The SstI polymorphism in the apolipoprotein 3 gene (apoC3) has been identified in many ethnic groups. In addition, the S2 allele of the SstI polymorphism is shown to be associated with increased plasm Show more
The SstI polymorphism in the apolipoprotein 3 gene (apoC3) has been identified in many ethnic groups. In addition, the S2 allele of the SstI polymorphism is shown to be associated with increased plasma triglyceride (TG) levels. Plasma apoCIII is an important atherogenic factor, which interrupts lipid metabolism and is positively associated with plasma TG levels. However, the existence of the SstI polymorphism in the Li ethnic group in China remains to be confirmed. The relationship between the S2 allele of the SstI polymorphism and plasma apoCIII or TG and their roles in atherosclerosis are also unknown. A cohort of 628 participants was recruited (316 atherosclerotic patients and 312 healthy controls) from both the Li and Han ethnic groups. Blood samples were obtained to evaluate the SstI polymorphism in the apoC3 and lipid profiles. Chi-squared and t-tests and multiple unconditional logistic regression were employed to analyze the genotypic and allelic frequencies and lipid profiles using SPSS version 20.0 software. The SstI polymorphism in the apoC3 was identified in the Li ethnic group. The S2 allele and plasma apoCIII and TG levels were associated with the development of atherosclerosis (P < 0.01, S2 allele and apoCIII; P < 0.05, TG) in the Li ethnic group. The S2 allele was associated with increased plasma apoCIII levels in the atherosclerotic group (P < 0.01), but with increased plasma apoCIII and TG levels in control group (both P < 0.01). In addition to the increases in the S2 allele frequency and plasma TG and apoCIII levels, atherosclerotic patients in the Li ethnic group also exhibited increased apoB, decreased HDL-C and apoAI and a lower apoAI:apoB ratio (all P < 0.01). Our results indicate that the S2 allele of the SstI polymorphism in the apoC3 gene is associated with plasma apoCIII levels in the Li population. In combination with unfavorable lipid profiles, this might contribute to susceptibility to atherosclerosis. Show less
Exploring the biological functions of long non-coding RNAs (lncRNAs) has come to the foreground in recent years. Studies have indicated that the lncRNA metastasis‑associated lung adenocarcinoma transc Show more
Exploring the biological functions of long non-coding RNAs (lncRNAs) has come to the foreground in recent years. Studies have indicated that the lncRNA metastasis‑associated lung adenocarcinoma transcript 1 (MALAT1) not only regulates tumorigenesis in hepatocellular carcinoma, but also controls cell cycle progression in hematopoietic cells. The present study was designed to investigate the biological role of lncRNA MALAT1 in liver regeneration. We carried out a series of assays during liver regeneration following 2/3 partial hepatectomy in mice. We explored the functions of lncRNA MALAT1 with a series of functional analyses in vitro. We found that MALAT1 was upregulated during liver regeneration. Moreover, MALAT1 accelerated hepatocyte proliferation by stimulating cell cycle progression from the G1 to the S phase and inhibiting apoptosis in vitro. In addition, our findings also demonstrated that MALAT1 was regulated by p53 during liver regeneration, and that p53 may be a key upstream regulator of MALAT1 activity. Mechanistically, we found that MALAT1 activated the Wnt/β‑catenin pathway by inhibiting the expression of Axin1 and adenomatous polyposis coli (APC), and subsequently promoting the expression of cyclin D1. On the whole, the findings of this study suggest that MALAT1 is a critical molecule for liver regeneration. Pharmacological interventions targeting MALAT1 may thus prove to be therapeutically beneficial in liver failure or liver transplantation by promoting liver regeneration. Show less
Xin-Hua Ye, Hong Chen, Qin Yu+1 more · 2017 · Medical science monitor : international medical journal of experimental and clinical research · added 2026-04-24
BACKGROUND Liver X receptor (LXR) is a nuclear receptor presenting in macrophages; it works indispensably in lipid metabolism control and also negatively regulates the expression of inflammatory genes Show more
BACKGROUND Liver X receptor (LXR) is a nuclear receptor presenting in macrophages; it works indispensably in lipid metabolism control and also negatively regulates the expression of inflammatory genes in macrophages. There are many LXR-related studies in adults with metabolic syndrome but rare reports in obese children with obstructive sleep apnea-hypopnea syndrome (OSAHS). The aim of this study was to investigate the expression of LXR, cholesterol ester transfer protein (CETP), and cyclooxygenase-2 (COX-2) genes in obese children with OSAHS compared with obese children without OSAHS and non-obese children. MATERIAL AND METHODS Sleep monitoring was conducted in 80 obese children with sleep disorders. Fasting morning blood samples from the 80 obese children and 51 normal children were collected and separated, so that macrophages were obtained after culture. Fluorescence quantitative real-time PCR (RT-PCR) was used to detect expression levels of the LXR, CETP, and COX-2 genes. RESULTS LXR, COX-2, and CETP levels in the OSAHS group were higher than those in the other two groups (P<0.05), and the LXR levels in the group of obese children without OSAHS were higher than those in control group (P<0.05). COX-2 expression in the group with moderate to severe OSAHS was higher than that in the group with mild OSAHS (P<0.05). Meanwhile, there were no significant differences in the LXR and CETP levels between the moderate to severe OSAHS group and the mild OSAHS group (P>0.05). CONCLUSIONS LXR gene expression was significantly increased in obese children with OSAHS. The severity of OSAHS was positively correlated with COX-2 levels. Show less
Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed Show more
Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genome-wide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose-raising alleles were associated with a measure of first-phase insulin secretion at Show less
Usnea is a lichen of Usnea diffracta Vain and Usnea longissima Ach, which belongs to the genus Usnea Adans of Usneaceae. Usnea exerts numerous pharmacological activities, while its lipid regulatory ac Show more
Usnea is a lichen of Usnea diffracta Vain and Usnea longissima Ach, which belongs to the genus Usnea Adans of Usneaceae. Usnea exerts numerous pharmacological activities, while its lipid regulatory activities remain unreported. This study aims to evaluate the effects of aqueous and ethanol extracts of Usnea on the regulation of lipid metabolism and to explore the possible mechanism. Hyperlipidemia rat model was established by feeding with high-fat diet for 45days. Therapy rats were intragastrically administered with simvastatin (0.004g/kg/d), Usnea aqueous extract (2.766g/kg/d), or Usnea ethanol extract (2.766g/kg/d) for 20days. Pharmacodynamic effects, including body weight, serum and liver lipid levels, total bile acid (TBA), aspartate aminotransferase (AST), alanine aminotransferase (ALT), liver index, and hepatic morphological changes were evaluated. To explore the mechanisms, the lipase activities and protein expressions related to lipid metabolism were detected. Compared with the model group, aqueous and ethanol extracts of Usnea can slow down the weight gain of rats, significantly reduce the serum levels of total cholesterol, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and the liver contents of TG, LDL-C, as well as significantly increase the contents of high-density lipoprotein cholesterol in serum. In addition, aqueous and ethanol extracts of Usnea can significantly reduce the serum contents of AST and ALT. Furthermore, ethanol extract of Usnea can also significantly reduce the TBA content in serum and liver index. Liver tissue pathological observation showed that aqueous and ethanol extracts of Usnea can improve cell degeneration to a certain extent. Aqueous and ethanol extracts of Usnea can significantly reduce sterol regulatory element-binding proteins-1c, and liver X receptor α (LXR-α) protein expressions. Furthermore, aqueous extract of Usnea can significantly increase hepatic lipase activity and promote apoprotein A5 (ApoA5) protein expression. These findings strongly suggest that the aqueous and ethanol extracts of Usnea play significant roles in regulating lipid metabolism, and the ethanol extract exhibits higher activity than the aqueous extract. The mechanism of the regulation of lipid metabolism by Usnea aqueous extract may involve the increased ApoA5 protein expression via inhibition of the LXR-α signal pathway; however, the mechanism of the regulation of lipid metabolism by Usnea ethanol extract remains to be further studied. 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 e Show more
In the intestinal epithelium, the aberrant regulation of cell/cell junctions leads to intestinal barrier defects, which may promote the onset and enhance the severity of inflammatory bowel disease (IB Show more
In the intestinal epithelium, the aberrant regulation of cell/cell junctions leads to intestinal barrier defects, which may promote the onset and enhance the severity of inflammatory bowel disease (IBD). However, it remains unclear how the coordinated behaviour of cytoskeletal network may contribute to cell junctional dynamics. In this report, we identified ACF7, a crosslinker of microtubules and F-actin, as an essential player in this process. Loss of ACF7 leads to aberrant microtubule organization, tight junction stabilization and impaired wound closure in vitro. With the mouse genetics approach, we show that ablation of ACF7 inhibits intestinal wound healing and greatly increases susceptibility to experimental colitis in mice. ACF7 level is also correlated with development and progression of ulcerative colitis (UC) in human patients. Together, our results reveal an important molecular mechanism whereby coordinated cytoskeletal dynamics contributes to cell adhesion regulation during intestinal wound repair and the development of IBD. 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 re Show more
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
Carbohydrate-response element-binding protein (ChREBP) is the major transcription factor conferring glucose-induced gene expression in pancreatic islets, liver and adipose tissue. Recently, a novel Ch Show more
Carbohydrate-response element-binding protein (ChREBP) is the major transcription factor conferring glucose-induced gene expression in pancreatic islets, liver and adipose tissue. Recently, a novel ChREBP isoform, ChREBP-β, was identified in adipose tissue and found to be also expressed in islets and involved in glucose-induced beta cell proliferation. However, the physiological function of this less abundant β-isoform in the islet, and in diabetes, is largely unknown. The aims of the present study, therefore, were to determine how diabetes affects ChREBP-β and elucidate its physiological role in pancreatic beta cells. Non-obese diabetic and obese, diabetic ob/ob mice were used as models of T1D and T2D and human islets and the rat INS-1 beta cell line were exposed to low/high glucose and used for ChREBP isoform-specific gain-and-loss-of-function experiments. Changes in ChREBP-β and ChREBP-α were assessed by qRT-PCR, immunoblotting, promoter luciferase, and chromatin immunoprecipitation studies. Expression of the ChREBP-β isoform was highly induced in diabetes and by glucose, whereas ChREBP-α was downregulated. Interestingly, ChREBP-β gain-of-function experiments further revealed that it was ChREBP-β that downregulated ChREBP-α through a negative feedback loop. On the other hand, ChREBP-β knockdown led to unabated ChREBP-α activity and glucose-induced expression of target genes, suggesting that one of the physiological roles of this novel β-isoform is to help keep glucose-induced and ChREBP-α-mediated gene expression under control. We have identified a previously unappreciated negative feedback loop by which glucose-induced ChREBP-β downregulates ChREBP-α-signaling providing new insight into the physiological role of islet ChREBP-β and into the regulation of glucose-induced gene expression. Show less
