Partial hepatectomy (PH) promotes the reentry of quiescent hepatocytes into cell cycle for regrowth. miRNA profiles in livers with different mass deficits after PH have not been investigated and miRNAs implicated in liver regeneration remain unclear. We generated miRNA profiles from normal and remnant livers at 6, 12, 24, and 36 hours after 1/3 or 2/3PH using microarrays. Compared with normal livers, the proportion of altered miRNAs decreased with time after 1/3PH, but increased after 2/3PH. Most of altered miRNAs between 1/3 and 2/3PH exhibited similar up- or down-regulation, but lower expression magnitude for 1/3PH. Among differentially expressed miRNAs between 2/3PH with robust DNA replication and 1/3PH with a minimal replicative response, we identified miR-101a, miR-92a, miR-25, miR-93 and miR-106b as key regulators of cell cycle. In 2/3PH model, overexpression of miR-106b~25 cluster tended to accelerate liver regeneration, while inhibition of miR-106b~25 cluster markedly repressed regenerative response and delayed recovery of liver function. Mechanistically, RB1 and KAT2B with cell cycle arrest activity were identified as novel targets of miR-106b/93 and miR-25, respectively. Overall, we featured miRNA profiles and dynamics after 1/3 and 2/3PH, and identified miR-106b~25 cluster as being involved in timely cell cycle entry of hepatocytes after PH.

The number of percutaneous coronary interventions (PCI) in China has increased more than 20-fold over the last decade. Consequently, there is a need for national-level information to characterize PCI indications and long-term patient outcomes, including health status, to understand and improve evolving practice patterns.

Transcription factor CP2 (TFCP2) is overexpressed in hepatocellular carcinoma(HCC) and correlated with the progression of the disease. Here we report the use of an integrated systems biology approach to identify genome-wide scale map of TFCP2 targets as well as the molecular function and pathways regulated by TFCP2 in HCC.

Amid national efforts to improve the quality of care for people with cardiovascular disease in China, the use of traditional Chinese medicine (TCM) is increasing, yet little is known about its use in the early management of acute myocardial infarction (AMI).

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

In this prospective study, 36 patients with stage III non-small cell lung cancers (NSCLC), who underwent dynamic contrast-enhanced MRI (DCE-MRI) before concurrent chemo-radiotherapy (CCRT) were enrolled. Pharmacokinetic analysis was carried out after non-rigid motion registration. The perfusion parameters [including Blood Flow (BF), Blood Volume (BV), Mean Transit Time (MTT)] and permeability parameters [including endothelial transfer constant (Ktrans), reflux rate (Kep), fractional extravascular extracellular space volume (Ve), fractional plasma volume (Vp)] were calculated, and their relationship with tumor regression was evaluated. The value of these parameters on predicting responders were calculated by receiver operating characteristic (ROC) curve. Multivariate logistic regression analysis was conducted to find the independent variables. Tumor regression rate is negatively correlated with Ve and its standard variation Ve_SD and positively correlated with Ktrans and Kep. Significant differences between responders and non-responders existed in Ktrans, Kep, Ve, Ve_SD, MTT, BV_SD and MTT_SD (P < 0.05). ROC indicated that Ve < 0.24 gave the largest area under curve of 0.865 to predict responders. Multivariate logistic regression analysis also showed Ve was a significant predictor. Baseline perfusion and permeability parameters calculated from DCE-MRI were seen to be a viable tool for predicting the early treatment response after CCRT of NSCLC.

Hepatogenous diabetes (HD) occurs as a complication of cirrhosis. Whether genetic factors, rather than only liver damage, play roles in the development of HD is unknown. TCF7L2 gene has been reported to be associated with type 2 diabetes and also cancer risks. We aim to evaluate the impact of TCF7L2 gene on the susceptibility of HD and hepatocellular carcinoma (HCC) in a Chinese Han population.

