Platinum Nanoparticles-Enhanced Ferritin-Mn2+ Interaction for Magnetic Resonance Contrast Enhancement and Efficient Tumor Photothermal Therapy.

Nanoplatforms with high Mn2+ coordination can display efficient T1 magnetic resonance imaging (MRI) contrast enhancement. Herein, an earth gravity-like method for enhanced interaction between Ferritin (Fn) and Mn2+ by the growth of platinum nanoparticles (PNs) in Fn's cage structure via a biomineralization method is first proposed. Fn has good biocompatibility and can provide a suitable growth site for PNs. PNs with negative charge have certain attraction to Mn2+ with positive charge, improving Fn's loading capacity of Mn2+ by attraction force; and thus, achieving efficient MRI contrast enhancement. In addition, PNs can be applied for efficient photothermal therapy (PTT) under near infrared ray (NIR) irradiation. Systemic delivery of this nanoplatform shows obvious MRI contrast enhancement and tumor progression inhibition after NIR irradiation, as well as no obvious side effects. Therefore, this nanoplatform has the potential to contribute to nanotheranostic for clinical transformation.

Design, synthesis, and biological evaluation of pyrido[2,3-d]pyrimidine and thieno[2,3-d]pyrimidine derivatives as novel EGFRL858R/T790M inhibitors.

EGFR mutations have been identified in 20,000 reported NSCLC (non-small cell lung cancer) samples, and exon 19 deletions and L858R mutations at position 21, known as "classical" mutations, account for 85-90% of the total EGFR (epidermal growth factor receptor) mutations. In this paper, two series of EGFR kinase inhibitors were designed and synthesised. Among them, compound B1 showed an IC50 value of 13 nM for kinase inhibitory activity against EGFRL858R/T790M and more than 76-fold selectivity for EGFRWT. Furthermore, in an in vitro anti-tumour activity test, compound B1 showed an effective anti-proliferation activity against H1975 cells with an IC50 value of 0.087 µΜ. We also verified the mechanism of action of compound B1 as a selective inhibitor of EGFRL858R/T790M by cell migration assay and apoptosis assay.

Development of a risk assessment scale for use by nurses to assess the risk of deep vein thrombosis in gynaecology in China: A Delphi-based study.

AIM: Risk assessment models for deep vein thrombosis (DVT) used worldwide are based on multidisciplinary data from Western countries. We aimed to establish a DVT risk assessment model that is applicable to Chinese patients with gynaecological conditions. DESIGN: A risk assessment tool for DVT in gynaecology using the Delphi method. METHODS: A three-round Delphi study was conducted among experts who were asked to rate the importance of each risk factor in the Caprini scale. The consensus for each item was defined as a mean rating of >3 and a coefficient of variation (CV) of <0.5 in the first round, as CV <0.3 in the second round. RESULTS: Eleven experts participated in the Delphi method, with a response rate of 100%. Kendall's coefficients of concordance (W) were 0.264 and 0.322 in the first and second rounds, respectively (p < 0.001). The DVT risk assessment scale includes 8 dimensions and 34 items.

DRAM1 increases the secretion of PKM2-enriched EVs from hepatocytes to promote macrophage activation and disease progression in ALD.

DNA damage-regulated autophagy modulator 1 (DRAM1) could play important roles in inflammation and hepatic apoptosis, while its roles in alcohol-related liver disease (ALD), which is characterized by hepatic inflammation and apoptosis, are still unclear. In this study, we explored the expression, role, and mechanism of DRAM1 in ALD. Firstly, our results showed that DRAM1 was significantly increased in liver tissues of mice at the early stage of alcohol treatment. In addition, DRAM1 knockout reduced, and liver-specific overexpression of DRAM1 aggravated, alcohol-induced hepatic steatosis, injury, and expressions of M1 macrophage markers in mice. Furthermore, ethanol-induced DRAM1 of hepatic cells increased pyruvate kinase M2 (PKM2)-enriched extracellular vesicles (EVs), and ectosomes derived from hepatic cells with DRAM1 overexpression promoted macrophage activation. Mechanistic investigations showed that DRAM1 interacted with PKM2 and increased the PKM2 level in plasma membrane. At last, DRAM1 was significantly increased in liver tissues of ALD patients, and it was positively correlated with M1 macrophage markers. Taken together, this study revealed that ethanol-induced DRAM1 of hepatic cells could increase the PKM2-enriched EVs, promote macrophage activation, and aggravate the disease progression of ALD. These findings suggested that DRAM1 might be a potentially promising target for the therapy of ALD.

