👤 Zijun Zhou

Paeoniflorin (PF), an effective composition that is extracted from Radix Paeoniae Alba, plays a role in protecting against various kidney diseases. However, the mechanism of PF on nephrotic syndrome (NS) remains unclear. The aim of this study was to investigate the protective role of PF on Adriamycin (ADR)-induced NS in vivo and vitro as well as its potential mechanism. In animal study, PF significantly decreased the levels of 24-h urine protein, blood urea nitrogen, serum creatinine, total cholesterol and triglycerides in NS rats, but increased the total protein and albumin levels. Hematoxylin-eosin (HE) staining revealed that the kidney lesion was resolved upon PF treatment. After treatment with PF, the morphology and number of podocytes in renal tissue were restored to normal. PF increased expression of synaptopodin and decreased expression of desmin, demonstrating a protective effect in podocyte injury. Further studies revealed that PF upregulated Peroxisome proliferator-activated receptor gamma (PPARγ) and restrained Angiopointin-like 4 (ANGPTL4) in kidney tissue. In vitro study, PF reduced Caspase3 and Bax and increased Bcl-2, indicating that the apoptosis rate of podocytes induced by ADR was reduced by PF. Furthermore, PF ameliorated podocyte injury by upregulating synaptopodin and reducing desmin. In accordance with animal study, PF downregulated ANGPTL4 by activating PPARγ. However, the therapeutic effects of PF were reversed by GW9662 (PPARγ inhibitor), likely by suppressing ANGPTL4 degradation. In general, these results demonstrate that PF has a good therapeutic effect on NS by activating PPARγ and subsequently inhibiting ANGPTL4. Show less

The objective of the study was to evaluate the effect of overfeeding a moderate energy diet and a 2,4-thiazolidinedione (TZD) injection on blood and hepatic tissue biomarkers of lipid metabolism, oxidative stress, and inflammation as it relates to insulin sensitivity. Fourteen dry non-pregnant cows were fed a control (CON) diet to meet 100% of NRC requirements for 3 wk, after which half of the cows were assigned to a moderate-energy diet (OVE) and half of the cows continued on CON for 6 wk. All cows received an intravenous injection of 4 mg TZD/kg of body weight (BW) daily from 2 wk after initiation of dietary treatments and for 2 additional week. Compared with CON cows and before TZD treatment, the OVE cows had lower concentration of total protein, urea and albumin over time. The concentration of cholesterol and tocopherol was greater after 2 wk of TZD regardless of diet. Before and after TZD, the OVE cows had greater concentrations of AST/GOT, while concentrations of paraoxonase, total protein, globulin, myeloperoxidase, and haptoglobin were lower compared with CON cows. Regardless of diet, TZD administration increased the concentration of ceruloplasmin, ROMt, cholesterol, tocopherol, total protein, globulin, myeloperoxidase and beta-carotene. In contrast, the concentration of haptoglobin decreased at the end of TZD injection regardless of diet. Prior to TZD injection, the mRNA expression of Based on molecular and blood data, administration of TZD enhanced some aspects of insulin sensitivity while causing contradictory results in terms of inflammation and oxidative stress. The bovine liver is TZD-responsive and level of dietary energy can modify the effects of TZD. Because insulin sensitizers have been proposed as useful tools to manage dairy cows during the transition period, further studies are required to investigate the potential hepatotoxicity effect of TZD (or similar compounds) in dairy cattle. Show less

