophagosomes were also upregulated by RSV. Suppression of autophagy by 3-methyladenine abolished the favorable effects of RSV on Aß25-35-induced neurotoxicity. Furthermore, RSV promoted the expression of sirtuin 1 (SIRT1), auto-poly-ADP-ribosylation of poly (ADP-ribose) polymerase 1 (PARP1), as well as tyrosyl transfer-RNA (tRNA) synthetase (TyrRS). Nevertheless, RSV-mediated autophagy was markedly abolished with the addition of inhibitors of SIRT1 (EX527), nicotinamide phosphoribosyltransferase (STF-118804), PARP1 (AG-14361), as well as SIRT1 and TyrRS small interfering RNA transfection, indicating that the action of RSV on autophagy induction was dependent on TyrRS, PARP1 and SIRT1. In conclusion, RSV attenuated neurotoxicity caused by Aß25-35 through inducing autophagy in PC12 cells, and the autophagy was partially mediated via activation of the TyrRS-PARP1-SIRT1 signaling pathway.

Apple polysaccharide reduces NF-Kb mediated colitis-associated colon carcinogenesis.

Nuclear factor-kappa B (NF-κB) is an important molecule in mediating inflammatory colitis, which can lead to colorectal cancer (CRC). The aim of this study was to evaluate the chemopreventive efficacy of apple polysaccharide extract (AP) in inhibiting NF-κB-mediated inflammation pathways in CRC. We evaluated AP in vitro in HT-29 and SW620 human CRC cells. We also used the azoxymethane and dextran sodium sulphate (AOM/DSS) model to induce colon carcinogenesis in vivo. The chemoprotective effects of AP were assessed using Western blot, immunofluorescence assay, real-time PCR, electrophoretic mobility shift assay, and flow cytometry. AP reduced AOM/DSS-associated toxicities, prevented carcinogenesis, and decreased the expression of TLR4, MD2, MyD88, TRAM, TRIF-related adapter molecule, interferon-ß, tumor necrosis factor-α, and interleukin-6. The protective effects of AP may be related to the inhibition of TLR4/MD2-mediated signaling, including MyD88 and TRIF, as well as the inhibition of NF-κB-mediated inflammatory signaling pathways. Therefore, AP could be used in combination therapy for the prevention of colitis-associated colon cancer.

Genistein inhibits DNA methylation and increases expression of tumor suppressor genes in human breast cancer cells.

It has been previously demonstrated that genistein exhibits anticancer activity against breast cancer. However, the precise mechanisms underlying the anticancer effect of genistein, in particular the epigenetic basis, remain unclear. In this study, we investigated whether genistein could modulate the DNA methylation status and expression of cancer-related genes in breast cancer cells. We treated MCF-7 and MDA-MB-231 human breast cancer cells with genistein in vitro. We found that genistein decreased the levels of global DNA methylation, DNA methyltransferase (DNMT) activity and expression of DNMT1. Yet, the expression of DNMT3A and DNMT3B showed no significant change. Using molecular modeling, we observed that genistein might directly interact with the catalytic domain of DNMT1, thus competitively inhibiting the binding of hemimethylated DNA to the catalytic domain of DNMT1. Furthermore, genistein decreased DNA methylation in the promoter region of multiple tumor suppressor genes (TSGs) such as ataxia telangiectasia mutated (ATM), adenomatous polyposis coli (APC), phosphatase and tensin homolog (PTEN), mammary serpin peptidase inhibitor (SERPINB5), and increased the mRNA expression of these genes. However, we detected no significant changes in the DNA methylation status or mRNA expression of stratifin (SFN). These results suggest that the anticancer effect of genistein on breast cancer may be partly due to its ability to demethylate and reactivate methylation-silenced TSGs through direct interaction with the DNMT1 catalytic domain and inhibition of DNMT1 expression.

[Photothermal effects of metallic carbon nanotubes on human breast cancer cells].

