Identification and utility exploration of a highly potent and long-acting bullfrog GLP-1 analogue in GLP-1 and amylin combination therapy.

This study assesses the efficacy of an innovative therapeutic approach that combines GLP-1 and amylin analogues for weight reduction. Focusing on GLP-1 analogues from bullfrog (Rana catesbeiana), we designed ten bGLP-1 analogues with various modifications. Among them, bGLP-10 showed high potency in binding and activating GLP-1 receptors, with superior albumin affinity. In diet-induced obesity (DIO) mice fed a high-fat diet, bGLP-10 demonstrated significant superiority over semaglutide in reducing blood sugar and food intake at a dose of 10 nmol/kg (P < 0.001). Notably, in a chronic study involving DIO mice, the combination of bGLP-10 with the amylin analogue cagrilintide led to a more substantial weight loss (-38.4%, P < 0.001) compared to either the semaglutide-cagrilintide combination (-23.0%) or cagrilintide (-5.7%), bGLP-10 (-16.1%), and semaglutide (-10.9%) alone. Furthermore, the bGLP-10 and cagrilintide combination exhibited superior glucose control and liver lipid management compared to the semaglutide-cagrilintide combination (P < 0.001). These results highlight bGLP-10's potential in GLP-1 and amylin-based therapies and suggest exploring more GLP-1 analogues from natural sources for anti-obesity and anti-diabetic treatments.

m6A-induced TRIB3 regulates Hippo pathway through interacting with LATS1 to promote the progression of lung adenocarcinoma.

Recent studies have indicated that dysregulation of the Hippo/Yes-associated protein (YAP) axis is associated with tumor progression and therapy resistance in various cancer types, including lung adenocarcinoma (LUAD). Understanding the regulation of Hippo signaling in LUAD is of great significance. Elevated levels of TRIB3, a pseudo kinase, have been observed in certain lung malignancies and are associated with an unfavorable prognosis. Our research aims to investigate whether increased TRIB3 levels enhance the malignant characteristics of LUAD cells and tumor progression through its interaction with the Hippo signaling pathway. In this study, we reported a positive correlation between elevated expression of TRIB3 and LUAD progression. Additionally, TRIB3 has the ability to enhance TEAD luciferase function and suppress Hippo pathway activity. Moreover, TRIB3 increases total YAP protein levels and promotes YAP nuclear localization. Mechanistic experiments revealed that TRIB3 directly interacts with large tumor suppressor kinase 1 (LATS1), thereby suppressing Hippo signaling. Moreover, the decrease in METTL3-mediated N6-methyladenosine modification of TRIB3 results in a substantial elevation of its expression levels in LUAD cells. Collectively, our research unveils a novel discovery that TRIB3 enhances the growth and invasion of LUAD cells by interacting with LATS1 and inhibiting the Hippo signaling pathway. TRIB3 may serve as a potential biomarker for an unfavorable prognosis and a target for novel treatments in YAP-driven lung cancer.

Ailanthone synergizes with PARP1 inhibitor in tumour growth inhibition through crosstalk of DNA repair pathways in gastric cancer.

In our previous research, we proved that ailanthone (AIL) inhibits the growth of gastric cancer (GC) cells and causes apoptosis by inhibiting P23. However, we still find some GC organoids are insensitive to AIL. We have done some sequencing analysis and found that the insensitive strains are highly expressed in PARP1. In this study, we investigated whether AIL can enhance the anti-tumour effect of PARPi in GC. CCK8 and spheroid colony formation assay were used to measure anti-tumour effects. SynergyFinder software was used to calculate the synergy score of the drug combination and flow cytometry was used to detect apoptosis. Western blot, IHC, IF tests were used to measure protein expression. Finally, nude mouse xenograft models were used to verify the in vitro mechanisms. High expression of PARP1 was found to be the cause of drug insensitivity. When AIL is paired with a PARP1 inhibitor, olaparib (OLP), drug sensitivity improves. We discovered that this combination functions by blocking off HSP90-BRCA1 interaction and inhibiting the activity of PARP1, thus in turn inhibiting the homologous recombination deficiency and base excision repair pathway to finally achieve synthetic lethality through increased sensitivity. Moreover, P23 can regulate BRCA1 in GC in vitro. This study proves that the inhibitory effect of AIL on BRCA1 allowed even cancer cells with normal BRCA1 function to be sensitive to PARP inhibitors when it is simultaneously administered with OLP. The results greatly expanded the scope of the application of PARPi.