The systematic mechanisms of acute intracerebral hemorrhage are still unknown and unverified, although many recent researches have indicated the secondary insults. This study was aimed to disclose the pathological mechanism and identify novel biomarker and therapeutic target candidates by plasma proteome. Patients with AICH (n = 8) who demographically matched healthy controls (n = 4) were prospectively enrolled, and their plasma samples were obtained. The TMT-LC-MS/MS-based proteomics approach was used to quantify the differential proteome across plasma samples, and the results were analyzed by Ingenuity Pathway Analysis to explore canonical pathways and the relationship involved in the uploaded data. Compared with healthy controls, there were 31 differentially expressed proteins in the ICH group ( Our analysis provided several intriguing pathways involved in ICH, like LXR/RXR activation, acute phase response signaling, and production of NO and ROS in macrophages pathways. The three upstream regulators: IL-6, TNF, LPS, and seven biomarker candidates: APCS, APOA4, FGB, IGFBP2, LBP, LYZ, and MGMT were uncovered. LPS, APOA4, IGFBP2, LBP, LYZ, and MGMT are novel potential biomarkers in ICH development. The identified proteins and pathways provide new perspectives to the potential pathological mechanism and therapeutic targets underlying ICH. Show less

Metabolic syndrome (MetS), a cluster of metabolic disturbances that increase the risk for cardiovascular disease and diabetes, was because of genetic susceptibility and environmental risk factors. To identify the genetic variants associated with MetS and metabolic components, we conducted a genome-wide association study followed by replications in totally 12,720 participants from the north, north-eastern and eastern China. In combined analyses, independent of the top known signal at rs651821 on APOA5, we newly identified a secondary triglyceride-associated signal at rs180326 on BUD13 (P Show less

Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a life-threatening condition, and the lipid metabolism disorder is common in the development of this disease. This prospective observational study aimed to define the characteristics of plasma apolipoprotein A-V (apoA-V) in long-term outcome prediction of HBV-ACLF, and a total of 330 HBV-ACLF patients were included and followed for more than 12 months. In this cohort, the 4-week, 12-week, 24-week and 48-week cumulative mortality of HBV-ACLF was 18.2%(60/330), 50.9%(168/330), 59.7%(197/330) and 63.3%(209/330), respectively. As compared to survivors, the non-survivors had significantly lower concentrations of plasma apoA-V on admission. Plasma apoA-V concentrations were positively correlated with prothrombin time activity (PTA), and negatively correlated with interleukin-10, tumor necrosis factor-α, and iMELD scores. Though plasma apoA-V, PTA, total bilirubin(TBil) and blood urea nitrogen(BUN) were all independent factors to predict one-year outcomes of HBV-ACLF, plasma apoA-V had the highest prediction accuracy. And its optimal cutoff value for one-year survival prediction was 480.00 ng/mL, which had a positive predictive value of 84.68% and a negative predictive value of 92.23%. In summary, plasma apoA-V decreases significantly in non-survivors of HBV-ACLF, and it may be regarded as a new predictive marker for the prognosis of patients with HBV-ACLF. Show less

The purpose of this study was to investigate the correlation between serum levels of serum apolipoprotein M (ApoM), A5 (ApoA5), and high-density lipoprotein (HDL) in patients with obstructive sleep apnea hypopnea syndrome (OSAHS) and study the effects of nasal continuous positive airway pressure treatment on these serum biomarkers. Thirty OSAHS patients and 15 non-OSAHS probands as control were selected for the study. Serum HDL, ApoM, and ApoA5 levels in two groups were detected; differences and association among them were analyzed. Patients with moderate and severe OSAHS underwent 3-month auto-continuous positive airway pressure treatment, and a comparative study was conducted to investigate the changes in blood lipids, serum ApoM, and ApoA5. In comparison to the control group, the HDL, ApoM, and ApoA5 serum levels were lower (P < 0.05). HDL was positively correlated to ApoM and ApoA5 (P < 0.001), and ApoM was positively correlated to ApoA5 (r = 0.536, P < 0.001). HDL, ApoM, and ApoA5 were significantly increased in the patients of moderate and severe OSAHS after auto-continuous positive airway pressure treatment for 3 months (P < 0.05). The HDL level was significantly lower in OSAHS patients. The decrease in serum ApoM and ApoA5 in OSAHS patients was correlated to the severity of OSAHS and HDL levels. Auto-continuous positive airway pressure treatment increased serum levels of ApoM, ApoA5, and HDL in OSAHS patients. Show less