SWNTs are a mixture of 1/3 metallic SWNTs (m-SWNTs) and 2/3 semiconducting SWNTs (s-SWNTs). It is desirable to separate the metallic SWNTs from the semi-conducting ones. In this study m-SWNTs was separated by using a poly[(m-phenylenevinylene)-alt-(p-phenylenevinylene)] (PmPV) derivative and used as photo-thermal media instead of SWNTs. The separation effects of m-SWNTs were evaluated by Raman spectra, molecular modeling and TEM images. The effects of m-SWNTs on MCF-7 cell proliferation and apoptosis were evaluated with MTT assay and flow cytometry, respectively. m-SWNTs were separated with high purity. A strong inhibition of MCF-7 cell growth was observed with the m-SWNTs under near-infrared (NIR) light irradiation. Our results will be helpful for the potential applications of m-SWNTs in clinical photothermal cancer therapy.

Polydopamine-Based Biomaterials in Orthopedic Therapeutics: Properties, Applications, and Future Perspectives.

Polydopamine is a versatile and modifiable polymer, known for its excellent biocompatibility and adhesiveness. It can also be engineered into a variety of nanoparticles and biomaterials for drug delivery, functional modification, making it an excellent choice to enhance the prevention and treatment of orthopedic diseases. Currently, the application of polydopamine biomaterials in orthopedic disease prevention and treatment is in its early stages, despite some initial achievements. This article aims to review these applications to encourage further development of polydopamine for orthopedic therapeutic needs. We detail the properties of polydopamine and its biomaterial types, highlighting its superior performance in functional modification on nanoparticles and materials. Additionally, we also explore the challenges and future prospects in developing optimal polydopamine biomaterials for clinical use in orthopedic disease prevention and treatment.

Osteocalcin-expressing neutrophils from skull bone marrow exert immunosuppressive and neuroprotective effects after TBI.

Neutrophils from skull bone marrow (Nskull) are activated under some brain stresses, but their effects on traumatic brain injury (TBI) are lacking. Here, we find Nskull infiltrates brain tissue quickly and persistently after TBI, which is distinguished by highly and specifically expressed osteocalcin (OCN) from blood-derived neutrophils (Nblood). Reprogramming of glucose metabolism by reducing glycolysis-related enzyme glyceraldehyde 3-phosphate dehydrogenase expression is involved in the antiapoptotic and proliferative abilities of OCN-expressing Nskull. The transcription factor Fos-like 1 governs the specific gene profile of Nskull including C-C motif chemokine receptor-like 2 (CCRL2), arginase 1 (Arg1), and brain-derived neurotrophic factor (BDNF) in addition to OCN. Selective knockout of CCRL2 in Nskull demonstrates that CCRL2 mediates its recruitment, whereas high Arg1 expression is consistent with its immunosuppressive effects on Nblood, and the secretion of BDNF facilitating dendritic growth contributes to its neuroprotection. Thus, our findings provide insight into the roles of Nskull in TBI.

FOXO1 reshapes neutrophils to aggravate acute brain damage and promote late depression after traumatic brain injury.

BACKGROUND: Neutrophils are traditionally viewed as first responders but have a short onset of action in response to traumatic brain injury (TBI). However, the heterogeneity, multifunctionality, and time-dependent modulation of brain damage and outcome mediated by neutrophils after TBI remain poorly understood. METHODS: Using the combined single-cell transcriptomics, metabolomics, and proteomics analysis from TBI patients and the TBI mouse model, we investigate a novel neutrophil phenotype and its associated effects on TBI outcome by neurological deficit scoring and behavioral tests. We also characterized the underlying mechanisms both in vitro and in vivo through molecular simulations, signaling detections, gene expression regulation assessments [including dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays], primary cultures or co-cultures of neutrophils and oligodendrocytes, intracellular iron, and lipid hydroperoxide concentration measurements, as well as forkhead box protein O1 (FOXO1) conditional knockout mice. RESULTS: We identified that high expression of the FOXO1 protein was induced in neutrophils after TBI both in TBI patients and the TBI mouse model. Infiltration of these FOXO1high neutrophils in the brain was detected not only in the acute phase but also in the chronic phase post-TBI, aggravating acute brain inflammatory damage and promoting late TBI-induced depression. In the acute stage, FOXO1 upregulated cytoplasmic Versican (VCAN) to interact with the apoptosis regulator B-cell lymphoma-2 (BCL-2)-associated X protein (BAX), suppressing the mitochondrial translocation of BAX, which mediated the antiapoptotic effect companied with enhancing interleukin-6 (IL-6) production of FOXO1high neutrophils. In the chronic stage, the "FOXO1-transferrin receptor (TFRC)" mechanism contributes to FOXO1high neutrophil ferroptosis, disturbing the iron homeostasis of oligodendrocytes and inducing a reduction in myelin basic protein, which contributes to the progression of late depression after TBI. CONCLUSIONS: FOXO1high neutrophils represent a novel neutrophil phenotype that emerges in response to acute and chronic TBI, which provides insight into the heterogeneity, reprogramming activity, and versatility of neutrophils in TBI.