Wen-li Song, Yu Tian, Xian-e Wang+7 more · 2016 · Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences · added 2026-04-24
To investigate the potential association between FADS1 rs174537 polymorphism and serum proteins in patients with aggressive periodontitis, which may provide benefits for diagnosis and treatment of agg Show more
To investigate the potential association between FADS1 rs174537 polymorphism and serum proteins in patients with aggressive periodontitis, which may provide benefits for diagnosis and treatment of aggressive periodontitis. A total of 353 patients with aggressive periodontitis (group AgP) and 125 matched controls (group HP) were recruited in the study. Genotyping of FADS1 rs174537 and serum biochemical indexes were tested at the study's start. The relationships between the levels of TP, GLB, ALB, A/G and genotyping were analyzed. (1) The detection rate of allele G in group AgP was higher than that in group HP(68.1% vs. 61.2%, P=0.046,OR=1.35,95% CI 1.00-1.83); the detection rate of genotype GG in group AgP was higher than in group HP(45.5% vs. 34.4%,P=0.029, OR=1.60, 95% CI 1.05-2.44). (2) In group AgP, the patients with GG genotype exhibited significantly lower TP, GLB than the patients with GT+TT genotype [(77.08 ± 7.88) g/L vs. (79.00 ± 4.66) g/L, P=0.007; (28.17 ± 7.63) g/L vs.(29.88 ± 3.49) g/L,P=0.007) and the higher A/G(1.72 ± 0.22 vs.1.67 ± 0.22, P=0.040), but there was no significant difference in ALB between the patients with GG genotype and the patients with GT+TT genotype. In group HP, there were no significant differences in TP, GLB, A/G and ALB between individuals with genotype GT+TT and with genotype GG. (3)Compared with individuals with genotype GT+TT in group HP, the AgP patients with genotype GT+TT exhibited significantly higher TP, GLB [(79.00 ± 4.66) g/L vs. (75.20 ± 4.53) g/L, P<0.01; (29.88 ± 3.49) g/L vs.(26.55 ± 2.94) g/L, P<0.01) and the lower A/G(1.67 ± 0.22 vs. 1.88 ± 0.30, P<0.01), but there was no significant difference in ALB. There were no significant differences in TP, GLB, A/G and ALB the between the AgP patients with genotype GG and the healthy subjects with the same genotype either. FADS1 rs174537 polymorphism is associated with aggressive periodontitis. The patients with genotype GG in group AgP had relatively lower TP,GLB and higher A/G. Genotype GG might be a risk indicator for aggressive periodontitis by reducing host defense capability and contributing to inflammatory response in the occurrence and development of aggressive periodontitis. Show less
Apolipoprotein A5 (apoA5) is a key regulator of triglyceride (TG) metabolism. This study is to investigate the role of apoA5 in obesity-associated hypertriglyceridemia and metformin-related hypotrigly Show more
Apolipoprotein A5 (apoA5) is a key regulator of triglyceride (TG) metabolism. This study is to investigate the role of apoA5 in obesity-associated hypertriglyceridemia and metformin-related hypotriglyceridemic actions. Two obese mouse models, including high-fat diet-induced obese mice and ob/ob obese mice, were adopted. The effects of low- and high-dose metformin were determined on plasma and hepatic TG and apoA5 of these obese mice. Besides, the effects of metformin on TG and apoA5 were also detected in mouse and human hepatocytes in vitro. (1) Plasma apoA5 levels in the obese mice were markedly elevated and positively correlated with TG. Hepatic TG contents and apoA5 expressions were also remarkably increased in the obese mice. (2) Metformin dose-dependently decreased hepatic and plasma TG and apoA5 in the obese mice. Similarly, metformin dose-dependently reduced cellular TG contents and apoA5 expressions in hepatocytes in vitro. Compared to APOA5 knock-down (KD), metformin plus APOA5 KD resulted in more TG reduction of hepatocytes. Increased hepatic and plasma apoA5 could be a result of obesity-associated hypertriglyceridemia, and metformin displays hypotriglyceridemic effects on obese mice partly via the apoA5 pathway. Show less
Although major depressive disorder (MDD) has low heritability, a genome-wide association study in humans has recently implicated type 3 adenylyl cyclase (AC3; ADCY3) in MDD. Moreover, the expression l Show more
Although major depressive disorder (MDD) has low heritability, a genome-wide association study in humans has recently implicated type 3 adenylyl cyclase (AC3; ADCY3) in MDD. Moreover, the expression level of AC3 in blood has been considered as a MDD biomarker in humans. Nevertheless, there is a lack of supporting evidence from animal studies. We employed multiple approaches to experimentally evaluate if AC3 is a contributing factor for major depression using mouse models lacking the Adcy3 gene. We found that conventional AC3 knockout (KO) mice exhibited phenotypes associated with MDD in behavioral assays. Electroencephalography/electromyography recordings indicated that AC3 KO mice have altered sleep patterns characterized by increased percentage of rapid eye movement sleep. AC3 KO mice also exhibit neuronal atrophy. Furthermore, synaptic activity at cornu ammonis 3-cornu ammonis 1 synapses was significantly lower in AC3 KO mice, and they also exhibited attenuated long-term potentiation as well as deficits in spatial navigation. To confirm that these defects are not secondary responses to anosmia or developmental defects, we generated a conditional AC3 floxed mouse strain. This enabled us to inactivate AC3 function selectively in the forebrain and to inducibly ablate it in adult mice. Both AC3 forebrain-specific and AC3 inducible knockout mice exhibited prodepression phenotypes without anosmia. This study demonstrates that loss of AC3 in mice leads to decreased neuronal activity, altered sleep pattern, and depression-like behaviors, providing strong evidence supporting AC3 as a contributing factor for MDD. Show less