In quantitative analysis of protein biomarkers and therapeutic proteins by liquid chromatography/mass spectrometry (LC/MS), it is a preferred and well-established approach to digest with proteolytic enzymes to produce smaller peptide fragments which are more suitable for LC/MS analysis than the intact protein. In-solution digestion is one widely used method for protein digestion. Proteolytically resistant proteins often require digestion times that extend beyond normal working hours and prohibit same day analysis. We evaluated the performance of an immobilized enzyme reactor (IMER) to determine if this technology could reduce method development time, digestion time and increase throughput. We digested human plasma samples using a commercially available IMER, Flash Digest, and compared it to an in-solution digestion method for analysis of three different apolipoprotein biomarkers APOE, APOC2, and APOC3. The plasma digests were analyzed via LC/MS using electrospray ionization (ESI) and multiple reaction monitoring (MRM). Value assigned calibrators were selected over a relevant physiological concentration range for each protein of interest. Quality control samples (QCs) and 'unknown' human plasma samples were analyzed with both methods. Flash Digest significantly reduced digestion time for APOC3, the most proteolytically resistant of the three proteins, to 30 min compared with overnight used with in-solution digestion. The Flash Digest achieved comparable digestion efficiency with minimal method development and reduced sample preparation time. Both methods showed linearity over a physiologically relevant concentration range. Precision was evaluated and a percentage coefficient of variance (% CV) less than 8% was obtained during intra-day reproducibility evaluation for all three apolipoproteins with Flash Digest. Concentrations observed for QCs and unknown samples using Flash Digest were comparable to the in-solution method. An IMER such as Flash Digest may be a potential alternative to in-solution digestion to accelerate digestion of proteolytically resistant proteins in a quantitative proteomics experiments, reduce method development time and increase throughput. Copyright © 2016 John Wiley & Sons, Ltd. Show less

The purpose of the present study is to investigate the association between the polymorphisms in AXIN1 with susceptibility to clear cell renal cell carcinoma (ccRCC). A total of 284 ccRCC patients and 439 healthy volunteers were enrolled. Totally three tag single nucleotide polymorphisms in AXIN1 gene were genotyped using PCR & restriction fragment length polymorphism. Significantly increased ccRCC risk was observed to be associated with the CT/CC genotypes of rs1805105 and AA genotype of rs12921862. Patients carrying the rs1805105 CT genotype had a 1.92-fold increased risk to developing clinical stage III and IV cancer. Our results suggested the rs1805105 CT/CC genotypes and rs12921862 AA genotype may relate to ccRCC development. Show less

A series of pentacyclic triterpene 3β-ester derivatives were designed, synthesized and evaluated as a new class of cholesteryl ester transfer protein (CETP) inhibitors for the treatment of dyslipidemia. In vitro screening assay showed that 5 out of 30 compounds displayed moderate inhibiting human CETP activity with IC Show less

Lp(a) [lipoprotein (a)] is composed of apoB (apolipoprotein B) and apo(a) [apolipoprotein (a)] and is an independent risk factor for cardiovascular disease and aortic stenosis. In clinical trials, anacetrapib, a CETP (cholesteryl ester transfer protein) inhibitor, causes significant reductions in plasma Lp(a) levels. We conducted an exploratory study to examine the mechanism for Lp(a) lowering by anacetrapib. We enrolled 39 participants in a fixed-sequence, double-blind study of the effects of anacetrapib on the metabolism of apoB and high-density lipoproteins. Twenty-nine patients were randomized to atorvastatin 20 mg/d, plus placebo for 4 weeks, and then atorvastatin plus anacetrapib (100 mg/d) for 8 weeks. The other 10 subjects were randomized to double placebo for 4 weeks followed by placebo plus anacetrapib for 8 weeks. We examined the mechanisms of Lp(a) lowering in a subset of 12 subjects having both Lp(a) levels >20 nmol/L and more than a 15% reduction in Lp(a) by the end of anacetrapib treatment. We performed stable isotope kinetic studies using Anacetrapib reduces Lp(a) levels by decreasing its production. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00990808. Show less