Design, synthesis, and biological evaluation of novel capsaicin-tacrine hybrids as multi-target agents for the treatment of Alzheimer's disease.

A series of novel hybrid compounds were designed, synthesized, and utilized as multi-target drugs to treat Alzheimer's disease (AD) by connecting capsaicin and tacrine moieties. The biological assays indicated that most of these compounds demonstrated strong inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities with IC50 values in the nanomolar, as well as good blood-brain barrier permeability. Among the synthesized hybrids, compound 5s displayed the most balanced inhibitory effect on hAChE (IC50 = 69.8 nM) and hBuChE (IC50 = 68.0 nM), and exhibited promising inhibitory activity against ß-secretase-1 (BACE-1) (IC50 = 3.6 µM). Combining inhibition kinetics and molecular model analysis, compound 5s was shown to be a mixed inhibitor affecting both the catalytic active site (CAS) and peripheral anionic site (PAS) of hAChE. Additionally, compound 5s showed low toxicity in PC12 and BV2 cell assays. Moreover, compound 5s demonstrated good tolerance at the dose of up to 2500 mg/kg and exhibited no hepatotoxicity at the dose of 3 mg/kg in mice, and it could effectively improve memory ability in mice. Taken together, these findings suggest that compound 5s is a promising and effective multi-target agent for the potential treatment of AD.

Identification of Cuproptosis-Related Genes in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent hepatic pathology worldwide. However, the precise molecular mechanisms for NAFLD are still not sufficiently explained. Recently, a new mode of cell death (cuproptosis) is found. However, the relationship between NAFLD and cuproptosis remains unclear. We analyzed three public datasets (GSE89632, GSE130970, and GSE135251) to identify cuproptosis-related genes stably expressed in NAFLD. Then, we performed a series of bioinformatics analyses to explore the relationship between NAFLD and cuproptosis-related genes. Finally, 6 high-fat diet- (HFD-) induced NAFLD C57BL/6J mouse models were established to carry out transcriptome analysis. The results of gene set variation analysis (GSVA) revealed that the cuproptosis pathway was abnormally activated to a certain degree (p = 0.035 in GSE89632, p = 0.016 in GSE130970, p = 0.22 in GSE135251), and the principal component analysis (PCA) of the cuproptosis-related genes showed that the NAFLD group separated from the control group, with the first two principal components accounting for 58.63%-74.88% of the variation. Among three datasets, two cuproptosis-related genes (DLD and PDHB, p < 0.01 or 0.001) were stably upregulated in NAFLD. Additionally, both DLD (AUC = 0.786-0.856) and PDHB (AUC = 0.771-0.836) had favorable diagnostic properties, and the multivariate logistics regression model further improved the diagnostic properties (AUC = 0.839-0.889). NADH, flavin adenine dinucleotide, and glycine targeted DLD, and pyruvic acid and NADH targeted PDHB in the DrugBank database. The DLD and PDHB were also associated with clinical pathology, especially with steatosis (DLD, p = 0.0013-0.025; PDHB, p = 0.002-0.0026) and NAFLD activity score (DLD, p = 0.004-0.02; PDHB, p = 0.003-0.031). What is more, DLD and PDHB were correlated with stromal score (DLD, R = 0.38, p < 0.001; PDHB, R = 0.31, p < 0.001) and immune score (DLD, R = 0.26, p < 0.001; PDHB, R = 0.27, p < 0.001) in NAFLD. Furthermore, Dld and Pdhb were also significantly upregulated in the NAFLD mouse model. In conclusion, cuproptosis pathways, especially DLD and PDHB, could be potential candidate genes for NAFLD diagnostic and therapeutic options.

Identification of potential biomarkers in Barrett's esophagus derived esophageal adenocarcinoma.