A predictive model for the diagnosis of non-alcoholic fatty liver disease based on an integrated machine learning method.

Diagnostic markers for non-alcoholic fatty liver disease (NAFLD) are still needed for screening individuals at risk. In recent years, the machine learning method was used to search for the diagnostic markers of multiple diseases. In this study, we developed and validated a machine learning model to diagnose NAFLD using laboratory indicators. NAFLD patients and non-NAFLD controls were recruited in the training and validation cohorts. The laboratory indicators of the participants in the training cohort were collected, and six indicators including alanine aminotransferase/aspartate aminotransferase (ALT/AST), white blood cells (WBC), alpha-L-fucosidase (AFU), hemoglobin (Hb), triglycerides (TG) and gamma-glutamyl transpeptidase (GGT) were screened out with higher weights by an integrate machine learning method. The areas under the receiver operating characteristic curves (AUROCs) for the selected indicators using logistic regression (LR), random forest (RF) and support vector machine (SVM) were 0.814, 0.837 and 0.810, respectively. Then the binary logistic regression was used to construct the predictive model. What's more, the AUROC of the predicted model was 0.732 in the validation cohort of patients with NAFLD. And the combined AUROC of the six parameters was 0.716 in the mouse model fed with high-fat diet (HFD). In summary, we created a predictive model with six laboratory indicators for the diagnosis of NAFLD based on the machine learning method, which has the potential value for the diagnosis of the NAFLD.

Lipid-induced DRAM recruits STOM to lysosomes and induces LMP to promote exosome release from hepatocytes in NAFLD.

The biogenesis and diagnostic value of exosomes in nonalcoholic fatty liver disease (NAFLD) are unclear. In this study, we revealed that the plasma exosome level was higher in patients with NAFLD than that in healthy controls. Damage-regulated autophagy modulator (DRAM) was identified as one of the genes related to exosome secretion in patients with NAFLD. Then, loss or knockdown of DRAM down-regulated exosome secretion from hepatic cells using a knockout mouse model and a knockdown cell model. DRAM knockout reversed high-fat diet­induced increase of secreted exosomes. Furthermore, DRAM knockdown inhibited fatty acid (FA)­induced lysosomal membrane permeabilization and lysosome inhibitor reversed the down-regulation of exosome release in DRAM knockout mice. Last, FA-induced DRAM interacted with stomatin and promoted its lysosomal localization to enhance exosome secretion from hepatic cells. We revealed a DRAM-mediated mechanism for exosome secretion and provided the foundation for plasma exosomes as a potential biomarker for NAFLD.

Relationship between AGT rs2493132 polymorphism and the risk of coronary artery disease in patients with NAFLD in the Chinese Han population.

OBJECTIVE: To investigate the relationship between angiotensin (AGT) rs2493132 gene polymorphism and the risk of developing non-alcoholic fatty liver disease (NAFLD) and coronary artery disease (CAD) in the Chinese Han population. METHODS: Polymerase chain reaction was performed to determine AGT genotypes. Anthropometric and clinical data were investigated and statistically analyzed in the clinical laboratory department of Qingdao Municipal Hospital. RESULTS: The AGT rs2493132 CT + TT genotype was an important risk factor for CAD in patients with NAFLD and NAFLD + CAD in healthy controls. The AGT rs2493132 T allele increased the risk of NAFLD + CAD in healthy controls. The AGT rs2493132 CT + TT genotype and T allele also significantly increased the risk of CAD in patients with NAFLD after adjustments for age, sex, and body mass index. In addition, AGT rs2493132 T allele carriers showed higher total cholesterol (TC) and low-density lipoprotein (LDL) levels compared with non-carriers. CONCLUSIONS: The AGT rs2493132 CT + TT genotype and T allele significantly increased the risk of developing CAD in patients with NAFLD in the Chinese Han population. The AGT rs2493132 T allele was associated with increased serum TC and LDL levels.

Roles and regulatory mechanisms of miR-30b in cancer, cardiovascular disease, and metabolic disorders (Review).

MicroRNAs (miRNAs) are non-coding RNAs 21-23 nucleotides in length that regulate gene expression, and thereby modulate signaling pathways and protein synthesis in both physiological and pathogenic processes. miR-30b inhibits cell proliferation, migration, invasion and epithelial-mesenchymal transformation in multiple types of cancer. In addition to its role in several types of neoplasias, miR-30b has been shown to exhibit essential roles in cardiovascular and metabolic diseases. In the present review, an overview of the biological functions of miR-30b and its role in the pathogenesis of neoplastic, cardiovascular and metabolic diseases is provided. miR-30b is a potential candidate for clinical development as a diagnostic and prognostic biomarker, therapeutic agent and drug target. However, further research is required to elucidate its role in health and disease and to harness its potential clinical utility.