Fetal akinesia deformation sequence (FADS) refers to a broad spectrum of disorder with the absent fetal movement as the unifying feature. The etiology of FADS is heterogeneous, and the majority remain Show more
Macroautophagy/autophagy is a conserved catabolic process that recycles cytoplasmic material during low energy conditions. BECN1/Beclin1 (Beclin 1, autophagy related) is an essential protein for funct Show more
Macroautophagy/autophagy is a conserved catabolic process that recycles cytoplasmic material during low energy conditions. BECN1/Beclin1 (Beclin 1, autophagy related) is an essential protein for function of the class 3 phosphatidylinositol 3-kinase (PtdIns3K) complexes that play a key role in autophagy nucleation and elongation. Here, we show that AMP-activated protein kinase (AMPK) regulates autophagy by phosphorylating BECN1 at Thr388. Phosphorylation of BECN1 is required for autophagy upon glucose withdrawal. BECN1(T388A), a phosphorylation defective mutant, suppresses autophagy through decreasing the interaction between PIK3C3 (phosphatidylinositol 3-kinase catalytic subunit type 3) and ATG14 (autophagy-related 14). The BECN1(T388A) mutant has a higher affinity for BCL2 than its wild-type counterpart; the mutant is more prone to dimer formation. Conversely, a BECN1 phosphorylation mimic mutant, T388D, has stronger binding to PIK3C3 and ATG14, and promotes higher autophagy activity than the wild-type control. These findings uncover a novel mechanism of autophagy regulation. Show less
Targeting leukemia-initiating cells (LICs) is the key to eradicating leukemia and preventing its relapse. Recent studies have indicated that metabolic regulation may play a critical role in the mainte Show more
Targeting leukemia-initiating cells (LICs) is the key to eradicating leukemia and preventing its relapse. Recent studies have indicated that metabolic regulation may play a critical role in the maintenance of stemness in LICs, although the detailed mechanisms are poorly understood. Herein, we provide intriguing evidence showing that a glucose-responsive transcription factor, carbohydrate responsive element binding protein (ChREBP), served as a tumor suppressor rather than an oncogene, as previously described, to inhibit the development of acute myeloid leukemia by promoting the differentiation of LICs. Using an MLL-AF9-induced murine leukemia model, we demonstrated that the deletion of ChREBP resulted in the blockage of the differentiation of LICs and significantly reduced survival in ChREBP-null leukemic mice. However, ChREBP was not required for the normal repopulation abilities of hematopoietic stem cells. ChREBP promoted leukemia cell differentiation through the direct inhibition of RUNX1 or the transactivation of TXNIP to downregulate the RUNX1 level and ROS generation. Moreover, knockdown of ChREBP in human leukemia THP1 cells led to markedly enhanced proliferation and decreased differentiation upon PMA treatment. Collectively, we unraveled an unexpected role of ChREBP in leukemogenesis, which may provide valuable clues for developing novel metabolic strategies for leukemia treatment. Show less
Autophagy is an important catabolic process, which sustains intracellular homeostasis and lengthens cell survival under stress. Here we identify the ankyrin-repeat-containing, SH3-domain-containing, a Show more
Autophagy is an important catabolic process, which sustains intracellular homeostasis and lengthens cell survival under stress. Here we identify the ankyrin-repeat-containing, SH3-domain-containing, and proline-rich region-containing protein 2 (ASPP2), a haploinsufficient tumor suppressor, as a molecular regulator of starvation-induced autophagy in hepatocellular carcinoma (HCC). ASPP2 expression is associated with an autophagic response upon nutrient deprivation and downregulation of ASPP2 facilitates autophagic flux, whereas overexpression of ASPP2 blocks this starvation-induced autophagy in HCC cells. Mechanistically, ASPP2 inhibits autophagy through regulating BECN1 transcription and formation of phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) complex. Firstly, ASPP2 inhibits p65/RelA-induced transcription of BECN1, directly by an ASPP2-p65/RelA-IκBα complex which inhibits phosphorylation of IκBα and the translocation of p65/RelA into the nucleus. Secondly, ASPP2 binds to BECN1, leading to decreased binding of PIK3C3 and UV radiation resistance-associated gene (UVRAG), and increased binding of Rubicon in PIK3C3 complex. Downregulation of ASPP2 enhances the pro-survival and chemoresistant property via autophagy in HCC cells in vitro and in vivo. Decreased ASPP2 expression was associated with increased BECN1 and poor survival in HCC patients. Therefore, ASPP2 is a key regulator of BECN1-dependent autophagy, and decreased ASPP2 may contribute to tumor progression and chemoresistance via promoting autophagy. Show less
Recent studies have shown that activation of liver X receptors (LXRs) attenuates the development of atherosclerosis, not only by regulating lipid metabolism but also by suppressing inflammatory signal Show more