Almost 50% of esophageal adenocarcinoma (EAC) patients progressed from Barrett's esophagus (BE). EAC is often diagnosed at late stages and is related to dismal prognosis. However, there are still no effective methods for stratification and therapy in BE and EAC. Two public datasets (GSE26886 and GSE37200) were analyzed to identify differentially expressed genes (DEGs) between BE and EAC. Then, a series of bioinformatics analyses were performed to explore potential biomarkers associated with BE-EAC. 27 up- and 104 down-regulated genes were observed between GSE26886 and GSE37200. The GO and KEGG enrichment analysis indicated that the DEGs were highly involved in tumorigenesis. Subsequently, Weighted Gene Co-Expression Network Analysis (WGCNA) were performed to explore the potential genes related to BE-EAC, which were validated in The Cancer Genome Atlas (TCGA) database, and 5 up-regulated genes (MYO1A, ACE2, COL1A1, LGALS4, and ADRA2A) and 3 down-regulated genes (AADAC, RAB27A, and P2RY14) were found in EAC. Meanwhile, ADRA2A and AADAC could contribute to EAC pathogenesis and progression. MYO1A, ACE2, COL1A1, LGALS4, ADRA2A, AADAC, RAB27A, and P2RY14 could be potential novel diagnostic and prognostic biomarkers in BE-EAC.

A new pyroptosis-related signature for predicting the immune status and injury of liver ischemia-reperfusion.

OBJECTIVE: Pyroptosis is a type of programmed cell death. This study aimed to explore the roles of key pyroptosis-related genes in liver ischemia-reperfusion injury. METHODS: After collection and standardization of the transcriptome data from GSE12720 database, differentially expressed pyroptosis-related genes were identified. The risk genes screened by a random forest model were used to establish the line graph model. Consensus clustering was used to classify all samples according to the differentially expressed pyroptosis-related genes. Single-sample Gene Set Enrichment Analysis (ssGSEA) was performed to investigate the immune cell infiltration after hepatic ischemia-reperfusion. Cytoscape was used to visualize the regulatory network of transcription factor (TF)-microRNA (miRNA)-target genes. RESULTS: We identified 18 significantly and differentially expressed pyroptosis-related genes between the disease and normal samples. Among these 18 genes, IL1ß was positively correlated with CXCL8 (r = 0.791) and BIRC3 (r = 0.78), while ADORA3 was negatively correlated with GZMB (r = -0.567) and CXCL8 (r = -0.566). Furthermore, the random forest model constructed using the top 10 pyroptosis-related genes could predict the risk of hepatic ischemia-reperfusion. Importantly, the decision curve analysis showed that patients could benefit from the risk prediction model. Moreover, we found that the expression of TXNIP, IRF1, and GJA1 was the mostly regulated by miRNAs, while the expression of BIRC3, NFκB1, and TXNIP was regulated by the TF RELA. RELA had the most hub genes involved in the regulation. CONCLUSION: Our study provides an overview of the expression landscape and the functional significance of pyroptosis-related genes in liver ischemia-reperfusion. Our findings also shed light on the clinical application of pyroptosis-related genes in the treatment of hepatic ischemia-reperfusion injury.

CUL4B increases platinum-based drug resistance in colorectal cancer through EMT: A study in its mechanism.

Platinum-based chemotherapy drugs play a very important role in the treatment of patients with advanced colorectal cancer, but the drug resistance of platinum-based chemotherapy drugs is an important topic that puzzles us. If we can find mechanisms of resistance, it will be revolutionary for us. We analysed the differential genes, core genes and their enrichment pathways in platinum-resistant and non-resistant patients through a public database. Platinum-resistant cell lines were cultured in vitro for in vitro colony and Transwell analysis. Tumorigenesis analysis of nude mice in vivo. Verify the function of core genes. Through differential gene and enrichment analysis, we found that CUL4B was the main factor affecting platinum drug resistance and EMT. Our hypothesis was further verified by in vitro drug-resistant and wild-type cell lines and in vivo tumorigenesis analysis of nude mice. CUL4B leads to platinum drug resistance in colorectal cancer by affecting tumour EMT.