Different clinical presentations and prognoses have been implied between pancreatic head and body/tail cancers. We aimed to identify the prognostic relevance of primary tumor location in patients undergoing resection for pancreatic ductal adenocarcinoma (PDAC). Thirty-two pairs of patients with strictly matched early stage (II) pancreatic head and body/tail cancers were enrolled. The molecular feature of the two subtypes of PDAC was assessed on the level of miRNA expression. Out of the 64 patients, 34 (53.1%) had tumor recurrence after radical resection during the follow-up period (2.3 ± 0.8 years). Both overall and tumor-free survival were significantly higher in the patients with pancreatic body/tail cancer compared with those with pancreatic head cancer. Patient age and tumor location were the independent prognostic factors for tumor recurrence. A remarkably lower expression of miR-501-3p and higher expression of miR-375 were found and were further verified in pancreatic body/tail cancer tissues compared with pancreatic head cancer tissues. The low expression of miR-501-3p was significantly associated with a low risk of tumor recurrence. Both, subcutaneous and orthotopic PDAC mouse models presented highly invasive tumor phenotypes upon up-regulated miR-501-3p expression. An in vitro study showed that miR-501-3p promoted the invasiveness of PDAC cells possibly via suppressing E-cadherin. In summary, at resectable early stage, pancreatic body/tail cancer presents a less malignant phenotype associated with deregulation of miR-501-3p compared with pancreatic head cancer.

Carcinoma associated fibroblasts (CAFs), an important component of tumor microenvironment, are capable of enhancing tumor cells invasion and migration through initiation of epithelial-mesenchymal transition (EMT). MRC-5 fibroblasts are one of the CAFs expressing alpha-smooth muscle actin. It is ascertained that medium conditioned by MRC-5 fibroblasts stimulate motility and invasion of breast cancer cells. However, its role in hepatocellular carcinoma (HCC) is less clear. The aim of our study was to investigate the effect of MRC-5-CM on HCC and explore the underlying mechanisms.

Although several long non-coding RNAs (lncRNAs) have been found to be involved in gastric cancer tumorigenesis, the more comprehensive contributions of lncRNAs to gastric cancer require further investigation. Here, we identify a cytoplasmic lncRNA, LINC01485, which promotes tumor growth and migration in gastric cancer.

Both PNPLA3 I148M and hepatic inflammation are associated with nonalcoholic fatty liver disease (NAFLD) progression. This study aimed to elucidate whether PNPLA3 I148M is involved in NF-kB-related inflammation regulation in NAFLD. HepG2 cells homozygous for the PNPLA3 I148M mutation were used. The human PNPLA3 promoter sequence was screened for NF-kB binding sites using the MATCH and PATCH tools. NF-kB-mediated transcriptional regulation of the PNPLA3 gene was assessed by luciferase reporter assay, EMSA and ChIP-qPCR. Wild-type (I148I) and mutant (M148M) PNPLA3 were overexpressed using stable lentivirus-mediated transfection. The pCMV vector and siRNA were transiently transfected into cells to direct NF-kB overexpression and PNPLA3 silencing, respectively. A putative NF-kB binding site in the human PNPLA3 promoter was shown to be necessary for basal and NF-kB-driven transcriptional activation of PNPLA3 and protein/DNA complex formation. Supershift analysis demonstrated a protein/DNA complex specifically containing the NF-kB p65 and p50 subunits. ChIP-qPCR confirmed the endogenous binding of NF-kB to the human PNPLA3 promoter in response to NF-kB overexpression and palmitic acid (PA) challenge. The silencing of PNPLA3 blocked the overexpression of NF-kB or PA-induced TNF-α up-regulation. Moreover, mutant PNPLA3 overexpression prevented NF-kB inhibitor-induced down-regulation of TNF-α expression in PA-treated HepG2 cells. Finally, the overexpression of mutant but not wild-type PNPLA3 increased TNF-α expression and activated the ER stress-mediated and NF-kB-independent inflammatory IRE-1α/JNK/c-Jun pathway. Human PNPLA3 was shown to be a target of NF-kB, and PNPLA3 I148M mediated the regulatory effect of NF-kB on inflammation in PA-treated HepG2 cells, most likely via the IRE-1α/JNK/c-Jun ER stress pathway.