This study aimed to explore the associations of the cholesteryl ester transfer protein (CETP) gene TaqIB and D442G polymorphisms with essential hypertension (EH). In this case-control study, 883 hypertensive patients and 1044 normal controls were randomly selected from the Mongolian population of China. Polymerase chain reaction (PCR) and direct sequencing of PCR products were used to identify the genotypes. Haplotype analysis was performed by estimating the haplotype frequencies using the online SHEsis package. The distribution frequency of the B2-G haplotype was significantly lower in the EH group than in the control group (0.7% vs. 1.9%, P = 0.001, OR = 0.359 [0.188-0.689]). Subjects with the B2B2 genotype showed significantly lower levels of total cholesterol (TC) (P < 0.05). When subgrouped by sex, male subjects with the B2B2 genotype showed significantly increased high-density lipoprotein cholesterol and decreased TC levels (P < 0.05), and those with the B2 allele showed significantly lower triglyceride levels as compared to the subjects with the B1B1 homozygote (P < 0.05). TaqIB and D442G polymorphisms of the CETP gene did not independently affect the risk of developing EH in the Chinese Mongolian population, while the B2-G haplotype obviously decreased the susceptibility to EH. The B2 allele could alter the blood lipid level and reduce the risk of developing cardiovascular diseases. Show less

DExD/H-box helicase 36 (DHX36) is known to be an ATP-dependent RNA helicase that unwinds the guanine-quadruplexes DNA or RNA, but emerging data suggest that it also functions as pattern recognition receptor in innate immunity. Porcine reproductive and respiratory syndrome virus (PRRSV) is an Show less

Hemangioblastomas (HBs) are uncommon tumors characterized by the presence of inactivating alterations in the von Hippel-Lindau (VHL) gene in inherited cases and by infrequent somatic mutation in sporadic entities. We performed whole exome sequencing on 11 HB patients to further elucidate the genetics of HBs. A total of 270 somatic variations in 219 genes, of which there were 86 mutations in 67 genes, were found in sporadic HBs, and 184 mutations were found in 154 genes in familial HBs. C: G>T: A and T: A>C: G mutations are relatively common in most HB patients. Genes harboring the most significant mutations include PCDH9, KLHL12, DCAF4L1, and VHL in sporadic HBs, and ZNF814, DLG2, RIMS1, PNN, and MUC7 in familial HBs. The frequency of CNV varied considerably within sporadic HBs but was relatively similar within familial HBs. Five genes, including OTOGL, PLCB4, SCEL, THSD4, and WWOX, have CNVs in the six patients with sporadic HBs, and three genes, including ABCA6, CWC27, and LAMA2, have CNVs in the five patients with familial HBs. We found new genetic mutations and CNVs that might be involved in HBs; these findings highlight the complexity of the tumorigenesis of HBs and pinpoint potential therapeutic targets for the treatment of HBs. Show less