ACE2, TMPRSS2 distribution and extrapulmonary organ injury in patients with COVID-19.

At the end of 2019, the coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China. Currently, it is breaking out globally and posing a serious threat to public health. The typically clinical characteristics of COVID-19 patients were fever and respiratory symptoms, and a proportion of patients were accompanied by extrapulmonary symptoms including cardiac injury, kidney injury, liver injury, digestive tract injury, and neurological symptoms. Angiotensin converting enzyme 2 (ACE2) has been proven to be a major receptor for SARS-CoV-2 and could mediate virus entry into cells. And transmembrane protease serine 2 (TMPRSS2) could cleave the spike (S) protein of SARS-CoV-2, which facilitates the fusion of SARS-CoV-2 and cellular membranes. The mRNA expressions of both ACE2 and TMPRSS2 were observed in the heart, digestive tract, liver, kidney, brain and other organs. SARS-CoV-2 may have a capacity to infect extrapulmonary organs due to the expressions of ACE2 and TMPRSS2 in the cells and tissues of these organs. It seems that there is a potential involvement of ACE2 and TMPRSS2 expressions in the virus infection of extrapulmonary organs and the manifestation of symptoms related to these organs in patients with COVID-19. Here, we revealed the expressions of ACE2 and TMPRSS2 in extrapulmonary organs, and we also summarized the clinical manifestation and the management of extrapulmonary complications in patients with COVID-19.

The association between SNPs rs1800591 and rs3816873 of the MTTP gene and nonalcoholic fatty liver disease: A meta-analysis.

BACKGROUND/AIMS: : The role of two polymorphisms rs1800591 and rs3816873 of the microsomal triglyceride transfer protein (MTTP) gene in the development of nonalcoholic fatty liver disease (NAFLD) remains controversial. A meta-analysis was conducted to determine the correlation between these MTTP polymorphisms and NAFLD. MATERIALS AND METHODS: : A systematic search was carried out using PubMed, Embase, and Cochrane Library to retrieve English studies that reported the relationship between MTTP polymorphisms (rs1800591 and rs3816873) and NAFLD published before February 18, 2020. Odds ratio (OR) and 95% confidence interval (CI) were used to appraise the risk of MTTP polymorphism in NAFLD. RESULTS: : A total of 10 case-control studies, including 1388 cases and 1690 healthy subjects, were included. No significant correlation between the rs1800591 (G vs. T: OR = 1.08, 95% CI = 0.68-1.70, P = 0.76) and rs3816873 (CT + CC vs. TT: OR = 1.23, 95% CI = 0.76-2.01, P = 0.398) polymorphisms of MTTP and NAFLD was found in any of the models. However, when NASH patients confirmed by liver biopsy were extracted alone for rs1800591 polymorphism analysis, it was found that the G allele significantly increased the risk of NASH under the heterozygote model (GT vs. TT: OR = 3.16, 95% CI = 1.13-8.83, P = 0.028) and dominant model (GT + GG vs. TT: OR = 3.03, 95% CI = 1.13-8.09, P = 0.027). CONCLUSION: The present meta-analysis revealed that the rs1800591 and rs3816873 polymorphisms of the MTTP gene are uncommon in NAFLD. However, the G allele of rs1800591 was more likely to be correlated to NASH susceptibility.

Association between nonalcoholic fatty liver disease and extrahepatic cancers: a systematic review and meta-analysis.