Background: Holly (Ilex latifolia Thunb.) polyphenols extracts (HPE) contain high amounts of polyphenols, including phenolic acids, triterpenoids, tannic acids, and so on, which have strong antioxidant function. This experiment was aimed to explore the protective effect and mechanism of HPE against hepatic injury induced by diquat. Methods: Thirty-two weaned piglets were allotted by a 2 × 2 factorial experiment design with diet type (basal diet vs. HPE diet) and diquat challenge (saline vs. diquat). On the 21st day, piglets were injected with diquat or saline. One week later, blood samples were collected. Then all piglets were slaughtered and hepatic samples were collected. Results: Dietary HPE supplementation improves hepatic morphology, the activities of plasma aspartate aminotransferase, alanine aminotransferase, and glutamyl transpeptidase, and enhances hepatic anti-oxidative capacity, while it regulates the expression of ferroptosis mediators (transferrin receptor protein 1, heat shock protein beta 1, solute carrier family 7 member 11, and glutathione peroxidase 4) in diquat-challenged piglets. Conclusion: These results indicate that dietary HPE supplementation enhances hepatic morphology and function, which is involved in modulating antioxidant capacity and ferroptosis.

BACKGROUND The potential roles of alternative splicing (AS) in HCC remain unknown. This study aimed to identify AS signatures associated with the prognosis that influence the immune microenvironment of HCC. MATERIAL AND METHODS The SpliceSeq tool was employed for genome-wide profiling of 7 AS events in 361 HCC patients from The Cancer Genome Atlas (TCGA). A prognostic signature was built by integrating Cox regression and the least absolute shrinkage and selection operator (LASSO). The support vector machine (SVM) and receiver operating characteristic curve (ROC) were employed to analyze the AS events in the signatures to discriminate the immune microenvironment. RESULTS There were 3546 AS events highly linked to the survival of patients with HCC. The AS signature could effectively stratify HCC patients. Clustering analysis revealed 3 different immune clusters characterized with significantly different prognoses and were significantly correlated with AS signatures. The AS events in the final prognostic signature classified the immune cluster with an average AUC of the ROC (0.88). Moreover, a potential regulatory network of splicing events in HCC is presented. CONCLUSIONS We established the prognostic signature based on AS, which can effectively stratify HCC patients and predict the immune subtypes. Moreover, novel RNA splicing patterns and splicing-regulatory networks involved in HCC were discovered.

Long noncoding RNAs (lncRNAs) are versatile in functions and can regulate cancer development, including the modulation of cancer immunity. Immune-related lncRNA signatures predicting prognosis have been reported in multiple cancers, but relevant studies in gastric cancer (GC) are still lacking.

Hepatocellular carcinoma (HCC) is a very common neoplasm worldwide, and competitive endogenous RNA (ceRNA) plays an important role in the development of HCC. The purpose of this study is to investigate the molecular mechanisms of ceRNAs in HCC.

Neuroinflammation, specifically the NLRP3 inflammasome cascade, is a common underlying pathological feature of many neurodegenerative diseases. Evidence suggests that NLRP3 activation involves changes in intracellular K+. Nuclear Enriched Transcript Sort Sequencing (NETSseq), which allows for deep sequencing of purified cell types from human post-mortem brain tissue, demonstrated a highly specific expression of the tandem pore domain halothane-inhibited K+ channel 1 (THIK-1) in microglia compared to other glial and neuronal cell types in the human brain. NETSseq also showed a significant increase of THIK-1 in microglia isolated from cortical regions of brains with Alzheimer's disease (AD) relative to control donors. Herein, we report the discovery and pharmacological characterisation of C101248, the first selective small-molecule inhibitor of THIK-1. C101248 showed a concentration-dependent inhibition of both mouse and human THIK-1 (IC50: ∼50 nM) and was inactive against K2P family members TREK-1 and TWIK-2, and Kv2.1. Whole-cell patch-clamp recordings of microglia from mouse hippocampal slices showed that C101248 potently blocked both tonic and ATP-evoked THIK-1 K+ currents. Notably, C101248 had no effect on other constitutively active resting conductance in slices from THIK-1-depleted mice. In isolated microglia, C101248 prevented NLRP3-dependent release of IL-1β, an effect not seen in THIK-1-depleted microglia. In conclusion, we demonstrated that inhibiting THIK-1 (a microglia specific gene that is upregulated in brains from donors with AD) using a novel selective modulator attenuates the NLRP3-dependent release of IL-1β from microglia, which suggests that this channel may be a potential therapeutic target for the modulation of neuroinflammation in AD.