Directional cell migration is of fundamental importance to a variety of biological events, including metastasis of malignant cells. Herein, we specifically investigated SET oncoprotein, a subunit of the recently identified inhibitor of acetyltransferases (INHAT) complex and identified its role in the establishment of front-rear cell polarity and directional migration in Esophageal Squamous Cell Carcinoma (ESCC). We further define the molecular circuits that govern these processes by showing that SET modulated DOCK7/RAC1 and cofilin signaling events. Moreover, a detailed analysis of the spatial distribution of RAC1 and cofilin allowed us to decipher the synergistical contributions of the two in coordinating the advancing dynamics by measuring architectures, polarities, and cytoskeletal organizations of the lamellipodia leading edges. In further investigations in vivo, we identified their unique role at multiple levels of the invasive cascade for SET cell and indicate the necessity for their functional balance to enable efficient invasion as well. Additionally, SET epigenetically repressed miR-30c expression by deacetylating histones H2B and H4 on its promoter, which was functionally important for the biological effects of SET in our cell-context. Finally, we corroborated our findings in vivo by evaluating the clinical relevance of SET signaling in the metastatic burden in mice and a large series of patients with ESCC at diagnosis, observing it's significance in predicting metastasis formation. Our findings uncovered a novel signaling network initiated by SET that epigenetically modulated ESCC properties and suggest that targeting the regulatory axis might be a promising strategy to inhibit migration and metastasis. Show less

The anti-obesity effects of two types of resistant starch (RS) in high-fat-diet-induced obese rats were investigated. The serum triglycerides, total cholesterol and malondialdehyde concentrations were significantly reduced, and the total antioxidant capacity, superoxide dismutase levels and glutathione peroxidase activity were increased by RS2 and RS4 consumption compared to the obesity group. A significant reduction in the serum glucose level and elevations in hepatic lipid metabolic enzyme activities were observed only for RS4 administration. Moreover, the expression levels of the fatty acid synthesis associated genes ACC and Fads1, the triglyceride synthesis and metabolism-related gene SREBP-1, the adipocyte differentiation gene PPARγ, the cholesterol synthesis associated gene HMGCR, and the gluconeogenesis associated gene GAPDH were all significantly down-regulated, whilst the lipid oxidation gene Acox1 and the liver function genes Gsta2, Nqo1, and Gclm were up-regulated in both administered groups. Additionally, RS4 performed well in up-regulating the expressions of Gsta2, Gsta3, Nqo1, and Egfr, and down-regulating LXRα, Igfbp1, and Pml. RS4 exhibited great advantages in reducing oxidative stress compared with RS2. Show less

Kras mutations and increased Notch activation occur frequently in gallbladder cancer. However, their roles in gallbladder carcinogenesis have not been defined. This study was aimed at determining whether expression of mutant Kras was sufficient to induce gallbladder carcinoma and whether Notch deregulation played a role in this context. We determined Cre recombination activity of Kras Show less

Noncompaction cardiomyopathy is characterized by the presence of extensive trabeculations, which could lead to heart failure and malignant arrhythmias. How trabeculations resolve to form compact myocardium is poorly understood. Elucidation of this process is critical to understanding the pathophysiology of noncompaction disease. Here we use genetic lineage tracing to mark the Nppa Show less

Gene fusion is one of the hallmarks of cancer. Recent advances in RNA-seq of cancer transcriptomes have facilitated the discovery of fusion transcripts. In this study, we report identification of a surprisingly large number of fusion transcripts, including six Show less

A lack of sufficient oligodendrocyte myelination contributes to remyelination failure in demyelinating disorders. miRNAs have been implicated in oligodendrogenesis; however, their functions in myelin regeneration remained elusive. Through developmentally regulated targeted mutagenesis, we demonstrate that miR-219 alleles are critical for CNS myelination and remyelination after injury. Further deletion of miR-338 exacerbates the miR-219 mutant hypomyelination phenotype. Conversely, miR-219 overexpression promotes precocious oligodendrocyte maturation and regeneration processes in transgenic mice. Integrated transcriptome profiling and biotin-affinity miRNA pull-down approaches reveal stage-specific miR-219 targets in oligodendrocytes and further uncover a novel network for miR-219 targeting of differentiation inhibitors including Lingo1 and Etv5. Inhibition of Lingo1 and Etv5 partially rescues differentiation defects of miR-219-deficient oligodendrocyte precursors. Furthermore, miR-219 mimics enhance myelin restoration following lysolecithin-induced demyelination as well as experimental autoimmune encephalomyelitis, principal animal models of multiple sclerosis. Together, our findings identify context-specific miRNA-regulated checkpoints that control myelinogenesis and a therapeutic role for miR-219 in CNS myelin repair. Show less