Activation of nuclear factor erythroid 2-related factor 2 and PPARγ plays a role in the genistein-mediated attenuation of oxidative stress-induced endothelial cell injury.

We investigate the cytoprotective effects and the molecular mechanism of genistein in oxidative stress-induced injury using an endothelial cell line (EA.hy926). An oxidative stress model was established by incubating endothelial cells with H2O2. According to the present results, genistein pretreatment protected endothelial cells against H2O2-induced decreases in cell viability and increases in apoptosis. Genistein also prevented the inhibition of B-cell lymphoma 2 and the activation of caspase-3 induced by H2O2. Genistein increased superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) levels and attenuated the decrease in these antioxidants during oxidative stress. We also found that genistein induced the promoter activity of both nuclear factor erythroid 2-related factor 2 (Nrf2) and PPARγ. Additionally, genistein induced the nuclear translocation of Nrf2 and PPARγ. While genistein caused the up-regulation of both Nrf2 and PPARγ, it also activated and up-regulated the protein expression and transcription of a downstream protein, haem oxygenase-1 (HO-1). Moreover, the use of Nrf2 small interfering RNA transfection and HO-1- or PPARγ-specific antagonists (Znpp and GW9662, respectively) blocked the protective effects of genistein on endothelial cell viability during oxidative stress. Therefore, we conclude that oxidative stress-induced endothelial cell injury can be attenuated by treatment with genistein, which functions via the regulation of the Nrf2 and PPARγ signalling pathway. Additionally, the endogenous antioxidants SOD, CAT and GSH appear to play a role in the antioxidant activity of genistein. The present findings suggest that the beneficial effects of genistein involving the activation of cytoprotective antioxidant genes may represent a novel strategy in the prevention and treatment of cardiovascular endothelial damage.

Isoflavones for hypercholesterolaemia in adults.

BACKGROUND: Hypercholesterolaemia is a significant risk factor for cardiovascular diseases. Isoflavones may be effective in improving hypercholesterolaemia. OBJECTIVES: To assess the effects of isoflavones for hypercholesterolaemia. SEARCH METHODS: We searched the following databases: The Cochrane Library (Issue 9, 2012), MEDLINE, EMBASE, Chinese BioMedical Database and China National Knowledge Infrastructure (all to September 2012). SELECTION CRITERIA: We considered randomized controlled clinical trials in hypercholesterolaemic participants comparing isoflavones versus placebo, or soy isolated protein added with isoflavones versus soy isolated protein alone. DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted relevant population and intervention characteristics. We resolved any disagreements through discussion, or if required by a third party. We assessed the risk of bias of trials against key criteria: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other sources of bias. MAIN RESULTS: We included five randomized trials (208 participants, 104 in the intervention group and 104 in the control group). Interventions ranged from three to six months. Four trials reported results in non-Asian populations published in English. One trial reported results in Chinese people published in Chinese. Overall, the risk of bias of included trials was high or unclear. There were no outcome data on death from any cause, morbidity, complications, health-related quality of life and costs. Two trials reported adverse effects, including gastrointestinal discomfort (bloating and constipation) and an increased number of hot flushes. None of the trials found serious adverse events. There was a slight significant effect on triglycerides in favour of isoflavones when compared with placebo (mean difference (MD) -0.46 mmol/L (95% confidence interval (CI) -0.84 to -0.09; P = 0.02; 52 participants; 2 trials). No statistically significant effects on total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol were shown in favour of isoflavones. AUTHORS' CONCLUSIONS: We found no evidence for effects of isoflavones on patient-important outcomes or lowering of cholesterol levels in people with hypercholesterolaemia. Our findings have to be interpreted with caution due to high or unclear risk of bias in several risk of bias domains, and low number of participants in trials.

Chemical structures of 4-oxo-flavonoids in relation to inhibition of oxidized low-density lipoprotein (LDL)-induced vascular endothelial dysfunction.