Recent studies have shown that activation of liver X receptors (LXRs) attenuates the development of atherosclerosis, not only by regulating lipid metabolism but also by suppressing inflammatory signaling. Sphingosine 1-phosphate receptor 2 (S1PR2), an important inflammatory gene product, plays a role in the development of various inflammatory diseases. It was proposed that S1PR2 might be regulated by LXR-α. In the present study, the effect of LXR-α on tumor necrosis factor-α (TNF-α)-induced S1PR2 expression in human umbilical vein endothelial cells (HUVECs) was investigated and the underlying mechanism was explored. The results demonstrated that TNF-α led to an increase in S1PR2 expression and triggered a downregulation of LXR-α expression in HUVECs as well. Downregulation of LXR-α with specific small interfering RNA (siRNA) remarkably enhanced the primary as well as TNF-α-induced expression of S1PR2 in HUVECs. Activation of LXR-α by agonist GW3965 inhibited both primary and TNF-α-induced S1PR2 expression. GW3965 also attenuated S1PR2-induced endothelial barrier dysfunction. The data further showed that TNF-α induced a significant decrease in miR-130a-3p expression. Overexpression of miR-130a-3p with mimic product reduced S1PR2 protein expression, and inhibition of miR-130a-3p by specific inhibitor resulted in an increase in S1PR2 protein expression. Furthermore, activation of LXRs with agonist enhanced the expression of miR-130a-3p, and knockdown of LXR-α by siRNA suppressed miR-130a-3p expression. These results suggest that LXR-α might downregulate S1PR2 expression via miR-130a-3p in quiescent HUVECs. Stimulation of TNF-α attenuates the activity of LXR-α and results in enhanced S1PR2 expression. Show less
Turnover of focal adhesions allows cell retraction, which is essential for cell migration. The mammalian spectraplakin protein, ACF7 (Actin-Crosslinking Factor 7), promotes focal adhesion dynamics by Show more
Turnover of focal adhesions allows cell retraction, which is essential for cell migration. The mammalian spectraplakin protein, ACF7 (Actin-Crosslinking Factor 7), promotes focal adhesion dynamics by targeting of microtubule plus ends towards focal adhesions. However, it remains unclear how the activity of ACF7 is regulated spatiotemporally to achieve focal adhesion-specific guidance of microtubule. To explore the potential mechanisms, we resolve the crystal structure of ACF7's NT (amino-terminal) domain, which mediates F-actin interactions. Structural analysis leads to identification of a key tyrosine residue at the calponin homology (CH) domain of ACF7, whose phosphorylation by Src/FAK (focal adhesion kinase) complex is essential for F-actin binding of ACF7. Using skin epidermis as a model system, we further demonstrate that the phosphorylation of ACF7 plays an indispensable role in focal adhesion dynamics and epidermal migration in vitro and in vivo. Together, our findings provide critical insights into the molecular mechanisms underlying coordinated cytoskeletal dynamics during cell movement. Show less
Axin-1, a negative regulator of Wnt signaling, is a versatile scaffold protein involved in centrosome separation and spindle assembly in mitosis, but its function in mammalian oogenesis remains unknow Show more
Axin-1, a negative regulator of Wnt signaling, is a versatile scaffold protein involved in centrosome separation and spindle assembly in mitosis, but its function in mammalian oogenesis remains unknown. Here we examined the localization and function of Axin-1 during meiotic maturation in mouse oocytes. Immunofluorescence analysis showed that Axin-1 was localized around the spindle. Knockdown of the Axin1 gene by microinjection of specific short interfering (si)RNA into the oocyte cytoplasm resulted in severely defective spindles, misaligned chromosomes, failure of first polar body (PB1) extrusion, and impaired pronuclear formation. However, supplementing the culture medium with the Wnt pathway activator LiCl improved spindle morphology and pronuclear formation. Downregulation of Axin1 gene expression also impaired the spindle pole localization of γ-tubulin/Nek9 and resulted in retention of the spindle assembly checkpoint protein BubR1 at kinetochores after 8.5 h of culture. Our results suggest that Axin-1 is critical for spindle organization and cell cycle progression during meiotic maturation in mouse oocytes. Show less
PTEN is a lipid phosphatase that converts phosphatidylinositol 3,4,5-phosphate (PIP3) to phosphatidylinositol 4,5-phosphate (PIP2) and plays a critical role in the regulation of tumor growth. PTEN is Show more
PTEN is a lipid phosphatase that converts phosphatidylinositol 3,4,5-phosphate (PIP3) to phosphatidylinositol 4,5-phosphate (PIP2) and plays a critical role in the regulation of tumor growth. PTEN is subject to regulation by a variety of post-translational modifications, including phosphorylation on a C-terminal cluster of four Ser/Thr residues (380, 382, 383, and 385) and ubiquitylation by various E3 ligases, including NEDD4-1 and WWP2. It has previously been shown that C-terminal phosphorylation of PTEN can increase its cellular half-life. Using in vitro ubiquitin transfer assays, we show that WWP2 is more active than NEDD4-1 in ubiquitylating unphosphorylated PTEN. The mapping of ubiquitylation sites in PTEN by mass spectrometry showed that both NEDD4-1 and WWP2 can target a broad range of Lys residues in PTEN, although NEDD4-1 versus WWP2 showed a stronger preference for ubiquitylating PTEN's C2 domain. Whereas tetraphosphorylation of PTEN did not significantly affect its ubiquitylation by NEDD4-1, it inhibited PTEN ubiquitylation by WWP2. Single-turnover and pull-down experiments suggested that tetraphosphorylation of PTEN appears to weaken its interaction with WWP2. These studies reveal how the PTEN E3 ligases WWP2 and NEDD4-1 exhibit distinctive properties in Lys selectivity and sensitivity to PTEN phosphorylation. Our findings also provide a molecular mechanism for the connection between PTEN Ser/Thr phosphorylation and PTEN's cellular stability. Show less