Preclinical findings: The pharmacological targets and molecular mechanisms of ferulic acid treatment for COVID-19 and osteosarcoma via targeting autophagy.

The variant virus-based 2019 coronavirus disease (COVID-19) pandemic has reportedly impacted almost all populations globally, characterized by a huge number of infected individuals. Clinical evidence proves that patients with cancer are more easily infected with severe acute respiratory disease coronavirus 2 (SARS-CoV-2) because of immunologic deficiency. Thus, there is an urgent need to develop candidate medications to treat patients with cancer plus COVID-19, including those with osteosarcoma (OS). Ferulic acid, a latent theriacal compound that has anti-tumor and antivirus activities, is discovered to have potential pharmacological use. Thus, in this study, we aimed to screen and determine the potential therapeutic targets of ferulic acid in treating patients with OS plus COVID-19 as well as the pharmacological mechanisms. We applied a well-established integrated methodology, including network pharmacology and molecular docking technique, to detail target prediction, network construction, gene ontology, and pathway enrichment in core targets. The network pharmacology results show that all candidate genes, by targeting autophagy, were the core targets of ferulic acid in treating OS and COVID-19. Through molecular docking analysis, the signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase 1 (MAPK1), and phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) were identified as the pharmacological targets of ferulic acid in treating OS. These preclinical findings from bioinformatics analysis altogether effectively determined the pharmacological molecules and mechanisms via targeting autophagy, demonstrating the therapeutic effectiveness of ferulic acid against COVID-19 and OS.

circ_PTN contributes to -cisplatin resistance in glioblastoma via PI3K/AKT signaling through the miR-542-3p/PIK3R3 pathway.

Glioblastoma has been identified as the most common and aggressive primary brain tumor in adults. Recently, it has been found that cisplatin (DDP) treatment is a common chemotherapeutic method for GBM patients. circ_PTN (ID number: hsa_circ_0003949) is a newly found circular (circRNA) which has been proved to be highly expressed in GBM cells, while its role in GBM remains unclear. Therefore, our study focused on investigating the role of circ_PTN in the DDP resistance of GBM cells. The expression of circ_PTN in DDP-sensitive and DDP-resistant GBM cells was detected in our assay. Functional experiments were utilized to unveil the effects of circ_PTN on the DDP resistance of GBM cells. Moreover, mechanism assays were conducted to confirm the mechanism of how circ_PTN affected the DDP resistance of GBM cells. According to the results, we found that circ_PTN promoted the DDP resistance of GBM cells through activation of the PI3K/AKT pathway. Moreover, circ_PTN silencing inhibited the DDP resistance of GBM tumors in vivo. To conclude, our study unveiled the influence of circ_PTN on the DDP resistance of GBM cells, which might provide a therapeutic target for GBM treatment via DDP.

lncRNA PRR34-AS1 promotes HCC development via modulating Wnt/ß-catenin pathway by absorbing miR-296-5p and upregulating E2F2 and SOX12.

Hepatocellular carcinoma (HCC) belongs to the most frequent cancer with a high death rate worldwide. Thousands of long non-coding RNAs (lncRNAs) have been confirmed to influence the development of human cancers, including HCC. Nevertheless, the biological role of PRR34 antisense RNA 1 (PRR34-AS1) in HCC remains obscure. Here, we observed via quantitative real-time reverse transcriptase polymerase chain reaction (quantitative real-time RT-PCR) that PRR34-AS1 was highly expressed in HCC cells. Functional assays revealed that PRR34-AS1 promoted HCC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) process in vitro and facilitated tumor growth in vivo. In addition, western blot analysis and TOP Flash/FOP Flash reporter assays verified that PRR34-AS1 stimulated Wnt/ß-catenin pathway in HCC cells. Furthermore, RNA immunoprecipitation (RIP), RNA pull-down, and luciferase reporter assays uncovered that PRR34-AS1 sequestered microRNA-296-5p (miR-296-5p) to positively modulate E2F transcription factor 2 (E2F2) and SRY-box transcription factor 12 (SOX12) in HCC cells. Importantly, chromatin immunoprecipitation (ChIP) and luciferase reporter assays uncovered that E2F2 transcriptionally activated PRR34-AS1 in turn. Further, rescue experiments reflected that PRR34-AS1 affected HCC progression through targeting miR-296-5p/E2F2/SOX12/Wnt/ß-catenin axis. Our findings found that PRR34-AS1 elicited oncogenic functions in HCC, which indicated that PRR34-AS1 might be a novel therapeutic target for HCC.