Vascular endothelial dysfunction induced by oxidative stress has been demonstrated to be the initiation step of atherosclerosis (AS), and flavonoids may play an important role in AS prevention and therapy. Twenty-three flavonoids categorized into flavones, flavonols, isoflavones, and flavanones, all with 4-oxo-pyronenucleus, were examined for what structural characteristics are required for the inhibitory effects on endothelial dysfunction induced by oxidized low-density lipoprotein (oxLDL). Human vascular endothelial cells EA.hy926 were pretreated with different 4-oxo-flavonoids for 2 hs, and then exposed to oxLDL for another 24 hs. Cell viability and the level of malondialdehyde (MDA), nitric oxide (NO) and soluble intercellular adhesion molecule-1 (sICAM-1) were measured, respectively. Then, correlation analysis and paired comparison were used to analyze the structure-activity relationships. Significant correlations were observed between the number of -OH moieties in total or in B-ring and the inhibitory effectson endothelial dysfunction. Furthermore, 3',4'-ortho-dihydroxyl on B-ring, 3-hydroxyl on C-ring and 2,3-double bondwere correlated closely to the inhibitory effects of flavonolson cell viability decrease and lipid peroxidation. 5,7-meta-dihydroxyl group on A-ring was crucial for the anti-inflammatory effects of flavones and isoflavones in endothelial cells. Moreover, the substituted position of B-ring on C3 rather than C2 was important for NO release. Additionally, hydroxylation at C6 position significantly attenuated the inhibitory effects of 4-oxo-flavonoids on endothelial dysfunction. Our findings indicated that the effective agents in inhibiting endothelial dysfunction include myricetin, quercetin, luteolin, apigenin, genistein and daidzein. Our work might provide some evidence for AS prevention and a strategy for the design of novel AS preventive agents.

Machine learning algorithm outperforms fibrosis markers in predicting significant fibrosis in biopsy-confirmed NAFLD.

BACKGROUND: The presence of significant liver fibrosis is a key determinant of long-term prognosis in non-alcoholic fatty liver disease (NAFLD). We aimed to develop a novel machine learning algorithm (MLA) to predict fibrosis severity in NAFLD and compared it with the most widely used non-invasive fibrosis biomarkers. METHODS: We used a cohort of 553 adults with biopsy-proven NAFLD, who were randomly divided into a training cohort (n = 278) for the development of both logistic regression model (LRM) and MLA, and a validation cohort (n = 275). Significant fibrosis was defined as fibrosis stage F ≥ 2. MLA and LRM were derived from variables that were selected using a least absolute shrinkage and selection operator (LASSO) logistic regression algorithm. RESULTS: In the training cohort, the variables selected by LASSO algorithm were body mass index, pro-collagen type III, collagen type IV, aspartate aminotransferase and albumin-to-globulin ratio. The diagnostic accuracy of MLA showed the highest values of area under the receiver operator characteristic curve (AUROC: 0.902, 95% CI 0.869-0.904) for identifying fibrosis F ≥ 2. The LRM AUROC was 0.764, 95% CI 0.710-0.816 and significantly better than the AST-to-Platelet ratio (AUROC 0.684, 95% CI 0.605-0.762), FIB-4 score (AUROC 0.594, 95% CI 0.503-0.685) and NAFLD Fibrosis Score (AUROC 0.557, 95% CI 0.470-0.644). In the validation cohort, MLA also showed the highest AUROC (0.893, 95% CI 0.864-0.901). The diagnostic accuracy of MLA outperformed that of LRM in all subgroups considered. CONCLUSIONS: Our newly developed MLA algorithm has excellent diagnostic performance for predicting fibrosis F ≥ 2 in patients with biopsy-confirmed NAFLD.