Dengue results in a significant public health burden in endemic regions. The World Health Organization (WHO) recommended the use of warning signs (WS) to stratify patients at risk of severe dengue dis Show more
Dengue results in a significant public health burden in endemic regions. The World Health Organization (WHO) recommended the use of warning signs (WS) to stratify patients at risk of severe dengue disease in 2009. However, WS is limited in stratifying adult dengue patients at early infection (Day 1-3 post fever), who require close monitoring in hospitals to prevent severe dengue. The aim of this study is to identify and validate prognostic models, built with differentially expressed biomarkers, that enable the early identification of those with early dengue infection that require close clinical monitoring. RNA microarray and protein assays were performed to identify differentially expressed biomarkers of severity among 92 adult dengue patients recruited at early infection from years 2005-2008. This comprised 47 cases who developed WS after first presentation and required hospitalization (WS+Hosp), as well as 45 controls who did not develop WS after first presentation and did not require hospitalization (Non-WS+Non-Hosp). Independent validation was conducted with 80 adult dengue patients recruited from years 2009-2012. Prognostic models were developed based on forward stepwise and backward elimination estimation, using multiple logistic regressions. Prognostic power was estimated by the area under the receiver operating characteristic curve (AUC). The WS+Hosp group had significantly higher viral load (P<0.001), lower platelet (P<0.001) and lymphocytes counts (P = 0.004) at early infection compared to the Non-WS+Non-Hosp group. From the RNA microarray and protein assays, the top single RNA and protein prognostic models at early infection were CCL8 RNA (AUC:0.73) and IP-10 protein (AUC:0.74), respectively. The model with CCL8, VPS13C RNA, uPAR protein, and with CCL8, VPS13C RNA and platelets were the best biomarker models for stratifying adult dengue patients at early infection, with sensitivity and specificity up to 83% and 84%, respectively. These results were tested in the independent validation group, showing sensitivity and specificity up to 96% and 54.6%, respectively. At early infection, adult dengue patients who later presented WS and require hospitalization have significantly different pathophysiology compared with patients who consistently presented no WS and / or require no hospitalization. The molecular prognostic models developed and validated here based on these pathophysiology differences, could offer earlier and complementary indicators to the clinical WHO 2009 WS guide, in order to triage adult dengue patients at early infection. Show less
To explore the association of the APOA5 gene c.553G>T polymorphism with hypertriglyceridemia (HTG) susceptibility and altered triglyceride levels. We searched the PubMed, Google Scholar, and CNKI data Show more
To explore the association of the APOA5 gene c.553G>T polymorphism with hypertriglyceridemia (HTG) susceptibility and altered triglyceride levels. We searched the PubMed, Google Scholar, and CNKI databases for published studies relating to analyses of these associations. Case-control and comparative studies of the association between the APOA5 c.553G>T variant and altered triglyceride levels were included. In total, the meta-analysis involved 10 studies on HTG, which provided 2219 cases and 3401 controls. To measure the correlation between the c.553G>T polymorphism and HTG susceptibility, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. The overall OR was calculated using a random-effects model. Compared with APOA5 c.553 GG carriers, c.553T carriers displayed an increased risk of HTG in the Asian population, with an overall random effects OR of 3.55 (95% CI: 2.46-5.13) in the dominant model. There was significant heterogeneity among the studies (P Our results suggest that APOA5 c. 553T is an independent risk factor for HTG and increased triglyceride levels in the Asian population. APOA5 c. 553T could be employed as a genetic risk marker for HTG and increased triglyceride levels. Show less
Recent molecular and pathological studies suggest that endometriosis may serve as a precursor of ovarian cancer (endometriosis-associated ovarian cancer, EAOC), especially of the endometrioid and clea Show more
Recent molecular and pathological studies suggest that endometriosis may serve as a precursor of ovarian cancer (endometriosis-associated ovarian cancer, EAOC), especially of the endometrioid and clear cell subtypes. Accordingly, this study had two cardinal aims: first, to obtain mutation profiles of EAOC from Taiwanese patients; and second, to determine whether somatic mutations present in EAOC can be detected in preneoplastic lesions. Formalin-fixed paraffin-embedded (FFPE) tissues were obtained from ten endometriosis patients with malignant transformation. Macrodissection was performed to separate four different types of cells from FFPE sections in six patients. The four types of samples included normal endometrium, ectopic endometriotic lesion, atypical endometriosis, and carcinoma. Ultra-deep (>1000×) targeted sequencing was performed on 409 cancer-related genes to identify pathogenic mutations associated with EAOC. The most frequently mutated genes were PIK3CA (6/10) and ARID1A (5/10). Other recurrently mutated genes