Association of cytotoxic T lymphocyte-associated protein 4 gene -1772T/C polymorphism with gastric cancer risk: A prisma-compliant meta-analysis.

BACKGROUND: We performed a meta-analysis to more precisely evaluate the association between the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) -1772T/C polymorphism and overall gastric cancer (GC) risk and the influence of ethnicity and the source of controls on that association. METHODS: A systematic literature search was performed in PubMed, EMBASE, the Cochrane Library, Web of Science (WOS) Database, Chinese National Knowledge Infrastructure (CNKI), China biomedical literature database (CBM), Wanfang database, and VIP. Two investigators independently reviewed the articles, and disagreements were resolved by discussion and consensus. The odds ratio (OR) with 95% confidence intervals (CIs) was used to assess the strength of the association between the CTLA-4 -1722T/C polymorphism and GC risk, based on the genotype frequencies in cases and controls. The meta-analyses were performed with Stata 12.0, using two-sided P values. Trial sequential analysis (TSA) was calculated by TSA Software. RESULTS: Overall, we identified 5 studies including 1039 GC cases and 2136 controls that evaluated the association of the CTLA-4 -1722T/C polymorphism and GC risk. Overall, there was no significant association between the CTLA-4-1722T/C polymorphism and the risk of GC. In the subgroup analysis based on ethnicity, the results showed that the relationship between the CTLA-4 -1722T/C polymorphism and GC susceptibility was strongest in the Chinese population rather than in the Iranian population (TC vs CC: OR = 1.405, 95% CI: 1.100-1.796, P = .007; TC+TT vs CC: OR = 1.329, 95% CI: 1.052-1.680, P = .017). Then, there was a significant association between the CTLA-4 -1722T/C polymorphism and the risk of GC in studies with HB controls. However, the above correlation can only be reflected in specific populations and gene models. Therefore, we believe that the evidence of this correlation is insufficient. CONCLUSION: Our meta-analysis showed that the CTLA-4 -1722T/C polymorphism may be associated with the susceptibility to GC. However, the slight correlation can only be reflected in specific populations and gene models. Therefore, we believe that this association is negligible. The large and well-designed case-control studies are needed to validate our findings.

LncRNA LL22NC03-N14H11.1 promoted hepatocellular carcinoma progression through activating MAPK pathway to induce mitochondrial fission.

Involvement of long non-coding RNAs (lncRNAs) in hepatocarcinogenesis has been largely documented. Mitochondrial dynamics is identified to impact survival and metastasis in tumors including hepatocellular carcinoma (HCC), but the underlying mechanism remains poorly understood. This study planned to explore the regulation of lncRNA LL22NC03-N14H11.1 on HCC progression and mitochondrial fission. Dysregulated lncRNAs in HCC are identified through circlncRNAnet and GEPIA bioinformatics tools. Biological function of LL22NC03-N14H11.1 in HCC was detected by CCK-8 assay, flow cytometry analysis, transwell invasion, and wound healing assays. Molecular interactions were determined by RNA immunoprecipitation, RNA pull-down, and co-immunoprecipitation assays. Results showed that LL22NC03-N14H11.1 was upregulated in HCC tissues and cells. Functionally, LL22NC03-N14H11.1 contributed to cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT) in HCC. Moreover, LL22NC03-N14H11.1 facilitated mitochondrial fission in HCC cells. Mechanistically, LL22NC03-N14H11.1 recruited Myb proto-oncogene (c-Myb) to repress the transcription of leucine zipper-like transcription regulator 1 (LZTR1), so as to inhibit LZTR1-mediated ubiquitination of H-RAS (G12V), leading to the activation of mitogen-activated protein kinase (MAPK) signaling and induction of p-DRP1 (Serine 616). In conclusion, this study firstly revealed that lncRNA LL22NC03-N14H11.1 promoted HCC progression through activating H-RAS/MAPK pathway to induce mitochondrial fission, indicating LL22NC03-N14H11.1 as a novel potential biomarker for HCC treatment.