Hepatic de novo lipogenesis (DNL) converts carbohydrates into triglycerides and is known to influence systemic lipid homoeostasis. Here, we demonstrate that the zinc finger protein Zbtb20 is required for DNL. Mice lacking Zbtb20 in the liver exhibit hypolipidemia and reduced levels of liver triglycerides, along with impaired hepatic lipogenesis. The expression of genes involved in glycolysis and DNL, including that of two ChREBP isoforms, is decreased in livers of knockout mice. Zbtb20 binds to and enhances the activity of the ChREBP-α promoter, suggesting that altered metabolic gene expression is mainly driven by ChREBP. In addition, ChREBP-β overexpression largely restores hepatic expression of genes involved in glucose and lipid metabolism, and increases plasma and liver triglyceride levels in knockout mice. Finally, we show that Zbtb20 ablation protects from diet-induced liver steatosis and improves hepatic insulin resistance. We suggest ZBTB20 is an essential regulator of hepatic lipogenesis and may be a therapeutic target for the treatment of fatty liver disease. Show less

Carbohydrate-responsive element-binding protein (ChREBP) has been reported to regulate glucose and lipids metabolism in the liver. However, its role in the complicated pathophysiology of diabetic nephropathy is not understood. C57BL/6 mice treated with streptozotocin (STZ) or vehicle control to induce diabetic models. The mRNA and protein levels of ChREBP in kidneys of control and diabetic mice were determined by real-time PCR or Western Blot, respectively. The expression of inflammatory and endoplasmic reticulum stress markers in ChREBP deficient or Wild-type mice was also determined by real-time PCR or Western Blot. Urine was collected over 16 hours on the day prior to sacrifice, and albuminuria and urine creatinine were determined by Elisa or Creatinine Assay Kit. We found that expression of ChREBP and its downstream target genes were up-regulated in C57BL/6 mice with diabetic nephropathy. Subsequently, we demonstrated that ChREBP knockout mice were protected against the development of diabetic nephropathy induced by streptozotocin (STZ), showing less albuminuria, inflammation and glomerular hypertrophy as compared to diabetic wild-type mice. Reduced expression of inflammatory and endoplasmic reticulum stress markers were also observed in ChREBP deficient mice. Our data indicate that ablation or inhibition of ChREBP might improve kidney injury in streptozotocin-induced diabetic animals. Show less

Non-alcoholic fatty liver disease (NAFLD) and its causal factors of hepatic insulin resistance (IR) and type 2 diabetes are rapidly growing worldwide. Developing new therapeutic methods for these conditions requires a comprehensive understanding between hepatic lipid metabolism and IR. Sterol regulatory element-binding transcription factor 1c (SREBP-1c) and carbohydrate responsive-element binding protein (ChREBP) are the major regulators of fatty acid synthase (FASN), a key enzyme of de novo fatty acid synthesis. They are induced by insulin, which directly binds to the sterol regulatory elements (SRE) or carbohydrate-responsive elements (ChORE) of the FASN promoter to induce its expression. The insulin pathway involved in NAFLD has well studied, but the role of histone modification in NAFLD is just beginning to be investigated, and there is minimal data regarding its involvement. In the current study, we investigated histone modifications in FASN under insulin stimulation. H3K4 hypertrimethylation and H3, H4 hyperacetylation in the FASN promoter was found in HepG2 cells and primary hepatocytes following insulin stimulation. We also found that insulin treatment induced the transcription factor SREBP-1c, ChREBP and could accelerate FASN expression by enhancing SREBP-1c, SRE, and ChREBP ChORE binding and inducing H3, H4 hyperacetylation at SRE, ChORE, or transcription start site (TSS) regions of the FASN promoter in hepatocellular carcinoma cell line (HepG2) and primary hepatocytes. Finally, histone acetylation could influence FASN expression by impairing SREBP-1c SRE and ChREBP ChORE binding. Show less