included ETS1, MLH1, PRKDC (3/10 each), and AMER1, ARID2, BCL11A, CREBBP, ERBB2, EXT1, FANCD2, MSH6, NF1, NOTCH1, NUMA1, PDE4DIP, PPP2R1A, RNF213, and SYNE1 (2/10 each). Importantly, in five of the six patients, identical somatic mutations were detected in atypical endometriosis and tumor lesions. In two patients, genetic alterations were also detected in ectopic endometriotic lesions, indicating the presence of genetic alterations in preneoplastic lesion. Genetic analysis in preneoplastic lesions may help to identify high-risk patients at early stage of malignant transformation and also shed new light on fundamental aspects of the molecular pathogenesis of EAOC. Molecular characterization of endometriosis-associated ovarian cancer genes by targeted NGS. Candidate genes predictive of malignant transformation were identified. Chromatin remodeling, PI3K-AKT-mTOR, Notch signaling, and Wnt/β-catenin pathway may promote cell malignant transformation. Show less
Moringa oleifera is a promising plant species for oil and forage, but its genetic improvement is limited. Our current breeding program in this species focuses on exploiting the functional genes associ Show more
Moringa oleifera is a promising plant species for oil and forage, but its genetic improvement is limited. Our current breeding program in this species focuses on exploiting the functional genes associated with important agronomical traits. Here, we screened reliable reference genes for accurately quantifying the expression of target genes using the technique of real-time quantitative polymerase chain reaction (RT-qPCR) in M. oleifera. Eighteen candidate reference genes were selected from a transcriptome database, and their expression stabilities were examined in 90 samples collected from the pods in different developmental stages, various tissues, and the roots and leaves under different conditions (low or high temperature, sodium chloride (NaCl)- or polyethyleneglycol (PEG)- simulated water stress). Analyses with geNorm, NormFinder and BestKeeper algorithms revealed that the reliable reference genes differed across sample designs and that ribosomal protein L1 (RPL1) and acyl carrier protein 2 (ACP2) were the most suitable reference genes in all tested samples. The experiment results demonstrated the significance of using the properly validated reference genes and suggested the use of more than one reference gene to achieve reliable expression profiles. In addition, we applied three isotypes of the superoxide dismutase (SOD) gene that are associated with plant adaptation to abiotic stress to confirm the efficacy of the validated reference genes under NaCl and PEG water stresses. Our results provide a valuable reference for future studies on identifying important functional genes from their transcriptional expressions via RT-qPCR technique in M. oleifera. Show less
Integration of human papillomavirus (HPV) viral DNA into the human genome has been postulated as an important etiological event during cervical carcinogenesis. Several recent reports suggested a possi Show more
Integration of human papillomavirus (HPV) viral DNA into the human genome has been postulated as an important etiological event during cervical carcinogenesis. Several recent reports suggested a possible role for such integration-targeted cellular genes (ITGs) in cervical carcinogenesis. Therefore, a comprehensive analysis of HPV integration events was undertaken using data collected from 14 publications, with 499 integration loci on human chromosomes included. It revealed that HPV DNA preferred to integrate into intragenic regions and gene-dense regions of human chromosomes. Intriguingly, the host cellular genes nearby the integration sites were found to be more transcriptionally active compared with control. Furthermore, analysis of the integration sites in the human genome revealed that there were several integration hotspots although all chromosomes were represented. The ITGs identified were found to be enriched in tumor-related terms and pathways using gene ontology and KEGG analysis. In line with this, three of six ITGs tested were found aberrantly expressed in cervical cancer tissues. Among them, it was demonstrated for the first time that MPPED2 could induce HeLa cell and SiHa cell G1/S transition block and cell proliferation retardation. Moreover, "knocking out" the integrated HPV fragment in HeLa cell line decreased expression of MYC located ∼500 kb downstream of the integration site, which provided the first experimental evidence supporting the hypothesis that integrated HPV fragment influence MYC expression via long distance chromatin interaction. Overall, the results of this comprehensive analysis implicated that dysregulation of ITGs caused by viral integration as possibly having an etiological involvement in cervical carcinogenesis. Show less
Recently, a large-scale meta-analysis of genome-wide association study (GWAS) data identified several new risk loci that can modulate the risk of Parkinson's disease (PD). These associations have yet Show more