BACKGROUND: NAFLD is tightly associated with various diseases such as diabetes, cardiovascular disease, kidney disease, and cancer. Previous studies had investigated the association between NAFLD and various extrahepatic cancers, but the available data to date is not conclusive. The aim of this study was to investigate the association between NAFLD and various extrahepatic cancers comprehensively. METHODS: Searches were conducted of various electronic databases (PubMed, EMBASE, Medline, and the Cochrane Library) to identify observational studies published between 1996 and January 2020 which investigated the association between NAFLD and extrahepatic cancers. The pooled OR/HR/IRR of the association between NAFLD and various extrahepatic cancers were analyzed. RESULTS: A total of 26 studies were included to investigate the association between NAFLD and various extrahepatic cancers. As the results shown, the pooled OR values of the risk of colorectal cancer and adenomas in patients with NAFLD were 1.72 (95%CI: 1.40-2.11) and 1.37 (95%CI: 1.29-1.46), respectively. The pooled OR values of the risk of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma in patients with NAFLD were 2.46 (95%CI: 1.77-3.44) and 2.24 (95%CI: 1.58-3.17), respectively. The pooled OR value of the risk of breast cancer in patients with NAFLD was 1.69 (95%CI: 1.44-1.99). In addition, NAFLD was also tightly associatied with the risk of gastric cancer, pancreatic cancer, prostate cancer, and esophageal cancer. CONCLUSIONS: NAFLD could significantly increase the development risk of colorectal adenomas and cancer, intrahepatic and extrahepatic cholangiocarcinoma, breast, gastric, pancreatic, prostate, and esophageal cancer. NAFLD could be considered as one of the influencing factors during the clinical diagnosis and treatment for the extrahepatic cancers.

MiR-30b-5p regulates the lipid metabolism by targeting PPARGC1A in Huh-7 cell line.

BACKGROUND: MiRNAs are a group of multifunctional non-coding RNAs which play an important role in the various physiological processes including the development of NAFLD. Recent studies have shown that miR-30b-5p tightly associated with the abnormal lipid metabolism in patients with NAFLD, but the detailed mechanism of miR-30b-5p in the lipid metabolism was remain unclear. The aim of this study was to investigate the effect of miR-30b-5p on the lipid metabolism in hepatocellular carcinoma Huh-7 cells. MATERIAL AND METHODS: The correlation of intracellular fat content with the expression of miR-30b-5p in Huh-7 cells and HepG2 cells was investigated by treated cells with different concentrations of FFAs. The effect of miR-30b-5p on the lipid deposition in Huh-7 cells was tested by oil red O staining and TG concentrations measurement. qRT-PCR and western blot were used to investigate the lipid metabolism-related genes PPAR-α, SREBP-1, and GULT1 in miR-30b-5p overexpressed or inhibited Huh-7 cells. Target genes of miR-30b-5p were predicted using starBase, miRDB, and TargetScan databases and verified by qRT-PCR and western blot. RESULTS: The expression of miR-30b-5p was significant decreased in the FFAs treated Huh-7 cells and HepG2 cells. Overexpressing miR-30b-5p in Huh-7 cells decreased the number and size of lipid droplets and intracellular TG concentrations in Huh-7 cells. Expression of fatty acid oxidation related gene PPAR-α was increased and expression of lipid synthesis related gene SREBP-1 was decreased in the miR-30b-5p overexpressed Huh-7 cells. In addition, miR-30b-5p regulates the intracellular lipid metabolism by targeting PPARGC1A. CONCLUSIONS: Overexpression of miR-30b-5p could reduce the intracellular fat deposition in Huh-7 cells, and miR-30b-5p might regulate the intracellular lipid metabolism by targeting the PPARGC1A in Huh-7 cells.

Proportion of NAFLD patients with normal ALT value in overall NAFLD patients: a systematic review and meta-analysis.

BACKGROUND: ALT value is often used to reflect the hepatic inflammation and injury in NAFLD patients, but many studies proved that ALT values were normal in many NAFLD patients. The aim of this study was to identify the summarized proportion of NAFLD patients with normal ALT value in the overall NAFLD patients. METHODS: Electronic databases PubMed, EMBASE, Ovid, and the Cochrane Library were searched for potential studies published from January 1, 2000 to September 30, 2019. Studies that have reported the number of NAFLD or NASH patients with normal and abnormal ALT value were included and analyzed. Abstracts, reviews, case reports, and letters were excluded. RESULTS: A total of 11 studies with 4084 patients were included for assessing the summarized proportion of NAFLD patients with normal ALT in overall NAFLD patients. As the results shown, the summarized proportion of NAFLD patients with normal ALT value in overall NAFLD patients was 25% (95%CI: 20-31%) which was calculated by the random-effects model. The summarized proportion of NASH patients with normal ALT value in overall NASH patients was 19% (95%CI: 13-27%). Subgroup analysis includes region, study type, diagnostic method, and group size were conducted to investigate the resource of heterogeneity in the summarized proportion of NAFLD and NASH patients with normal ALT value. CONCLUSIONS: 25% NAFLD patients and 19% NASH patients possess the normal ALT value in the clinical manifestation. The value of ALT in the clinical diagnosis of NAFLD and NASH remains need be further testified.