In this study, we aimed to clinically and genetically characterize LVNC patients and investigate the prevalence of variants in known and novel LVNC disease genes. Left ventricular non-compaction cardiomyopathy (LVNC) is an increasingly recognized cause of heart failure, arrhythmia, thromboembolism, and sudden cardiac death. We sought here to dissect its genetic causes, phenotypic presentation and outcome. In our registry with follow-up of in the median 61 months, we analysed 95 LVNC patients (68 unrelated index patients and 27 affected relatives; definite familial LVNC = 23.5%) by cardiac phenotyping, molecular biomarkers and exome sequencing. Cardiovascular events were significantly more frequent in LVNC patients compared with an age-matched group of patients with non-ischaemic dilated cardiomyopathy (hazard ratio = 2.481, P = 0.002). Stringent genetic classification according to ACMG guidelines revealed that TTN, LMNA, and MYBPC3 are the most prevalent disease genes (13 patients are carrying a pathogenic truncating TTN variant, odds ratio = 40.7, Confidence interval = 21.6-76.6, P < 0.0001, percent spliced in 76-100%). We also identified novel candidate genes for LVNC. For RBM20, we were able to perform detailed familial, molecular and functional studies. We show that the novel variant p.R634L in the RS domain of RBM20 co-segregates with LVNC, leading to titin mis-splicing as revealed by RNA sequencing of heart tissue in mutation carriers, protein analysis, and functional splice-reporter assays. Our data demonstrate that the clinical course of symptomatic LVNC can be severe. The identified pathogenic variants and distribution of disease genes-a titin-related pathomechanism is found in every fourth patient-should be considered in genetic counselling of patients. Pathogenic variants in the nuclear proteins Lamin A/C and RBM20 were associated with worse outcome. Show less

Allicin is considered anti-atherosclerotic due to its antioxidant and anti-inflammatory effects, which makes it an important drug for the prevention and treatment of atherosclerosis. However, the effects of allicin on foam cells are unclear. Thus, in this study, we examined the effects of allicin on lipid accumulation via peroxisome proliferator-activated receptor γ (PPARγ)/liver X receptor α (LXRα) in THP‑1 macrophage-derived foam cells. THP‑1 cells were exposed to 100 nM phorbol myristate acetate (PMA) for 24 h, and then to oxydized low-density lipoprotein (ox-LDL; 50 mg/ml) to induce foam cell formation. The results of Oil Red O staining and high-performance liquid chromatography (HPLC) revealed showed that pre-treatment of the foam cells with allicin decreased total cholesterol, free cholesterol (FC) and cholesterol ester levels in cells, and also decreased lipid accumulation. Moreover, allicin upregulated ATP binding cassette transporter A1 (ABCA1) expression and promoted cholesterol efflux. However, these effects were significantly abolished by transfection with siRNA targeting ABCA1. Furthermore, PPARγ/LXRα signaling was activated by allicin treatment. The allicin-induced upregulation of ABCA1 expression was also abolished by PPARγ inhibitor (GW9662) and siRNA or LXRα siRNA co-treatment. Overall, our data demonstrate that the allicin-induced upregulation of ABCA1 promotes cholesterol efflux and reduces lipid accumulation via PPARγ/LXRα signaling in THP‑1 macrophage-derived foam cells. Show less

The class III phosphoinositide 3-kinase VPS34 plays a key role in the regulation of vesicular trafficking and macroautophagy. So far, we know little about the molecular mechanism of VPS34 activation besides its interaction with regulatory proteins to form complexes. Here, we report that VPS34 is specifically acetylated by the acetyltransferase p300, and p300-mediated acetylation represses VPS34 activity. Acetylation at K771 directly diminishes the affinity of VPS34 for its substrate PI, while acetylation at K29 hinders the VPS34-Beclin 1 core complex formation. Inactivation of p300 induces VPS34 deacetylation, PI3P production, and autophagy, even in AMPK Show less