Recently, a large-scale meta-analysis of genome-wide association study (GWAS) data identified several new risk loci that can modulate the risk of Parkinson's disease (PD). These associations have yet to be examined in PD patients in Chinese or Asian population. Because ethnic-specific effect is an important concern for GWAS analysis, we genotyped single-nucleotide polymorphisms in the new genetic loci, GCH1 (rs11158026), SIPA1L2 (rs10797576), VPS13C (rs2414739), and MIR4697 (rs329648), to investigate their associations with risk of PD in Taiwan. Another single-nucleotide polymorphism GCH1 rs7155501, previously identified by GWAS listed at the top 20 genes in PDGene database was also included. A total of 1151 study subjects comprising 598 patients with PD and 553 unrelated healthy controls were recruited. The frequency of minor allele (C allele) of GCH1 rs11158026 was found to be significantly higher in PD cases than in controls (p = 0.003). The CC genotype of rs11158026 increased PD risk compared to TT genotype (odds ratio [OR] = 1.29, 95% confidence interval [CI] = 1.09, 1.53, p = 0.004). Under additive model, the GCH1 rs11158026 increased the risk of developing PD (OR = 1.30, 95% CI = 1.10, 1.54, p = 0.002). In recessive model, the genotype TT of MIR4697 rs329648 marginally decreased the PD risk (OR = 0.62, 95% CI = 0.43, 0.90, p = 0.01). The PD patients demonstrated similar genotypic and allelic frequencies in GCH1 rs7155501, SIPA1L2 rs10797576, and VPS13C rs2414739 with the controls. These findings suggest that the GCH1 and MIR4697 but not SIPA1L2 and VPS13C are genetic loci influencing risk of PD in Taiwan. Show less
The formation of the autophagosome is controlled by an orderly action of ATG proteins. However, how these proteins are recruited to autophagic membranes remain poorly clarified. In this study, we have Show more
The formation of the autophagosome is controlled by an orderly action of ATG proteins. However, how these proteins are recruited to autophagic membranes remain poorly clarified. In this study, we have provided a line of evidence confirming that EVA1A (eva-1 homolog A)/TMEM166 (transmembrane protein 166) is associated with autophagosomal membrane development. This notion is based on dotted EVA1A structures that colocalize with ZFYVE1, ATG9, LC3B, ATG16L1, ATG5, STX17, RAB7 and LAMP1, which represent different stages of the autophagic process. It is required for autophagosome formation as this phenotype was significantly decreased in EVA1A-silenced cells and Eva1a KO MEFs. EVA1A-induced autophagy is independent of the BECN1-PIK3C3 (phosphatidylinositol 3-kinase, catalytic subunit type 3) complex but requires ATG7 activity and the ATG12-ATG5/ATG16L1 complex. Here, we present a molecular mechanism by which EVA1A interacts with the WD repeats of ATG16L1 through its C-terminal and promotes ATG12-ATG5/ATG16L1 complex recruitment to the autophagic membrane and enhances the formation of the autophagosome. We also found that both autophagic and apoptotic mechanisms contributed to EVA1A-induced cell death while inhibition of autophagy and apoptosis attenuated EVA1A-induced cell death. Overall, these findings provide a comprehensive view to our understanding of the pathways involved in the role of EVA1A in autophagy and programmed cell death. Show less
Xian-Bin Lin, Lei Jiang, Mao-Hua Ding+13 more · 2016 · Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · Springer · added 2026-04-24
Phenoxybenzamine hydrochloride (PHEN) is a selective antagonist of both α-adrenoceptor and calmodulin that exhibits anticancer properties. The aim of this study was to explore the anti-tumor function Show more
Phenoxybenzamine hydrochloride (PHEN) is a selective antagonist of both α-adrenoceptor and calmodulin that exhibits anticancer properties. The aim of this study was to explore the anti-tumor function of PHEN in glioma. Cell proliferation assay was used to assess glioma cell growth. Migration and invasion capacity of glioma cells was monitored by wound-healing and transwell assay, respectively. Neurosphere formation test was adopted for the tumorigenesis of glioma cells, which was also confirmed by soft agar cloning formation test in vitro and a nude mouse model in vivo. Finally, we explored the potential pathway utilized by PHEN using Western blot and immunofluoresce staining. PHEN exhibited a significant inhibitory effect on the proliferation of both U251 and U87MG glioma cell lines in a positive dose-dependent manner. PHEN apparently attenuated the malignancy of glioma in terms of migration and invasion and also suppressed the tumorigenic capacity both in vitro and in vivo. Mechanism study showed that PHEN promoted tumor suppression by inhibiting the TrkB-Akt pathway. The results of the present study demonstrated that PHEN suppressed the proliferation, migration, invasion, and tumorigenesis of glioma cells, induced LINGO-1 expression, and inhibited the TrkB-Akt pathway, which may prove to be the mechanisms underlying the anti-tumor effect of PHEN on glioma cells. Show less
Dyslipidemia is common in polycystic ovary syndrome (PCOS). This study was aimed to investigate whether fatty acid desaturase genes (FADS), a dyslipidemia-related gene cluster, are associated with PCO Show more
Dyslipidemia is common in polycystic ovary syndrome (PCOS). This study was aimed to investigate whether fatty acid desaturase genes (FADS), a dyslipidemia-related gene cluster, are associated with PCOS. We scanned variations of FADS genes using our previous data of genome-wide association study (GWAS) for PCOS and selected rs174570 for further study. The case-control study was conducted in an independent cohort of 1918 PCOS cases and 1889 age-matched controls and family-based study was conducted in a set of 243 core family trios with PCOS probands. Minor allele frequency (allele T) of rs174570 was significantly lower in PCOS cases than that in age-matched controls (P = 2.17E-03, OR = 0.85), even after adjustment of BMI and age. PCOS subjects carrying CC genotype had higher testosterone level and similar lipid/glucose level compared with those carrying TT or TC genotype. In trios, transmission disequilibrium test (TDT) analysis revealed risk allele C of rs174570 was significantly over-transmitted (P = 2.00E-04). Decreased expression of FADS2 was detected in PCOS cases and expression quantitative trait loci (eQTL) analysis revealed the risk allele C dosage was correlated with the decline of FADS2 expression (P = 0.002). Our results demonstrate that FADS1-FADS2 are susceptibility genes for PCOS. Show less