Utilizing the copolymerization modification of dimethyl diallyl ammonium chloride (DMDAAC), the high positive charge density of the copolymer could be maintained, thereby facilitating the deficiency of its monomer in the application. In this paper, poly (DMDAAC-co-DAMBAC) (9:1) was synthesized with an aqueous polymerization method using DMDAAC and methyl benzyl diallyl ammonium chloride (DAMBAC) as monomers and 2,2'-azobis [2-methylpropionamidine] dihydrochloride (V50) as an initiator. Targeted to the product's weight-average relative molecular mass (Mw), the response surface methodology (RSM) was used to optimize the preparation process. The optimal process conditions were obtained as follows: w (M) = 80.0%, m (V50):m (M) = 0.00700%, m (Na4EDTA):m (M) = 0.00350%, T1 = 50.0 °C, T2 = 60.0 °C, and T3 = 72.5 °C. The intrinsic viscosity ([η]) of the product was 1.780 dL/g, and the corresponding double bond conversion (Conv.) was 90.25 %. Poly (DMDAAC-co-DAMBAC) (9:1) revealed a highest Mw of 5.637 × 105, together with the polydispersity index d (Mw/Mn) as 1.464. For the demulsification performance of simulated crude oil O/W emulsions, the demulsification rate of poly (DMDAAC-co-DAMBAC) (9:1) could reach 97.73%. Our study has illustrated that the copolymerization of DMDAAC and a small amount of DAMBAC with poor reactivity could significantly improve the relative molecular weight of the polymer, enhance its lipophilicity, and thus the application scope of the polymer.

Primary ovarian insufficiency (POI) is a clinical syndrome of ovarian dysfunction characterized by premature exhaustion of primordial follicles. POI causes infertility, severe daily life disturbances and long-term health risks. However, the underlying mechanism remains largely unknown. We previously identified a Basonuclin 1 (BNC1) mutation from a large Chinese POI pedigree and found that mice with targeted Bnc1 mutation exhibit symptoms of POI. In this study, we found that BNC1 plays key roles in ovarian reserve and maintaining lipid metabolism and redox homeostasis in oocytes during follicle development. Deficiency of BNC1 results in premature follicular activation and excessive follicular atresia. Mechanistically, BNC1 deficiency triggers oocyte ferroptosis via the NF2-YAP pathway. We demonstrated that pharmacologic inhibition of YAP signaling or ferroptosis significantly rescues Bnc1 mutation-induced POI. These findings uncover a pathologic mechanism of POI based on BNC1 deficiency and suggest YAP and ferroptosis inhibitors as potential therapeutic targets for POI.

High-grade serous ovarian cancer (HGSOC) is a common cause of death from gynecological cancer, with an overall survival rate that has not significantly improved in decades. Reliable bio-markers are needed to identify high-risk HGSOC to assist in the selection and development of treatment options.

Liensinine, an important alkaloid in lotus seed, exhibits multiple functions such as anti-AIDS, anticancer, antidepressant, and antihypertensive properties. In this study, a highly sensitive HPLC-MS/MS method was developed and validated for the quantification of liensinine in microvolume rat plasma as low as 45 μL. Chromatographic separation was carried out using a reverse-phase Gemini-C18 column (100 mm × 3 mm i.d. × 5 μm), and mass selective detection using multiple reaction monitoring was attained using an electrospray ionization source, which operated in the positive mode. Dauricine was used as the internal standard. The precursor-to-product ion transition m/z 611.15 > 206.10 was selected for the detection of liensinine; m/z 625.25 > 206.10 was used for the detection of dauricine. The developed method is linear over the concentration range of 0.05-1000 ng/mL with an excellent coefficient of determination (R 2 = 0.991). The recoveries ranged from 92.57% to 95.88% at three quality control levels. Intraday and interday precision and accuracy are less than 12.2% and 6.59%, respectively. The lower limit of quantification (LLOQ) is 0.05 ng/mL. The matrix effect was insignificant and acceptable. The validated method was successfully applied to the pharmacokinetic study of liensinine in rats. This method can be used for in vivo studies as well as quality control of traditional Chinese medicines and herbal tea containing liensinine alkaloid.