Involvement of the RGS17 oncogene in the promotion of non-small-cell lung cancer (NSCLC) has been reported, but the regulation mechanism in NSCLC remains unclear. MicroRNAs (miRNAs) negatively regulate gene expression, and their dysregulation has been implicated in tumorigenesis. To understand the role of miRNAs in Regulator of G Protein Signaling 17 (RGS17)-induced NSCLC, we showed that miR-203 was downregulated during tumorigenesis, and inhibited the proliferation and invasion of lung cancer cells. We then determined whether miR-203 regulated NSCLC by targeting RGS17. To characterize the regulatory effect of miR-203 on RGS17, we used lung cancer cell lines, A549 and Calu-1, and the constructed miR-203 and RGS17 overexpression vectors. The CCK8 kit was used to determine cell proliferation, and the Transwell® assay was used to measure cell invasion and migration. RT-PCR, western blots, and immunofluorescence were used to analyze expression of miR-203 and RGS17, and the luciferase reporter assay was used to examine the interaction between miR-203 and RGS17. Nude mice were used to characterize in vivo tumor growth regulation. Expression of miR-203 inhibited proliferation, invasion, and migration of lung cancer cell lines A549 and Calu-1 by targeting RGS17. The regulatory effect of miR-203 was inhibited after overexpression of RGS17. The luciferase reporter assay showed that miR-203 downregulated RGS17 by direct integration into the 3'-UTR of RGS17 mRNA. In vivo studies showed that expression of miR-203 significantly inhibited growth of tumors. Taken together, the results suggested that expression of miR-203 inhibited tumor growth and metastasis by targeting RGS17. Show less

TNKS1BP1 is a member of the poly(ADP-ribose) polymerase (PARP) superfamily. Our previous studies have demonstrated that TNKS1BP1 plays an important role in DNA damage response. But whether and how TNKS1BP1 associates with cancer is still not clear. Here, we found that TNKS1BP1 was upregulated in human lung adenocarcinoma (LAC) tissues, and was associated with poor overall survival (OS) in LAC patients. Dysregulation of TNKS1BP1 affected the sensitivity of A549 cells to several DNA damage agents including cisplatin, bleomycin, and ionizing radiation. Mechanically, overexpression of TNKS1BP1 increased the accumulation of S phase cells, which was accompanied by a decrease in M phase cells. More importantly, we found TNKS1BP1 regulated genome stability, mainly through affecting the homologous recombination pathway of DNA double-strand breaks by inhibiting the RAD51 foci formation. Overall, our study indicates that, in LAC, aberrant expressions of TNKS1BP1 are common events, and overexpression of TNKS1BP1 might affect outcomes of cancer patients to chemotherapy and radiotherapy. Show less

Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer-related mortality in China with increasing incidence. This study is designed to explore early genetic changes implicated in HCC tumorigenesis and progression by whole-exome sequencing. We firstly sequenced the whole exomes of 5 paired hepatitis B virus-related early-stage HCC and peripheral blood samples, followed by gene ontological analysis and pathway analysis of the single-nucleotide variants discovered. Then, the mutations of high frequency were further confirmed by Sanger sequencing. We identified a mutational signature of dominant T:A>A:T transversion in early HCC and significantly enriched pathways including ECM-receptor interaction, axon guidance, and focal adhesion and enriched biological processes containing cell adhesion, axon guidance, and regulation of pH. Eight genes, including MUC16, UNC79, USH2A, DNAH17, PTPN13, TENM4, PCLO, and PDE1C, were frequently mutated. This study reveals a mutational profile and a distinct mutation signature of T:A>A:T transversion in early-stage HCC with HBV infection, which will enrich our understanding of genetic characteristics of the early-stage HCC. Show less