Bioinformatics analysis reveals novel core genes associated with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is the most frequent liver disease and associated with a wide spectrum of hepatic disorders ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). NASH is projected to become the most common indication for liver transplantation, and the annual incidence rate of NASH-related HCC is 5.29 cases per 1000 person-years. Owing to the epidemics of NAFLD and the unclear mechanism of NAFLD progression, it is important to elucidate the underlying NAFLD mechanisms in detail. NASH is mainly caused by the development of NAFL Therefore, it is also of great significance to understand the mechanism of progression from NAFL to NASH. Gene expression chip data for NAFLD and NASH were downloaded from the Gene Expression Omnibus database to identify differentially expressed genes (DEGs) between NAFLD and normal controls (called DEGs for NAFLD), as well as between NASH and normal tissue (called DEGs for NASH-Normal), and between NASH and NAFL tissue (called DEGs for NASH-NAFL). For DEGs for the NAFLD group, key genes were identified by studying the form of intersection. Potential functions of DEGs for NASH were then analyzed by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. A protein-protein interaction network (PPI) was constructed using the STRING database. A total of 249 DEGs and one key gene for NAFLD were identified. For NASH-Normal, 514 DEGs and 11 hub genes were identified, three of which were closely related to the survival analysis of HCC, and potentially closely related to progression from NASH to HCC. One key gene for NASH-NAFL (AKR1B10) was identified. These genes appear to mediate the molecular mechanism underlying NAFLD and may be promising biomarkers for the presence of NASH.

Clinical Features of COVID-19 Patients in Xiaogan City.

On February 6, 2020, Xiaogan City became the second most seriously affected city with coronavirus disease 2019 (COVID-19), outside Wuhan district, Hubei Province, China. The objectives are to study the clinical features of COVID-19 patients and assess the relationship between the severity of COVID-19, age, and C-reactive protein (CRP) levels. The retrospective data of 134 COVID-19 patients hospitalized in 3 hospitals of Xiaogan City, between February 1 and March 1, 2020, was collected. This study documented COVID-19 patients. Clinical data in terms of body temperature, history of travel, and direct contact with COVID-19 patients, and incubation period was collected. Out of the 134 patients, only 5 required intensive care. Moreover, 2 patients succumbed during this period. The median age of patients was 45 (33-56) years. The most common symptoms at the onset of disease were fever (66.4%), cough (33, 6%), and sore throat (14.7%). Amongst the medicines used, antiviral agents (92.3%) followed by the traditional Chinese medicine (89.5%) were most commonly used. In both the crude and adjusted (I to III) models, odds ratio and its 95% confidence interval for both age and CRP levels were > 1. Moreover, the smooth curve fitting graph reflected that the severity of COVID-19 was positively correlated with both age and CRP levels (all P value < 0.05). The signs and symptoms of COVID-19 patients were fairly moderate. The health care professionals treating the COVID-19 patients should be aware of the increased likelihood of progression to severe COVID-19 in elderly patients and those with high CRP levels.

Synergy between dihydromyricetin intervention and irinotecan chemotherapy delays the progression of colon cancer in mouse models.

Colorectal cancer (CRC) is the third highest cause of cancer-related death and the main option for prolonged survival is chemotherapeutic intervention. There is increasing interest in dietary intervention using natural agents to enhance the sensitivity of such invasive chemical treatment. In this study, the chemotherapeutic efficacy of dihydromyricetin (DMY) intervention on treatments involving irinotecan (CPT-11) or gemcitabine (GM) was evaluated in an AOM/DSS-induced colitis-associated colon cancer model and a Min (Apc Min/+) mice model. Our data showed that DMY could promote the CPT-11 effect both in the mouse model of AOM/DSS and Apc Min/+ cancer and had no influence on the GM effect. In AOM/DSS cancer, tumors were sensitive to 100 mg kg-1 DMY chemotherapy under 100 mg kg-1 or 200 mg kg-1 CPT-11. DMY-driven CPT-11 chemotherapy induced enhanced IgG levels and the reduction of Fusobacterium abundance in the gut. In the Min model, CPT-11 with 20 mg kg-1 DMY prevented tumor formation but not with 100 mg kg-1 DMY. Mechanically, chloride ion-dependent CFTR, CLCN4, and CLIC4 signaling are not involved in DMY mediated chemotherapeutic colon tumorigenesis. These results suggested that a suitable dose of DMY could act as a coadjuvant to CPT-11 chemotherapy.

A simpler diagnostic formula for screening nonalcoholic fatty liver disease.