Role of long noncoding RNA MEG3/miR-378/GRB2 axis in neuronal autophagy and neurological functional impairment in ischemic stroke.

Autophagy has been shown to maintain neural system homeostasis during stroke. However, the molecular mechanisms underlying neuronal autophagy in ischemic stroke remain poorly understood. This study aims to investigate the regulatory mechanisms of the pathway consisting of MEG3 (maternally expressed gene 3), microRNA-378 (miR-378), and GRB2 (growth factor receptor-bound protein 2) in neuronal autophagy and neurological functional impairment in ischemic stroke. A mouse model of the middle cerebral artery occluded-induced ischemic stroke and an in vitro model of oxygen-glucose deprivation-induced neuronal injury were developed. To understand the role of the MEG3/miR-378/GRB2 axis in the neuronal regulation, the expression of proteins associated with autophagy in neurons was measured by Western blotting analysis, and neuron death was evaluated using a lactate dehydrogenase leakage rate test. First, it was found that the GRB2 gene, up-regulated in middle cerebral artery occluded-operated mice and oxygen-glucose deprivation-exposed neurons, was a target gene of miR-378. Next, miR-378 inhibited neuronal loss and neurological functional impairment in mice, as well as neuronal autophagy and neuronal death by silencing of GRB2. Confirmatory in vitro experiments showed that MEG3 could specifically bind to miR-378 and subsequently up-regulate the expression of GRB2, which in turn suppressed the activation of Akt/mTOR pathway. Taken together, these findings suggested that miR-378 might protect against neuronal autophagy and neurological functional impairment and proposed that a MEG3/miR-378/GRB2 regulatory axis contributed to better understanding of the pathophysiology of ischemic stroke.

Exosomal linc-FAM138B from cancer cells alleviates hepatocellular carcinoma progression via regulating miR-765.

Exosomes are small vesicles with a diameter of 30-150 nm secreted by cells, which can be used as signal carriers to transfer nucleic acids, proteins, lipids and other functional substances to the recipient cells and play a role in cell communication. Hepatocellular carcinoma is the fourth most common cause of cancer-related death worldwide. Studies have shown that long non-coding RNAs (lncRNAs) are involved in the development and progression of many types of tumors. Our present study found that linc-FAM138B was reduced in HCC tissues and cell lines, low expression of linc-FAM138B indicated a poor prognosis in HCC patients. Interestingly, linc-FAM138B could be packaged into cancer cells. And exo-FAM138B inhibited the proliferation, migration and invasion of HCC cells. Furthermore, linc-FAM138B sponged miR-765 levels. And exo-si-FAM138B promoted HCC progression, while deletion of miR-765 reversed the role of exo-si-FAM138B. In vivo tumorigenesis experiments showed that exo-FAM138B suppressed HCC growth via modulating miR-765. In conclusion, exo-linc-FAM138B secreted by cancer cells inhibited HCC development via targeting miR-765, which provided a new idea and perspective for in-depth understanding of the complex signal regulation in HCC process.

Long noncoding RNA 91H overexpression contributes to the growth and metastasis of HCC by epigenetically positively regulating IGF2 expression.