OBJECTIVE: To increase the accuracy of non-invasive diagnosis of nonalcoholic fatty liver disease (NAFLD), clinical and laboratory NAFLD indicators were integrated into a diagnostic formula. METHODS: A total of 141 patients with clinically diagnosed NAFLD and 30 healthy controls were enrolled. We collected case history, body weight, height and mass index (BMI), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase, blood urea nitrogen and blood uric acid (UA), serum creatinine, plasma total cholesterol, triglyceride, low density lipoprotein, glycosylated hemoglobin, fasting plasma glucose, fasting insulin, ultrasonic tests, Fibroscans, and other data. Linear correlation, multiple linear regressions, and receiver operating characteristic (ROC) curve methods were used to process and analyze the collected data. The performance of Fibroscan and our diagnostic formula was compared in reference to the findings of liver biopsy. RESULTS: The identified NAFLD diagnostic indices consisted of BMI, ALT, AST and UA. A regression formula was proposed as: CAP = 113.163 + 0.252 * ALT + 6.316 * BMI. Diagnosis of the area under the ROC curve was 0.927, the sensitivity was 87.68%, and specificity was 90%. The cutoff was 277.67 (p < 0.01). The accuracy of the NAFLD diagnosis with the proposed formula was significantly higher than FibroScan (82.6% vs 69.6%; p = 0.005). CONCLUSIONS: NAFLD diagnosis with the proposed formula demonstrated both high sensitivity and specificity, and its accuracy was significantly higher than FibroScan. This formula only utilized non-invasive clinical and laboratory findings and the calculation was simple. It can be conveniently used for clinical diagnosis of NAFLD.

Effects of different dietary fatty acids on the fatty acid compositions and the expression of lipid metabolic-related genes in mammary tumor tissues of rats.

In this study, the effects of dietary fatty acids on the fatty acid compositions and lipid metabolic-related genes expression in N-methyl-N-nitrosourea (MNU)-induced rat mammary carcinogenesis were evaluated. The 50-day-old female Sprague-Dawley rats were intervened by different dietary fats (15% wt/wt), including saturated fatty acid (SFA), monounsaturated fatty acid (MUFA), n-6 polyunsaturated fatty acid (PUFA), n-3 PUFA, 1:1 n-6/n-3, 5:1 n-6/n-3, 10:1 n-6/n-3, and 1:2:1 S/M/P (1:1 n-6/n-3), alone or in combination with MNU. There was no mammary tumor occurrence in the control and MNU-treated n-3 PUFA groups after 18 wk. n-3 PUFA diet retarded the weight growth of rats. 1:1 n-6/n-3 diet significantly reduced the MNU-induced tumor incidence and tumor multiplicity compared with SFA, MUFA, n-6 PUFA, 5:1 n-6/n-3, 10:1 n-6/n-3 and 1:2:1 S/M/P diets (42.86% vs. 83.33%-92.31%, 0.79 vs. 2.62-2.85, P < 0.01). Additionally, 1:1 n-6/n-3 diet substantially increased cis-5,8,11,14,17-eicosapentaenoic acid and cis-4,7,10,13,16,19-docosahexaenoic acid levels, whereas it decreased C20:4 level and the mRNA expressions of fatty acid synthase, Cyclooxygenase-2 (COX-2), and 5-lipoxygenase (5-LOX) in mammary tissues (P < 0.05). These results suggest that 1:1 n-6/n-3 in the diet is effective in the prevention of mammary tumor development by increasing the n-3 PUFA content and reducing the expression of lipid metabolic-related genes.

Dietary Factors Modulate Colonic Tumorigenesis Through the Interaction of Gut Microbiota and Host Chloride Channels.

SCOPE: In recent decades, the association among diet, gut microbiota, and the risk of colorectal cancer (CRC) has been established. Gut microbiota and associated metabolites, such as bile acids and butyrate, are now known to play a key role in CRC development. The aim of this study is to identify that the progression to CRC is influenced by cholic acid, sodium butyrate, a high-fat diet, or different dose of dihydromyricetin (DMY) interacted with gut microbiota. METHODS AND RESULTS: An AOM/DSS (azoxymethan/dextran sodium sulfate) model is established to study the gut microbiota compsition before and after tumor formation during colitis-induced tumorigenesis. All above dietary factors profoundly influence the composition of gut microbiota and host colonic tumorigenesis. In addition, mice with DMY-modified initial microbiota display different degrees of chemically induced tumorigenesis. Mechanism analysis reveals that gut microbiota-associated chloride channels participated in colon tumorigenesis. CONCLUSION: Gut microbiota changes occur in the hyperproliferative stage before tumor formation. Gut microbiota and host chloride channels, both of which are regulated by dietary factors, are associated with CRC development.