BACKGROUND & AIMS: Long noncoding RNA 91H is transcribed from the H19/IGF2 locus and contributes to the development of breast and oesophagus cancers by regulating the expression of IGF2, but the regulation mechanism remains poorly characterized. Here, we explored the role of 91H in hepatocellular carcinoma (HCC) and the mechanism of IGF2 expression regulation by 91H. METHODS: Firstly, the expression of 91H was analysed in HCC by quantitative RT-PCR, the association of 91H with survival was evaluated by the Kaplan-Meier method and the effect of 91H on the growth and invasion of HCC was investigated by the in vitro and in vivo studies. Then, the association of 91H with the expression of IGF2 was evaluated in HCC tissues, and the effect of 91H on the expression of IGF2 was investigated by 91H knockdown. Finally, the binding of RBBP5 to 91H and the binding of RBBP5, activating H3K4me3 mark and repressive H3K27me3 mark to the P3 and P4 promoters of IGF2 gene were studied by RIP and ChIP respectively. RESULTS: The overexpression of 91H was found in HCC and in association with the growth, metastasis and shorter survival time of HCC. The knockdown of 91H down-regulated the IGF2 expression in HCC, and the mechanism was correlated with the decreased enrichment of RBBP5 and H3K4me3 and increased enrichment of H3K27me3 at the bivalent P3 and P4 promoters. CONCLUSIONS: The overexpression of 91H promotes tumour growth and metastasis, and is associated with a poor prognosis of HCC at least partially by positively regulating the expression of IGF2 through bivalent histone modification changes characterized by H3K4me3 and H3K27me3 at the P3 and P4 promoters.

MiR-483-5p promotes IGF-II transcription and is associated with poor prognosis of hepatocellular carcinoma.

The human insulin-like growth factor-II (IGF-II) gene transcribes four mRNAs (P1 mRNA-P4 mRNA), and P3 mRNA overexpression contributes to hepatocarcinogenesis. IGF-II-derived miR-483-5p is implicated in the development of cancers. Here, we investigated the involvement of miR-483-5p in P3 mRNA overexpression regulation and its role in hepatocellular carcinoma. Our results showed that miR-483-5p up-regulated P3 mRNA transcription by targeting the 5'-untranslated region (5'UTR) of P3 mRNA in hepatocellular carcinoma. The mechanism was involved in recruiting of an argonaute 1(Ago1)-argonaute 2 (Ago2) complex to the P3 mRNA 5'UTR and the P3 promoter of IGF-II gene by miR-483-5p, accompanied by increased enrichment of RNA polymerase II and activating histone marks histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 27 acetylation (H3K27ac), and histone 4 lysine 5/8/12/16 acetylation (H4Kac) at the P3 promoter. High miR-483-5p expression was an independent predictor for shorter survival of HCC patients. The findings suggest that miR-483-5p promotes P3 mRNA transcription by recruiting the Ago1-Ago2 complex to the P3 mRNA 5'UTR and is associated with poor prognosis of HCC. Our results display a potential new model for miRNAs to up-regulate gene expression.

Alcohol consumption and risk of fatty liver disease: a meta-analysis.

BACKGROUND: Observational studies have shown inconsistent results regarding alcohol consumption and risk of fatty liver. We performed a meta-analysis of published literature to investigate the association between alcohol consumption and fatty liver disease (FLD). METHODS: We searched Medline, Embase, Web of Science, and several Chinese databases, identifying studies that reported an association between alcohol consumption and the risk of FLD. RESULTS: A total of 16 studies with 76,608 participants including 13 cross-sectional studies, two cross-sectional following longitudinal studies, and one cohort study met the inclusion criteria. For light to moderate alcohol consumption (LMAC), there was a 22.6% reduction in risk of FLD (odds ratio [OR] = 0.774, 95% confidence interval CI [0.695-0.862], P <0.001), and subgroup analysis showed that a greater reduction in risk of FLD was found in the female drinkers (30.2%) and the drinkers with BMI ≥25 kg/m2(31.3%) compared with the male drinkers (22.6%) and the drinkers with BMI <25 kg/m2(21.3%), respectively. For heavy alcohol consumption, there was no significant influence on risk of FLD (OR = 0.869, 95% CI [0.553-1.364], P = 0.541) in Japanese women, but there was a 33.7% reduction in risk of FLD (OR = 0.663, 95% CI [0.574-0.765], P < 0.001) in Japanese men and a significant increased risk of FLD (OR = 1.785, 95% CI [1.064-2.996], P = 0.028) in Germans. CONCLUSION: LMAC is associated with a significant protective effect on FLD in the studied population, especially in the women and obese population. However, the effect of heavy alcohol consumption on FLD remains unclear due to limited studies and small sample sizes.